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A partnership between University of Oxford, the Earlham Institute, and the global pharmaceutical companies Biogen Inc and Boehringer Ingelheim has been announced to investigate a new drug target for the treatment of schizophrenia.
The relationship between sleep disturbance, symptoms and daytime functioning in psoriasis: a prospective study integrating actigraphy and experience sampling methodology.
OBJECTIVE/BACKGROUND: Sleep disturbance is common in individuals with psoriasis and appears to be related to both physical and psychological factors. We sought to examine whether psoriasis symptoms, night-time arousal and low mood predicted subsequent objective and self-reported sleep; and whether objective and self-reported sleep predicted next-day psoriasis symptoms and day-time functioning. PARTICIPANTS/METHODS: A total of 19 individuals (Female: 11 [57.9%], median age: 39 years) with chronic plaque psoriasis and poor sleep quality (mean Pittsburgh Sleep Quality Index, PSQI = 9.11) participated. Momentary assessments of psoriasis symptoms, mood and daytime functioning were completed at five pseudo-random intervals each day for 15 days using time-stamped digital diary entry. Objective sleep was estimated using wrist-worn actigraphy. Self-reported sleep and night-time arousal were assessed each morning using validated measures. RESULTS AND CONCLUSIONS: Two-level random intercept models showed that increased night-time arousal was associated with poorer diary-reported sleep. Neither self-reported nor objective sleep parameters were associated with daytime psoriasis symptoms in bi-directional analyses. Diary-reported sleep predicted next-day functioning, specifically sleepiness, concentration, and fatigue. Actigraphy-defined total sleep time predicted next-day fatigue. Night-time arousal is associated with poorer self-reported sleep in people with psoriasis, and sleep predicts next-day functioning. Contrary to our hypothesis, sleep disturbance does not appear to be associated with momentary assessments of psoriasis symptoms.
This article discusses information extracted from 53 studies that have measured adherence to cognitive behavior therapy for insomnia. There has been an increase in more complex and less biased methods for assessing adherence that move beyond simply asking the patients whether they have adhered to the intervention or not. There is a need for a consensus around how to measure adherence, if clinicians want to arrive at an estimate of optimal adherence. Heterogeneity of studies, particularly in the way adherence is operationalized, prohibited conclusions about the relationship between adherence and outcome, as well as about predictors of adherence.
INTRODUCTION: Shift work causes misalignment between internal circadian time and the external light/dark cycle and is associated with metabolic disorders and cancer. Approximately 20% of the working population in industrialised countries work permanent or rotating night shifts, exposing this large population to the risk of circadian misalignment-driven disease. Analysis of the impact of shift work on chronic inflammatory diseases is lacking. We investigated the association between shift work and asthma. METHODS: We describe the cross-sectional relationship between shift work and prevalent asthma in >280000 UK Biobank participants, making adjustments for major confounding factors (smoking history, ethnicity, socioeconomic status, physical activity, body mass index). We also investigated chronotype. RESULTS: Compared with day workers, 'permanent' night shift workers had a higher likelihood of moderate-severe asthma (OR 1.36 (95% CI 1.03 to 1.8)) and all asthma (OR 1.23 (95% CI 1.03 to 1.46)). Individuals doing any type of shift work had higher adjusted odds of wheeze/whistling in the chest. Shift workers who never or rarely worked on nights and people working permanent nights had a higher adjusted likelihood of having reduced lung function (FEV1 <80% predicted). We found an increase in the risk of moderate-severe asthma in morning chronotypes working irregular shifts, including nights (OR 1.55 (95% CI 1.06 to 2.27)). CONCLUSIONS: The public health implications of these findings are far-reaching due to the high prevalence and co-occurrence of both asthma and shift work. Future longitudinal follow-up studies are needed to determine if modifying shift work schedules to take into account chronotype might present a public health measure to reduce the risk of developing inflammatory diseases such as asthma.
