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Life's Little Ironies (a phrase coined by Hardy) was Thomas Hardy's third collection of short stories. The volume's eight stories and one sequence of shorter tales (presented in a Canterbury Tales-type framework) had all appeared first in magazines before being gathered together in 1894. Not only do they reflect the strengths and themes of his great novels – they are also themselves powerful works, encompassing tragedy and humour. Part of the Cambridge Edition of the Novels and Short Stories of Thomas Hardy, this volume presents an authoritative text which aims to reflect Hardy's original artistic intentions. A full scholarly apparatus includes every authorial revision, from manuscript (where extant) onwards, enabling readers to trace Hardy's creative process. An introductory essay gives details of the stories' composition, publishing history and critical reception; there are comprehensive explanatory notes and a glossary, and the illustrations that accompanied the stories' magazine publication also provide valuable context.
Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma Aβ42/40, p-tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another.
Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for Aβ42, Aβ40, GFAP and NfL, and incorporated previously-collected p-tau181 from this same cohort.
Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower Aβ42/40 (p = 0.06). GFAP and p-tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time (p = 0.011).
Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p-tau181 in distinguishing MCI overall, and its subgroups, from healthy controls.
A late Pliocene (3.36–3.06 Ma) exposure of the Tangahoe Formation on the North Island of New Zealand preserves close fossil relatives of many extant seabird clades. Here, we report an extinct member of the little penguin (Eudyptula Bonaparte, 1856) lineage from the Tangahoe Formation—the smallest extinct crown penguin yet known. Eudyptula wilsonae n. sp. is based on the nearly complete skulls of an adult and a fledged but immature individual. Both skulls show more slender proportions than modern little penguins and precede genome-derived estimates for the divergence between Eudyptula minor minor Forster, 1781 (endemic to New Zealand) and Eudyptula m. novaehollandiae Stephens, 1826 (native to Australia and recently established in New Zealand). This raises the possibility that the fossil taxon represents a lineage directly ancestral to extant little penguins. Our results support a Zealandian origin for little penguins, with subsequent Pleistocene dispersal to Australia and a more recent Holocene range expansion of Eudyptula m. novaehollandiae back into New Zealand.
Applications of machine learning technologies are becoming ubiquitous in many sectors and their impacts, both positive and negative, are widely reported. As a result, there is substantial interest from the engineering community to integrate machine learning technologies into design workflows with a view to improving the performance of the product development process. In essence, machine learning technologies are thought to have the potential to underpin future generations of data-enabled engineering design system that will deliver radical improvements to product development and so organisational performance. In this paper we report learning from experiments where we applied machine learning to two shape-based design challenges: in a given collection of designed shapes, clustering (i) visually similar shapes and (ii) shapes that are likely to be manufactured using the same primary process. Both challenges were identified with our industry partners and are embodied in a design case study. We report early results and conclude with issues for design descriptions that need to be addressed if the full potential of machine learning is to be realised in engineering design.
Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians.
In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance.
Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12.
Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.
The anesthesia workstation, commonly referred to as the “anesthesia machine,” is a complex and very specialized piece of equipment that is relatively unique in medical practice. It is, in essence, a device to control the delivery of medical gases to patients, including oxygen, air, nitrous oxide, and volatile anesthetics, along with a specialized ventilator adapted to operating room conditions. The safe use of the anesthesia workstation requires proper training, preuse checkout, and continuous monitoring of its function. The medical literature is replete with examples of patient harm from inappropriate use of the anesthesia workstation and from mechanical or electrical failure of its components. Additionally, volatile anesthetics, while valuable in medical practice, have a very low therapeutic index and manifest severe, and even fatal, side effects when administered improperly. Finally, many patients under general anesthesia are paralyzed for surgery and ventilated through an endotracheal tube. Their safety is completely dependent on the anesthesia professional’s use of the anesthesia workstation to deliver breathing gases, remove carbon dioxide from exhaled gas, and precise administration of volatile anesthetics.
