Implementation of individualised polygenic risk score analysis: a test case of a family of four

Background Polygenic risk scores (PRS) have been widely applied in research studies, showing how population groups can be stratified into risk categories for many common conditions. As healthcare systems consider applying PRS to keep their populations healthy, little work has been carried out demonstrating their implementation at an individual level. Case presentation We performed a systematic curation of PRS sources from established data repositories, selecting 15 phenotypes, comprising an excess of 37 million SNPs related to cancer, cardiovascular, metabolic and autoimmune diseases. We tested selected phenotypes using whole genome sequencing data for a family of four related individuals. Individual risk scores were given percentile values based upon reference distributions among 1000 Genomes Iberians, Europeans, or all samples. Over 96 billion allele effects were calculated in order to obtain the PRS for each of the individuals analysed here. Conclusions Our results highlight the need for further standardisation in the way PRS are developed and shared, the importance of individual risk assessment rather than the assumption of inherited averages, and the challenges currently posed when translating PRS into risk metrics

Synthetic cannabinoid use in a case series of patients with psychosis presenting to acute psychiatric settings : Clinical presentation and management issues

Background: Novel Psychoactive Substances (NPS) are a heterogeneous class of synthetic molecules including synthetic cannabinoid receptor agonists (SCRAs). Psychosis is associated with SCRAs use. There is limited knowledge regarding the structured assessment and psychometric evaluation of clinical presentations, analytical toxicology and clinical management plans of patients presenting with psychosis and SCRAs misuse. Methods: We gathered information regarding the clinical presentations, toxicology and care plans of patients with psychosis and SCRAs misuse admitted to inpatients services. Clinical presentations were assessed using the PANSS scale. Vital signs data were collected using the National Early Warning Signs tool. Analytic chemistry data were collected using urine drug screening tests for traditional psychoactive substances and NPS. Results: We described the clinical presentation and management plan of four patients with psychosis and misuse of SCRAs. Conclusion: The formulation of an informed clinical management plan requires a structured assessment, identification of the index NPS, pharmacological interventions, increases in nursing observations, changes to leave status and monitoring of the vital signs. The objective from using these interventions is to maintain stable physical health whilst rapidly improving the altered mental state.Peer reviewedFinal Published versio

Illicit COVID-19 products online: A mixed-method approach for identifying and preventing online health risks

© 2023 Catalani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Aims: The COVID-19 pandemic triggered a demand for vaccines, cures, and the need of related documentation for travel, work and other purposes. Our project aimed to identify the illicit availability of such products across the Dark Web Markets (DWMs). Methods: A retrospective search for COVID-19 related products was carried out across 118 DWMs since the start of the pandemic (March 2020-October 2021). Data on vendors as well as advertised goods such as asking price, marketplace, listed date were collected and further validated through additional searches on the open web to verify the information relating to specific marketplaces. Both quantitative and qualitative methods were used for data analysis. Results: Forty-two listings of unlicenced COVID-19 cures and vaccination certificates were identified across 8 marketplaces sold by 25 vendors with significant variation in prices. The listings were found to be geographically specific and followed the progression of the pandemic in terms of availability. Correlations between vendor portfolios of COVID-19 products and variety of goods of other illicit nature such as illegal weaponry, medication/drugs of abuse also emerged from our analysis. Conclusion: This study is one of the first attempts to identify the availability of unlicenced COVID-19 products on DWMs. The easy accessibility to vaccines, fake test certificates and hypothetical/illegal cures poses serious health risks to (potential) buyers due to the uncontrolled nature of such products. It also exposes buyers to an unwanted contact with vendors selling a variety of other dangerous illicit goods. Further monitoring and regulatory responses should be implemented to protect the health and safety of citizens especially at times of global crisis.Peer reviewe

Brain structural signatures of negative symptoms in depression and schizophrenia.

Negative symptoms occur in several major mental health disorders with undetermined mechanisms and unsatisfactory treatments; identification of their neural correlates might unveil the underlying pathophysiological basis and pinpoint the therapeutic targets. In this study, participants with major depressive disorder (n = 24), schizophrenia (n = 22), and healthy controls (n = 20) were assessed with 10 frequently used negative symptom scales followed by principal component analysis (PCA) of the scores. A linear model with the prominent components identified by PCA was then regressed on gray and white-matter volumes estimated from T1-weighted magnetic resonance imaging. In depressed patients, negative symptoms such as blunted affect, alogia, withdrawal, and cognitive impairment, assessed mostly via clinician-rated scales were inversely associated with gray matter volume in the bilateral cerebellum. In patients with schizophrenia, anhedonia, and avolition evaluated via self-rated scales inversely related to white-matter volume in the left anterior limb of internal capsule/anterior thalamic radiation and positively in the left superior longitudinal fasiculus. The pathophysiological mechanisms underlying negative symptoms might differ between depression and schizophrenia. These results also point to future negative symptom scale development primarily focused on detecting and monitoring the corresponding changes to brain structure or function.This work was supported by Brain and Behavior Research Foundation (NARSAD) and Medical Research Council (MRC) awards to GKM, and by the Wellcome Trust/MRC Behavioural and Clinical Neuroscience Institute, University of Cambridge. We thank Dr. Zheng Ye for her help with image analysis and technical support, Niels Reinders and staff at the Wolfson Brain Imaging Centre for help with data collection, and staff at IAPT, CAMEO and the Rehabilitation and Recovery Service in the Cambridgeshire and Peterborough NHS Foundation Trust for help with recruitment. The study was supported by infrastructure provided by the Wellcome Trust/MRC Behavioural and Clinical Neuroscience Institute at the University of Cambridge.This is the final version published by Frontiers here: http://journal.frontiersin.org/Journal/10.3389/fpsyt.2014.00116/abstract

