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Evidence suggests that early trauma may have a negative effect on cognitive functioning in individuals with psychosis, yet the relationship between childhood trauma and cognition among those at clinical high risk (CHR) for psychosis remains unexplored. Our sample consisted of 626 CHR children and 279 healthy controls who were recruited as part of the North American Prodrome Longitudinal Study 2. Childhood trauma up to the age of 16 (psychological, physical, and sexual abuse, emotional neglect, and bullying) was assessed by using the Childhood Trauma and Abuse Scale. Multiple domains of cognition were measured at baseline and at the time of psychosis conversion, using standardized assessments. In the CHR group, there was a trend for better performance in individuals who reported a history of multiple types of childhood trauma compared with those with no/one type of trauma (Cohen d = 0.16). A history of multiple trauma types was not associated with greater cognitive change in CHR converters over time. Our findings tentatively suggest there may be different mechanisms that lead to CHR states. Individuals who are at clinical high risk who have experienced multiple types of childhood trauma may have more typically developing premorbid cognitive functioning than those who reported minimal trauma do. Further research is needed to unravel the complexity of factors underlying the development of at-risk states.
Childhood adversity is associated with poor mental and physical health outcomes across the life span. Alterations in the hypothalamic–pituitary–adrenal axis are considered a key mechanism underlying these associations, although findings have been mixed. These inconsistencies suggest that other aspects of stress processing may underlie variations in this these associations, and that differences in adversity type, sex, and age may be relevant. The current study investigated the relationship between childhood adversity, stress perception, and morning cortisol, and examined whether differences in adversity type (generalized vs. threat and deprivation), sex, and age had distinct effects on these associations. Salivary cortisol samples, daily hassle stress ratings, and retrospective measures of childhood adversity were collected from a large sample of youth at risk for serious mental illness including psychoses (n = 605, mean age = 19.3). Results indicated that childhood adversity was associated with increased stress perception, which subsequently predicted higher morning cortisol levels; however, these associations were specific to threat exposures in females. These findings highlight the role of stress perception in stress vulnerability following childhood adversity and highlight potential sex differences in the impact of threat exposures.
To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.
Background
In the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.
Method
Patients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.
Results
343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.
Conclusions
Patients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
Background
In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.
Method
Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).
Results
343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.
Conclusions
These results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
Much of the interest in youth at clinical high risk (CHR) of psychosis has been in understanding conversion. Recent literature has suggested that less than 25% of those who meet established criteria for being at CHR of psychosis go on to develop a psychotic illness. However, little is known about the outcome of those who do not make the transition to psychosis. The aim of this paper was to examine clinical symptoms and functioning in the second North American Prodrome Longitudinal Study (NAPLS 2) of those individuals whose by the end of 2 years in the study had not developed psychosis.
Methods
In NAPLS-2 278 CHR participants completed 2-year follow-ups and had not made the transition to psychosis. At 2-years the sample was divided into three groups – those whose symptoms were in remission, those who were still symptomatic and those whose symptoms had become more severe.
Results
There was no difference between those who remitted early in the study compared with those who remitted at one or 2 years. At 2-years, those in remission had fewer symptoms and improved functioning compared with the two symptomatic groups. However, all three groups had poorer social functioning and cognition than healthy controls.
Conclusions
A detailed examination of the clinical and functional outcomes of those who did not make the transition to psychosis did not contribute to predicting who may make the transition or who may have an earlier remission of attenuated psychotic symptoms.
