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Theoretical accounts suggest heightened uncertainty about the state of the world underpin aberrant belief updates, which in turn increase the risk of developing a persecutory delusion. However, this raises the question as to how an agent’s uncertainty may relate to the precise phenomenology of paranoia, as opposed to other qualitatively different forms of belief. We tested whether the same population (n = 693) responded similarly to non-social and social contingency changes in a probabilistic reversal learning task and a modified repeated reversal Dictator game, and the impact of paranoia on both. We fitted computational models that included closely related parameters that quantified the rigidity across contingency reversals and the uncertainty about the environment/partner. Consistent with prior work we show that paranoia was associated with uncertainty around a partner’s behavioural policy and rigidity in harmful intent attributions in the social task. In the non-social task we found that pre-existing paranoia was associated with larger decision temperatures and commitment to suboptimal cards. We show relationships between decision temperature in the non-social task and priors over harmful intent attributions and uncertainty over beliefs about partners in the social task. Our results converge across both classes of model, suggesting paranoia is associated with a general uncertainty over the state of the world (and agents within it) that takes longer to resolve, although we demonstrate that this uncertainty is expressed asymmetrically in social contexts. Our model and data allow the representation of sociocognitive mechanisms that explain persecutory delusions and provide testable, phenomenologically relevant predictions for causal experiments.

This text offers a comprehensive survey of contemporary sports technology and engineering, providing a complete overview of academic, professional and industrial knowledge and technique. The book is divided into four main sections.

Fabry disease (FD) results from X-linked inheritance of a mutation in the GLA gene, encoding for alpha galactosidase A, and is characterized by heterogeneous clinical manifestations. Two phenotypes have been described \"Classic\" and \"late onset\" which cannot be predicted exclusively by genotype. The latter has been considered an attenuated form of the disease often affecting a single organ system commonly the heart. Recent studies have demonstrated that cardiac outcomes are similar in patients with classic and late onset mutations. In this study we investigate the relationship between clinical heterogeneity and plasma lyso-Gb3 in a large single centre cohort of N215S patients and compare this to patients with other mutations. In this single-centre, retrospective, cross-sectional study we analysed a cohort of 251 FD patients: 84 N215S mutation (37 males) and 167 non-N215S mutations (58 males). The Mainz severity score index (MSSI) was used as an index of overall disease severity. Cardiac function and morphology were assessed by electrocardiogram and echocardiogram. Left ventricular mass was calculated using the Devereux formula and the left ventricular mass index (LVMI) calculated to adjust for height (g/m2.7). The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). GFR was measured by radio-isotope (chromium-EDTA) method and adjusted for patient height (ml/min/m2.7), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients. N215S patients showed later symptom onset (males: p< 0.0001, females: p<0.03), later development of left ventricular hypertrophy (LVH) (median survival without LVH: 41 (non-N215S) vs. 64 (N215S) years, p< 0.0001), later development of proteinuria (median survival without proteinuria 43 (non-N215S) vs 71 years (N215S), p< 0.0001), later occurrence of cerebrovascular events (stroke/ Transient Ischaemic Attacks (TIA); median survival without stroke: 74 years (non-N215S) vs. not reached (N215S), p< 0.02), later decline in renal function to GFR <60 ml/min/1.73m2 (median survival: 56 (non-N215S) vs. 72 (N215S) years, p< 0.01), and greater overall survival (median survival 81 (N215S) vs. 66 (non-N215S) years, p< 0.0006). Lyso-Gb3 was found to be less elevated in N215S compared to non-N215S male and female patients. However, the N215S population eventually reached an overall severity measured by MSSI comparable to the non-N215S without equivalent elevation of lyso-Gb3 (means: 6.7 vs. 74.3 nmol/L, p < 0.001). In addition, N215S patients showed strong correlations between lyso-Gb3 levels and LVMI, GFR, and MSSI. These associations became stronger when we investigated individuals' life time exposure to lyso-Gb3 (calculated as [lyso-Gb3]*age): MSSI (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001). These results demonstrate that the N215S mutation results in a late onset phenotype involving the heart and other organs. Correlations between clinical manifestations and plasma lyso-Gb3 variations in this group suggest a Fabry-relevant disease mechanism for the heterogeneity observed in this group.

