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Mild cognitive impairment (MCI) may gradually worsen to dementia, but often remains stable for extended periods of time. Little is known about the predictors of decline to help explain this variation. We aimed to explore whether this heterogeneous course of MCI may be predicted by the presence of Lewy body (LB) symptoms in a prospectively-recruited longitudinal cohort of MCI with Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD).
A prospective cohort (n = 76) aged ⩾60 years underwent detailed assessment after recent MCI diagnosis, and were followed up annually with repeated neuropsychological testing and clinical review of cognitive status and LB symptoms. Latent class mixture modelling identified data-driven sub-groups with distinct trajectories of global cognitive function.
Three distinct trajectories were identified in the full cohort: slow/stable progression (46%), intermediate progressive decline (41%) and a small group with a much faster decline (13%). The presence of LB symptomology, and visual hallucinations in particular, predicted decline v. a stable cognitive trajectory. With time zeroed on study end (death, dementia or withdrawal) where available (n = 39), the same subgroups were identified. Adjustment for baseline functioning obscured the presence of any latent classes, suggesting that baseline function is an important parameter in prospective decline.
These results highlight some potential signals for impending decline in MCI; poorer baseline function and the presence of probable LB symptoms – particularly visual hallucinations. Identifying people with a rapid decline is important but our findings are preliminary given the modest cohort size.
Novel commercially available software has enabled registration of both CT and MRI images to rapidly fuse with X-ray fluoroscopic imaging. We describe our initial experience performing cardiac catheterisations with the guidance of 3D imaging overlay using the VesselNavigator system (Philips Healthcare, Best, NL). A total of 33 patients with CHD were included in our study. Demographic, advanced imaging, and catheterisation data were collected between 1 December, 2016 and 31 January, 2019. We report successful use of this technology in both diagnostic and interventional cases such as placing stents and percutaneous valves, performing angioplasties, occlusion of collaterals, and guidance for lymphatic interventions. In addition, radiation exposure was markedly decreased when comparing our 10–15-year-old coarctation of the aorta stent angioplasty cohort to cases without the use of overlay technology and the most recently published national radiation dose benchmarks. No complications were encountered due to the application of overlay technology. 3D CT or MRI overlay for CHD intervention with rapid registration is feasible and aids decisions regarding access and planned angiographic angles. Operators found intraprocedural overlay fusion registration using placed vessel guidewires to be more accurate than attempts using bony structures.
We present a sediment-mixing process model of till genesis based on data from surface tills of the Saginaw lobe terrain in lower Michigan. Our research uses a spatial approach to understanding glacial landsystems and till genesis. We sampled calcareous till at 336 upland sites and at 17 sites in lacustrine sediment of the Saginaw Lake plain. The loamy tills have bimodal grain-size curves, with a fine-texture mode near the silt–clay boundary and a sand mode. Spatial grouping analysis suggests that tills can be divided into six groups, each with different textures and clay mineral compositions that vary systematically down-ice. The similarity among groups with respect to the silt–clay mode and clay mineralogy argues for a common origin for the fines—illite-rich lacustrine sediment of the Saginaw Lake plain. Fine-textured sediments were probably entrained, transported, and deposited down-ice as till, which also becomes sandier and enriched in kaolinite, reflecting increasing mixing with shallow sandstone bedrock with distance from the lacustrine clay source. Clayey tills on the flanks of the Saginaw terrain may reflect proglacial ponding against nearby uplands. A process model of progressive down-ice mixing of preexisting fine lake sediments with crushed/abraded sandstone bedrock helps to better explain till textures compared with a purely crushing/abrasion process model.
