Assessment of pre-, peri-, and post-surgical practices for elective colorectal patients in a model 4 hospital in Ireland.

INTRODUCTION: The ERAS protocol is a set of international guidelines established to expedite patients' discharge after colorectal surgery. It does this by aiming to prevent postoperative complications early, and return the patient to normal function allowing earlier discharge. Complications such as PONV, DVT, ileus and pain are common after surgery to name a few, and delay discharge. Early treatment and prevention of these complications however is suggested to aid a patients' return to home at earlier rates than traditional practice. METHODS: A prospective chart review and questionnaire was performed on patients undergoing colorectal surgery in UHL in a 6-month period from February to September 2023. Patients were approached on the 3rd day postoperatively and informed about the project. Exclusion criteria included patients who went to HDU or ICU postoperatively. RESULTS: In total, 33 patients were recruited. A target of greater than 70% compliance was reached for a variety of the elements of the ERAS protocol such as laparoscopic surgery, preoperative assessments, nutritional drinks, LMWH, oral intake within 24 h of surgery, and intraoperative antiemetics. Unsatisfactory compliance was found with documentation of postoperative antibiotics use of preoperative gabapentin. CONCLUSION: UHL has a satisfactory compliance of over 70% with a large variety of elements of the ERAS protocol. Areas of improvement required include postoperative antibiotic and preoperative gabapentin usage. With the collective effort of the multidisciplinary team, along with education, the ERAS protocol can successfully be applied and implemented in a model 4 hospital in Ireland.

Artificial intelligence in digital histopathology for predicting patient prognosis and treatment efficacy in breast cancer.

INTRODUCTION: Histological images contain phenotypic information predictive of patient outcomes. Due to the heavy workload of pathologists, the time-consuming nature of quantitatively assessing histological features, and human eye limitations to recognize spatial patterns, manually extracting prognostic information in routine pathological workflows remains challenging. Digital pathology has facilitated the mining and quantification of these features utilizing whole-slide image (WSI) scanners and artificial intelligence (AI) algorithms. AI algorithms to identify image-based biomarkers from the tumor microenvironment (TME) have the potential to revolutionize the field of oncology, reducing delays between diagnosis and prognosis determination, allowing for rapid stratification of patients and prescription of optimal treatment regimes, thereby improving patient outcomes. AREAS COVERED: In this review, the authors discuss how AI algorithms and digital pathology can predict breast cancer patient prognosis and treatment outcomes using image-based biomarkers, along with the challenges of adopting this technology in clinical settings. EXPERT OPINION: The integration of AI and digital pathology presents significant potential for analyzing the TME and its diagnostic, prognostic, and predictive value in breast cancer patients. Widespread clinical adoption of AI faces ethical, regulatory, and technical challenges, although prospective trials may offer reassurance and promote uptake, ultimately improving patient outcomes by reducing diagnosis-to-prognosis delivery delays.

Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer.

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter: A randomised placebo-controlled single-dose crossover trial.

BACKGROUND: Alterations in the serotonergic control of brain pathways responsible for facial emotion processing in people with autism spectrum disorder (ASD) may be a target for intervention. However, the molecular underpinnings of autistic-neurotypical serotonergic differences are challenging to access in vivo. Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) has helped define molecular-enriched functional magnetic resonance imaging (fMRI) brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates. METHODS: We used REACT to estimate the dominant fMRI signal related to the serotonin (5-HT) transporter (SERT) distribution during processing of aversive facial emotion in adults with and without ASD. We first predicted a group difference in baseline (placebo) functioning of this system. We next used a single 20 mg oral dose of citalopram, a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of SERT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A and 5-HT4 receptor maps. RESULTS: Using REACT with the SERT map, we found a baseline group difference in the SERT-enriched response to faces in the ventromedial prefrontal cortex. A single oral dose of citalopram 'shifted' the response in the ASD group towards the neurotypical baseline but did not alter response in the control group. Similar differences in SERT-enriched response were observed after controlling for other 5-HT maps. CONCLUSIONS: Our findings suggest that the SERT-enriched functional network is dynamically different in ASD during processing of socially relevant stimuli. Whether this acute neurobiological response to citalopram in ASD translates to a clinical target will be an important next step.

Colorectal microbiota after removal of colorectal cancer.