Reduction in ventral striatal activity when anticipating a reward in depression and schizophrenia: a replicated cross-diagnostic finding.

In the research domain framework (RDoC), dysfunctional reward expectation has been proposed to be a cross-diagnostic domain in psychiatry, which may contribute to symptoms common to various neuropsychiatric conditions, such as anhedonia or apathy/avolition. We used a modified version of the Monetary Incentive Delay (MID) paradigm to obtain functional MRI images from 22 patients with schizophrenia, 24 with depression and 21 controls. Anhedonia and other symptoms of depression, and overall positive and negative symptomatology were also measured. We hypothesized that the two clinical groups would have a reduced activity in the ventral striatum when anticipating reward (compared to anticipation of a neutral outcome) and that striatal activation would correlate with clinical measures of motivational problems and anhedonia. Results were consistent with the first hypothesis: two clusters in both the left and right ventral striatum were found to differ between the groups in reward anticipation. Post-hoc analysis showed that this was due to higher activation in the controls compared to the schizophrenia and the depression groups in the right ventral striatum, with activation differences between depression and controls also seen in the left ventral striatum. No differences were found between the two patient groups, and there were no areas of abnormal cortical activation in either group that survived correction for multiple comparisons. Reduced ventral striatal activity was related to greater anhedonia and overall depressive symptoms in the schizophrenia group, but not in the participants with depression. Findings are discussed in relation to previous literature but overall are supporting evidence of reward system dysfunction across the neuropsychiatric continuum, even if the specific clinical relevance is still not fully understood. We also discuss how the RDoC approach may help to solve some of the replication problems in psychiatric fMRI research.Supported by the Wellcome Trust Institutional Strategic Support Fund [097814/Z/11], a MRC Clinician Scientist [G0701911], a Brain and Behavior Research Foundation Young Investigator, and an Isaac Newton Trust award to Dr Murray; an award to Dr Segarra from the Secretary for Universities and Research of the Ministry of Economy and Knowledge of the Government of Catalonia and the European Union; by the University of Cambridge Behavioural and Clinical Neuroscience Institute, funded by a joint award from the Medical Research Council [G1000183]and Wellcome Trust [093875/Z/10/Z]; by awards from the Wellcome Trust [095692] and the Bernard Wolfe Health Neuroscience Fund to Dr. Fletcher, and by the Cambridge NIHR Biomedical Research Centre.This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fpsyg.2015.0128

Ethnic Minority Status, Age-at-Immigration and Psychosis Risk in Rural Environments:Evidence From the SEPEA Study

Objective: Several ethnic minority groups experience elevated rates of first-episode psychosis (FEP), but most studies have been conducted in urban settings. We investigated whether incidence varied by ethnicity, generation status, and age-at-immigration in a diverse, mixed rural, and urban setting. Method: We identified 687 people, 16–35 years, with an ICD-10 diagnosis of FEP, presenting to Early Intervention Psychosis services in the East of England over 2 million person-years. We used multilevel Poisson regression to examine incidence variation by ethnicity, rural–urban setting, generation status, and age-at-immigration, adjusting for several confounders including age, sex, socioeconomic status, population density, and deprivation. Results: People of black African (incidence rate ratio: 4.06; 95% confidence interval [CI]: 2.63–6.25), black Caribbean (4.63; 95% CI: 2.38–8.98) and Pakistani (2.31; 95% CI: 1.35–3.94) origins were at greatest FEP risk relative to the white British population, after multivariable adjustment. Non-British white migrants were not at increased FEP risk (1.00; 95% CI: 0.77–1.32). These patterns were independently present in rural and urban settings. For first-generation migrants, migration during childhood conferred greatest risk of psychotic disorders (2.20; 95% CI: 1.33–3.62). Conclusions: Elevated psychosis risk in several visible minority groups could not be explained by differences in postmigratory socioeconomic disadvantage. These patterns were observed across rural and urban areas of our catchment, suggesting that elevated psychosis risk for some ethnic minority groups is not a result of selection processes influencing rural–urban living. Timing of exposure to migration during childhood, an important social and neurodevelopmental window, may also elevate risk

The Epidemiology of First-Episode Psychosis in Early Intervention in Psychosis Services: Findings From the Social Epidemiology of Psychoses in East Anglia [SEPEA] Study.

