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Pilot randomized double-blind-controlled trial of repetitive paired associative stimulation (rPAS), a paradigm that combines transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) with peripheral median nerve stimulation.
To study the impact of rPAS on DLPFC plasticity and working memory performance in Alzheimer’s disease (AD).
Thirty-two patients with AD (females = 16), mean (SD) age = 76.4 (6.3) years were randomized 1:1 to receive a 2-week (5 days/week) course of active or control rPAS. DLPFC plasticity was assessed using single session PAS combined with electroencephalography (EEG) at baseline and on days 1, 7, and 14 post-rPAS. Working memory and theta–gamma coupling were assessed at the same time points using the N-back task and EEG.
There were no significant differences between the active and control rPAS groups on DLPFC plasticity or working memory performance after the rPAS intervention. There were significant main effects of time on DLPFC plasticity, working memory, and theta–gamma coupling, only for the active rPAS group. Further, on post hoc within-group analyses done to generate hypotheses for future research, as compared to baseline, only the rPAS group improved on post-rPAS day 1 on all three indices. Finally, there was a positive correlation between working memory performance and theta–gamma coupling.
This study did not show a beneficial effect of rPAS for DLPFC plasticity or working memory in AD. However, post hoc analyses showed promising results favoring rPAS and supporting further research on this topic. (Clinicaltrials.gov-NCT01847586)
In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to ‘use the lowest possible dose’ of antipsychotic drugs, but provide no information on optimal dosing.
This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548).
A statistical model, which described the concentration–time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS.
The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann–Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance.
Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.
Life course research embraces the complexity of health and disease development, tackling the extensive interactions between genetics and environment. This interdisciplinary blueprint, or theoretical framework, offers a structure for research ideas and specifies relationships between related factors. Traditionally, methodological approaches attempt to reduce the complexity of these dynamic interactions and decompose health into component parts, ignoring the complex reciprocal interaction of factors that shape health over time. New methods that match the epistemological foundation of the life course framework are needed to fully explore adaptive, multilevel, and reciprocal interactions between individuals and their environment. The focus of this article is to (1) delineate the differences between lifespan and life course research, (2) articulate the importance of complex systems science as a methodological framework in the life course research toolbox to guide our research questions, (3) raise key questions that can be asked within the clinical and translational science domain utilizing this framework, and (4) provide recommendations for life course research implementation, charting the way forward. Recent advances in computational analytics, computer science, and data collection could be used to approximate, measure, and analyze the intertwining and dynamic nature of genetic and environmental factors involved in health development.
Impaired illness awareness or insight into illness (IIA) is a common feature of schizophrenia that contributes to medication nonadherence and poor clinical outcomes. Neuroimaging studies suggest IIA may arise from interhemispheric imbalance in frontoparietal regions, particularly in the posterior parietal area (PPA) and the dorsolateral prefrontal cortex (dlPFC). In this pilot study, we examined the effects of transcranial direct current stimulation (tDCS) on brain regions implicated in IIA.
Eleven patients with schizophrenia with IIA (≥3 PANSS G12) and 10 healthy controls were included. A crossover design was employed where all participants received single-session bi-frontal, bi-parietal, and sham stimulation in random order. For each condition, we measured (i) blood oxygen level-dependent (BOLD) response to an illness awareness task pre- and post-stimulation, (ii) regional cerebral blood-flow (rCBF) prior to and during stimulation, and (iii) changes in illness awareness.
At baseline, patients with schizophrenia showed higher BOLD-response to an illness awareness task in the left-PPA compared to healthy controls. Bi-parietal stimulation reduced the interhemispheric imbalance in the PPA compared to sham stimulation. Relatedly, bi-parietal stimulation increased rCBF beneath the anode (21% increase in the right-PPA), but not beneath the cathode (5.6% increase in the left-PPA). Bi-frontal stimulation did not induce changes in rCBF. We found no changes in illness awareness.
Although single-session tDCS did not improve illness awareness, this pilot study provides mechanistic justification for future investigations to determine if multi-session bi-parietal tDCS can induce sustained changes in brain activity in the PPA in association with improved illness awareness.
An outbreak of mumps within a student population in Scotland was investigated to assess the effect of previous vaccination on infection and clinical presentation, and any genotypic variation. Of the 341 cases, 79% were aged 18–24. Vaccination status was available for 278 cases of whom 84% had received at least one dose of mumps containing vaccine and 62% had received two. The complication rate was 5·3% (mainly orchitis), and 1·2% were admitted to hospital. Genetic sequencing of mumps virus isolated from cases across Scotland classified 97% of the samples as genotype G. Two distinct clusters of genotype G were identified, one circulating before the outbreak and the other thereafter, suggesting the virus that caused this outbreak was genetically different from the previously circulating virus. Whilst the poor vaccine effectiveness we found may be due to waning immunity over time, a contributing factor may be that the current mumps vaccine is less effective against some genotypes. Although the general benefits of the measles–mumps–rubella (MMR) vaccine should continue to be promoted, there may be value in reassessing the UK vaccination schedule and the current mumps component of the MMR vaccine.
