Social Cognition in Individuals at Ultra-High Risk for Psychosis: A Meta-Analysis

Objective

Treatment in the ultra-high risk stage for a psychotic episode is critical to the course of symptoms. Markers for the development of psychosis have been studied, to optimize the detection of people at risk of psychosis. One possible marker for the transition to psychosis is social cognition. To estimate effect sizes for social cognition based on a quantitative integration of the published evidence, we conducted a meta-analysis of social cognitive performance in people at ultra high risk (UHR).

Methods

A literature search (1970-July 2015) was performed in PubMed, PsychINFO, Medline, Embase, and ISI Web of Science, using the search terms ‘social cognition’, ‘theory of mind’, ‘emotion recognition’, ‘attributional style’, ‘social knowledge’, ‘social perception’, ‘empathy’, ‘at risk mental state’, ‘clinical high risk’, ‘psychosis prodrome’, and ‘ultra high risk’. The pooled effect size (Cohen’s D) and the effect sizes for each domain of social cognition were calculated. A random effects model with 95% confidence intervals was used.

Results

Seventeen studies were included in the analysis. The overall significant effect was of medium magnitude (d = 0.52, 95% Cl = 0.38–0.65). No moderator effects were found for age, gender and sample size. Sub-analyses demonstrated that individuals in the UHR phase show significant moderate deficits in affect recognition and affect discrimination in faces as well as in voices and in verbal Theory of Mind (TOM). Due to an insufficient amount of studies, we did not calculate an effect size for attributional bias and social perception/ knowledge. A majority of studies did not find a correlation between social cognition deficits and transition to psychosis, which may suggest that social cognition in general is not a useful marker for the development of psychosis. However some studies suggest the possible predictive value of verbal TOM and the recognition of specific emotions in faces for the transition into psychosis. More research is needed on these subjects.

Conclusion

The published literature indicates consistent general impairments in social cognition in people in the UHR phase, but only very specific impairments seem to predict transition to psychosis.     

Neurocognitive and Clinical Predictors of Long-Term Outcome in Adolescents at Ultra-High Risk for Psychosis: A 6-Year Follow-Up

Background

Most studies aiming to predict transition to psychosis for individuals at ultra-high risk (UHR) have focused on either neurocognitive or clinical variables and have made little effort to combine the two. Furthermore, most have focused on a dichotomous measure of transition to psychosis rather than a continuous measure of functional outcome. We aimed to investigate the relative value of neurocognitive and clinical variables for predicting both transition to psychosis and functional outcome.

Methods

Forty-three UHR individuals and 47 controls completed an extensive clinical and neurocognitive assessment at baseline and participated in long-term follow-up approximately six years later. UHR adolescents who had converted to psychosis (UHR-P; n = 10) were compared to individuals who had not (UHR-NP; n = 33) and controls on clinical and neurocognitive variables. Regression analyses were performed to determine which baseline measures best predicted transition to psychosis and long-term functional outcome for UHR individuals.

Results

Low IQ was the single neurocognitive parameter that discriminated UHR-P individuals from UHR-NP individuals and controls. The severity of attenuated positive symptoms was the only significant predictor of a transition to psychosis and disorganized symptoms were highly predictive of functional outcome.

Conclusions

Clinical measures are currently the most important vulnerability markers for long-term outcome in adolescents at imminent risk of psychosis.     

Intrinsic Functional Connectivity in Salience and Default Mode Networks and Aberrant Social Processes in Youth at Ultra-High Risk for Psychosis