OBJECTIVE: Few studies have characterized the epidemiology of first-episode psychoses in rural or urban settings since the introduction of early intervention psychosis services. To address this, the authors conducted a naturalistic cohort study in England, where such services are well established. METHOD: All new first-episode psychosis cases, 16-35 years old, presenting to early intervention psychosis services in the East of England were identified during 2 million person-years follow-up. Presence of ICD-10 F10-33 psychotic disorder was confirmed using OPCRIT [operational criteria for psychotic illness]. Incidence rate ratios were estimated following multivariable Poisson regression, adjusting for age, sex, ethnicity, socioeconomic status, neighborhood-level deprivation, and population density. RESULTS: Of 1,005 referrals, 687 participants (68.4%) fulfilled epidemiological and diagnostic criteria for first-episode psychosis (34.0 new cases per 100,000 person-years; 95% CI=31.5-36.6). Median age at referral was similar for men (22.5 years; interquartile range: 19.5-26.7) and women (23.4 years; interquartile range: 19.5-29.1); incidence rates were highest for men and women before 20 years of age. Rates increased for ethnic minority groups (incidence rate ratio: 1.4; 95% CI=1.1-1.6), as well as with lower socioeconomic status (incidence rate ratio: 1.3; 95% CI=1.2-1.4) and in more urban (incidence rate ratio: 1.4;95%CI=1.0-1.8) and deprived (incidence rate ratio: 2.1; 95% CI=1.3-3.3) neighborhoods, after adjustment for confounders. CONCLUSIONS: Pronounced variation in psychosis incidence, peaking before 20 years old, exists in populations served by early intervention psychosis services. Excess rates were restricted to urban and deprived communities, suggesting that a threshold of socioenvironmental adversity may be necessary to increase incidence. This robust epidemiology can inform service development in various settings about likely population-level need.Wellcome Trust (Sir Henry Wellcome Research Fellowship; Grant ID: WT085540)This is the author accepted manuscript. The final version is available from the American Psychiatric Association via http://dx.doi.org/10.1176/appi.ajp.2016.1601010

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Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 2006Texto paralelo en italiano y españolEl autor consta en el interior del textoSign.: [A]-D\p4\s, E\p5\sAntep.Port. encarada

Abnormal Frontostriatal Activity During Unexpected Reward Receipt in Depression and Schizophrenia: Relationship to Anhedonia.

Alterations in reward processes may underlie motivational and anhedonic symptoms in depression and schizophrenia. However it remains unclear whether these alterations are disorder-specific or shared, and whether they clearly relate to symptom generation or not. We studied brain responses to unexpected rewards during a simulated slot-machine game in 24 patients with depression, 21 patients with schizophrenia, and 21 healthy controls using functional magnetic resonance imaging. We investigated relationships between brain activation, task-related motivation, and questionnaire rated anhedonia. There was reduced activation in the orbitofrontal cortex, ventral striatum, inferior temporal gyrus, and occipital cortex in both depression and schizophrenia in comparison with healthy participants during receipt of unexpected reward. In the medial prefrontal cortex both patient groups showed reduced activation, with activation significantly more abnormal in schizophrenia than depression. Anterior cingulate and medial frontal cortical activation predicted task-related motivation, which in turn predicted anhedonia severity in schizophrenia. Our findings provide evidence for overlapping hypofunction in ventral striatal and orbitofrontal regions in depression and schizophrenia during unexpected reward receipt, and for a relationship between unexpected reward processing in the medial prefrontal cortex and the generation of motivational states.Supported by a MRC Clinician Scientist award (G0701911), a Brain and Behaviour Research Foundation Young Investigator, and an Isaac Newton Trust award to Dr Murray; an award to Dr Segarra from the Secretary for Universities and Research of the Ministry of Economy and Knowledge of the Government of Catalonia and the European Union; by the University of Cambridge Behavioural and Clinical Neuroscience Institute, funded by a joint award from the Medical Research Council and Wellcome Trust (G1000183 and 093875/Z/10Z respectively); by awards from the Wellcome Trust (095692) and the Bernard Wolfe Health Neuroscience Fund to Professor Fletcher, and by awards from the Wellcome Trust Institutional Strategic Support Fund (097814/Z/11) and Cambridge NIHR Biomedical Research Centre. The authors are grateful for the help of clinical staff in CAMEO, in the Cambridge Rehabilitation and Recovery service and Pathways, and in the Cambridge IAPT service, for help with participant recruitment.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/npp.2015.37

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence.

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction.The research was carried out at the NIHR/Wellcome Trust Imperial Clinical Research Facility, the NIHR/Wellcome Trust Cambridge Research Facility and Clinical Trials Unit at Salford Royal NHS Foundation Trust, and is supported by the North West London, Eastern and Greater Manchester NIHR Clinical Research Networks