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The association between cannabis and psychosis is established, but the role of underlying genetics is unclear. We used data from the EU-GEI case-control study and UK Biobank to examine the independent and combined effect of heavy cannabis use and schizophrenia polygenic risk score (PRS) on risk for psychosis.
Methods
Genome-wide association study summary statistics from the Psychiatric Genomics Consortium and the Genomic Psychiatry Cohort were used to calculate schizophrenia and cannabis use disorder (CUD) PRS for 1098 participants from the EU-GEI study and 143600 from the UK Biobank. Both datasets had information on cannabis use.
Results
In both samples, schizophrenia PRS and cannabis use independently increased risk of psychosis. Schizophrenia PRS was not associated with patterns of cannabis use in the EU-GEI cases or controls or UK Biobank cases. It was associated with lifetime and daily cannabis use among UK Biobank participants without psychosis, but the effect was substantially reduced when CUD PRS was included in the model. In the EU-GEI sample, regular users of high-potency cannabis had the highest odds of being a case independently of schizophrenia PRS (OR daily use high-potency cannabis adjusted for PRS = 5.09, 95% CI 3.08–8.43, p = 3.21 × 10−10). We found no evidence of interaction between schizophrenia PRS and patterns of cannabis use.
Conclusions
Regular use of high-potency cannabis remains a strong predictor of psychotic disorder independently of schizophrenia PRS, which does not seem to be associated with heavy cannabis use. These are important findings at a time of increasing use and potency of cannabis worldwide.
Neuropsychiatric symptoms are common after traumatic brain injury (TBI) and often resolve within 3 months post-injury. However, the degree to which individual patients follow this course is unknown. We characterized trajectories of neuropsychiatric symptoms over 12 months post-TBI. We hypothesized that a substantial proportion of individuals would display trajectories distinct from the group-average course, with some exhibiting less favorable courses.
Methods
Participants were level 1 trauma center patients with TBI (n = 1943), orthopedic trauma controls (n = 257), and non-injured friend controls (n = 300). Trajectories of six symptom dimensions (Depression, Anxiety, Fear, Sleep, Physical, and Pain) were identified using growth mixture modeling from 2 weeks to 12 months post-injury.
Results
Depression, Anxiety, Fear, and Physical symptoms displayed three trajectories: Stable-Low (86.2–88.6%), Worsening (5.6–10.9%), and Improving (2.6–6.4%). Among symptomatic trajectories (Worsening, Improving), lower-severity TBI was associated with higher prevalence of elevated symptoms at 2 weeks that steadily resolved over 12 months compared to all other groups, whereas higher-severity TBI was associated with higher prevalence of symptoms that gradually worsened from 3–12 months. Sleep and Pain displayed more variable recovery courses, and the most common trajectory entailed an average level of problems that remained stable over time (Stable-Average; 46.7–82.6%). Symptomatic Sleep and Pain trajectories (Stable-Average, Improving) were more common in traumatically injured groups.
Conclusions
Findings illustrate the nature and rates of distinct neuropsychiatric symptom trajectories and their relationship to traumatic injuries. Providers may use these results as a referent for gauging typical v. atypical recovery in the first 12 months post-injury.
Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP.
Methods
We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately.
Results
Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia.
Conclusions
Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.
Evidence development for medical devices is often focused on satisfying regulatory requirements with the result that health professional and payer expectations may not be met, despite considerable investment in clinical trials. Early engagement with payers and health professionals could allow companies to understand these expectations and reflect them in clinical study design, increasing chances of positive coverage determination and adoption into clinical practice.
Methods
An example of early engagement through the EXCITE International model using an early technology review (ETR) is described which includes engagement with payers and health professionals to better inform companies to develop data that meet their expectations. ETR is based on an early evidence review, a framework of expectations that guides the process and identified gaps in evidence. The first fourteen ETRs were reviewed for examples of advice to companies that provided additional information from payers and health professionals that was thought likely to impact on downstream outcomes or strategic direction. Given that limitations were imposed by confidentiality, examples were genericized.
Results
Advice through early engagement can inform evidence development that coincides with expectations of payers and health professionals through a structured, objective, evidence-based approach. This could reduce the risk of business-related adverse outcomes such as failure to secure a positive coverage determination and/or acceptance by expert health professionals.