The colonic microbiome has been implicated in the pathogenesis of colorectal cancer (CRC) and intestinal microbiome alterations are not confined to the tumour. Since data on whether the microbiome normalises or remains altered after resection of CRC are conflicting, we studied the colonic microbiota of patients after resection of CRC. We profiled the microbiota using 16S rRNA gene amplicon sequencing in colonic biopsies from patients after resection of CRC (n = 63) in comparison with controls (n = 52), subjects with newly diagnosed CRC (n = 93) and polyps (i = 28). The colonic microbiota after surgical resection remained significantly different from that of controls in 65% of patients. Genus-level profiling and beta-diversity confirmed two distinct groups of patients after resection of CRC: one with an abnormal microbiota similar to that of patients with newly diagnosed CRC and another similar to non-CRC controls. Consumption levels of several dietary ingredients and cardiovascular drugs co-varied with differences in microbiota composition suggesting lifestyle factors may modulate differential microbiome trajectories after surgical resection. This study supports investigation of the colonic microbiota as a marker of risk for development of CRC.

Adults with autism spectrum disorder and the criminal justice system: An investigation of prevalence of contact with the criminal justice system, risk factors and sex differences in a specialist assessment service.

LAY ABSTRACT: There has been growing interest in offending and contact with the criminal justice system (CJS) by people with autism spectrum disorder (ASD). However, it is not clear whether people with ASD offend more than those without ASD. Studies have started to look at whether there are particular offences people with ASD are more likely to commit and whether there are any factors that can affect whether someone comes into contact with the CJS as a potential suspect. This study looked at the patients who attended an ASD diagnostic service over a 17-year period to see the rate of contact with the CJS of those who were diagnosed with ASD and whether there were any particular factors that might increase the risk of CJS contact. Nearly a quarter of the ASD group had some contact with the CJS as a potential suspect. Factors that seemed to increase whether someone with ASD was more likely to have contact with the CJS were being male, being diagnosed with ADHD, and being diagnosed with psychosis. This study is one of the largest studies to investigate the rate of CJS contact as a potential suspect in a sample of adults with ASD in an attempt to give a clearer picture of what might influence someone with ASD to engage in offending behaviour in order to try to see what mental health services can offer to reduce the likelihood of someone with ASD coming into contact with the CJS, for example, treatment for another condition or support.

Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine.

BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD. METHOD: We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls. RESULTS: Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices. LIMITATIONS: We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome. CONCLUSIONS: Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms.

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.

Neural Correlates of Theory of Mind in Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, and the Comorbid Condition.

Theory of mind (ToM) or mentalizing difficulties is reported in attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), but the mechanism underpinning these apparently shared deficits is relatively unknown. Eighty-three young adult males, 19 with ASD alone, 21 with ADHD alone, 18 with dual diagnosis of ASD and ADHD, and 25 typically developing (TD) controls completed the functional magnetic resonance imaging version of the Frith-Happé animated-triangle ToM task. We compared neural function during ToM with two non-ToM conditions, random and goal directed motions, using whole-brain and region-of-interest analysis of brain activation and functional connectivity analyses. The groups showed comparable ToM task performance. All three clinical groups lacked local connectivity increase shown by TD controls during ToM in the right temporoparietal cortex, a key mentalizing region, with a differentially increased activation pattern in both ASD and comorbid groups relative to ADHD. Both ASD groups also showed reduced connectivity between right inferior lateral prefrontal and posterior cingulate cortices that could reflect an atypical information transmission to the mentalizing network. In contrast, with mentalizing both ADHD groups showed decreasing connectivity between the medial prefrontal and left temporoparietal cortices when compared to TD controls. Therefore, despite the complex pattern of atypical brain function underpinning ToM across the three disorders, some neurofunctional abnormalities during ToM are associated with ASD and appeared differentiable from those associated with ADHD, with the comorbid group displaying combined abnormalities found in each condition.

Neuroanatomical underpinnings of autism symptomatology in carriers and non-carriers of the 22q11.2 microdeletion.