Recent fossil discoveries from New Zealand have revealed a remarkably diverse assemblage of Paleocene stem group penguins. Here, we add to this growing record by describing nine new penguin specimens from the late Paleocene (upper Teurian local stage; 55.5–59.5 Ma) Moeraki Formation of the South Island, New Zealand. The largest specimen is assigned to a new species, Kumimanu fordycei n. sp., which may have been the largest penguin ever to have lived. Allometric regressions based on humerus length and humerus proximal width of extant penguins yield mean estimates of a live body mass in the range of 148.0 kg (95% CI: 132.5 kg–165.3 kg) and 159.7 kg (95% CI: 142.6 kg–178.8 kg), respectively, for Kumimanu fordycei. A second new species, Petradyptes stonehousei n. gen. n. sp., is represented by five specimens and was slightly larger than the extant emperor penguin Aptenodytes forsteri. Two small humeri represent an additional smaller unnamed penguin species. Parsimony and Bayesian phylogenetic analyses recover Kumimanu and Petradyptes crownward of the early Paleocene mainland NZ taxa Waimanu and Muriwaimanu, but stemward of the Chatham Island taxon Kupoupou. These analyses differ, however, in the placement of these two taxa relative to Sequiwaimanu, Crossvallia, and Kaiika. The massive size and placement of Kumimanu fordycei close to the root of the penguin tree provide additional support for a scenario in which penguins reached the upper limit of sphenisciform body size very early in their evolutionary history, while still retaining numerous plesiomorphic features of the flipper.
The Red Sea is a largely homogeneous water column beyond the top 300 m, unique in exhibiting warm bottom water (~21.5 °C) at depths down to ~2900 m. The unusual conditions coupled with barriers to colonization by primary deep-sea species has resulted in an impoverished but distinct deep fauna. This study presents a rare investigation of the deep Red Sea. The bigeye hound shark Iago omanensis is a known deep-sea shark in the Red Sea. However, its full depth distribution has never been conclusively studied. Here, we confirm with videographic evidence the presence of I. omanensis at depths to 2522 m in the Red Sea, along with observations of other deep-sea species. Iago omanensis was the only species of scavenging fish observed and only in moderate numbers. The additional six species were mostly crustacea in low abundance. The lack of scavenging species present in the deep Red Sea is likely explained by the low productivity of the overlying surface waters and unusually warm water temperature resulting in low energetic input but high metabolic demands in deep communities.
To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up.
Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo.
Community settings and care homes in 26 UK centers.
People with probable or possible Alzheimer’s disease and agitation.
Primary outcome included incremental cost of participants’ health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants’ and unpaid carers’ gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives.
One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment.
On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.
To identify characteristics of US health systems and end users that report antimicrobial use and resistance (AUR) data, to determine how NHSN AUR data are used by hospitals and health systems and end users, and to identify barriers to AUR reporting.
An anonymous survey was sent to Society of Infectious Diseases Pharmacists (SIDP) and Society for Healthcare Epidemiology of America (SHEA) Research Network members.
Data were collected via Survey Monkey from January 21 to February 21, 2020. Respondent and hospital data were analyzed using descriptive statistics.
We received responses from 238 individuals across 43 US states. Respondents were primarily pharmacists (84%), from urban areas, (44%), from nonprofit medical centers (81%), and from hospitals with >250 beds (72%). Also, 62% reported data to the AU module and 19% reported data to the AR module. Use of software for local AU or AR tracking was associated with increased reporting to the AU module (19% vs 64%) and the AR module (2% vs 30%) (P < .001 each). Only 36% of those reporting data to the AU module used NHSN AUR data analysis tools regularly and only 9% reported data to the AR module regularly. Technical challenges and time and/or salary support were the most common barriers to AUR participation cited by all respondents. Among those not reporting AUR data, increased local expectations to report and better software solutions were the most commonly identified solutions to increase AUR reporting.
Efforts to increase AUR reporting should focus on software solutions and salary support for data-entry activities. Increasing expectations to report may incentivize local resource allocation to improve AUR reporting rates.
Limited data exist on training of European paediatric and adult congenital cardiologists.
A structured and approved questionnaire was circulated to national delegates of Association for European Paediatric and Congenital Cardiology in 33 European countries.