We demonstrate that the surface topography of a sample can be reconstructed from electron backscatter diffraction (EBSD) patterns collected with a commercial EBSD system. This technique combines the location of the maximum background intensity with a correction from Monte Carlo simulations to determine the local surface normals at each point in an EBSD scan. A surface height map is then reconstructed from the local surface normals. In this study, a Ni sample was machined with a femtosecond laser, which causes the formation of a laser-induced periodic surface structure (LIPSS). The topography of the LIPSS was analyzed using atomic force microscopy (AFM) and reconstructions from EBSD patterns collected at 5 and 20 kV. The LIPSS consisted of a combination of low frequency waviness due to curtaining and high frequency ridges. The morphology of the reconstructed low frequency waviness and high frequency ridges matched the AFM data. The reconstruction technique does not require any modification to existing EBSD systems and so can be particularly useful for measuring topography and its evolution during in situ experiments.
Celebrity firms are firms that attract a high level of public attention and generate positive affective responses from stakeholder audiences (Rindova, Pollock, and Hayward 2006). Recent research has explored how and why firms become celebrities (Rindova et al. 2006; Zavyalova and Pfarrer 2015) and how celebrity creates value for firms (Pfarrer, Pollock, and Rindova 2010). Celebrity firms are more likely to have unexpectedly high performance – and gain additional benefits when they do so – while suffering fewer penalties when their performance is lower than expected (Pfarrer et al. 2010).
Rindova and colleagues have also argued that firms can engender “infamy,” which results from generating a high level of public attention and negative affective responses from stakeholder audiences. Central to both celebrity and infamy is that firms must engage in “deviant” or non-conforming behaviors. When viewed positively, these behaviors create a “rebel” celebrity persona attractive to at least some stakeholders; however, if the non-conforming behaviors are viewed negatively they can lead to an “outlaw” persona that at a minimum results in a loss of celebrity and possibly increases infamy.
Although researchers have begun to explore the causes and consequences of firm celebrity, little research (for a recent exception, see Zavyalova and Pfarrer ) has considered how firms become infamous. Building on Rindova and colleagues (2006), Zavyalova and Pfarrer (2015) argued that celebrity occurs through audience members’ identification with a firm's values and beliefs as presented in media-created narratives, and that infamy results from dis-identification with the organization's values and beliefs. Because firms face a plethora of stakeholder audiences with differing priorities and values, they further argued that the same firm can possess both celebrity and infamy simultaneously, as the same set of organizational values and beliefs can be the cause for identification with the firm by one stakeholder audience and dis-identification by another. Consequently, firms can lose celebrity in their quest to maintain it by eventually engaging in behaviors or revealing information that is inconsistent with audience members’ bases for identification.
Fundamental to the process of becoming infamous is the belief by a stakeholder group or groups that the firm is engaging in deviant behaviors that they consider wrongdoing.
Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD).
In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression.
Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure.
We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.
Cryptosporidium parvum (C. parvum) is one of the most prevalent protozoan pathogens responsible for inducing human and animal disease worldwide. In this study, the glycoprotein-60 (gp60) subtyping tool was employed to assess the molecular diversity of C. parvum from human feces throughout Scotland during potential outbreaks. Over a 24-month period, microscopy analysis revealed 1139 positive feces containing Cryptosporidium species with 256 identified by molecular methods specifically as C. parvum. Cryptosporidium parvum was shown to be more prevalent in rural areas of Scotland and subtyping of 87 isolates demonstrated the predominant family as IIa, which occurred in 94% (n = 82) of isolates. The IIaA15G1R1 subtype was most common, being isolated from 47% (n = 41) of Scottish human cases. Non-IIa strains constituted a total of 5 isolates and included subtypes from the IIc, IId and IIg families. This information contributes significantly to existing knowledge and understanding of C. parvum subtypes in Scotland which is vital in assisting with the management of future local and national outbreaks.
Giardiasis, caused by the intestinal protozoan parasite Giardia intestinalis (synonyms: G. lamblia, G. duodenalis), is one of the most frequent parasites to infect the Scottish population. Transmission of the infective cysts in faecal matter is commonly via food and/or water. Giardia is subdivided into assemblages, where clinical and epidemiological differences have been described between assemblages A and B. This snapshot descriptive epidemiological study examines 30 positive cases of Giardia of which 72% (n = 21) were shown to be assemblage A, 14% (n = 4) assemblage B and 10% (n = 3) mixed assemblages (A and B). There was a 2:3 female:male ratio of affected individuals with foreign travel recorded in 22 of these cases. The commonest symptom was diarrhoea which was reported in 80% of cases followed by tiredness. Five cases required hospitalization emphasizing the importance of gaining a greater understanding of how Giardia assemblages influence clinical outcomes to assist in formulating guidelines to manage potential Giardia outbreaks.
The associations with weather and bathing water quality on infectious intestinal disease (IID) were investigated using data from two Scottish NHS Board areas. Monthly counts of viral and non-viral gastrointestinal infections were modelled as a smooth function of temperature, relative humidity and average monthly counts of faecal indicator organisms, respectively, adjusting for season and long-term trend effects. Strong seasonal patterns were observed for each group of pathogens. Peak viral gastrointestinal infection was in May while that of non-viral gastrointestinal infections was in July. A statistically significant negative association existed between weather (temperature and humidity) and viral infection. Average levels of non-viral gastrointestinal infections increased as temperature and relative humidity increased. Increasing levels of faecal indicator organisms in bathing waters were also associated with an increase in the average number of viral and non-viral gastrointestinal infections at the ecological level. Future climate change and prolonged precipitation events may result in increasing levels of faecal indicator organisms in bathing waters leading to likely increases in IIDs.
Previous evidence has suggested an association between cryptosporidiosis and consumption of unfiltered drinking water from Loch Katrine in Scotland. Before September 2007, the water was only micro-strained and chlorinated; however, since that time, coagulation and rapid gravity filtration have been installed. In order to determine risk factors associated with cryptosporidiosis, including drinking water, we analysed data on microbiologically confirmed cases of cryptosporidiosis from 2004 to 2010. We identified an association between the incidence of cryptosporidiosis and unfiltered Loch Katrine drinking water supplied to the home (odds ratio 1·86, 95% confidence interval 1·11–3·11, P = 0·019). However, while filtration appears to be associated with initially reduced rates of cryptosporidiosis, evidence suggests it may paradoxically make those consumers more susceptible to other transmission routes in the long-term. These findings support implementation of similar treatment for other unfiltered drinking-water supplies, as a means of reducing cryptosporidiosis associated with drinking water.
Older adults are among the most vulnerable to adverse cognitive effects of psychotropic medications and, therefore, the personalization of psychotropic treatment based on adverse drug reactions in this demographic is of great importance. We examined changes on neuropsychological tests of attention attributable to selective serotonin reuptake inhibitor (SSRI) treatment in anxious older adults. We also examined whether variation in serotonin receptor genes was associated with reduced attentional performance with SSRIs. We examined change from pre- to post-treatment in two attention measures – digit span and coding – in 133 adults aged ⩾60 yr with generalized anxiety disorder in a 12-wk trial of escitalopram vs. placebo. We also examined attentional change in relation to genetic variability in four central serotonin receptors: the serotonin transporter and serotonin 1A, 2A and 1B receptors. Digit span scores were significantly lowered in patients receiving escitalopram relative to placebo, indicating reduced attentional performance attributable to the SSRI. Individuals with high-transcription variants in the receptors 5-HTR2A rs6311 and 5-HTR1B rs11568817 had greater reductions in attention with SSRI treatment compared to placebo. We conclude that SSRIs reduce attention in older adults, particularly in those with high-expression genetic variants at the serotonin 2A and 1B receptors. Analysing neuropsychological changes with SSRIs in relation to genetic variation in the serotonin system may be a useful strategy for detecting subgroups of older adults who are more susceptible to side-effects of SSRIs. These results, if confirmed, could lead to the personalization of SSRI use to reduce adverse neurocognitive effects.
We present preliminary results of a 4-month campaign carried out in the framework of the Mons project, where time-resolved Hα observations are used to study the wind and circumstellar properties of a number of OB stars.
We present the results from the spectroscopic follow-up of WR140 (WC7 + O4-5) during its last periastron passage in january 2009. This object is known as the archetype of colliding wind binaries and has a relatively large period (≃8 years) and eccentricity (≃0.89). We provide updated values for the orbital parameters, new estimates for the WR and O star masses and new constraints on the mass-loss rates.
Research has shown that up to 83% of friends and family members of people diagnosed with schizophrenia experience financial, emotional, and practical burdens. In their pioneering study of family psychoeducation, Falloon and colleagues found that reductions in family burden associated with family psychoeducation were associated with improvements in patient clinical status and reductions in relapse over time. The design of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) permits investigation of the impact of random assignment to the first-generation antipsychotic perphenazine and four second-generation drugs on family outcomes over an 18-month study period. In addition, family members frequently take an active role in helping patients manage their medication and in other aspects of preventing relapse and promoting recovery. The findings of the CATIE study underscore the importance of involving family caregivers in treatment planning for their relatives with schizophrenia.
Extreme Ultraviolet (EUV) and X-ray emission is of great importance in several phenomena related to the formation of planetary systems and the atmospheres of planets. The atmospheric composition, and the mass of an exoplanet, are partly dependent on the X-ray and EUV radiation received during the first stages of formation and even during main sequence of the star. Biological life developing on exoplanets would depend severely on the high energy radiation arriving from its parent star.
Here we present a database of the X-ray and EUV emission of all the stars currently known to host exoplanets. The archive is public and accessible through the Spanish Virtual Observatory (SVO). The database gives the user the option to download observed X-rays and EUV spectra. Synthetic spectra covering the spectral range 1–912 Å are also available (present day telescopes do not give access to the EUV range at λ > 180 Å). These spectra are created using coronal models after fitting observed spectra.