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Weibo Zhang,1,2,&ast; Siyuan He,1,&ast; Liam Wilson,3 Astrid Foix-Colonier,4 Maud Pacou,4 Youwei Zhu,1 Yi Zhu,1 Lili Xue,1 Yanfeng Wang,1 Junmei Li,1 Yanli Liu,1 Jun Cai1,2 1Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Mental Health Branch, China Hospital Development Institute, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Amaris Consulting, Shanghai, People’s Republic of China; 4Amaris Consulting, Paris, France&ast;These authors contributed equally to this workCorrespondence: Jun Cai, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai, 200030, People’s Republic of China, Email caijun533@163.comPurpose: This study aimed to quantify the preferences of Chinese patients with schizophrenia and their caregivers for antipsychotic treatment.Patients and Methods: Patients with schizophrenia (aged 18– 35) and their caregivers were recruited via six outpatient mental health clinics in Shanghai, People’s Republic of China. In a discrete choice experiment (DCE), participants chose between two hypothetical treatment scenarios that varied regarding the type of treatment, rate of hospitalization, severity of positive symptoms, treatment cost and rates of improvement in daily and social functioning. Data for each group were analyzed using the modelling approach that yielded the lower deviance information criterion. The relative importance score (RIS) for each treatment attribute was also determined.Results: A total of 162 patients and 167 caregivers participated. Frequency of hospital admission was the most important treatment attribute for patients (average scaled RIS=27%), followed by mode and frequency of treatment administration (24%). Improvement in ability to carry out daily activities (8%) and improvement in social functioning (8%) were least important. Patients in full-time employment placed more importance on the frequency of hospital admission than unemployed patients (p< 0.01). Frequency of hospital admission was also the most important attribute for caregivers (RIS=33%), followed by improvement in positive symptoms (20%), while improvement in daily activities (7%) was the least important.Conclusion: Patients with Schizophrenia in China prefer treatments that help reduce the number of times they are admitted to hospital, as do their caregivers. These results may bring insight for physicians and health authorities in China regarding the treatment characteristics that patients value the most.Keywords: conjoint analysis, discrete choice experiment, schizophrenia, preference study, patients, caregivers

Marek's disease (MD) is caused by virulent strains of Gallid alphaherpesvirus type 2 (MD virus serotype 1; MDV 1) and frequently causes a lymphoproliferative disorder in poultry and other galliform birds worldwide. However, within the peafowl (Phasianinae) subfamily, there are only rare confirmed reports of MD. Here we report MD in an Indian peafowl (Pavo cristatus), which clinically presented with hindlimb paraparesis and intraocular swelling of the right eye. Soft, off-white to tan masses within the right eye, sciatic nerves and coelomic cavity were identified at post-mortem examination which effaced the cranial pole of the kidneys and diffusely effaced the testes. Lymphoid neoplasia was identified histologically at all of these sites and there was extensive hepatic lymphoid cell infiltration, which had not been grossly evident. The T-cell origin of the lymphoid cells was confirmed by immunohistochemistry for CD3 antigen. A virulent strain of MDV 1 was detected by real-time polymerase chain reaction in DNA samples extracted from the kidney and testes. As MD is rare in peafowl it should be considered as a differential diagnosis for intraocular and coelomic masses with associated clinical signs.

Background: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer’s disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases. Objective: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS. Methods: We analyzed peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line. Results: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death. Conclusion: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets.

People with Down syndrome (DS) have a neurodevelopmentally distinct brain and invariably developed amyloid neuropathology by age 50. This cross-sectional study aimed to provide a detailed account of DS brain morphology and the changes occuring with amyloid neuropathology. Forty-six adults with DS underwent structural and amyloid imaging—the latter using Pittsburgh compound B (PIB) to stratify the cohort into PIB-positive (n = 19) and PIB-negative (n = 27). Age-matched controls (n = 30) underwent structural imaging. Group differences in deep gray matter volumetry and cortical thickness were studied. PIB-negative people with DS have neurodevelopmentally atypical brain, characterized by disproportionately thicker frontal and occipitoparietal cortex and thinner motor cortex and temporal pole with larger putamina and smaller hippocampi than controls. In the presence of amyloid neuropathology, the DS brains demonstrated a strikingly similar pattern of posterior dominant cortical thinning and subcortical atrophy in the hippocampus, thalamus, and striatum, to that observed in non-DS Alzheimer's disease. Care must be taken to avoid underestimating amyloid-associated morphologic changes in DS due to disproportionate size of some subcortical structures and thickness of the cortex.

Individuals with Down syndrome (DS) are more likely to experience earlier onset of multiple facets of physiological aging. This includes brain atrophy, beta amyloid deposition, cognitive decline, and Alzheimer's disease—factors indicative of brain aging. Here, we employed a machine learning approach, using structural neuroimaging data to predict age (i.e., brain-predicted age) in people with DS (N = 46) and typically developing controls (N = 30). Chronological age was then subtracted from brain-predicted age to generate a brain-predicted age difference (brain-PAD) score. DS participants also underwent [11C]-PiB positron emission tomography (PET) scans to index the levels of cerebral beta amyloid deposition, and cognitive assessment. Mean brain-PAD in DS participants’ was +2.49 years, significantly greater than controls (p < 0.001). The variability in brain-PAD was associated with the presence and the magnitude of PiB-binding and levels of cognitive performance. Our study indicates that DS is associated with premature structural brain aging, and that age-related alterations in brain structure are associated with individual differences in the rate of beta amyloid deposition and cognitive impairment.

The work presented in this thesis aims to design, develop and investigate the effectiveness of a Virtual Reality (VR) tool for conducting research in gambling behaviour. The majority of existing gambling studies are conducted in laboratories, rather than in vivo, raising questions over the generalisability of results [1]. VR is well established as an effective tool for exposure therapy, often motivated by an ability to create ecologically valid conditions whilst retaining experimental control, which is difficult to do in vivo. Whilst VR has also been used in some gambling studies, no work has considered how VR environments should be designed to best create ecological validity, and the differences in experience between laboratory and VR conditions. This thesis presents the process of designing and developing a VR tool, featuring a gambling task and VR environment to create an experience of gambling in a betting shop. A prototype artefact was tested within a pilot study to identify and fix bugs prior to starting user studies. Approached from the perspective of immersion, arousal and user experience; a within-subjects study (N = 48) was conducted. During this, participants were tasked with playing through the gambling task on a touch-screen tablet in a laboratory, before repeating the same task on a Virtual Gambling Machine (VGM) within the VR simulation of a betting shop. Subjective measures were applied to measure immersion, emotional involvement and workload. The results of user studies show that participants reported higher levels of arousal, in addition to higher levels of immersion in the gambling game when playing in VR. There was also a significant difference in self-reported physical task load in VR. These findings suggest that VR offers high levels of immersion which enable a user to better engage and focus on a research task, without a negative impact upon cognitive workload due to the VR equipment. Increased levels of arousal in the VR condition also mirror affects observed in existing work comparing in vivo conditions to laboratory-based methods [2], [3]. Based on these findings, we argue that VR should see wider use within gambling research, and propose that future work should compare VR with in vivo methods. This thesis also details the design and development steps required to create a tool which can effectively combine ecological validity and experimental control, demonstrating how key challenges were tackled and offering insight for future work. Additionally, the work presented in this thesis resulted in the creation of a VR environment which was designed and implemented to accommodate any gambling task. This VR tool offers psychology researchers the opportunity to create a game suited to their research needs and easily integrate it into a VR environment, offering ecological validity for experiments with little additional effort. This integration system can be ported into any VR environment created within the Unity engine to help suit the needs of specific research.

Figure S4. Reproducibility of comorbidity odds ratios observed in NIS13 (hospitalizations) and NEDS13 (emergency departments) HCUP datasets. The correlation R2 is 0.62 and 0.63 respectively. Top disease comorbidity was measured and compared directionally, and odds ratios are shown in a log scale. (DOCX 54 kb)

INTRODUCTION: Adults with Down syndrome (DS) invariably develop Alzheimer's disease (AD) neuropathology. Understanding amyloid deposition in DS can yield crucial information about disease pathogenesis. METHODS: Forty-nine adults with DS aged 25-65 underwent positron emission tomography with Pittsburgh compound-B (PIB). Regional PIB binding was assessed with respect to age, clinical, and cognitive status. RESULTS: Abnormal PIB binding became evident from 39 years, first in striatum followed by rostral prefrontal-cingulo-parietal regions, then caudal frontal, rostral temporal, primary sensorimotor and occipital, and finally parahippocampal cortex, thalamus, and amygdala. PIB binding was related to age, diagnostic status, and cognitive function. DISCUSSION: PIB binding in DS, first appearing in striatum, began around age 40 and was strongly associated with dementia and cognitive decline. The absence of a substantial time lag between amyloid accumulation and cognitive decline contrasts to sporadic/familial AD and suggests this population's suitability for an amyloid primary prevention trial.

Figure S4. Reproducibility of comorbidity odds ratios observed in NIS13 (hospitalizations) and NEDS13 (emergency departments) HCUP datasets. The correlation R2 is 0.62 and 0.63 respectively. Top disease comorbidity was measured and compared directionally, and odds ratios are shown in a log scale. (DOCX 54 kb)

Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross‐sectional study, we employed 11C‐Pittsburgh Compound‐B (PiB) positron emission tomography in order to group participants with Down's syndrome based on the presence of fibrillar beta‐amyloid neuropathology. We also acquired resting state functional magnetic resonance imaging data to interrogate the connectivity of the default mode network; a large‐scale system with demonstrated links to Alzheimer's disease. The results revealed widespread positive connectivity of the default mode network in people with Down's syndrome (n = 34, ages 30–55, median age = 43.5) and a stark lack of anti‐correlation. However, in contrast to typically developing controls (n = 20, ages 30–55, median age = 43.5), the Down's syndrome group also showed significantly weaker connections in localised frontal and posterior brain regions. Notably, while a comparison of the PiB‐negative Down's syndrome group (n = 19, ages 30–48, median age = 41.0) to controls suggested that alterations in default mode connectivity to frontal brain regions are related to atypical development, a comparison of the PiB‐positive (n = 15, ages 39–55, median age = 48.0) and PiB‐negative Down's syndrome groups indicated that aberrant connectivity in posterior cortices is associated with the presence of Alzheimer's disease neuropathology. Such distinct profiles of altered connectivity not only further our understanding of the brain physiology that underlies these two inherently linked conditions but may also potentially provide a biomarker for future studies of neurodegeneration in people with Down's syndrome.