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Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders.
We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific.
We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001).
Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.
The Repugnant Conclusion is an implication of some approaches to population ethics. It states, in Derek Parfit's original formulation,
For any possible population of at least ten billion people, all with a very high quality of life, there must be some much larger imaginable population whose existence, if other things are equal, would be better, even though its members have lives that are barely worth living. (Parfit 1984: 388)
Roads affect wildlife in a variety of negative ways. Road ecology studies have mostly concentrated on areas in the northern hemisphere despite the potentially greater impact of roads on biodiversity in tropical habitats. Here, we examine 4 years (January 2016–December 2019) of opportunistic observations of mammalian roadkill along a road intersecting Jozani-Chwaka Bay National Park, Unguja, Zanzibar. In particular, we assess the impact of collisions on the population of an endemic primate, the Endangered Zanzibar red colobus Piliocolobus kirkii. Primates accounted for the majority of roadkill in this dataset. Monthly rainfall was not associated with roadkill frequency for mammals generally, nor for the Zanzibar red colobus. No single age–sex class of colobus was found dead more often than expected given their occurrence in the local population. The overall effect of roadkill on colobus populations in habitats fragmented by roads is unknown given the lack of accurate, long-term life history data for this species. Our findings suggest that mortality from collisions with vehicles in some groups of colobus is within the range of mortality rates other primates experience under natural predation. Unlike natural predators, however, vehicles do not kill selectively, so their impact on populations may differ. Although a comparison with historical accounts suggests that the installation of speedbumps along the road near the Park's entrance has led to a significant decrease in colobus roadkill, further actions to mitigate the impact of the road could bring substantial conservation benefits.
Despite evidence for the general effectiveness of psychological therapies, there exists substantial heterogeneity in patient outcomes. We aimed to identify factors associated with baseline severity of depression and anxiety symptoms, rate of symptomatic change over the course of therapy, and symptomatic recovery in a primary mental health care setting.
Using data from a service evaluation involving 35 527 patients in England's psychological and wellbeing [Improving Access to Psychological Therapies (IAPT)] services, we applied latent growth models to explore which routinely-collected sociodemographic, clinical, and therapeutic variables were associated with baseline symptom severity and rate of symptomatic change. We used a multilevel logit model to determine variables associated with symptomatic recovery.
Being female, younger, more functionally impaired, and more socioeconomically disadvantaged was associated with higher baseline severity of both depression and anxiety symptoms. Being older, less functionally impaired, and having more severe baseline symptomatology was associated with more rapid improvement of both depression and anxiety symptoms (male gender and greater socioeconomic disadvantage were further associated with rate of change for depression only). Therapy intensity and appointment frequency seemed to have no correlation with rate of symptomatic improvement. Patients with lower baseline symptom severity, less functional impairment, and older age had a greater likelihood of achieving symptomatic recovery (as defined by IAPT criteria).
We must continue to investigate how best to tailor psychotherapeutic interventions to fit patients’ needs. Patients who begin therapy with more severe depression and/or anxiety symptoms and poorer functioning merit special attention, as these characteristics may negatively impact recovery.
Influential theories predict that antidepressant medication and psychological therapies evoke distinct neural changes.
To test the convergence and divergence of antidepressant- and psychotherapy-evoked neural changes, and their overlap with the brain's affect network.
We employed a quantitative synthesis of three meta-analyses (n = 4206). First, we assessed the common and distinct neural changes evoked by antidepressant medication and psychotherapy, by contrasting two comparable meta-analyses reporting the neural effects of these treatments. Both meta-analyses included patients with affective disorders, including major depressive disorder, generalised anxiety disorder and panic disorder. The majority were assessed using negative-valence tasks during neuroimaging. Next, we assessed whether the neural changes evoked by antidepressants and psychotherapy overlapped with the brain's affect network, using data from a third meta-analysis of affect-based neural activation.
Neural changes from psychotherapy and antidepressant medication did not significantly converge on any region. Antidepressants evoked neural changes in the amygdala, whereas psychotherapy evoked anatomically distinct changes in the medial prefrontal cortex. Both psychotherapy- and antidepressant-related changes separately converged on regions of the affect network.
This supports the notion of treatment-specific brain effects of antidepressants and psychotherapy. Both treatments induce changes in the affect network, but our results suggest that their effects on affect processing occur via distinct proximal neurocognitive mechanisms of action.
Plant-derived proteins have been suggested to have less anabolic properties when compared with animal-derived proteins. Whether blends of plant- and animal-derived proteins can compensate for their lesser anabolic potential has not been assessed. The present study compares post-prandial muscle protein synthesis rates following the ingestion of milk protein with wheat protein or a blend of wheat plus milk protein in healthy, young males. In a randomised, double-blind, parallel-group design, 36 males (23 (sd 3) years) received a primed continuous L-[ring-13C6]-phenylalanine infusion after which they ingested 30 g milk protein (MILK), 30 g wheat protein (WHEAT) or a 30 g blend combining 15 g wheat plus 15 g milk protein (WHEAT+MILK). Blood and muscle biopsies were collected frequently for 5 h to assess post-prandial plasma amino acid profiles and subsequent myofibrillar protein synthesis rates. Ingestion of protein increased myofibrillar protein synthesis rates in all treatments (P < 0·001). Post-prandial myofibrillar protein synthesis rates did not differ between MILK v. WHEAT (0·053 (sd 0·013) v. 0·056 (sd 0·012) %·h−1, respectively; t test P = 0·56) or between MILK v. WHEAT+MILK (0·053 (sd 0·013) v. 0·059 (sd 0·025) %·h−1, respectively; t test P = 0·46). In conclusion, ingestion of 30 g milk protein, 30 g wheat protein or a blend of 15 g wheat plus 15 g milk protein increases muscle protein synthesis rates in young males. Furthermore, muscle protein synthesis rates following the ingestion of 30 g milk protein do not differ from rates observed after ingesting 30 g wheat protein or a blend with 15 g milk plus 15 g wheat protein in healthy, young males.
Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n = 3261) completing the C-19 COVID-19 symptom tracker app allowed classical twin studies of COVID-19 symptoms, including predicted COVID-19, a symptom-based algorithm to predict true infection, derived from app users tested for SARS-CoV-2. We found heritability of 49% (32−64%) for delirium; 34% (20−47%) for diarrhea; 31% (8−52%) for fatigue; 19% (0−38%) for anosmia; 46% (31−60%) for skipped meals and 31% (11−48%) for predicted COVID-19. Heritability estimates were not affected by cohabiting or by social deprivation. The results suggest the importance of host genetics in the risk of clinical manifestations of COVID-19 and provide grounds for planning genome-wide association studies to establish specific genes involved in viral infectivity and the host immune response.
The prevalence of psychotic experiences (PEs) is higher in low-and-middle-income-countries (LAMIC) than in high-income countries (HIC). Here, we examine whether this effect is explicable by measurement bias.
A community sample from 13 countries (N = 7141) was used to examine the measurement invariance (MI) of a frequently used self-report measure of PEs, the Community Assessment of Psychic Experiences (CAPE), in LAMIC (n = 2472) and HIC (n = 4669). The CAPE measures positive (e.g. hallucinations), negative (e.g. avolition) and depressive symptoms. MI analyses were conducted with multiple-group confirmatory factor analyses.
MI analyses showed similarities in the structure and understanding of the CAPE factors between LAMIC and HIC. Partial scalar invariance was found, allowing for latent score comparisons. Residual invariance was not found, indicating that sum score comparisons are biased. A comparison of latent scores before and after MI adjustment showed both overestimation (e.g. avolition, d = 0.03 into d = −0.42) and underestimation (e.g. magical thinking, d = −0.03 into d = 0.33) of PE in LAMIC relative to HIC. After adjusting the CAPE for MI, participants from LAMIC reported significantly higher levels on most CAPE factors but a significantly lower level of avolition.
Previous studies using sum scores to compare differences across countries are likely to be biased. The direction of the bias involves both over- and underestimation of PEs in LAMIC compared to HIC. Nevertheless, the study confirms the basic finding that PEs are more frequent in LAMIC than in HIC.
Treatment resistance causes significant burden in psychosis. Clozapine is the only evidence-based pharmacologic intervention available for people with treatment-resistant schizophrenia; current guidelines recommend commencement after two unsuccessful trials of standard antipsychotics.
This paper aims to explore the prevalence of treatment resistance and pathways to commencement of clozapine in UK early intervention in psychosis (EIP) services.
Data were taken from the National Evaluation of the Development and Impact of Early Intervention Services study (N = 1027) and included demographics, medication history and psychosis symptoms measured by the Positive and Negative Syndrome Scale (PANSS) at baseline, 6 months and 12 months. Prescribing patterns and pathways to clozapine were examined. We adopted a strict criterion for treatment resistance, defined as persistent elevated positive symptoms (a PANSS positive score ≥16, equating to at least two items of at least moderate severity), across three time points.
A total of 143 (18.1%) participants met the definition of treatment resistance of having continuous positive symptoms over 12 months, despite treatment in EIP services. Sixty-one (7.7%) participants were treatment resistant and eligible for clozapine, having had two trials of standard antipsychotics; however, only 25 (2.4%) were prescribed clozapine over the 12-month study period. Treatment-resistant participants were more likely to be prescribed additional antipsychotic medication and polypharmacy, instead of clozapine.
Prevalent treatment resistance was observed in UK EIP services, but prescription of polypharmacy was much more common than clozapine. Significant delays in the commencement of clozapine may reflect a missed opportunity to promote recovery in this critical period.
Mycoprotein consumption has been shown to improve acute postprandial glycaemic control and decrease circulating cholesterol concentrations. We investigated the impact of incorporating mycoprotein into the diet on insulin sensitivity (IS), glycaemic control and plasma lipoprotein composition. Twenty healthy adults participated in a randomised, parallel-group trial in which they consumed a 7 d fully controlled diet where lunch and dinner contained either meat/fish (control group, CON) or mycoprotein (MYC) as the primary source of dietary protein. Oral glucose tolerance tests were performed pre- and post-intervention, and 24 h continuous blood glucose monitoring was applied throughout. Fasting plasma samples were obtained pre- and post-intervention and were analysed using quantitative, targeted NMR-based metabonomics. There were no changes within or between groups in blood glucose or serum insulin responses, nor in IS or 24 h glycaemic profiles. No differences between groups were found for 171 of the 224 metabonomic targets. Forty-five lipid concentrations of different lipoprotein fractions (VLDL, LDL, intermediate-density lipoprotein and HDL) remained unchanged in CON but showed a coordinated decrease (7–27 %; all P < 0·05) in MYC. Total plasma cholesterol, free cholesterol, LDL-cholesterol, HDL2-cholesterol, DHA and n-3 fatty acids decreased to a larger degree in MYC (14–19 %) compared with CON (3–11 %; P < 0·05). Substituting meat/fish for mycoprotein twice daily for 1 week did not modulate whole-body IS or glycaemic control but resulted in changes to plasma lipid composition, the latter primarily consisting of a coordinated reduction in circulating cholesterol-containing lipoproteins.
OBJECTIVES/GOALS: The North Carolina Translational and Clinical Sciences Institute (NC TraCS) supports faculty and staff in carrying out clinical and translational research at UNC-Chapel Hill. To better understand customer satisfaction and impact, a survey was administered among NC TraCS users. METHODS/STUDY POPULATION: NC TraCS has 13 program areas that range from Biostatistics to Community and Stakeholder Engagement. These programs provide services to faculty, staff, students, and outside researchers in the area of clinical and translational science. A customer feedback survey was administered in Spring 2019 to anyone who had used at least one NC TraCS service between March 1st, 2017 and February 28th, 2019. A total of 856 survey invitations were sent. The survey included questions around users’ perception of the ease of access, helpfulness, outcome, and promptness of the services received using 6-point Likert scale. The survey also addressed career impact, communications, and suggestions for improvement. RESULTS/ANTICIPATED RESULTS: We received 268 responses, (31% response). Majority of respondents were satisfied with Overall Helpfulness (95%), Outcome of Service (96%), Ease of Access (93%), and Promptness of Service (90%). They also noted that their careers had at least slightly improved in the following areas: Mentorship (76%), Research Methods (75%), Skill Development (77%), Research Direction (71%) and Collaboration (80%). Furthermore, 96% responded positively to returning to TraCS. The feedback received was shared with service administrators and NC TraCS leadership to identify areas of improvement and further strengthen their services. Concerns, when present, were addressed by service directors or the overall PI’s. DISCUSSION/SIGNIFICANCE OF IMPACT: Need to communicate expectations to customers the expected turn-around time for help emerged as a clear take-away. In response, TraCS leadership is working to improve staffing and workflows for efficient service delivery including expectation management, especially among the most popular services.
OBJECTIVES/GOALS: The goals of this evaluation were 1) to describe the pilot grant application cycle and processes at NC TraCS, 2) to illustrate the impact of pilot grants on extramural grant funding, and 3) to provide a framework for other institutions to utilize for the evaluation of pilot grant programs. METHODS/STUDY POPULATION: From 2009-2019 the NC TraCS pilot program funded 925 projects, varying from $2,000 to $100,000. Pilot grants are available to any researcher affiliated with the university as well as partner institutions and community stakeholders. For this evaluation we analyzed data on pilot applicants (demographics, type of pilot, funding status, resubmissions, etc.) and outcomes (extramural funding, publications, etc.) yielded from funded pilots. In addition to summary statistics, we also calculated return on investment (ROI) for the program as a whole and by specific grant type. We will use bibliometric network analysis to assess productivity, citation impact, and scope of collaboration. RESULTS/ANTICIPATED RESULTS: There have been 2,777 submitted proposals with an acceptance rate of 33.3%. Unfunded proposals can resubmit, 61.8% of resubmitted applications are successfully funded, and 29.6% of funded applications are resubmissions. The $2,000 awards accounted for 43.4% of all grants awarded but only accounted for 6.4% of all pilot funds awarded. Success of proposals was proportional to the number of applications from each academic unit. 60.8% of funded applicants were affiliated with the School of Medicine and account for 65.3% of all funding awarded from 2009-2019. Additionally, we plan on analyzing return on investment rates to illustrate the impact of pilot awards on future research funding. DISCUSSION/SIGNIFICANCE OF IMPACT: Pilot grants can lead to subsequent extramural grants, publications, and successful translation of research into practice. This evaluation will assist our institution in understanding the impact of pilot grants and will provide a road map for other institutions evaluating their own programs.
Conservation scientists continue to debate the strengths and weaknesses of REDD+ as an instrument to slow greenhouse gas emissions in the developing world. We propose that general positions on this debate are less helpful than drawing lessons from specific investigations into the features of individual projects that make them successful or not. Here, focusing on a site-specific REDD+ intervention in Pemba, Zanzibar (Tanzania), we examine the circumstances under which REDD+ has a chance of success, teasing out specific features of both REDD+ interventions and the socio-economic and institutional contexts that render REDD+ a potentially valuable complement to community forestry. Additionally, we highlight some unanticipated positive outcomes associated with the design features of REDD+ projects. Our broader goal is to move away from ideologically-driven debate to empirically-based identification of general conditions where REDD+ could work, and to provide policy recommendations.
Electroconvulsive therapy (ECT) is recommended in treatment guidelines as an efficacious therapy for treatment-resistant depression. However, it has been associated with loss of autobiographical memory and short-term reduction in new learning.
To provide clinically useful guidelines to aid clinicians in informing patients regarding the cognitive side-effects of ECT and in monitoring these during a course of ECT, using complex data.
A Committee of clinical and academic experts from Australia and New Zealand met to the discuss the key issues pertaining to ECT and cognitive side-effects. Evidence regarding cognitive side-effects was reviewed, as was the limited evidence regarding how to monitor them. Both issues were supplemented by the clinical experience of the authors.
Meta-analyses suggest that new learning is impaired immediately following ECT but that group mean scores return at least to baseline by 14 days after ECT. Other cognitive functions are generally unaffected. However, the finding of a mean score that is not reduced from baseline cannot be taken to indicate that impairment, particularly of new learning, cannot occur in individuals, particularly those who are at greater risk. Therefore, monitoring is still important. Evidence suggests that ECT does cause deficits in autobiographical memory. The evidence for schedules of testing to monitor cognitive side-effects is currently limited. We therefore make practical recommendations based on clinical experience.
Despite modern ECT techniques, cognitive side-effects remain an important issue, although their nature and degree remains to be clarified fully. In these circumstances it is useful for clinicians to have guidance regarding what to tell patients and how to monitor these side-effects clinically.
Schizophrenia is characterized by poor social interaction contributing to poor functional outcome. Particularly nonverbal communication is disturbed. Neural correlates of impaired gesturing are currently unclear. We thus tested functional correlates of gesturing in schizophrenia patients and healthy controls.
We tested 22 patients and 25 controls with an event-related fMRI (instructed delay) paradigm to dissociate brain activation during planning and execution of meaningful (e.g. use scissors) and meaningless novel gestures. Preprocessing included realignment, coregistration, normalization and spatial smoothing. We used a two stage mixed effects model for statistical analysis. Conditions were contrasted against a linguistic control within and between groups. We correlated psychopathological characteristics with beta estimates of brain areas with between group effects.
During planning and execution of both gesture subtypes both groups activated brain areas of the ventral and dorsal stream. However patients’ activity was less prominent and more left lateralized. During planning patients showed additional activity in bilateral temporal poles, amygdala and hippocampus associated with the level of delusions. Furthermore patients had increased dorsomedial prefrontal cortex and precuneus activity when planning meaningless gestures.
During the planning of meaningless gestures we detected aberrant activation of limbic structures in patients typically implicated in delusion formation, which also correlated with current severity of delusions. Moreover, planning of meaningless gestures relied on areas relevant for strategic control and attention. These results argue for a pathologic search for meaning in neutral gestures and increased control effort during planning of meaningless gestures in schizophrenia.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Prevalence estimates of autistic traits in individuals with psychotic disorders (PD) vary greatly and it is unclear whether individuals with a familial risk (FR) for psychosis have an increased propensity to display autistic traits. Furthermore, it is unknown whether the presence of comorbid autism traits disproportionally affects the cognitive and behavioral aspects of social functioning in PD.
In total, 504 individuals with PD, 587 unaffected siblings with FR, and 337 typical comparison (TC) individuals (16–50 years) were included. Autistic and psychotic traits were measured with the Autism Spectrum Quotient (AQ) and the Community Assessment of Psychic Experiences (CAPE). Social cognition was assessed with the Picture Sequencing Task (PST) and social behavior with the Social Functioning Scale (SFS).
For PD 6.5% scored above AQ clinical cut-off (⩾32), 1.0% for FR, and 1.2% for TC. After accounting for age, sex, and IQ, the PD group showed significantly more autistic traits and alterations in social behavior and cognition, while FR and TC only displayed marginal differences. Within the PD group autistic traits were a robust predictor of social behavior and there were no interactions with positive psychotic symptoms.
Levels of autistic traits are substantially elevated in PD and have a profoundly negative association with social functioning. In contrast, autistic traits above the clinical cut-off are not elevated in those with FR, and only marginally on a dimensional level. These findings warrant specific clinical guidelines for psychotic patients who present themselves with autistic comorbidity to help address their social needs.
Very preterm infants experience poor postnatal growth relative to intra-uterine growth rates but have increased percentage body fat (%fat). The aim of the present study was to identify nutritional and other clinical predictors of infant %fat, fat mass (FM) (g) and lean mass (LM) (g) in very preterm infants during their hospital stay. Daily intakes of protein, carbohydrate, lipids and energy were recorded from birth to 34 weeks postmenstrual age (PMA) in fifty infants born <32 weeks. Clinical illness variables and anthropometric data were also collected. Body composition was assessed at 34–37 weeks PMA using the PEA POD Infant Body Composition System. Multiple regression analysis was used to identify independent predictors of body composition (%fat, FM or LM). Birth weight, birth weight z-score and PMA were strong positive predictors of infant LM. After adjustment for these factors, the strongest nutrient predictors of LM were protein:carbohydrate ratios (102–318 g LM/0·1 increase in ratio, P = 0·006–0·015). Postnatal age (PNA) and PMA were the strongest predictors of infant FM or %fat. When PNA and PMA were accounted for a higher intake of energy (–1·41 to –1·61 g FM/kJ per kg per d, P = 0·001–0·012), protein (–75·5 to –81·0 g FM/g per kg per d, P = 0·019–0·038) and carbohydrate (–27·2 to –30·0 g FM/g per kg per d, P = 0·012–0·019) were associated with a lower FM at 34–37 weeks PMA. Higher intakes of energy, protein and carbohydrate may reduce fat accumulation in very preterm infants until at least 34–37 weeks PMA.
Translocation and rehabilitation programmes are critical tools for wildlife conservation. These methods achieve greater impact when integrated in a combined strategy for enhancing population or ecosystem restoration. During 2002–2016 we reared 37 orphaned southern sea otter Enhydra lutris nereis pups, using captive sea otters as surrogate mothers, then released them into a degraded coastal estuary. As a keystone species, observed increases in the local sea otter population unsurprisingly brought many ecosystem benefits. The role that surrogate-reared otters played in this success story, however, remained uncertain. To resolve this, we developed an individual-based model of the local population using surveyed individual fates (survival and reproduction) of surrogate-reared and wild-captured otters, and modelled estimates of immigration. Estimates derived from a decade of population monitoring indicated that surrogate-reared and wild sea otters had similar reproductive and survival rates. This was true for males and females, across all ages (1–13 years) and locations evaluated. The model simulations indicated that reconstructed counts of the wild population are best explained by surrogate-reared otters combined with low levels of unassisted immigration. In addition, the model shows that 55% of observed population growth over this period is attributable to surrogate-reared otters and their wild progeny. Together, our results indicate that the integration of surrogacy methods and reintroduction of juvenile sea otters helped establish a biologically successful population and restore a once-impaired ecosystem.
The aggregation of neurocognitive deficits among the non-psychotic first-degree relatives of adult- and childhood-onset schizophrenia patients suggests that there may be a common etiology for these deficits in childhood- and adult-onset illness. However, there is considerable heterogeneity in the presentation of neurobiological abnormalities, and whether there are differences in the extent of familial transmission for specific domains of cognitive function has not been systematically addressed.
We employed variance components analysis, as implemented in SOLAR-Eclipse, to evaluate the evidence of familial transmission for empirically derived composite scores representing attention, working memory, verbal learning, verbal retention, and memory for faces. We contrast estimates for adult- and childhood-onset schizophrenia families and matched community control pedigrees, and compare our findings to previous reports based on analogous neurocognitive assessments.
We observed varying degrees of familial transmission; attention and working memory yielded comparable, significant estimates for adult-onset and community control pedigrees; verbal learning was significant for childhood-onset and community control pedigrees; and facial memory demonstrated significant familial transmission only for childhood-onset schizophrenia. Model-fitting analyses indicated significant differences in familiality between adult- and childhood-onset schizophrenia for attention, working memory, and verbal learning.
By comprehensively assessing a wide range of neurocognitive domains in adult- and childhood-onset schizophrenia families, we provide additional support for specific neurocognitive domains as schizophrenia endophenotypes. Whereas comparable estimates of familial transmission for certain dimensions of cognitive functioning support a shared etiology of adult- and childhood-onset neurocognitive function, observed differences may be taken as preliminary evidence of partially divergent multifactorial architectures.