Genetically modified pig kidney xenografts were transplanted into two brain-dead human recipients. The xenografts functioned immediately and showed no evidence of acute rejection on serial biopsy over a period of 54 hours. The serum creatinine level decreased in both recipients.

Summary Objective To review the efficacy, safety, and clinical applicability of liraglutide for weight management from phase III clinical trials. Methods A search of the English language literature was performed using PubMed search terms: “liraglutide”, “glucagon‐like peptide‐1 receptor agonist”, and “randomized clinical trial”. Articles and bibliographies relevant to the subject were reviewed and additional references known to the authors were included. Results Five randomized, placebo‐controlled trials of liraglutide for weight management were identified. In addition to recommended diet and physical activity, liraglutide consistently resulted in a 4 to 6 kg weight loss, with a greater proportion of patients achieving at least 5 and 10% weight loss compared with placebo. The most common adverse effects were gastrointestinal and primarily occurred early in the treatment course. Comparative data suggest that weight loss with liraglutide is greater than that seen with orlistat or lorcaserin, but slightly less that seen with phentermine/topiramate. Liraglutide 1.8 mg was recently shown to have cardiovascular benefit in a large outcomes trial; applicability of these results for the 3.0 mg formulation in a more diverse weight loss population at high cardiovascular risk is not currently known. Barriers to real‐world clinical use as a first‐line agent include gastrointestinal side effects, high cost, and need for injection. Conclusions Liraglutide helps to induce and sustain weight loss in patients with obesity. Its efficacy is comparable to other available agents but it offers the unique benefit of improved glycemic control. Additional studies are needed to determine its long term efficacy and safety profile.

Few disciplines in contemporary clinical research have experienced the high expectations directed at the gene therapy field. However, gene therapy has been challenging to translate to the clinic, often because the therapeutic gene is expressed at insufficient levels in the patient or because the gene delivery vector integrates near protooncogenes, which can cause leukemia (see the Perspective by Verma ). Biffi et al. ( 1233158 , published online 11 July) and Aiuti et al. ( 1233151 ; published online 11 July) report progress on both fronts in gene therapy trials of three patients with metachromatic leukodystrophy (MLD), a neurodegenerative disorder, and three patients with Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder. Optimized lentiviral vectors were used to introduce functional MLD or WAS genes into the patients' hematopoietic stem cells (HSCs) ex vivo, and the transduced cells were then infused back into the patients, who were then monitored for up to 2 years. In both trials, the patients showed stable engraftment of the transduced HSC and high expression levels of functional MLD or WAS genes. Encouragingly, there was no evidence of lentiviral vector integration near proto-oncogenes, and the gene therapy treatment halted disease progression in most patients. A longer follow-up period will be needed to further validate efficacy and safety. Lentivirus-mediated gene therapy produces encouraging results in three children with a rare lysosomal storage disease. [Also see Perspective by Verma ] Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.

The COVID-19 pandemic (including lockdown) is likely to have had profound but diverse implications for mental health and well-being, yet little is known about individual experiences of the pandemic (positive and negative) and how this relates to mental health and well-being, as well as other important contextual variables. Here, we analyse data sampled in a large-scale manner from 379,875 people in the United Kingdom (UK) during 2020 to identify population variables associated with mood and mental health during the COVID-19 pandemic, and to investigate self-perceived pandemic impact in relation to those variables. We report that while there are relatively small population-level differences in mood assessment scores pre- to peak-UK lockdown, the size of the differences is larger for people from specific groups, e.g. older adults and people with lower incomes. Multiple dimensions underlie peoples’ perceptions, both positive and negative, of the pandemic’s impact on daily life. These dimensions explain variance in mental health and can be statistically predicted from age, demographics, home and work circumstances, pre-existing conditions, maladaptive technology use and personality traits (e.g., compulsivity). We conclude that a holistic view, incorporating the broad range of relevant population factors, can better characterise people whose mental health is most at risk during the COVID-19 pandemic. The COVID-19 pandemic has affected people’s health and well-being. Here, the authors characterize self-reported impact of the pandemic (positive and negative) at a large scale in the United Kingdom, and show variance among individual circumstances.