Conclusions
Early engagement with key stakeholders exemplified by the ETR approach offers an alternative to the current approach of focusing on regulatory expectations. This could reduce the time to reimbursement and clinical adoption and benefit patient outcomes and/or health system efficiencies.
The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT’s are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the study caused an additional 94 participants to not take any doses of study drug. Therefore, 1323 participants were in the modified intention-to-treat sample, which was the a priori primary study sample. Only 1.4% of participants were lost to follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT trial without any in-person contact by expediting intervention delivery, expanding trial access geographically, limiting contagion exposure, and making it easy for participants to complete follow-up visits. Remotely completed consent and follow-up facilitated enrollment.
The eastern Great Lakes Late Quaternary timescale is based on older thermoluminescence dates and on uncalibrated radiocarbon dates from extensive sections along the north shores of Lakes Erie and Ontario. New optically stimulated luminescence dates from Late Quaternary delta sediments from the north shores of Lake Erie at Sand Hills Park give consistent ages of 23.5 to 20.5 ka. This is 4 to 7 ka older than previously assigned based on lithologic correlation with 16.5 ka calibrated radiocarbon dated sediments 5 km to the west at Vanderven. On the existing eastern Great Lakes stratigraphy, it puts deposition of these Sand Hills Park sediments in the Erie interstadial and not in the fluctuating postglacial glacial retreat of the Mackinaw phase to which the Vanderven sediments belong. The Sand Hills delta and underlying diamicts must have been overridden by the Porty Bruce advance at 18 ka. IntCal20 calibration of existing radiocarbon ages suggests that the physical stratigraphic relations of the various Wisconsin units are accurate and that the existing timescale is simply too young.
While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis.
Methods
We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case–control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.
We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case–control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case–control status.
Results
Controls (86.1%) and FEPp (75.63%) were most likely to report ‘because of friends’ as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: ‘to feel better’ as their RFUC (χ2 = 50.97; p < 0.001). RFUC ‘to feel better’ was associated with being a FEPp (OR 1.74; 95% CI 1.03–2.95) while RFUC ‘with friends’ was associated with being a control (OR 0.56; 95% CI 0.37–0.83). The path model indicated an association between RFUC ‘to feel better’ with heavy cannabis use and with FEPp-control status.
Conclusions
Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use ‘to feel better’. People who reported their reason for first using cannabis to ‘feel better’ were more likely to progress to heavy use and develop a psychotic disorder than those reporting ‘because of friends’.
Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case–control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD).
Methods
Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons.
Results
In case–control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case–case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54–0.92] and PRS-D (OR = 1.31, 95% CI 1.06–1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23–3.74).
Conclusions
Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.
A global ageing population presents opportunities and challenges to designing urban environments that support ageing in place. The World Health Organization's Global Age-Friendly Cities movement has identified the need to develop communities that optimise health, participation and security in order to enhance quality of life as people age. Ensuring that age-friendly urban environments create the conditions for active ageing requires cities and communities to support older adults’ rights to access and move around the city (‘appropriation’) and for them to be actively involved in the transformation (‘making and remaking’) of the city. These opportunities raise important questions: What are older adults’ everyday experiences in exercising their rights to the city? What are the challenges and opportunities in supporting a rights to the city approach? How can the delivery of age-friendly cities support rights to the city for older adults? This paper aims to respond to these questions by examining the lived experiences of older adults across three cities and nine neighbourhoods in the United Kingdom. Drawing on 104 semi-structured interviews with older adults between the ages of 51 and 94, the discussion centres on the themes of: right to use urban space; respect and visibility; and the right to participate in planning and decision-making. These themes are illustrated as areas in which older adults’ rights to access and shape urban environments need to be addressed, along with recommendations for age-friendly cities that support a rights-based approach.