Mating changes female behaviour and physiology across a wide range of taxa, with important effects for male and female fitness. These changes are often induced by components of the male ejaculate, such as sperm and seminal fluid proteins. However, males can vary significantly in their ejaculates, due to factors such as age, mating history or nutritional status. This male variation may therefore lead to variation in the strength of responses males can stimulate in females, with alterations in fitness outcomes for both sexes. Using the fruit fly, Drosophila melanogaster, we tested whether three aspects of male condition shape an important, but understudied, post-mating response—increased female–female aggression. We found that females mated to old males fought less than females mated to young males. This effect was exacerbated in mates of old, sexually active males, but there was no effect of male starvation status on mating-induced female aggression. There was also a significant effect of age and mating history on female post-mating feeding duration. Our results add to a growing body of literature that variation in male condition can shape sexual selection through post-mating responses in females, including female–female interactions. Studying such variation may therefore be useful for understanding how the condition of one sex affects the behaviour of the other. A free plain language summary can be found within the Supporting Information of this article.
Inference of brain networks with approximate Bayesian computation - assessing face validity with an example application in Parkinsonism.
This paper describes and validates a novel framework using the Approximate Bayesian Computation (ABC) algorithm for parameter estimation and model selection in models of mesoscale brain network activity. We provide a proof of principle, first pass validation of this framework using a set of neural mass models of the cortico-basal ganglia thalamic circuit inverted upon spectral features from experimental, in vivo recordings. This optimization scheme relaxes an assumption of fixed-form posteriors (i.e. the Laplace approximation) taken in previous approaches to inverse modelling of spectral features. This enables the exploration of model dynamics beyond that approximated from local linearity assumptions and so fit to explicit, numerical solutions of the underlying non-linear system of equations. In this first paper, we establish a face validation of the optimization procedures in terms of: (i) the ability to approximate posterior densities over parameters that are plausible given the known causes of the data; (ii) the ability of the model comparison procedures to yield posterior model probabilities that can identify the model structure known to generate the data; and (iii) the robustness of these procedures to local minima in the face of different starting conditions. Finally, as an illustrative application we show (iv) that model comparison can yield plausible conclusions given the known neurobiology of the cortico-basal ganglia-thalamic circuit in Parkinsonism. These results lay the groundwork for future studies utilizing highly nonlinear or brittle models that can explain time dependant dynamics, such as oscillatory bursts, in terms of the underlying neural circuits.
No safe level of alcohol consumption for brain health: observational cohort study of 25,378 UK Biobank participants
Objectives To estimate the relationship between moderate alcohol consumption and brain health, determining the threshold intake for harm and identifying whether population subgroups are at differential risk. Design Observational cohort study. Alcohol consumption was determined at baseline assessment visit using touchscreen questionnaire (2016-10). Multi-modal MRI brain and cognitive testing were performed subsequently (2014-20). Clinical data was extracted from linked Hospital Episode Statistics. Setting UK Biobank study. Brain imaging was performed on identical scanners with identical protocols at three UK centres (2014-20). Participants 25,378 participants (mean age 54.9±7.4 years). Main outcome measures Brain health as defined by structural and functional MRI brain measures. Results Alcohol consumption was negatively linearly associated with global brain grey matter volume (beta= -0.1, 95%CI= -0.11 to -0.09, p<2x10 -16 ). The association with alcohol was stronger than other modifiable factor tested and robust to unobserved confounding. Widespread negative associations were observed with white matter microstructure (beta= -0.08, 95%CI= -0.09 to -0.06, p<2x10 -16 ) and positive correlations with functional connectivity. Higher blood pressure and body mass index increased risk of alcohol-related harm (SBP*alcohol: beta= - 0.01, 95%CI = -0.02 to -0.004, p=0.005; BMI*alcohol: beta= -0.01, 95%CI = -0.02 to -0.002, p=0.02). Binging on alcohol had additive negative effects on brain structure on top of the absolute volume consumed (daily compared to never binging: beta= -0.19, 95%CI= -0.30 to -0.08, p<0.01). No evidence was found for differential effects of drinking wine, beer or spirits. Conclusions No safe dose of alcohol for the brain was found. Moderate consumption is associated with more widespread adverse effects on the brain than previously recognised. Individuals who binge drink or with high blood pressure and BMI may be more susceptible. Detrimental effects of drinking appear to be greater than other modifiable factors. Current ‘low risk’ drinking guidelines should be revisited to take account of brain effects.