Post-COVID Syndrome has emerged as a significant public health concern worldwide with increasing evidence to suggest that individuals who have had an acute COVID-19 infection report lingering memory and attention difficulties, even in individuals who have fully recovered and no longer experiencing symptoms of COVID-19. The present study sought to investigate the profile of objective and subjective cognitive difficulties in people who have Post-COVID Syndrome, people who have fully recovered from an acute COVID infection and people who have never had COVID-19. We further sought to explore the extent to which self-reported fatigue and stress are related to subjective and objective cognitive difficulties. 162 participants including 50 people living with Post-COVID Syndrome, 59 people who have had COVID-19 but have fully recovered and 53 people who have never experienced symptoms of COVID-19 and had never tested positive for COVID-19 were recruited from Academic Prolific to complete a series of online questionnaires and neurocognitive tasks. Subjective cognitive function was measured using the Cognitive Failures Questionnaire and objective cognitive function was measured using the Cognitron cognitive test battery. We found that objective and subjective measures of cognitive function were not significantly related, suggesting that self-reports of “brain fog” are not reflecting objectively measured cognitive dysfunction. A MANOVA revealed that subjective cognitive deficits were driven by heightened perceived stress and fatigue and not significantly related to COVID-19 status. Objective cognitive function, however, was significantly related to perceived stress and COVID status whereby we observed significant objective cognitive deficits in people who have been exposed to an acute COVID-19 infection regardless of whether they had Post-COVID Syndrome or had fully recovered, as compared to people who had never had COVID-19. This suggests that an acute infection can have long term effects on cognitive function, even without persistent COVID-19 symptoms. Encouragingly, objective cognitive function was significantly associated with time since initial infection showing that cognitive deficits improved over time for people who had recovered from COVID-19. However, we did not observe the same improvement in individuals with Post-COVID Syndrome and observed that cognitive dysfunction was significantly related to the number of neurological symptoms presently experienced. These results add to the accumulating literature that COVID-19 is associated with significant cognitive difficulties following a COVID-19 infection, which appear to improve over time for those who have recovered from COVID-19 yet persist in people living with Post-COVID Syndrome.

Efficient behavior involves the coordinated activity of large-scale brain networks, but the way in which these networks interact is uncertain. One theory is that the salience network (SN)—which includes the anterior cingulate cortex, presupplementary motor area, and anterior insulae—regulates dynamic changes in other networks. If this is the case, then damage to the structural connectivity of the SN should disrupt the regulation of associated networks. To investigate this hypothesis, we studied a group of 57 patients with cognitive impairments following traumatic brain injury (TBI) and 25 control subjects using the stop-signal task. The pattern of brain activity associated with stop-signal task performance was studied by using functional MRI, and the structural integrity of network connections was quantified by using diffusion tensor imaging. Efficient inhibitory control was associated with rapid deactivation within parts of the default mode network (DMN), including the precuneus and posterior cingulate cortex. TBI patients showed a failure of DMN deactivation, which was associated with an impairment of inhibitory control. TBI frequently results in traumatic axonal injury, which can disconnect brain networks by damaging white matter tracts. The abnormality of DMN function was specifically predicted by the amount of white matter damage in the SN tract connecting the right anterior insulae to the presupplementary motor area and dorsal anterior cingulate cortex. The results provide evidence that structural integrity of the SN is necessary for the efficient regulation of activity in the DMN, and that a failure of this regulation leads to inefficient cognitive control.