Background: Identification of hospitalized patients with enteric multidrug-resistant organism (MDRO) carriage, combined with implementation of targeted infection control interventions, may help reduce MDRO transmission. However, the optimal surveillance approach has not been defined. We sought to determine whether daily serial rectal surveillance for MDROs detects more incident cases (acquisition) of MDRO colonization in medical intensive care unit (MICU) patients than admission and discharge surveillance alone. Methods: Prospective longitudinal observational single-center study from January 11, 2017, to January 11, 2018. Inclusion criteria were ≥3 consecutive MICU days and ≥2 rectal or stool swabs per MICU admission. Daily rectal or stool swabs were collected from patients and cultured for MDROs, including vancomycin-resistant Enterococcus (VRE), carbapenem-resistant Enterobacterales (CRE), third-generation cephalosporin-resistant Enterobacterales (3GCR), and extended-spectrum β-lactamase–producing Enterobacterales (ESBL-E) (as a subset of 3GCR). MDRO detection at any time during the MICU stay was used to calculate prevalent colonization. Incident colonization (acquisition) was defined as new detection of an MDRO after at least 1 prior negative swab. We then determined the proportion of prevalent and incident cases detected by daily testing that were also detected when only first swabs (admission) and last swabs (discharge) were tested. Data were analyzed using SAS version 9.4 software. Results: In total, 939 MICU stays of 842 patients were analyzed. Patient characteristics were median age 64 years (interquartile range [IQR], 51–74), median MICU length of stay 5 days (IQR, 3–8), median number of samples per admission 3 (IQR, 2–5), and median Charlson index 4 (IQR, 2–7). Prevalent colonization with any MDRO was detected by daily swabbing in 401 stays (42.7%). Compared to daily serial swabbing, an admission- and discharge-only approach detected ≥86% of MDRO cases (ie, overall prevalent MDRO colonization). Detection of incident MDRO colonization by an admission- or discharge-only approach would have detected fewer cases than daily swabbing (Figure 1); ≥34% of total MDRO acquisitions would have been missed. Conclusions: Testing patients upon admission and discharge to an MICU may fail to detect MDRO acquisition in more than one-third of patients, thereby reducing the effectiveness of MDRO control programs that are targeted against known MDRO carriers. The poor performance of a single discharge swab may be due to intermittent or low-level MDRO shedding, inadequate sampling, or transient MDRO colonization. Additional research is needed to determine the optimal surveillance approach of enteric MDRO carriage.
Secure forensic mental health services treat patients with high rates of treatment-resistant psychoses. High rates of obesity and medical comorbidities are common. Population-based studies have identified high-risk groups in the event of SARS-CoV-2 infection, including those with problems such as obesity, lung disease and immune-compromising conditions. Structured assessment tools exist to ascertain the risk of adverse outcome in the event of SARS-CoV-2 infection.
Aims
To assess risk of adverse outcome in the event of SARS-CoV-2 infection in a complete population of forensic psychiatry patients using structured assessment tools.
Method
All patients of a national forensic mental health service (n = 141) were rated for risk of adverse outcome in the event of SARS-CoV-2 infection, using two structured tools, the COVID-Age tool and the COVID-Risk tool.
Results
We found high rates of relevant physical comorbidities. Mean chronological age was 45.5 years (s.d. = 11.4, median 44.1), mean score on the COVID-Age tool was 59.1 years (s.d. = 19.4, median 58.0), mean difference was 13.6 years (s.d. = 15.6), paired t = 10.9, d.f. = 140, P < 0.001. Three patients (2.1%) were chronologically over 70 years of age, compared with 43 (30.5%) with a COVID-Age over 70 (χ2 = 6.99, d.f. = 1, P = 0.008, Fisher's exact test P = 0.027).
Conclusions
Patients in secure forensic psychiatric services represent a high-risk group for adverse outcomes in the event of SARS-COV-2 infection. Population-based guidance on self-isolation and other precautions based on chronological age may not be sufficient. There is an urgent need for better physical health research and treatment in this group.
In this chapter the major conservation issues bears face is reviewed and management actions that can address these conservation issues are highlighted. The future of bears across the world is bright for some species but dark for others. In some areas such as North America and in parts of Europe and Asia, bear populations have increased and stabilized because of increased management effort and increasing support for bears and their needs by the humans who share habitat with them. However, for most bear species, the future is uncertain. Andean bears continue to be threatened by habitat loss and human encroachment. In much of Asia outside Japan, Asiatic black bear, sloth bear, and sun bear populations are increasingly threatened by unmanaged excessive mortality combined with habitat loss to timber harvest, plantation agriculture, and human encroachment. The long-term future for polar bears is threatened by the unmanageable threat of climate change. Giant pandas are fragmented into small populations despite intense conservation efforts. Improving public and political support for bears is the most important need if we are to realize successful bear conservation and management.