Swimmer's itch (SI) is a painful rash caused by skin penetration by free-swimming infectious cercariae of avian schistosomes, snail-borne helminth parasites related to the causative agents of human schistosomiasis. The goal of this study was to determine if commonly collected environmental data could be used to predict daily fluctuations in SI incidence at an inland beach in northwestern Michigan. Lifeguards collected daily data over four summers, including the number of self-reported SI cases, total swimmers, water temperature, wind speed and wind direction. Mixed-effects binomial regression revealed that wind direction, wind speed and time of day were the best predictors of daily SI risk. Swimmers entering the water in the morning or on days with direct onshore wind perpendicular to the shoreline had the greatest SI risk. However, there was a negative effect of wind speed after accounting for direction, where SI risk was greatest on days with a gentle breeze originating directly offshore. These results suggest that at this beach, direct onshore winds generate a surface-water current that causes SI cercariae to aggregate in the shallow waters used by swimmers. Data are needed from additional sites to confirm whether the onshore wind is a generally important driver of SI incidence.
Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) have substantial clinical and biological overlap, with cognitive deficits typically observed in the executive and visuospatial domains. However, the neuropsychological profiles of mild cognitive impairment (MCI) associated with these disorders are not well understood.
This systematic review examined existing literature on cognition in MCI due to LB disease (MCI-LB) and PD (PD-MCI) using an electronic search of seven databases (Medline, Embase, Psychinfo, PubMed, ProQuest, Scopus, and ScienceDirect). MCI-LB results were reviewed narratively given the small number of resulting papers (n = 7). Outcome variables from PD-MCI studies (n = 13) were extracted for meta-analysis of standardised mean differences (SMD).
In MCI-LB, executive dysfunction and slowed processing speed were the most prominent impairments, while visuospatial and working memory (WM) functions were also poor. MCI-LB scored significantly lower on verbal memory tests relative to controls, but significantly higher than patients with MCI due to Alzheimer’s disease. Quantitative analysis of studies in PD-MCI showed a similar profile of impairment, with the largest deficits in visuospatial function (Benton Judgement of Line Orientation, SMD g = −2.09), executive function (Trail Making Test B, SMD g = −1.65), verbal ability (Naming Tests, SMD g = −0.140), and WM (Trail Making Test A, SMD g = −1.20). In both MCI-LB and PD-MCI, verbal and visuospatial memory retrieval was impaired, while encoding and storage appeared relatively intact.
The findings of this systematic review indicate similar neuropsychological profiles in the MCI stages of DLB and PDD. Executive impairment may at least partially explain poor performance in other domains.
Refractory depression is a major contributor to the economic burden of depression. Radically open dialectical behaviour therapy (RO DBT) is an unevaluated new treatment targeting overcontrolled personality, common in refractory depression, but it is not yet known whether the additional expense of RO DBT is good value for money.
To estimate the cost-effectiveness of RO DBT plus treatment as usual (TAU) compared with TAU alone in people with refractory depression (trial registration: ISRCTN85784627).
We undertook a cost-effectiveness analysis alongside a randomised trial evaluating RO DBT plus TAU versus TAU alone for refractory depression in three UK secondary care centres. Our economic evaluation, 12 months after randomisation, adopted the perspective of the UK National Health Service (NHS) and personal social services. It evaluated cost-effectiveness by comparing the net cost of RO DBT with the net gain in quality-adjusted life-years (QALYs), estimated using the EQ-5D-3L measure of health-related quality of life.
The additional cost of RO DBT plus TAU compared with TAU alone was £7048 and was associated with a difference of 0.032 QALYs, yielding an incremental cost-effectiveness ratio (ICER) of £220 250 per QALY. This ICER was well above the National Institute for Health and Care Excellence (NICE) upper threshold of £30 000 per QALY. A cost-effectiveness acceptability curve indicated that RO DBT had a zero probability of being cost-effective compared with TAU at the NICE £30 000 threshold.
In its current resource-intensive form, RO DBT is not a cost-effective use of resources in the UK NHS.