Social processes are key to navigating the world, and investigating their underlying mechanisms and cognitive architecture can aid in understanding disease states such as schizophrenia, where social processes are highly impacted. Evidence suggests that social processes are impaired in individuals at ultra high-risk for the development of psychosis (UHR). Understanding these phenomena in UHR youth may clarify disease etiology and social processes in a period that is characterized by significantly fewer confounds than schizophrenia. Furthermore, understanding social processing deficits in this population will help explain these processes in healthy individuals. The current study examined resting state connectivity of the salience (SN) and default mode networks (DMN) in association with facial emotion recognition (FER), an integral aspect of social processes, as well as broader social functioning (SF) in UHR individuals and healthy controls. Consistent with the existing literature, UHR youth were impaired in FER and SF when compared with controls. In the UHR group, we found increased connectivity between the SN and the medial prefrontal cortex, an area of the DMN relative to controls. In UHR youth, the DMN exhibited both positive and negative correlations with the somatosensory cortex/cerebellum and precuneus, respectively, which was linked with better FER performance. For SF, results showed that sensory processing links with the SN might be important in allowing for better SF for both groups, but especially in controls where sensory processing is likely to be unimpaired. These findings clarify how social processing deficits may manifest in psychosis, and underscore the importance of SN and DMN connectivity for social processing more generally.     

Cognitive Alexithymia Is Associated with the Degree of Risk for Psychosis

Alexithymia is a personality construct denoting emotion processing problems. It has been suggested to encompass two dimensions: a cognitive and affective dimension. The cognitive dimension is characterized by difficulties in identifying, verbalizing and analyzing emotions, while the affective dimension reflects the level of emotional arousal and imagination. Alexithymia has been previously proposed as a risk factor for developing psychosis. More specifically, the two alexithymia dimensions might be differentially related to the vulnerability for psychosis. Therefore, we examined the two dimensions of alexithymia, measured with the BVAQ in 94 siblings of patients with schizophrenia, 52 subjects at ultra-high risk (UHR) for developing psychosis, 38 patients with schizophrenia and 109 healthy controls. The results revealed that siblings and patients had higher levels of cognitive alexithymia compared to controls. In addition, subjects at UHR for psychosis had even higher levels of cognitive alexithymia compared to the siblings. The levels of affective alexithymia in siblings and patients were equal to controls. However, UHR individuals had significantly lower levels of affective alexithymia (i.e. higher levels of emotional arousal and fantasizing) compared to controls. Alexithymia was further related to subclinical levels of negative and depressive symptoms. These findings indicate that alexithymia varies parametrically with the degree of risk for psychosis. More specifically, a type-II alexithymia pattern, with high levels of cognitive alexithymia and normal or low levels of affective alexithymia, might be a vulnerability factor for psychosis.     

Family Perception and 6-Month Symptomatic and Functioning Outcomes in Young Adolescents at Clinical High Risk for Psychosis in a General Population in China

Background and Aims

Given the difficulty of treating schizophrenia and other forms of psychosis, researchers have shifted focus to early detection and intervention of individuals at clinical high risk (CHR) for psychosis. Previous studies have shown that elements in family functioning could predict symptom outcome in CHR individuals. However, associations between self reported family functioning and symptom or functioning outcome of CHR individuals was rarely reported. Our study aimed to investigate the characteristics and the role of family functioning in the development of CHR individuals among young adolescents.

Methods

A sample of 32 CHR individuals was recruited from 2800 university students. The characteristics of family perception were evaluated by both Family Assessment Device (FAD) and Family cohesion and adaptability evaluation Scale II (FACES II). 6 month follow up data was available with 25 of the recruited CHR individuals. Baseline socio-demographic characteristics and family functioning were compared between CHR and control group. We also measured the associations between different dimensions of perceived family functioning and both severity of prodromal symptoms and global functioning at baseline and 6-month follow up.

Results

CHR individuals showed more maladaptive family functioning compared to control in nearly all of the dimensions of FAD and FACES II except for Affective Involvement. Better Problem Solving and Affective Responsiveness predicted less severe positive and negative symptoms respectively. Family cohesion and adaptability were not only correlated with the baseline severity of general symptoms, but also positively associated with the general and disorganized symptom outcome.

Conclusions

This study contributed preliminary evidence towards the associations between family perception and symptom outcome of CHR individuals. It also provided evidence for the importance of family interventions on CHR individuals.     