BACKGROUND: A crucial step to understanding the mechanistic underpinnings of autism spectrum disorder (ASD), is to examine if the biological underpinnings of ASD in genetic high-risk conditions, like 22q11.2 deletion syndrome (22q11.2DS), are similar to those in idiopathic illness. This study aimed to examine if ASD symptomatology in 22q11.2DS is underpinned by the same-or distinct-neural systems that mediate these symptoms in non-deletion carriers. METHODS: We examined vertex-wise estimates of cortical volume (CV), surface area (SA), and cortical thickness across 131 individuals between 6 and 25 years of age including (1) 50 individuals with 22q11.2DS, out of which n = 25 had a diagnosis of ASD, (2) 40 non-carriers of the microdeletion with a diagnosis of ASD (i.e., idiopathic ASD), and (3) 41 typically developing (TD) controls. We employed a 2-by-2 factorial design to identify neuroanatomical variability associated with the main effects of 22q11.2DS and ASD, as well as their interaction. Further, using canonical correlation analysis (CCA), we compared neuroanatomical variability associated with the complex (i.e., multivariate) clinical phenotype of ASD between 22q11.2 deletion carriers and non-carriers. RESULTS: The set of brain regions associated with the main effect of 22q11.2DS was distinct from the neuroanatomical underpinnings of the main effect of ASD. Moreover, significant 22q11.2DS-by-ASD interactions were observed for CV and SA in the dorsolateral prefrontal cortex, precentral gyrus, and posterior cingulate cortex, suggesting that the neuroanatomy of ASD is significantly modulated by 22q11.2DS (p < 0.01). We further established that the multivariate patterns of neuroanatomical variability associated with differences in symptom profiles significantly differed between 22q11.2 deletion carriers and non-carriers. LIMITATIONS: We employed a multicenter design to overcome single-site recruitment limitations; however, FreeSurfer-derived measures of surface anatomy have been shown to be highly reliable across scanner platforms and field strengths. Further, we controlled for gender to address the differing distribution between idiopathic ASD individuals and the other groups. Nonetheless, the gender distribution in our sample reflects that of the respective populations, adding to the generalizability of our results. Last, we included individuals with a relatively wide age range (i.e., 6-25 years). CONCLUSIONS: Our findings indicate that neuroanatomical correlates of ASD symptomatology in carriers of the 22q11.2 microdeletion diverge from those in idiopathic ASD.

Serotonin differentially modulates the temporal dynamics of the limbic response to facial emotions in male adults with and without autism spectrum disorder (ASD): a randomised placebo-controlled single-dose crossover trial.

Emotion processing-including signals from facial expressions-is often altered in individuals with autism spectrum disorder (ASD). The biological basis of this is poorly understood but may include neurochemically mediated differences in the responsivity of key 'limbic' regions (including amygdala, ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAc)). Emerging evidence also suggests that ASD may be a disorder of brain temporal dynamics. Moreover, serotonin (5-HT) has been shown to be a key regulator of both facial-emotion processing and brain dynamics, and 5-HT abnormalities have been consistently implicated in ASD. To date, however, no one has examined how 5-HT influences the dynamics of facial-emotion processing in ASD. Therefore, we compared the influence of 5-HT on the responsivity of brain dynamics during facial-emotion processing in individuals with and without ASD. Participants completed a facial-emotion processing fMRI task at least 8 days apart using a randomised double-blind crossover design. At each visit they received either a single 20-mg oral dose of the selective serotonin reuptake inhibitor (SSRI) citalopram or placebo. We found that citalopram (which increases levels of 5-HT) caused sustained activation in key limbic regions during processing of negative facial emotions in adults with ASD-but not in neurotypical adults. The neurotypical adults' limbic response reverted more rapidly to baseline following a 5-HT-challenge. Our results suggest that serotonergic homoeostatic control of the temporal dynamics in limbic regions is altered in adults with ASD, and provide a fresh perspective on the biology of ASD.

Patterns of Cortical Folding Associated with Autistic Symptoms in Carriers and Noncarriers of the 22q11.2 Microdeletion.

22q11.2 deletion syndrome (22q11.2DS) is a genetic condition accompanied by a range of psychiatric manifestations, including autism spectrum disorder (ASD). It remains unknown, however, whether these symptoms are mediated by the same or distinct neural mechanisms as in idiopathic ASD. Here, we examined differences in lGI associated with ASD in 50 individuals with 22q11.2DS (n = 25 with ASD, n = 25 without ASD) and 81 individuals without 22q11.2DS (n = 40 with ASD, n = 41 typically developing controls). We initially utilized a factorial design to identify the set of brain regions where lGI is associated with the main effect of 22q11.2DS, ASD, and with the 22q11.2DS-by-ASD interaction term. Subsequently, we employed canonical correlation analysis (CCA) to compare the multivariate association between variability in lGI and the complex clinical phenotype of ASD between 22q11.2DS carriers and noncarriers. Across approaches, we established that even though there is a high degree of clinical similarity across groups, the associated patterns of lGI significantly differed between carriers and noncarriers of the 22q11.2 microdeletion. Our results suggest that ASD symptomatology recruits different neuroanatomical underpinnings across disorders and that 22q11.2DS individuals with ASD represent a neuroanatomically distinct subgroup that differs from 22q11.2DS individuals without ASD and from individuals with idiopathic ASD.

Age-related differences in white matter diffusion measures in autism spectrum condition.