Precise instrumental calibration is of crucial importance to 21-cm cosmology experiments. The Murchison Widefield Array’s (MWA) Phase II compact configuration offers us opportunities for both redundant calibration and sky-based calibration algorithms; using the two in tandem is a potential approach to mitigate calibration errors caused by inaccurate sky models. The MWA Epoch of Reionization (EoR) experiment targets three patches of the sky (dubbed EoR0, EoR1, and EoR2) with deep observations. Previous work in Li et al. (2018) and (2019) studied the effect of tandem calibration on the EoR0 field and found that it yielded no significant improvement in the power spectrum (PS) over sky-based calibration alone. In this work, we apply similar techniques to the EoR1 field and find a distinct result: the improvements in the PS from tandem calibration are significant. To understand this result, we analyse both the calibration solutions themselves and the effects on the PS over three nights of EoR1 observations. We conclude that the presence of the bright radio galaxy Fornax A in EoR1 degrades the performance of sky-based calibration, which in turn enables redundant calibration to have a larger impact. These results suggest that redundant calibration can indeed mitigate some level of model incompleteness error.
There is a great deal of information about the management of the airway during many different scenarios, but very little of that information addresses the management of the airway during a mass casualty event following a disaster.
Following a major disaster from which a large number of casualties result, a community’s ability to rescue, triage, transport, evaluate, and treat these casualties quickly and effectively leads to the best possible outcome. The best outcomes occur if treatment is judiciously applied within the “golden hour,” the 60 minutes following the injury to the patient.
First episode psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in patients and controls and whether this differs between groups.
Methods
We analysed data on patients who had ever used cannabis (n = 655) and controls who had ever used cannabis (n = 654) across 15 sites from six countries in the EU-GEI study (2010–2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use.
Results
Caseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences (p ⩽ 0.001). For psychotic-like experiences (PEs) there was a significant interaction for caseness × frequency of use (p < 0.001) and caseness × money spent on cannabis (p = 0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no significant interaction for euphoric experiences (p > 0.5).
Conclusions
FEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher levels of cannabis use compared to controls. This suggests a specific psychotomimetic response in FEP patients related to heavy cannabis use. Clinicians should enquire regarding cannabis related PEs and advise that lower levels of cannabis use are associated with less frequent PEs.
The ‘jumping to conclusions’ (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ.
Methods
A total of 817 first episode psychosis patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC, and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.
Results
The estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia polygenic risk score was non-significantly associated with a higher number of beads drawn (B = 0.47, 95% CI −0.21 to 1.16, p = 0.17); whereas IQ PRS (B = 0.51, 95% CI 0.25–0.76, p < 0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with the higher level of psychotic-like experiences (PLEs) in controls, including after controlling for IQ (B = −1.7, 95% CI −2.8 to −0.5, p = 0.006), but did not relate to delusions in patients.
Conclusions
Our findings suggest that the JTC reasoning bias in psychosis might not be a specific cognitive deficit but rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to PLEs, independent of IQ. The work has the potential to inform interventions targeting cognitive biases in early psychosis.
While it is known that patients with schizophrenia recognize facial emotions, specifically negative emotions, less accurately, little is known about how they misattribute these emotions to other emotions and whether such misattribution biases are associated with symptoms, course of the disorder, or certain cognitive functions.
Method
Outpatients with schizophrenia or schizoaffective disorder (n = 73) and healthy controls (n = 30) performed a computerised Facial Emotion Attribution Test and Wisconsin Card Sorting Test (WCST). Patients were also rated on the Positive and Negative Syndrome Scale (PANSS).
Results
Patients were poor at recognizing fearful and angry emotions and attributed fear to angry and angry to neutral expressions. Fear-as-anger misattributions were predicted independently by a longer duration of illness and WCST perseverative errors.
Conclusion
The findings show a bias towards misattributing fearful and angry facial emotions. The propensity for fear-as-anger misattribution biases increases as the length of time that the disorder is experienced increases and a more rigid style of information processing is used. This, at least in part, may be perpetuated by subtle fearfulness expressed by others while interacting with people with schizophrenia.