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Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88) presented a critique of our recently published paper in Cell Reports entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ (Lam et al., Cell Reports, Vol. 21, 2017, 2597–2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229–237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from ‘inflation in the FDR [false discovery rate]’, as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88), and are not ‘more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence’.
The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models.
Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples.
We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected).
These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4’s developmental role.
The exposure of pigs to different pathogens compromises productivity (Greiner et al., 2000), i.e. reduces weight gain and food intake, even in the absence of clinical disease. Associations between productivity and a range of immunological traits have been demonstrated in apparently healthy animals facing the same infectious challenge (Clapperton et al., 2003). Specifically, it was demonstrated that some leucocyte proportions (monocytes, B cells, MIL-4 (NK) positive cells) increased significantly as performance decreased. This study aims to verify these previous results on an independent population of pigs, examine relationships between immune measures and actual bacterial counts in the gut, and examine the influence of diet type on these measurements.
Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.
This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).
Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (βstd = −0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.
Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.
DSM-5 proposes an Attenuated Psychosis Syndrome (APS) for further investigation, based upon the Attenuated Positive Symptom Syndrome (APSS) in the Structured Interview for Psychosis-Risk Syndromes (SIPS). SIPS Unusual Thought Content, Disorganized Communication and Total Disorganization scores predicted progression to psychosis in a 2015 NAPLS-2 Consortium report. We sought to independently replicate this in a large single-site high-risk cohort, and identify baseline demographic and clinical predictors beyond current APS/APSS criteria.
We prospectively studied 200 participants meeting criteria for both the SIPS APSS and DSM-5 APS. SIPS scores, demographics, family history of psychosis, DSM Axis-I diagnoses, schizotypy, and social and role functioning were assessed at baseline, with follow-up every 3 months for 2 years.
The conversion rate was 30% (n = 60), or 37.7% excluding participants who were followed under 2 years. This rate was stable across time. Conversion time averaged 7.97 months for 60% who developed schizophrenia and 15.68 for other psychoses. Mean conversion age was 20.3 for males and 23.5 for females. Attenuated odd ideas and thought disorder appear to be the positive symptoms which best predict psychosis in a logistic regression. Total negative symptom score, Asian/Pacific Islander and Black/African-American race were also predictive. As no Axis-I diagnosis or schizotypy predicted conversion, the APS is supported as a distinct syndrome. In addition, cannabis use disorder did not increase risk of conversion to psychosis.
NAPLS SIPS findings were replicated while controlling for clinical and demographic factors, strongly supporting the validity of the SIPS APSS and DSM-5 APS diagnosis.
Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth.
LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables.
Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%.
These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.
Patients with major mental illness are recognised to be at risk of premature death for a multitude of reasons. This initiative aimed to improve the physical health monitoring of patients prescribed depot antipsychotic medication in a catchment area of ~36 000 in Ireland.
International best practice recommends monitoring of blood tests, physical parameters such as weight, BMI, waist circumference and blood pressure, and side effects of patients prescribed antipsychotic medication. A clinic was established to target these interventions.
A cohort of patients receiving antipsychotics in long-acting injectable form was chosen. A twice-yearly, multidisciplinary health monitoring clinic was established. Evaluation involved an audit of medical records which measured the proportion of those attending the clinic who had blood test monitoring and physical parameters recorded.
Before the clinic’s implementation, 30% of patients had evidence of some blood test monitoring, 9% had evidence of complete blood testing and one patient had evidence of physical health parameters having been recorded. One year after the implementation 78% of patients had evidence of some blood test monitoring, 61% had evidence of full blood test monitoring and 100% had evidence of physical parameters recorded.
The clinic was positively received by patients, and led to improved teamwork. Recommendations include organising concurrent psychiatric and phlebotomy clinics so that patients may avail of psychiatric review and blood testing at a single appointment. As a result of the increased focus on physical health monitoring, a similar project is planned to target all patients prescribed antipsychotics.
To examine the delivery and assessment of psychiatry at undergraduate level in the six medical schools in the Republic of Ireland offering a medical degree programme.
A narrative description of the delivery and assessment of psychiatry at undergraduate level by collaborative senior faculty members from all six universities in Ireland.
Psychiatry is integrated to varying degrees across all medical schools. Clinical experience in general adult psychiatry and sub-specialities is provided by each medical school; however, the duration of clinical attachment varies, and the provision of some sub-specialities (i.e. forensic psychiatry) is dependent on locally available resources. Five medical schools provide ‘live’ large group teaching sessions (lectures), and all medical schools provide an array of small group teaching sessions. Continuous assessment encompasses 10–35% of the total assessment marks, depending on the medical school. Only one medical school does not provide a clinical examination in the form of an Objective Structured Clinical Examination with viva examinations occurring at three medical schools.
Many similarities exist in relation to the delivery of psychiatry at undergraduate level in Ireland. Significant variability exists in relation to assessment with differences in continuous assessment, written and clinical exams and the use of vivas noted. The use of e-learning platforms has increased significantly in recent years, with their role envisaged to include cross-disciplinary teaching sessions and analysis of examinations and individual components within examinations which will help refine future examinations and enable greater sharing of resources between medical schools.