BACKGROUND: Autism spectrum condition (ASC) is accompanied by developmental differences in brain anatomy and connectivity. White matter differences in ASC have been widely studied with diffusion imaging but results are heterogeneous and vary across the age range of study participants and varying methodological approaches. To characterize the neurodevelopmental trajectory of white matter maturation, it is necessary to examine a broad age range of individuals on the autism spectrum and typically developing controls, and investigate age × group interactions. METHODS: Here, we employed a spatially unbiased tract-based spatial statistics (TBSS) approach to examine age-related differences in white matter connectivity in a sample of 41 individuals with ASC, and 41 matched controls between 7-17 years of age. RESULTS: We found significant age-related differences between the ASC and control group in widespread brain regions. This included age-related differences in the uncinate fasciculus, corticospinal tract, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior longitudinal fasciculus and forceps major. Measures of fractional anisotropy (FA) were significantly positively associated with age in both groups. However, this relationship was significantly stronger in the ASC group relative to controls. Measures of radial diffusivity (RD) were significantly negatively associated with age in both groups, but this relationship was significantly stronger in the ASC group relative to controls. LIMITATIONS: The generalisability of our findings is limited by the restriction of the sample to right-handed males with an IQ > 70. Furthermore, a longitudinal design would be required to fully investigate maturational processes across this age group. CONCLUSIONS: Taken together, our findings suggest that autistic males have an altered trajectory of white matter maturation relative to controls. Future longitudinal analyses are required to further characterize the extent and time course of these differences.

Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and autism spectrum disorder based upon expert consensus.

BACKGROUND: Individuals with co-occurring hyperactivity disorder/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) can have complex presentations that may complicate diagnosis and treatment. There are established guidelines with regard to the identification and treatment of ADHD and ASD as independent conditions. However, ADHD and ASD were not formally recognised diagnostically as co-occurring conditions until the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) was published in 2013. Hence, awareness and understanding of both conditions when they co-occur is less established and there is little guidance in the clinical literature. This has led to uncertainty among healthcare practitioners when working with children, young people and adults who present with co-existing ADHD and ASD. The United Kingdom ADHD Partnership (UKAP) therefore convened a meeting of professional experts that aimed to address this gap and reach expert consensus on the topic that will aid healthcare practitioners and allied professionals when working with this complex and vulnerable population. METHOD: UK experts from multiple disciplines in the fields of ADHD and ASD convened in London in December 2017. The meeting provided the opportunity to address the complexities of ADHD and ASD as a co-occurring presentation from different perspectives and included presentations, discussion and group work. The authors considered the clinical challenges of working with this complex group of individuals, producing a consensus for a unified approach when working with male and female, children, adolescents and adults with co-occurring ADHD and ASD. This was written up, circulated and endorsed by all authors. RESULTS: The authors reached a consensus of practical recommendations for working across the lifespan with males and females with ADHD and ASD. Consensus was reached on topics of (1) identification and assessment using rating scales, clinical diagnostic interviews and objective supporting assessments; outcomes of assessment, including standards of clinical reporting; (2) non-pharmacological interventions and care management, including psychoeducation, carer interventions/carer training, behavioural/environmental and Cognitive Behavioural Therapy (CBT) approaches; and multi-agency liaison, including educational interventions, career advice, occupational skills and training, and (3) pharmacological treatments. CONCLUSIONS: The guidance and practice recommendations (Tables 1, 4, 5, 7, 8 and 10) will support healthcare practitioners and allied professionals to meet the needs of this complex group from a multidisciplinary perspective. Further research is needed to enhance our understanding of the diagnosis, treatment and management of individuals presenting with comorbid ADHD and ASD.

Defining gastrointestinal transit time using video capsule endoscopy: a study of healthy subjects.

Background and study aims Determining the etiology and location of gastrointestinal motility disorders can be challenging. A range of investigations targeting specific areas of gastrointestinal transit are available, but many provide clinical data for a given gastrointestinal region alone or for non-specific whole gut transit, and are otherwise of limited use. Video capsule endoscopy allows endoscopic visualisation of the entire gastrointestinal tract, and may also provide more specific data for regional transit time abnormalities. Patients and methods Data from video capsules ingested by 71 ambulatory healthy subjects were recorded and analyzed to determine gastric and small bowel transit times in the fasting state. Results Median, and interquartile range (IQR), gastric transit time was 22 (10-48) minutes, and median (IQR) small bowel transit time was 198.5 (157-240.5) minutes. Conclusion These data, for the first time to our knowledge, provide references for gastrointestinal transit times among healthy ambulatory subjects using video capsule endoscopy. This potentially strengthens clinical use of video capsule endoscopy in the investigation of patients with suspected gastrointestinal motility disorders.

Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome: Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness.

OBJECTIVE: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group. METHODS: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female). RESULTS: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. CONCLUSIONS: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study.

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.