Declaration of interest
R.H. is co-owner and director of Radically Open Ltd, the RO DBT training and dissemination company. D.K. reports grants outside the submitted work from the National Institute for Health Research (NIHR). T.L. receives royalties from New Harbinger Publishing for sales of RO DBT treatment manuals, speaking fees from Radically Open Ltd, and a grant outside the submitted work from the Medical Research Council. He was co-director of Radically Open Ltd between November 2014 and May 2015 and is married to Erica Smith-Lynch, the principal shareholder and one of two directors of Radically Open Ltd. H.O'M. reports personal fees outside the submitted work from the Charlie Waller Institute and Improving Access to Psychological Therapy. S.R. provides RO DBT supervision through her company S C Rushbrook Ltd. I.R. reports grants outside the submitted work from NIHR and Health & Care Research Wales. M. Stanton reports personal fees outside the submitted work from British Isles DBT Training, Stanton Psychological Services Ltd and Taylor & Francis. M. Swales reports personal fees outside the submitted work from British Isles DBT Training, Guilford Press, Oxford University Press and Taylor & Francis. B.W. was co-director of Radically Open Ltd between November 2014 and February 2015.
Individuals with depression often do not respond to medication or psychotherapy. Radically open dialectical behaviour therapy (RO DBT) is a new treatment targeting overcontrolled personality, common in refractory depression.
To compare RO DBT plus treatment as usual (TAU) for refractory depression with TAU alone (trial registration: ISRCTN 85784627).
RO DBT comprised 29 therapy sessions and 27 skills classes over 6 months. Our completed randomised trial evaluated RO DBT for refractory depression over 18 months in three British secondary care centres. Of 250 adult participants, we randomised 162 (65%) to RO DBT. The primary outcome was the Hamilton Rating Scale for Depression (HRSD), assessed masked and analysed by treatment allocated.
After 7 months, immediately following therapy, RO DBT had significantly reduced depressive symptoms by 5.40 points on the HRSD relative to TAU (95% CI 0.94–9.85). After 12 months (primary end-point), the difference of 2.15 points on the HRSD in favour of RO DBT was not significant (95% CI –2.28 to 6.59); nor was that of 1.69 points on the HRSD at 18 months (95% CI –2.84 to 6.22). Throughout RO DBT participants reported significantly better psychological flexibility and emotional coping than controls. However, they reported eight possible serious adverse reactions compared with none in the control group.
The RO DBT group reported significantly lower HRSD scores than the control group after 7 months, but not thereafter. The imbalance in serious adverse reactions was probably because of the controls' limited opportunities to report these.
Precise radiocarbon (14C) dating of sedimentary sequences is important for developing robust chronologies of environmental change, but sampling of suitable components can be challenging in highly dynamic landscapes. Here we investigate radiocarbon determinations of different peat size fractions from six peat sites, representing a range of geomorphological contexts on the South Atlantic subantarctic islands of the Falklands and South Georgia. To investigate the most suitable fraction for dating, 112 measurements were obtained from three components within selected horizons: a fine fraction <0.2 mm, a coarse fraction >0.2 mm, and bulk material. We find site selection is critical, with locations surrounded by high-ground and/or relatively slowly accumulating sites more susceptible to the translocation of older carbon. Importantly, in locations with reduced potential for redeposition of material, our results show that there is no significant or systematic difference between ages derived from bulk material, fine or coarse (plant macrofossil) material, providing confidence in the resulting age model. Crucially, in areas comprising complex terrain with extreme relief, we recommend dating macrofossils or bulk carbon rather than a fine fraction, or employing comprehensive dating of multiple sedimentary fractions to determine the most reliable fraction(s) for developing a robust chronological framework.
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.
To Investigate the peripheral inflammatory profile in patients with mild cognitive impairment (MCI) from three subgroups – probable Lewy body disease (probable MCI-LB), possible Lewy body disease, and probable Alzheimer’s disease (probable MCI-AD) – as well as associations with clinical features.
Memory clinics and dementia services.
Patients were classified based on clinical symptoms as probable MCI-LB (n = 38), possible MCI-LB (n = 18), and probable MCI-AD (n = 21). Healthy comparison subjects were recruited (n = 20).
Ten cytokines were analyzed from plasma samples: interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-alpha. C-reactive protein levels were investigated.
There was a higher level of IL-10, IL-1beta, IL-2, and IL-4 in MCI groups compared to the healthy comparison group (p < 0.0085). In exploratory analyses to understand these findings, the MC-AD group lower IL-1beta (p = 0.04), IL-2 (p = 0.009), and IL-4 (p = 0.012) were associated with increasing duration of memory symptoms, and in the probable MCI-LB group, lower levels of IL-1beta were associated with worsening motor severity (p = 0.002). In the possible MCI-LB, longer duration of memory symptoms was associated with lower levels of IL-1beta (p = 0.003) and IL-4 (p = 0.026).