Cardiopulmonary resuscitation (CPR) is an inherently traumatic procedure. Successful resuscitations are often complicated by iatrogenic injuries to structures of the neck, thorax, or abdomen. Rib and sternal fractures are the most frequently induced injuries. However, rare and life-threatening trauma to vital organs such as the heart may also occur during CPR. We describe a novel case of CPR-associated right ventricular rupture in a woman with acute-on-chronic pulmonary embolism and no known pre-existing cardiac disease. We propose that chest compressions in the setting of elevated right ventricular pressure resulted in cardiac rupture, in this case.
The Rosetta Radio Science Investigations (RSI) experiment was selected by the European Space Agency to be included in the International Rosetta Mission to comet P/Wirtanen (launch in 2003, arrival and operational phase at the comet 2011–2013). The RSI science objectives address fundamental aspects of cometary physics such as the mass and bulk density of the nucleus, the gravity field, non-gravitational forces, the size and shape, the internal structure, the composition and roughness of the nucleus surface, the abundance of large dust grains and the plasma content in the coma and the combined dust and gas mass flux on the orbiter. RSI will make use of the radio subsystem of the Rosetta spacecraft.
Offspring of parents with bipolar disorder (BD) (BO) are at higher risk of BD than offspring of parents with non-BD psychopathology (NBO), although both groups are at higher risk than offspring of psychiatrically healthy parents (HC) for other affective and psychiatric disorders. Abnormal functioning in reward circuitry has been demonstrated previously in individuals with BD. We aimed to determine whether activation and functional connectivity in this circuitry during risky decision-making differentiated BO, NBO and HC.
BO (n = 29; mean age = 13.8 years; 14 female), NBO (n = 28; mean age = 13.9 years; 12 female) and HC (n = 23; mean age = 13.7 years; 11 female) were scanned while performing a number-guessing reward task. Of the participants, 11 BO and 12 NBO had current non-BD psychopathology; five BO and four NBO were taking psychotropic medications.
A 3 (group) × 2 (conditions: win-control/loss-control) analysis of variance revealed a main effect of group on right frontal pole activation: BO showed significantly greater activation than HC. There was a significant main effect of group on functional connectivity between the bilateral ventral striatum and the right ventrolateral prefrontal cortex (Z > 3.09, cluster-p < 0.05): BO showed significantly greater negative functional connectivity than other participants. These between-group differences remained after removing youth with psychiatric disorders and psychotropic medications from analyses.
This is the first study to demonstrate that reward circuitry activation and functional connectivity distinguish BO from NBO and HC. The fact that the pattern of findings remained when comparing healthy BO v. healthy NBO v. HC suggests that these neuroimaging measures may represent trait-level neurobiological markers conferring either risk for, or protection against, BD in youth.
Novel and more conventional boron carbides were combined with n-type silicon to make heterojunction diodes, with neutron capture signal at zero applied bias. The boron carbides were based on the cross linking of closo-1,2-dicarbadodecaborane (ortho-carborane; 1,2-B10C2H12), and cross linking based on the combination of closo-1,2-dicarbadodecaborane (ortho-carborane; 1,2- B10C2H12) and pyridine. In the latter devices, pyridine concentration was varied; samples with a closo-1,2-dicarbadodecaborane (ortho-carborane; 1,2- B10C2H12) to pyridine ratio of 1:1 (BC:Py1) and 1:3 (BC:Py3). The result is a nonvolatile robust p-type semiconductor of boron carbide (B10C2Hx):(C5NHx)y. The I(V) curves for the resulting heterojunction diodes exhibit strong rectification where the normalized reverse bias leakage currents are largely unperturbed with increasing pyridine inclusion. The devices are largely gamma insensitive and yet neutron voltaic properties of these boron carbides is demonstrated. The neutron capture generated pulses from these heterojunction diodes were obtained at zero bias voltage although without the characteristic signatures of complete charge collection from boron neutron capture generated electron-hole pair production. These results, nonetheless, suggest that modifications to boron carbide may result in better neutron voltaic materials with linking groups chosen from family of aromatic compounds that stretch between borazine (B3N3H6) and benzene that point the way to a whole family of future studies that may ultimately lead to boron carbides better suited to low power and low flux neutron detection.
Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).
For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.
Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.
AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
We aimed to reparameterize and validate an existing dengue model, comprising an entomological component (CIMSiM) and a disease component (DENSiM) for application in Malaysia. With the model we aimed to measure the effect of importation rate on dengue incidence, and to determine the potential impact of moderate climate change (a 1 °C temperature increase) on dengue activity. Dengue models (comprising CIMSiM and DENSiM) were reparameterized for a simulated Malaysian village of 10 000 people, and validated against monthly dengue case data from the district of Petaling Jaya in the state of Selangor. Simulations were also performed for 2008-2012 for variable virus importation rates (ranging from 1 to 25 per week) and dengue incidence determined. Dengue incidence in the period 2010–2012 was modelled, twice, with observed daily weather and with a 1 °C increase, the latter to simulate moderate climate change. Strong concordance between simulated and observed monthly dengue cases was observed (up to r = 0·72). There was a linear relationship between importation and incidence. However, a doubling of dengue importation did not equate to a doubling of dengue activity. The largest individual dengue outbreak was observed with the lowest dengue importation rate. Moderate climate change resulted in an overall decrease in dengue activity over a 3-year period, linked to high human seroprevalence early on in the simulation. Our results suggest that moderate reductions in importation with control programmes may not reduce the frequency of large outbreaks. Moderate increases in temperature do not necessarily lead to greater dengue incidence.