Thyroid Cancer Risk Is Not Increased in Diabetic Patients

Objective

This study evaluated thyroid cancer risk with regards to diabetes status and diabetes duration, and with the use of anti-diabetic drugs including sulfonylurea, metformin, insulin, acarbose, pioglitazone and rosiglitazone, by using a population-based reimbursement database in Taiwan.

Methods

A random sample of 1,000,000 subjects covered by the National Health Insurance was recruited. After excluding patients with type 1 diabetes, 999730 subjects (495673 men and 504057 women) were recruited into the analyses. Logistic regression estimated the odds ratios (OR) and their 95% confidence intervals (CI) for independent variables including age, sex, diabetes status/duration, anti-diabetic drugs, other medications, comorbidities, living regions, occupation and examinations that might potentially lead to the diagnosis of thyroid cancer in various models.

Results

The diabetic patients had a significantly higher probability of receiving potential detection examinations (6.38% vs. 5.83%, P<0.0001). After multivariable-adjustment, the OR (95% CI) for diabetes status was 0.816 (0.652–1.021); and for diabetes duration <1 year, 1–3 years, 3–5 years and ≥5 years vs. non-diabetes was 0.071 (0.010–0.507), 0.450 (0.250–0.813), 0.374 (0.203–0.689) and 1.159 (0.914–1.470), respectively. Among the anti-diabetic agents, only sulfonylurea was significantly associated with thyroid cancer, OR (95% CI): 1.882 (1.202–2.947). The OR (95% CI) for insulin, metformin, acarbose, pioglitazone and rosiglitazone was 1.701 (0.860–3.364), 0.696 (0.419–1.155), 0.581 (0.202–1.674), 0.522 (0.069–3.926) and 0.669 (0.230–1.948), respectively. Furthermore, patients with benign thyroid disease or other cancer, living in Kao-Ping/Eastern regions, or receiving potential detection examinations might have a significantly higher risk; and male sex, hypertension, dyslipidemia, chronic obstructive pulmonary disease, vascular complications or use of statin, aspirin or non-steroidal anti-inflammatory drugs might be associated with a significantly lower risk.

Conclusions

There is a lack of an overall association between diabetes and thyroid cancer, but patients with diabetes duration <5 years have a significantly lower risk. Sulfonylurea may increase the risk of thyroid cancer.     

Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity

Objective

Given that helminth infections have been shown to improve insulin sensitivity in animal studies, which may be explained by beneficial effects on energy balance or by a shift in the immune system to an anti-inflammatory profile, we investigated whether soil-transmitted helminth (STH)-infected subjects are more insulin sensitive than STH-uninfected subjects.

Design

We performed a cross-sectional study on Flores island, Indonesia, an area with high prevalence of STH infections.

Methods

From 646 adults, stool samples were screened for Trichuris trichiura by microscopy and for Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Strongyloides stercoralis by qPCR. No other helminth was found. We collected data on body mass index (BMI, kg/m²), waist-to-hip ratio (WHR), fasting blood glucose (FBG, mmol/L), insulin (pmol/L), high sensitive C-reactive protein (ng/ml) and Immunoglobulin E (IU/ml). The homeostatic model assessment for insulin resistance (HOMAIR) was calculated and regression models were used to assess the association between STH infection status and insulin resistance.

Results

424 (66%) participants had at least one STH infection. STH infected participants had lower BMI (23.2 vs 22.5 kg/m², p value = 0.03) and lower HOMAIR (0.97 vs 0.81, p value = 0.05). In an age-, sex- and BMI-adjusted model a significant association was seen between the number of infections and HOMAIR: for every additional infection with STH species, the HOMAIR decreased by 0.10 (p for linear trend 0.01). This effect was mainly accounted for by a decrease in insulin of 4.9 pmol/L for every infection (p for trend = 0.07).

Conclusion

STH infections are associated with a modest improvement of insulin sensitivity, which is not accounted for by STH effects on BMI alone.     

Increased ATPase Activity Is Responsible for Acid Sensitivity of Nisin-Resistant Listeria monocytogenes ATCC 700302

The growth of the foodborne pathogen Listeria monocytogenes can be controlled by nisin, an antimicrobial peptide. A spontaneous mutant of L. monocytogenes shows both resistance to nisin and increased acid sensitivity compared to the wild type. Changes in the cell membrane correlated with nisin resistance, but the mechanism for acid sensitivity appears unrelated. When hydrochloric or lactic acid is added to cultures, intracellular ATP levels drop significantly in the mutant (P < 0.01) compared to the results seen with the wild type. Characterization of the F₀F₁ ATPase, which hydrolyzes ATP to pump protons from the cell cytoplasm, shows that the enzyme is more active in the mutant than in the wild type. These data support a model in which the increased activity of the mutant ATPase upon acid addition depletes the cells' supply of ATP, resulting in cell death.     

Independently Formed Multiple Fano Resonances for Ultra-High Sensitivity Plasmonic Nanosensor

We proposed a plasmonic nanosensor with an ultra-high sensitivity based on groove and ring resonator. Simulation results show that these sharp Fano profiles originate from the interference between the groove and ring resonator. The profile can be easily tuned by changing the parameters of the structure. Moreover, we introduce a new way to achieve multiple Fano resonances through independent processes by adding a side-coupled stub cavity, and the Fano resonances can be tuned independently. These characteristics offer flexibility in the design of the devices. This nanosensor yields an ultra-high sensitivity of ～2000 nm/RIU, which is rarely seen in the previous report. Our structures may have potential applications for nanosensors, slow light, and nonlinear devices in highly integrated circuits.     

Basal Level of Autophagy Is Increased in Aging Human Skin Fibroblasts In Vitro,but Not in Old Skin

Intracellular autophagy (AP) is a stress response that is enhanced under conditions of limitation of amino acids, growth factors and other nutrients, and also when macromolecules become damaged, aggregated and fibrillated. Aging is generally accompanied by an increase in intracellular stress due to all the above factors. Therefore, we have compared the basal levels of AP in serially passaged human facial skin fibroblasts undergoing aging and replicative senescence in vitro, and ex vivo in the skin biopsies from the photo-protected and photo-exposed area of the arms of 20 healthy persons of young and old ages. Immunofluorescence microscopy, employing antibodies against a specific intracellular microtubule-associated protein-1 light chain-3 (LC3) as a well established marker of AP, showed a 5-fold increase in the basal level of LC3 in near senescent human skin fibroblasts. However, no such age-related increase in LC3 fluorescence and AP could be detected in full thickness skin sections from the biopsies obtained from 10 healthy young (age 25 to 30 yr) and 10 old (age 60 to 65 yr) donors. Furthermore, there was no difference in the basal level of LC3 in the skin sections from photo-protected and photo-exposed areas of the arm. Thus, in normal conditions, the aging phenotype of the skin cells in culture and in the body appears to be different in the case of AP.     

Cortical Morphology Differences in Subjects at Increased Vulnerability for Developing a Psychotic Disorder: A Comparison between Subjects with Ultra-High Risk and 22q11.2 Deletion Syndrome

IntroductionSubjects with 22q11.2 deletion syndrome (22q11DS) and subjects with ultra-high risk for psychosis (UHR) share a risk of approximately 30% to develop a psychotic disorder. Studying these groups helps identify biological markers of pathophysiological processes involved in the development of psychosis. Total cortical surface area (cSA), total cortical grey matter volume (cGMV), cortical thickness (CT), and local gyrification index (LGI) of the cortical structure have a distinct neurodevelopmental origin making them important target markers to study in relation to the development of psychosis.Results22q11DS subjects had lower total cSA and total cGMV compared to UHR and HC subjects. The 22q11DS subjects showed bilateral lower LGI in the i) prefrontal cortex, ii) precuneus, iii) precentral gyrus and iv) cuneus compared to UHR subjects. Additionally, lower LGI was found in the left i) fusiform gyrus and right i) pars opercularis, ii) superior, and iii) inferior temporal gyrus in 22q11DS subjects compared to HC. In comparison to 22q11DS subjects, the UHR subjects had lower CT of the insula. For both risk groups, positive symptom severity was negatively correlated to rostral middle frontal gyrus CT.ConclusionA shared negative correlation between positive symptom severity and rostral middle frontal gyrus CT in UHR and 22q11DS may be related to their increased vulnerability to develop a psychotic disorder. 22q11DS subjects were characterised by widespread lower degree of cortical gyrification linked to early and postnatal neurodevelopmental pathology. No implications for early neurodevelopmental pathology were found for the UHR subjects, although they did have distinctively lower insula CT which may have arisen from defective pruning processes during adolescence. Implications of these findings in relation to development of psychotic disorders are in need of further investigation in longitudinal studies.     

Poor Metabolizers at the Cytochrome P450 2C19 Loci Is at Increased Risk of Developing Cancer in Asian Populations

Background

CYP2C19 encodes a member of the cytochrome P450 superfamily of enzymes, which play a central role in activating and detoxifying many carcinogens and endogenous compounds thought to be involved in the development of cancer. In the past decade, two common polymorphisms among CYP2C19 (CYP2C19*2 and CYP2C19*3) that are responsible for the poor metabolizers (PMs) phenotype in humans and cancer susceptibility have been investigated extensively; however, these studies have yielded contradictory results.

Methods and Results

To investigate this inconsistency, we conducted a comprehensive meta-analysis of 11,554 cases and 16,592 controls from 30 case-control studies. Overall, the odds ratio (OR) of cancer was 1.52 [95% confidence interval (CI): 1.23–1.88, P<10^-4] for CYP2C19 PMs genotypes. However, this significant association vanished when the analyses were restricted to 5 larger studies (no. of cases ≥ 500 cases). In the subgroup analysis for different cancer types, PMs genotypes had an effect of increasing the risks of esophagus cancer, gastric cancer, lung cancer and hepatocellular carcinoma as well as head neck cancer. Significant results were found in Asian populations when stratified by ethnicity; whereas no significant associations were found among Caucasians. Stratified analyses according to source of controls, significant associations were found only in hospital base controls.

Conclusions

Our meta-analysis suggests that the CYP2C19 PMs genotypes most likely contributes to cancer susceptibility, particularly in the Asian populations.     

Overweight in Adolescence Is Related to Increased Risk of Future Urothelial Cancer

Obesity has been linked to various malignancies, but a clear relation of overweight with urothelial cancer has not been established. We assessed the association between adolescent obesity and future risk for urothelial cancer. Medical data on 1,110,835 Israeli adolescents examined for fitness for military duty between 1967 and 2005 were linked to the National Cancer Registry in this nationwide population‐based cohort study. We used Cox proportional hazards modeling to estimate the covariate‐adjusted hazard ratio (HR) for urothelial cancer associated with BMI measured at age 17. The mean follow‐up of 17.6 ± 10.8 years reflected 19,576,635 person years, during which 661 examinees developed urothelial cancer of the bladder, ureter, or renal pelvis. BMI ≥85th standard percentile in adolescence significantly predicted increased risk of urothelial cancer with a HR (adjusted for year of birth, education and religiosity) of 1.42 (95% confidence interval (CI), 1.13–1.77, P = 0.002). Similar results were observed using the ≥25 kg/m² definition of overweight (HR = 1.36 (95% CI, 1.08–1.72), P = 0.008). Incidence of urothelial cancer was significantly lower in the more educated and among those who attended religious schools. Overweight in adolescence is related to increased risk of future urothelial cancer. In view of the growing incidence of both urothelial cancer and adolescent obesity, our study suggests an avenue for possible prevention of urothelial cancer.     

Increased Sensitivity to Chemotherapy Induced by CpG-ODN Treatment Is Mediated by microRNA Modulation

We recently reported that peritumoral CpG-ODN treatment, activating TLR-9 expressing cells in tumor microenvironment, induces modulation of genes involved in DNA repair and sensitizes cancer cells to DNA-damaging cisplatin treatment. Here, we investigated whether this treatment induces modulation of miRNAs in tumor cells and their relevance to chemotherapy response. Array analysis identified 20 differentially expressed miRNAs in human IGROV-1 ovarian tumor cells from CpG-ODN-treated mice versus controls (16 down- and 4 up-regulated). Evaluation of the role of the 3 most differentially expressed miRNAs on sensitivity to cisplatin of IGROV-1 cells revealed significantly increased cisplatin cytotoxicity upon ectopic expression of hsa-miR-302b (up-modulated in our array), but no increased effect upon reduced expression of hsa-miR-424 or hsa-miR-340 (down-modulated in our array). Accordingly, hsa-miR-302b expression was significantly associated with time to relapse or overall survival in two data sets of platinum-treated ovarian cancer patients. Use of bio-informatics tools identified 19 mRNAs potentially targeted by hsa-miR-302b, including HDAC4 gene, which has been reported to mediate cisplatin sensitivity in ovarian cancer. Both HDAC4 mRNA and protein levels were significantly reduced in IGROV-1 cells overexpressing hsa-miR-302b. Altogether, these findings indicate that hsa-miR-302b acts as a “chemosensitizer” in human ovarian carcinoma cells and may represent a biomarker able to predict response to cisplatin treatment. Moreover, the identification of miRNAs that improve sensitivity to chemotherapy provides the experimental underpinning for their possible future clinical use.     

Earlier Menarche Is Associated with Lower Insulin Sensitivity and Increased Adiposity in Young Adult Women

Objective

We aimed to assess whether age at menarche was associated with insulin sensitivity in young adult women.

Methods

We studied 54 healthy young women aged 20–30 years. Participants were grouped according to age at menarche: Early (≤11.0 years; n=13), Average (>12.0 and ≤13.0 years; n=28), and Late (≥14.0 years, n=13). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman’s minimal model. Body composition was assessed using whole-body dual-energy X-ray absorptiometry.

Results

Earlier menarche was associated with lower insulin sensitivity (p=0.015). There was also a continuous increase in adiposity with younger age at menarche, which was associated with increased weight (p=0.001), BMI (p=0.002), total body fat (p=0.049), and truncal fat (p=0.020). Stratified analyses showed that insulin sensitivity in Early women (5.5 x10^-4·min^-1(mU/l)) was lower than in Average (8.0 x10^-4·min^-1(mU/l), p=0.021) and Late (8.6 x10^-4·min^-1(mU/l), p=0.033) groups. Early women (weight=66.1 kg; BMI=24.1 kg/m²) were considerably heavier and fatter than Average (59.0 kg, p=0.004; 21.4 kg/m², p=0.002) and Late (57.0 kg, p=0.001; 20.8 kg/m², p=0.0009) women.

Conclusions

Early menarche is associated with lower insulin sensitivity and increased adiposity in young adulthood, potentially increasing the risk of type 2 diabetes and the metabolic syndrome later in life.     

Outdoor Light at Night (LAN) Is Correlated With Eveningness in Adolescents

External zeitgebers synchronize the human circadian rhythm of sleep and wakefulness. Humans adapt their chronotype to the day-night cycle, the strongest external zeitgeber. The human circadian rhythm shifts to evening-type orientation when daylight is prolonged into the evening and night hours by artificial light sources. Data from a survey of 1507 German adolescents covering questions about chronotype and electronic screen media use combined with nocturnal satellite image data suggest a relationship between chronotype and artificial nocturnal light. Adolescents living in brightly illuminated urban districts had a stronger evening-type orientation than adolescents living in darker and more rural municipalities. This result persisted when controlling for time use of electronic screen media, intake of stimulants, type of school, age, puberty status, time of sunrise, sex, and population density. Time spent on electronic screen media use—a source of indoor light at night—is also correlated with eveningness, as well as intake of stimulants, age, and puberty status, and, to a lesser degree, type of school and time of sunrise. Adequate urban development design and parents limiting adolescents' electronic screen media use in the evening could help to adjust adolescents' zeitgeber to early school schedules when they provide appropriate lighting conditions for daytime and for nighttime. (Author correspondence: vollmer@ph-heidelberg.de)