There is increased peripheral inflammation in patients with MCI compared to healthy comparison subjects regardless of the MCI subtype. These possible associations with clinical features are consistent with other work showing that inflammation is increased in early disease but require replication. Such findings have importance for timing of putative therapeutic strategies aimed at lowering inflammation.
Consumption Euler equations are important tools in empirical macroeconomics. When estimated on micro data, they are typically linearized, so standard IV or GMM methods can be employed to deal with the measurement error that is endemic to survey data. However, linearization, in turn, may induce serious approximation bias. We numerically solve and simulate six different life-cycle models, and then use the simulated data as the basis for a series of Monte Carlo experiments in which we evaluate the performance of linearized Euler equation estimation. We sample from the simulated data in ways that mimic realistic data structures. The linearized Euler equation leads to biased estimates of the EIS, but that bias is modest when there is a sufficient time dimension to the data, and sufficient variation in interest rates. However, a sufficient time dimension can only realistically be achieved with a synthetic cohort. Estimates from synthetic cohorts of sufficient length, while often exhibiting small mean bias, are quite imprecise. We also show that in all data structures, estimates are less precise in impatient models.
Although there has been extensive research on electoral system choice at the national level, we know relatively little about the dynamics of deciding the rules of the game for sub-state institutions. This article examines the factors that influenced the choice of a proportional electoral system for the new Scottish Parliament in 1999. Through the use of archival sources and interviews with key participants, we challenge the conventional rational choice explanation for the adoption of the mixed-member proportional (MMP) system. Although rational considerations on the part of the Labour Party were involved in the choice of MMP, our findings suggest that, as at the national level, theories of electoral system choice need to consider normative values as well.
Neuroimaging continues to be an exciting and rapidly evolving research field producing findings to inform clinical medical practice. Neuroimaging research has enabled a better understanding of in vivo structural, functional, and molecular neuropathology. Moreover, it has the potential to improve clinical care, where clinical assessment alone is sometimes insufficient to provide accurate diagnosis and prognosis. The future direction of neuroimaging is likely to focus on identifying imaging biomarkers suggestive of underlying preclinical disease, understanding the temporal progression from preclinical disease to overt clinical manifestation, and monitoring the therapeutic efficacy of potential disease-modifying agents.
Dopaminergic imaging has high diagnostic accuracy for dementia with Lewy bodies (DLB) at the dementia stage. We report the first investigation of dopaminergic imaging at the prodromal stage.
We recruited 75 patients over 60 with mild cognitive impairment (MCI), 33 with probable MCI with Lewy body disease (MCI-LB), 15 with possible MCI-LB and 27 with MCI with Alzheimer's disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)] dopaminergic imaging. FP-CIT scans were blindly rated by a consensus panel and classified as normal or abnormal.
The sensitivity of visually rated FP-CIT imaging to detect combined possible or probable MCI-LB was 54.2% [95% confidence interval (CI) 39.2–68.6], with a specificity of 89.0% (95% CI 70.8–97.6) and a likelihood ratio for MCI-LB of 4.9, indicating that FP-CIT may be a clinically important test in MCI where any characteristic symptoms of Lewy body (LB) disease are present. The sensitivity in probable MCI-LB was 61.0% (95% CI 42.5–77.4) and in possible MCI-LB was 40.0% (95% CI 16.4–67.7).
Dopaminergic imaging had high specificity at the pre-dementia stage and gave a clinically important increase in diagnostic confidence and so should be considered in all patients with MCI who have any of the diagnostic symptoms of DLB. As expected, the sensitivity was lower in MCI-LB than in established DLB, although over 50% still had an abnormal scan. Accurate diagnosis of LB disease is important to enable early optimal treatment for LB symptoms.