Using variational calculus, we investigate the time-dependent injection rate that minimises the growth of the Saffman–Taylor instability when a finite volume of fluid is injected in a finite time,
$t_{f}$
, into a Hele-Shaw cell. We first consider a planar interface, and show that, with a constant viscosity ratio, the constant injection rate is optimal. When the viscosity of the displacing fluid,
$\unicode[STIX]{x1D707}_{1}(t)$
, gradually increases over time, as may occur with a slowly gelling polymer solution, the optimal injection rate,
$U^{\ast }(t)$
, involves a gradual increase in the flow rate with time. This leads to a smaller initial value of flow rate than the constant injection rate, finishing with a larger value. Such optimisation can lead to a substantial suppression of the instability as compared to the constant injection case if the characteristic gelling time is comparable to
$t_{f}$
. In contrast, for either relatively slow or fast gelling, there is much less benefit in selecting the optimal injection rate,
$U^{\ast }(t)$
, as compared to the constant injection rate. In the case of a constant injection rate from a point source,
$Q$
, then with a constant viscosity ratio the fastest-growing perturbation on the radially spreading front involves axisymmetric modes whose wavenumber increases with time. Approximating the discrete azimuthal modes by a continuous distribution, we find the injection rate that minimises growth,
$Q^{\ast }(t)$
. We find that there is a critical time for injection,
$t_{f}^{\dagger }$
, such that if
$t_{f}>t_{f}^{\dagger }$
then
$Q^{\ast }(t)$
can be chosen so that the interface is always stable. This critical time emerges from the case with an injection rate given by
$Q^{\ast }\sim t^{-1/3}$
. As the total injection time is reduced to values
$t_{f}<t_{f}^{\dagger }$
, the system becomes progressively more unstable, and the optimal injection rate for an idealised continuous distribution of azimuthal modes asymptotes to a flow rate that increases linearly with time. As for the one-dimensional case, if the viscosity of the injection fluid gradually increases over time, then the optimal injection rate has a smaller initial value but gradually increases to larger values than for the analogous constant viscosity problem. If the displacing fluid features shear-thinning rheology, then the optimal injection rate involves a smaller flow rate at early times, although not as large a reduction as in the Newtonian case, and a larger flow rate at late times, although not as large an increase as in the Newtonian case.
Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.
Aims
To confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.
Method
The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.
Results
In the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β=0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO.
Conclusions
This meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
The developmental course of daily functioning prior to first psychosis-onset remains poorly understood. This study explored age-related periods of change in social and role functioning. The longitudinal study included youth (aged 12–23, mean follow-up years = 1.19) at clinical high risk (CHR) for psychosis (converters [CHR-C], n = 83; nonconverters [CHR-NC], n = 275) and a healthy control group (n = 164). Mixed-model analyses were performed to determine age-related differences in social and role functioning. We limited our analyses to functioning before psychosis conversion; thus, data of CHR-C participants gathered after psychosis onset were excluded. In controls, social and role functioning improved over time. From at least age 12, functioning in CHR was poorer than in controls, and this lag persisted over time. Between ages 15 and 18, social functioning in CHR-C stagnated and diverged from that of CHR-NC, who continued to improve (p = .001). Subsequently, CHR-C lagged behind in improvement between ages 21 and 23, further distinguishing them from CHR-NC (p < .001). A similar period of stagnation was apparent for role functioning, but to a lesser extent (p = .007). The results remained consistent when we accounted for the time to conversion. Our findings suggest that CHR-C start lagging behind CHR-NC in social and role functioning in adolescence, followed by a period of further stagnation in adulthood.
During
$\text{CO}_{2}$
sequestration into a deep saline aquifer of finite vertical extent,
$\text{CO}_{2}$
will tend to accumulate in structural highs such as offered by an anticline. Over times of tens to thousands of years, some of the
$\text{CO}_{2}$
will dissolve into the underlying groundwater to produce a region of relatively dense, saturated water directly below the plume of
$\text{CO}_{2}$
. Continued dissolution then requires the supply of unsaturated aquifer water. In an aquifer of finite vertical extent, this may be provided by a background hydrological flow, or a laterally-spreading buoyancy-driven flow caused by the greater density of the
$\text{CO}_{2}$
saturated water relative to the original aquifer water.
We investigate long time steady-state dissolution in the presence of a background hydrological flow. In steady state, the distribution of
$\text{CO}_{2}$
in the groundwater upstream of the aquifer involves a balance between three competing effects: (i) the buoyancy-driven flow of
$\text{CO}_{2}$
saturated water; (ii) the diffusion of
$\text{CO}_{2}$
from saturated to under-saturated water; and (iii) the advection associated with the oncoming background flow. This leads to three limiting regimes. In the limit of very slow diffusion, a nearly static intrusion of dense fluid may extend a finite distance upstream, balanced by the pressure gradient associated with the oncoming background flow. In the limit of fast diffusion relative to the flow, a gradient zone may become established in which the along-aquifer diffusive flux balances the advection associated with the background flow. However, if the buoyancy-driven flow speed exceeds the background hydrological flow speed, then a third, intermediate regime may become established. In this regime, a convective recirculation develops upstream of the anticline involving the vertical diffusion of
$\text{CO}_{2}$
from an upstream propagating flow of dense
$\text{CO}_{2}$
saturated water into the downstream propagating flow of
$\text{CO}_{2}$
unsaturated water. For each limiting case, we find analytical solutions for the distribution of
$\text{CO}_{2}$
upstream of the anticline, and test our analysis with full numerical simulations. A key result is that, although there may be very different controls on the distribution and extent of
$\text{CO}_{2}$
bearing water upstream of the anticline, in each case the dissolution rate is given by the product of the background volume flux and the difference in concentration between the
$\text{CO}_{2}$
saturated water and the original aquifer water upstream.