The Relationship Between Working Alliance and Symptom Improvement in Cognitive Therapy for Posttraumatic Stress Disorder.
Background: Working alliance has been shown to predict outcome of psychological treatments in multiple studies. Conversely, changes in outcome scores have also been found to predict working alliance ratings. Objective: To assess the temporal relationships between working alliance and outcome in 230 patients receiving trauma-focused cognitive behavioral treatment for posttraumatic stress disorder (PTSD). Methods: Ratings of working alliance were made by both the patient and therapist after sessions 1, 3, and 5 of a course of Cognitive Therapy for PTSD (CT-PTSD). Autoregressive, cross-lagged panel models were used to examine whether working alliance predicted PTSD symptom severity at the next assessment point and vice versa. Linear regressions tested the relationship between alliance and treatment outcome. Results: Both patients' and therapists' working alliance ratings after session 1 predicted PTSD symptom scores at the end of treatment, controlling for baseline scores. At each assessment point, higher therapist working alliance was associated with lower PTSD symptoms. Crossed-lagged associations were found for therapist-rated alliance, but not for patient-rated alliance: higher therapists' alliance ratings predicted lower PTSD symptom scores at the next assessment point. Similarly, lower PTSD symptoms predicted higher therapist working alliance ratings at the next assessment point. Ruminative thinking was negatively related to therapists' alliance ratings. Conclusions: Working alliance at the start of treatment predicted treatment outcome in patients receiving CT-PTSD and may be an important factor in setting the necessary conditions for effective treatment. For therapists, there was a reciprocal relationship between working alliance and PTSD symptom change in their patients during treatment, suggesting that their alliance ratings predicted symptom change, but were also influenced by patients' symptom change.
INTRODUCTION: Current prognostic models of dementia have had limited success in consistently identifying at-risk individuals. We aimed to develop and validate a novel dementia risk score (DRS) using the UK Biobank cohort. METHODS: After randomly dividing the sample into a training (n=166,487, 80%) and test set (n=41,621, 20%), logistic LASSO regression and standard logistic regression were used to develop the UKB-DRS. RESULTS: The score consisted of age, sex, education, apolipoprotein E4 genotype, a history of diabetes, stroke, and depression, and a family history of dementia. The UKB-DRS had good-to-strong discrimination accuracy in the UKB hold-out sample (AUC [95%CI]=0.79 [0.77, 0.82]) and in an external dataset (Whitehall II cohort, AUC [95%CI]=0.83 [0.79,0.87]). The UKB-DRS also significantly outperformed four published risk scores (i.e., Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia score (CAIDE), Dementia Risk Score (DRS), and the Framingham Cardiovascular Risk Score (FRS) across both test sets. CONCLUSION: The UKB-DRS represents a novel easy-to-use tool that could be used for routine care or targeted selection of at-risk individuals into clinical trials.
Several scientific, engineering, and medical advancements are based on breakthroughs made by people who excel in mathematics. Our current understanding of the underlying brain networks stems primarily from anatomical and functional investigations, but our knowledge of how neurotransmitters subserve numerical skills, the building block of mathematics, is scarce. Using 1H magnetic resonance spectroscopy (N=54, 3T, semi-LASER sequence, TE=32ms, TR=3.5s), the study examined the relation between numerical skills and the brain’s major inhibitory (GABA) and excitatory (glutamate) neurotransmitters. A negative association was found between the performance in a number sequences task and the resting concentration of GABA within the left intraparietal sulcus (IPS), a key region supporting numeracy. The relation between GABA in the IPS and number sequences was specific (i) to parietal but not frontal regions and (ii), and to GABA but not glutamate. It was additionally found that the resting functional connectivity of left IPS and left superior frontal gyrus is positively associated with number sequences performance. However, resting GABA concentration within the IPS explained number sequences performance above and beyond the resting frontoparietal connectivity measure. Our findings further motivate the study of inhibition mechanisms in the human brain and significantly contribute to our current understanding of numerical cognition's biological bases.
Intended for use with the Guideline, this book combines the best available research with expert clinical recommendations, to help readers make the clinical decisions that are best for their patients.
This is a critical resource for clinicians in interpreting somatic symptoms and co-occurring medical disorders.
This is a critical resource for clinicians in interpreting somatic symptoms and co-occurring medical disorders.
since baseline levels of anxiety and arousal strongly predict the levels reached during panic challenges, expectancy effects could play a very significant role in the outcome of panic induction studies reports preliminary findings of two experiments [with panic disorder patients] investigating this hypothesis by manipulating expectancy effects directly via instructions our results show strong and consistent effects of a simple expectancy manipulation on subsequent responses to HV [hyperventilation] stress in panic patients and normal controls
New to This Edition *Incorporates major advances in research and clinical practice. *Chapters on additional evidence-based individual treatments: prolonged exposure therapy, cognitive therapy, cognitive processing therapy, brief eclectic ...
This book bridges the gap between evidence-based guidelines and routine practice in the real world.
Niemann-Pick type C disease is a lysosomal storage disease affecting primarily the nervous system that results in premature death. Here we present the first report and investigation of Niemann-Pick type C disease in Australian Angus/Angus-cross calves. After a preliminary diagnosis of Niemann-Pick type C, samples from two affected calves and two obligate carriers were analysed using single nucleotide polymorphism genotyping and homozygosity mapping, and NPC1 was considered as a positional candidate gene. A likely causal missense variant on chromosome 24 in the NPC1 gene (NM_174758.2:c.2969C>G) was identified by Sanger sequencing of cDNA. SIFT analysis, protein alignment and protein modelling predicted the variant to be deleterious to protein function. Segregation of the variant with disease was confirmed in two additional affected calves and two obligate carrier dams. Genotyping of 403 animals from the original herd identified an estimated allele frequency of 3.5%. The Niemann-Pick type C phenotype was additionally confirmed via biochemical analysis of Lysotracker Green, cholesterol, sphingosine and glycosphingolipids in fibroblast cell cultures originating from two affected calves. The identification of a novel missense variant for Niemann-Pick type C disease in Angus/Angus-cross cattle will enable improved breeding and management of this disease in at-risk populations. The results from this study offer a unique opportunity to further the knowledge of human Niemann-Pick type C disease through the potential availability of a bovine model of disease.
Investigating the Mechanism of Cyclodextrins in the Treatment of Niemann-Pick Disease Type C Using Crosslinked 2-Hydroxypropyl-β-cyclodextrin.
Niemann-Pick disease type C (NPC) is a severe disorder that is characterized by intracellular transport abnormalities leading to cytoplasmic accumulation of lipids such as cholesterol and sphingolipids. The compound 2-hydroxypropyl-β-cyclodextrin (HPβCD) has high cholesterol complexation capacity and is currently under clinical investigation for the NPC treatment. However, due to its short blood half-life, high doses are required to produce a therapeutic effect. In this work, stable polymerized HPβCD is generated to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8-312 kDa) display a ninefold greater cholesterol complexation capacity than monomeric HPβCD but are taken up to a lower extent, resulting in an overall comparable in vitro effect. In vivo, the 19.3 kDa HPβCD exhibits a longer half-life than the monomeric HPβCD but it does not increase the life span of Npc1 mice, possibly due to reduced brain penetration. This is circumvented by the application of magnetic resonance imaging-guided low intensity-pulsed focused ultrasound (MRIg-FUS), which increases the brain penetration of the CD. In conclusion, stable polymerized HPβCDs can elucidate CDs' mechanism of action while the use of MRIg-FUS warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the NPC treatment.