High definition video from a towed camera system was used to describe the deep-sea benthic habitats within an elongate depression located at the western margin of Rockall Bank in the Hatton–Rockall Basin. At depths greater than 1190 m, an extensive area (10 km long by 1.5 km wide) of what appeared to be reduced sediments, bacterial mats and flocculent matter indicated possible cold-seep habitat. Plumes of sediment-rich fluid were observed alongside raised elongate features that gave topographic relief to the otherwise flat seafloor. In the deepest section of the depression (1215 m) dense flocculent matter was observed suspended in the water column, in places obscuring the seabed. Away from the bacterial mats, the habitat changed rapidly to sediments dominated by tube-dwelling polychaete worms and then to deep-sea sedimentary habitats more typical for the water depth (sponges and burrowing megafauna in areas of gentle slopes, and coral gardens on steeper slopes).
This paper investigates the effects of the Affordable Care Act (ACA) on retirement. The first part of the paper is a difference-in-difference analysis of changes in retirement (and retirement expectations) before and after adoption of the ACA. We find no statistically significant evidence that ACA increased the propensity to retire or changed retirement expectations. The second part of the analysis is based on a structural retirement model. For those age 50 at the time ACA was introduced, the overall reduction in full-time work over the age span 54–65 is simulated to be about 0.1 percentage points. Data are from the Health and Retirement Study.
The inadequacy of current diagnostics for the detection of low worm burdens in humans means that schistosomiasis mansoni is more widespread than previously acknowledged. With the inception of mass drug treatment programmes aimed at disease elimination and the advent of human vaccine trials, the need for more sensitive diagnostics is evident. In this review, we evaluate the merits and limitations of the principal diagnostic methods, namely detection of eggs in faeces; anti-schistosome antibodies in serum; parasite-derived proteins and glycans in serum or urine; parasite DNA in blood, faeces or urine. Only in the baboon model, where actual worm burden is determined by portal perfusion, have faecal smear and circulating antigen methods been calibrated, and shown to have thresholds of detection of 10–19 worm pairs. There is scope for improvement in all the four methods of detection, e.g. the identification of single targets for host antibodies to improve the specificity of enzyme linked immunosorbent assay. Despite recent advances in the definition of the schistosome secretome, there have been no comprehensive biomarker investigations of parasite products in the urine of infected patients. Certainly, the admirable goal of eliminating schistosomiasis will not be achieved unless individuals with low worm burdens can be diagnosed.
The accurate clinical characterisation of mild cognitive impairment (MCI) is becoming increasingly important. The aim of this study was to compare the neuropsychiatric symptoms and cognitive profile of MCI with Lewy bodies (MCI-LB) with Alzheimer's disease MCI (MCI-AD).
Participants were ⩾60 years old with MCI. Each had a thorough clinical and neuropsychological assessment and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single photon emission computed tomography FP-CIT SPECT). MCI-LB was diagnosed if two or more diagnostic features of dementia with Lewy bodies were present (visual hallucinations, cognitive fluctuations, motor parkinsonism, rapid eye movement sleep behaviour disorder or positive FP-CIT SPECT). A Lewy body Neuropsychiatric Supportive Symptom Count (LBNSSC) was calculated based on the presence or absence of the supportive neuropsychiatric symptoms defined by the 2017 DLB diagnostic criteria: non-visual hallucinations, delusions, anxiety, depression and apathy.
MCI-LB (n = 41) had a higher LBNSSC than MCI-AD (n = 24; 1.8 ± 1.1 v. 0.7 ± 0.9, p = 0.001). 67% of MCI-LB had two or more of those symptoms, compared with 16% of MCI-AD (Likelihood ratio = 4.2, p < 0.001). MCI-LB subjects scored lower on tests of attention, visuospatial function and verbal fluency. However, cognitive test scores alone did not accurately differentiate MCI-LB from MCI-AD.
MCI-LB is associated with neuropsychiatric symptoms and a cognitive profile similar to established DLB. This supports the concept of identifying MCI-LB based on the presence of core diagnostic features of DLB and abnormal FP-CIT SPECT imaging. The presence of supportive neuropsychiatric clinical features identified in the 2017 DLB diagnostic criteria was helpful in differentiating between MCI-LB and MCI-AD.