Several outbreaks of hepatitis A in men who have sex with men (MSM) were reported in the 1980s and 1990s in Australia and other countries. An effective hepatitis A virus (HAV) vaccine has been available in Australia since 1994 and is recommended for high-risk groups including MSM. No outbreaks of hepatitis A in Australian MSM have been reported since 1996. In this study, we aimed to estimate HAV transmissibility in MSM populations in order to inform targets for vaccine coverage in such populations. We used mathematical models of HAV transmission in a MSM population to estimate the basic reproduction number (R0) and the probability of an HAV epidemic occurring as a function of the immune proportion. We estimated a plausible range for R0 of 1·71–3·67 for HAV in MSM and that sustained epidemics cannot occur once the proportion immune to HAV is greater than ~70%. To our knowledge this is the first estimate of R0 and the critical population immunity threshold for HAV transmission in MSM. As HAV is no longer endemic in Australia or in most other developed countries, vaccination is the only means of maintaining population immunity >70%. Our findings provide impetus to promote HAV vaccination in high-risk groups such as MSM.
Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
Method
The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
Results
PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10−6). SLEs and CT were also associated with MDD status (p = 2.19 × 10−4 and p = 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
Conclusions
CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.
We examine the stability of a system with two radially spreading fronts in a Hele-Shaw cell in which the viscosity increases monotonically from the innermost to the outermost fluid. The critical parameters are identified as the viscosity ratio of the inner and outer fluids and the viscosity difference between the intermediate and outer fluids as a fraction of the viscosity difference between the inner and outer fluids. There is a minimum viscosity ratio of the inner and outer fluids above which, for each azimuthal mode, the system is stable to perturbations of that mode at any flow rate. This condition is directly analogous to the result for a single interface. Below this minimum ratio, the system may be stable at any flow rate early in the flow. However, once the inner radius reaches a critical fraction of the outer radius, this absolute stability ceases to apply owing to the coupling of the inner and outer interfaces. We determine the maximum flow rate, as a function of time, in order that all modes remain stable due to the effects of interfacial tension. These criteria for stability are then used to select the viscosity of the intermediate fluid so that a fixed volume of the intermediate and then inner fluid can be added to the system in the minimum time with the system remaining stable throughout. The optimal viscosity for this intermediate fluid depends on the relative volume of the inner and intermediate fluid and also on the overall viscosity ratio of the innermost fluid and the original fluid in the cell, with the balance being to suppress the early time instability of the outer interface and the late time instability of the inner interface. We discuss application of this approach to a problem of injection of treatment fluid in an oil well.
Background: Schema Theory proposes that the development of maladaptive schemas are based on a combination of memories, emotions and cognitions regarding oneself and one's relationship to others. A cognitive model of psychosis suggests that schemas are crucial to the development and persistence of psychosis. Little is known about the impact that schemas may have on those considered to be at clinical high risk (CHR) of developing psychosis. Aims: To investigate schemas over time in a large sample of CHR individuals and healthy controls. Method: Sample included 765 CHR participants and 280 healthy controls. Schemas were assessed at baseline, 6 and 12 months using the Brief Core Schema Scale (BCSS). Baseline schemas were compared to 2-year clinical outcome. Results: CHR participants evidenced stable and more maladaptive schemas over time compared to controls. Schemas at initial contact did not vary amongst the different clinical outcome groups at 2 years although all CHR outcome groups evidenced significantly worse schemas than healthy controls. Although there were no differences on baseline schemas between those who later transitioned to psychosis compared to those who did not, those who transitioned to psychosis had more maladaptive negative self-schemas at the time of transition. Associations between negative schemas were positively correlated with earlier abuse and bullying. Conclusions: These findings demonstrate a need for interventions that aim to improve maladaptive schemas among the CHR population. Therapies targeting self-esteem, as well as schema therapy may be important work for future studies.
A series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed.
Method
At baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models.
Results
CHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment.
Conclusions
In CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone.