The most common human microdeletion occurs at chromosome 22q11.2. The associated syndrome (22q11.2DS) has a complex and variable phenotype with a high risk of schizophrenia. While the role of stress in the etiopathology of schizophrenia has been under investigation for over 30 years (Walker et al. 2008), the stress-diathesis model has yet to be investigated in children with 22q11.2DS. Children with 22q11.2DS face serious medical, behavioral, and socioemotional challenges from infancy into adulthood. Chronic stress elevates glucocorticoids, decreases immunocompetence, negatively impacts brain development and function, and is associated with psychiatric illness in adulthood. Drawing knowledge from the extant and well-developed anxiety and stress literature will provide invaluable insight into the complex etiopathology of schizophrenia in people with 22q11.2DS while suggesting possible early interventions. Childhood anxiety is treatable and stress coping skills can be developed thereby improving quality of life in the short-term and potentially mitigating the risk of developing psychosis.

An open question in the developmental causal learning literature concerns how children's beliefs about causal systems impact their inferences. This study investigated how 4- and 5-year-olds' causal beliefs related to their “backwards blocking” abilities, as well as whether associative learning or Bayesian inference better explained their judgements. Children were taught either that two causes together produced a larger effect than that produced by each individually or that they produced the same size effect as that produced by either one. A third group received no training. Results indicated that 4-year-olds engaged in backwards blocking only after additivity training and that their inferences mainly matched an associative model. In contrast, 5-year-olds consistently engaged in backwards blocking and produced responses that largely matched a Bayesian model. These findings suggest that the effect of children's beliefs about causal systems on their inferences undergoes a developmental progression and implicate the role of multiple cognitive mechanisms.

Abstract Background Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) occurs in approximately 1:4,000 live births with a complex and variable presentation that includes medical, socioemotional and psychological symptoms with intellectual impairment. Cognitive impairments in spatiotemporal and visuospatial attention have also been reported. However, maintenance of selective attention to dynamic and interacting objects has not been systematically investigated in children with 22q11.2DS. Methods We used a multiple object tracking task to assay capacity and resolution performance of children with 22q11.2DS aged 7 to 14 years versus age-matched typically developing (TD) peers. Results Children with 22q11.2DS but not TD children demonstrated impaired performance when task demands increased due to an increase in the number of targets presented, but not from an increase in object speed. Task performance in children with 22q11.2DS was also unrelated to intelligence or measures of attention deficit hyperactivity disorder. Conclusions These findings suggest that children with 22q11.2DS may be particularly susceptible to dynamic crowding of objects with increasing cognitive demands related to monitoring multiple targets reflecting a reduced acuity in spatiotemporal cognitive representation.

Background

Chromosome 22q11.2 deletion syndrome (22q11.2DS), fragile X syndrome (FXS), and Turner syndrome (TS) are complex and variable developmental syndromes caused by different genetic abnormalities; yet, they share similar cognitive impairments in the domains of numbers, space, and time. The atypical development of foundational neural networks that underpin the attentional system is thought to result in further impairments in higher-order cognitive functions. The current study investigates whether children with similar higher-order cognitive impairments but different genetic disorders also show similar impairments in alerting, orienting, and executive control of attention.

Methods

Girls with 22q11.2DS, FXS, or TS and typically developing (TD) girls, aged 7 to 15 years, completed an attention network test, a flanker task with alerting and orienting cues. Exploration of reaction times and accuracy allowed us to test for potential commonalities in attentional functioning in alerting, orienting, and executive control. Linear regression models were used to test whether the predictors of group and chronological age were able to predict differences in attention indices.

Results

Girls with 22q11.2DS, FXS, or TS demonstrated unimpaired function of the alerting system and impaired function of the executive control system. Diagnosis-specific impairments were found such that girls with FXS made more errors and had a reduced orienting index, while girls with 22q11.2DS showed specific age-related deficits in the executive control system.

Conclusions

These results suggest that the control but not the implementation of attention is selectively impaired in girls with 22q11.2DS, TS or FXS. Additionally, the age effect on executive control in girls with 22q11.2DS implies a possible altered developmental trajectory.

Children with chromosome 22q11.2 deletion syndrome (22q11.2DS), Fragile X syndrome (FXS), or Turner syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders.

Background

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a complex genetic disorder with a variable clinical presentation that can include cardiac, neural, immunological, and psychological issues. Previous studies have measured elevated anxiety and depression in children with 22q11.2DS. Comorbity of anxiety and depression is well established in the pediatric literature but the nature of comorbidity patterns has not been empirically established in children with 22q11.2DS. Comorbidity of anxiety and depression has important implications for treatment and prognosis, and may be a marker of risk in this population of children at high-risk for developing schizophrenia.

Method

Participants were 131 boys and girls ages 8-14 with (n=76) and without (n=55) 22q11.2DS and their mothers. Children and mothers independently completed self- and parent-report measures of anxiety and depression. Mothers also completed measures of behavioral functioning including the Behavioral Assessment for Children, 2nd ed. (BASC-2). Cluster analyses were conducted to test if theoretically based groupings of anxiety and depression could be identified. We hypothesized four psychological profiles based on child- and mother-reports: low/no anxiety and low/no depression, higher depression and low/no anxiety, higher anxiety and no/low depression, and a comorbid profile of higher anxiety and higher depression. BASC-2 subscale scores were then compared across subgroups of children to determine if a comorbid profile would predict greater behavioral difficulties.

Results

In the full sample of children both with and without 22q11.2DS, cluster analyses of self and maternal reported anxiety and depression revealed the expected subgroups: (1) a group of children with higher anxiety/lower depression (anxious); (2) a group with primary depression (lower anxiety/higher depression (depressed)); (3) a comorbid group with higher anxiety/higher depression (comorbid); and, (4) a lowest anxiety/lowest depression group (NP). Mothers' reports produced highly similar groupings. Furthermore, the 22q11.2DS youth were more likely to be in anxiety, depressed or comorbid clusters than the typically developing (TD) youth. Children with 22q11.2DS comorbid for anxiety and depression exhibited the worst functional outcomes (e.g., poor poorer functional communication, and reduced daily life activities).

Conclusions

Anxiety, comorbid with depression may be of particular concern in children with 22q11.2DS who arguably carry a greater burden on their stress coping resources than children without a complex genetic disorder. Furthermore, the manifestation of negative mood, anxiety and difficult behavior is likely to reverberate between the child and her or his environment. This can lead to negative interactions with family, peers, and teachers, which in turn further taxes coping resources. Comorbidity of anxiety and depression within a vulnerable population highlights the need for the development of tailored interventions.

Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation.

Objective

Pain resulting from local tissue injury or inflammation typically resolves with time. Frequently, however, this pain may unexpectedly persist, becoming a pathological chronic state. Increasingly, the innate and adaptive immune systems are being implicated in the initiation and maintenance of these persistent conditions. In particular, Toll-like receptor 4 (TLR4) signaling has been shown to mediate the transition to a persistent pain state in a sex-dependent manner. In the present work, we explored this contribution using the TLR4 antagonist, TAK-242.

Methods

Male and female C57Bl/6 mice were given intravenous (IV), intrathecal (IT), or intraperitoneal (IP) TAK-242 prior to IT delivery of lipopolysaccharide (LPS), and tactile reactivity was assessed at regular intervals over 72-h. Additional groups of mice were treated with IP TAK-242 prior to intraplantar formalin, and flinching was monitored for 1-h. Tactile reactivity was assessed at 7-days after formalin delivery.

Results

LPS evoked TNF release from male and female macrophages and RAW267.4 cells, which was blocked in a concentration dependent fashion by TAK-242. In vivo, IT LPS evoked tactile allodynia to a greater degree in male than female mice. TAK-242, given by all routes, prevented development of IT LPS-induced tactile allodynia in male animals, but did not reverse their established allodynia. TLR4 deficiency and TAK-242 treatment attenuated IT LPS-induced allodynia in male, but not female mice. In the formalin model, pre-treatment with TAK-242 did not affect Phase 1 or Phase 2 flinching, but prevented the delayed tactile allodynia in both male and unexpectedly in female mice (Phase 3).

Conclusions

Together, these results suggest that TAK-242 is a TLR4 antagonist that has efficacy after systemic and intrathecal delivery and confirms the role of endogenous TLR4 signaling in triggering the development of a delayed allodynia in both male and female mice.

Background

The evaluation of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive test (CAT) in adults with systemic lupus erythematous (SLE) is an emerging field of research. We aimed to examine the test-retest reliability and construct validity of the PROMIS CAT in a Canadian cohort of patients with SLE.

Methods

Two hundred twenty-seven patients completed 14 domains of PROMIS CAT and seven legacy instruments during their clinical visits. Test-retest reliability of PROMIS was evaluated 7-10 days from baseline using intraclass correlation coefficient (ICC (2; 1)). The construct validity of the PROMIS CAT domains was evaluated against the commonly used legacy instruments, and also in comparison to disease activity and disease damage using Spearman correlations. A multitrait-multimethod matrix (MMM) approach was used to further assess construct validity comparing selected 10 domains of PROMIS and SF-36 domains.

Results

Moderate to excellent reliability was found for all domains (ICC [2;1] ranging from lowest, 0.66 for Sleep Disturbance and highest, 0.93 for the Mobility domain). Comparing seven legacy instruments with 14 domains of PROMIS CAT, moderate to strong correlations (0.51-0.91) were identified. The average time to complete all PROMIS CAT domains was 11.7 min. The MMM further established construct validity by showing moderate to strong correlations (0.55-0.87) between select PROMIS and SF-36 domains; the average correlations from similar traits (convergent validity) were significantly greater than the average correlations from different traits.

Conclusions

These results provide evidence on the reliability and validity of PROMIS CAT in SLE in a Canadian cohort.

Plasma photocathode wakefield acceleration combines energy gains of tens of GeV m^-1 with generation of ultralow emittance electron bunches, and opens a path towards 5D-brightness orders of magnitude larger than state-of-the-art. This holds great promise for compact accelerator building blocks and advanced light sources. However, an intrinsic by-product of the enormous electric field gradients inherent to plasma accelerators is substantial correlated energy spread-an obstacle for key applications such as free-electron-lasers. Here we show that by releasing an additional tailored escort electron beam at a later phase of the acceleration, when the witness bunch is relativistically stable, the plasma wave can be locally overloaded without compromising the witness bunch normalized emittance. This reverses the effective accelerating gradient, and counter-rotates the accumulated negative longitudinal phase space chirp of the witness bunch. Thereby, the energy spread is reduced by an order of magnitude, thus enabling the production of ultrahigh 6D-brightness beams.