Delegates from 30 countries (91%) responded. Paediatric cardiology was not recognised as a distinct speciality by the respective ministry of Health in seven countries (23%). Twenty countries (67%) have formally accredited paediatric cardiology training programmes, seven (23%) have substantial informal (not accredited or certified) training, and three (10%) have very limited or no programme. Twenty-two countries have a curriculum. Twelve countries have a national training director. There was one paediatric cardiology centre per 2.66 million population (range 0.87–9.64 million), one cardiac surgical centre per 4.73 million population (range 1.63–10.72 million), and one training centre per 4.29 million population (range 1.63–10.72 million population). The median number of paediatric cardiology fellows per training programme was 4 (range 1–17), and duration of training was 3 years (range 2–5 years). An exit examination in paediatric cardiology was conducted in 16 countries (53%) and certification provided by 20 countries (67%). Paediatric cardiologist number is affected by gross domestic product (R2 = 0.41).
Training varies markedly across European countries. Although formal fellowship programmes exist in many countries, several countries have informal training or no training. Only a minority of countries provide both exit examination and certification. Harmonisation of training and standardisation of exit examination and certification could reduce variation in training thereby promoting high-quality care by European congenital cardiologists.
Fibricola and Neodiplostomum are diplostomid genera with very similar morphology that are currently separated based on their definitive hosts. Fibricola spp. are normally found in mammals, while Neodiplostomum spp. typically parasitize birds. Previously, no DNA sequence data was available for any member of Fibricola. We generated nuclear ribosomal and mtDNA sequences of Fibricola cratera (type-species), Fibricola lucidum and 6 species of Neodiplostomum. DNA sequences were used to examine phylogenetic interrelationships among Fibricola and Neodiplostomum and re-evaluate their systematics. Molecular phylogenies and morphological study suggest that Fibricola should be considered a junior synonym of Neodiplostomum. Therefore, we synonymize the two genera and transfer all members of Fibricola into Neodiplostomum. Specimens morphologically identified as Neodiplostomum cratera belonged to 3 distinct phylogenetic clades based on mitochondrial data. One of those clades also included sequences of specimens identified morphologically as Neodiplostomum lucidum. Further study is necessary to resolve the situation regarding the morphology of N. cratera. Our results demonstrated that some DNA sequences of N. americanum available in GenBank originate from misidentified Neodiplostomum banghami. Molecular phylogentic data revealed at least 2 independent host-switching events between avian and mammalian hosts in the evolutionary history of Neodiplostomum; however, the directionality of these host-switching events remains unclear.
Diagnoses of personality disorder are prevalent among people using community secondary mental health services. Identifying cost-effective community-based interventions is important when working with finite resources.
To assess the cost-effectiveness of primary or secondary care community-based interventions for people with complex emotional needs who meet criteria for a diagnosis of personality disorder to inform healthcare policy-making.
Systematic review (PROSPERO: CRD42020134068) of databases. We included economic evaluations of interventions for adults with complex emotional needs associated with a diagnosis of personality disorder in community mental health settings published before 18 September 2019. Study quality was assessed using the CHEERS statement.
Eighteen studies were included. The studies mainly evaluated psychotherapeutic interventions. Studies were also identified that evaluated altering the setting in which care was delivered and joint crisis plans. No strong economic evidence to support a single intervention or model of community-based care was identified.
Robust economic evidence to support a single intervention or model of community-based care for people with complex emotional needs is lacking. The strongest evidence was for dialectical behaviour therapy, with all three identified studies indicating that it is likely to be cost-effective in community settings compared with treatment as usual. More robust evidence is required on the cost-effectiveness of community-based interventions on which decision makers can confidently base guidelines or allocate resources. The evidence should be based on consistent measures of costs and outcomes with sufficient sample sizes to demonstrate impacts on these.
Differentiating mild cognitive impairment with Lewy bodies (MCI-LB) from mild cognitive impairment due to Alzheimer’s disease (MCI-AD) is challenging due to an overlap of symptoms. Quantitative EEG analyses have shown varying levels of diagnostic accuracy, while visual assessment of EEG may be a promising diagnostic method. Additionally, a multimodal EEG-MRI approach may have greater diagnostic utility than individual modalities alone.
To evaluate the utility of (1) a structured visual EEG assessment and (2) a machine learning multimodal EEG-MRI approach to differentiate MCI-LB from MCI-AD.
300 seconds of eyes-closed, resting-state EEG from 37 MCI-LB and 36 MCI-AD patients were analysed. EEGs were visually assessed for the presence of diffuse, focal, and epileptiform abnormalities, overall grade of abnormalities and focal rhythmic delta activity (FIRDA). Random forest classifiers to discriminate MCI-LB from MCI-AD were trained on combinations of visual EEG, quantitative EEG and structural MRI features. Quantitative EEG features (dominant frequency, dominant frequency variability, theta/alpha ratio and measures of spectral power in the delta, theta, prealpha, alpha and beta bands) and structural MRI features (hippocampal and insular volumes) were obtained from previous analyses of our dataset.
Most patients had abnormal EEGs on visual assessment (MCI-LB = 91.9%, MCI-AD = 77.8%). Overall grade (Χ2 (73, 2) = 4.416, p = 0.110), diffuse abnormalities Χ2(73,1) = 3.790, p = 0.052, focal abnormalities Χ2 (73,1) = 3.113, p = 0.077 and FIRDA Χ2(73,1) = 0.862, p = 0.353 did not differ between groups. All multimodal classifiers had similar diagnostic accuracy (area underthe curve, AUC = 0.681 - 0.686) to a classifier that used quantitative EEG features only (AUC =0.668). The feature ‘beta power’ had the highest predictive power in all classifiers.
Visual EEG assessment was unable to discriminate between MCI-LB and MCI-AD. However, future work with a more sensitive visual assessment score may yield more promising results.A multimodal EEG-MRI approach does not enhance the diagnostic value of quantitative EEG alone in diagnosing MCI-LB.
Impaired olfaction may be a biomarker for early Lewy body disease, but its value in mild cognitive impairment with Lewy bodies (MCI-LB) is unknown. We compared olfaction in MCI-LB with MCI due to Alzheimer’s disease (MCI-AD) and healthy older adults. We hypothesized that olfactory function would be worse in probable MCI-LB than in both MCI-AD and healthy comparison subjects (HC).
Cross-sectional study assessing olfaction using Sniffin’ Sticks 16 (SS-16) in MCI-LB, MCI-AD, and HC with longitudinal follow-up. Differences were adjusted for age, and receiver operating characteristic (ROC) curves were used for discriminating MCI-LB from MCI-AD and HC.
Participants were recruited from Memory Services in the North East of England.
Thirty-eight probable MCI-LB, 33 MCI-AD, 19 possible MCI-LB, and 32HC.
Olfaction was assessed using SS-16 and a questionnaire.
Participants with probable MCI-LB had worse olfaction than both MCI-AD (age-adjusted mean difference (B) = 2.05, 95% CI: 0.62–3.49, p = 0.005) and HC (B = 3.96, 95% CI: 2.51–5.40, p < 0.001). The previously identified cutoff score for the SS-16 of ≤ 10 had 84% sensitivity for probable MCI-LB (95% CI: 69–94%), but 30% specificity versus MCI-AD. ROC analysis found a lower cutoff of ≤ 7 was better (63% sensitivity for MCI-LB, with 73% specificity vs MCI-AD and 97% vs HC). Asking about olfactory impairments was not useful in identifying them.
MCI-LB had worse olfaction than MCI-AD and normal aging. A lower cutoff score of ≤ 7 is required when using SS-16 in such patients. Olfactory testing may have value in identifying early LB disease in memory services.
The present study aimed to clarify the neuropsychological profile of the emergent diagnostic category of Mild Cognitive Impairment with Lewy bodies (MCI-LB) and determine whether domain-specific impairments such as in memory were related to deficits in domain-general cognitive processes (executive function or processing speed).
Patients (n = 83) and healthy age- and sex-matched controls (n = 34) underwent clinical and imaging assessments. Probable MCI-LB (n = 44) and MCI-Alzheimer’s disease (AD) (n = 39) were diagnosed following National Institute on Aging-Alzheimer’s Association (NIA-AA) and dementia with Lewy bodies (DLB) consortium criteria. Neuropsychological measures included cognitive and psychomotor speed, executive function, working memory, and verbal and visuospatial recall.
MCI-LB scored significantly lower than MCI-AD on processing speed [Trail Making Test B: p = .03, g = .45; Digit Symbol Substitution Test (DSST): p = .04, g = .47; DSST Error Check: p < .001, g = .68] and executive function [Trail Making Test Ratio (A/B): p = .04, g = .52] tasks. MCI-AD performed worse than MCI-LB on memory tasks, specifically visuospatial (Modified Taylor Complex Figure: p = .01, g = .46) and verbal (Rey Auditory Verbal Learning Test: p = .04, g = .42) delayed recall measures. Stepwise discriminant analysis correctly classified the subtype in 65.1% of MCI patients (72.7% specificity, 56.4% sensitivity). Processing speed accounted for more group-associated variance in visuospatial and verbal memory in both MCI subtypes than executive function, while no significant relationships between measures were observed in controls (all ps > .05)
MCI-LB was characterized by executive dysfunction and slowed processing speed but did not show the visuospatial dysfunction expected, while MCI-AD displayed an amnestic profile. However, there was considerable neuropsychological profile overlap and processing speed mediated performance in both MCI subtypes.
Patent ductus arteriosus stenting for ductal-dependent pulmonary blood flow is a technically challenging neonatal procedure to maintain a stable pulmonary circulation. Pre-procedural computed tomography imaging aids in outlining ductal origin, insertion, size, course and curvature. Computed tomography imaging may add value to procedural outcomes and reduce overall procedural morbidity in neonatal patent ductus arteriosus stenting. We conducted a single centre retrospective chart review of neonates with ductal-dependent pulmonary blood flow who underwent patent ductus arteriosus stenting between January 1, 2014 and June 31, 2020. We compared patients variables between patients who underwent pre-procedural computed tomography imaging to those who did not. A total of 64 patients were referred for patent ductus arteriosus stenting with 33 (52%) obtaining pre-procedural computed tomography imaging. Average age [19 days; range 1–242 days (p = 0.85)] and weight [3.3 kg (range 2.2–6.0 kg; p = 0.19)] was not significantly different between the groups. A diagnosis of pulmonary atresia was made in 42 out of 64 (66%) patients prior to patent ductus arteriosus stenting. The cohort with pre-intervention computed tomography imaging had a significant reduction in the total number of access sites (1.2 versus 1.5; p = 0.03), contrast needed (5.9 versus 8.2 ml/kg; p = 0.008), fluoroscopy (20.7 versus 38.8 minutes; p = 0.02) and procedural time (83.4–128.4 minutes; p = 0.002) for the intervention. There was no significant difference in radiation burden between the groups (p = 0.35). Pre-procedural computed tomography imaging adds value by aiding interventional planning for neonatal patent ductus arteriosus stenting. A statistically significant reduction in the number of access sites, contrast exposure, as well as fluoroscopic and procedural time was noted without significantly increasing the cumulative radiation burden.
Electroencephalographic (EEG) abnormalities are greater in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) than in MCI due to Alzheimer’s disease (MCI-AD) and may anticipate the onset of dementia. We aimed to assess whether quantitative EEG (qEEG) slowing would predict a higher annual hazard of dementia in MCI across these etiologies. MCI patients (n = 92) and healthy comparators (n = 31) provided qEEG recording and underwent longitudinal clinical and cognitive follow-up. Associations between qEEG slowing, measured by increased theta/alpha ratio, and clinical progression from MCI to dementia were estimated with a multistate transition model to account for death as a competing risk, while controlling for age, cognitive function, and etiology classified by an expert consensus panel.
Over a mean follow-up of 1.5 years (SD = 0.5), 14 cases of incident dementia and 5 deaths were observed. Increased theta/alpha ratio on qEEG was associated with increased annual hazard of dementia (hazard ratio = 1.84, 95% CI: 1.01–3.35). This extends previous findings that MCI-LB features early functional changes, showing that qEEG slowing may anticipate the onset of dementia in prospectively identified MCI.