Publications by authors named "Michael Gill"

365 Publications

CCR2 deficiency alters activation of microglia subsets in traumatic brain injury.

Cell Rep 2021 Sep;36(12):109727

Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco VA Health Care System, San Francisco, CA, USA. Electronic address:

In traumatic brain injury (TBI), a diversity of brain resident and peripherally derived myeloid cells have the potential to worsen damage and/or to assist in healing. We define the heterogeneity of microglia and macrophage phenotypes during TBI in wild-type (WT) mice and Ccr2 mice, which lack macrophage influx following TBI and are resistant to brain damage. We use unbiased single-cell RNA sequencing methods to uncover 25 microglia, monocyte/macrophage, and dendritic cell subsets in acute TBI and normal brains. We find alterations in transcriptional profiles of microglia subsets in Ccr2 TBI mice compared to WT TBI mice indicating that infiltrating monocytes/macrophages influence microglia activation to promote a type I IFN response. Preclinical pharmacological blockade of hCCR2 after injury reduces expression of IFN-responsive gene, Irf7, and improves outcomes. These data extend our understanding of myeloid cell diversity and crosstalk in brain trauma and identify therapeutic targets in myeloid subsets.
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http://dx.doi.org/10.1016/j.celrep.2021.109727DOI Listing
September 2021

A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.

Hum Brain Mapp 2021 Sep 8. Epub 2021 Sep 8.

Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS) [Georgia State University, Georgia Institute of Technology], Emory University, Atlanta, Georgia, USA.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.
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http://dx.doi.org/10.1002/hbm.25625DOI Listing
September 2021

Construct and Criterion-Related Validity of the Clinical Frailty Scale in Persons With HIV.

J Acquir Immune Defic Syndr 2021 Sep;88(1):110-116

Departments of Neurology and Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD; and.

Background: The co-occurrence of frailty and cognitive impairment in older (50+ years) persons with HIV (PWH) is common and increases the risk of poor outcomes. In HIV clinics, the most commonly used frailty measures are the frailty phenotype (FP), which requires measuring grip strength and gait speed to implement, and the frailty index (FI) based on comprehensive health data collected on patients. We examined construct and criterion-related validity (as it predicts cognition) of the Clinical Frailty Scale (CFS), a less resource-intensive approach for assessing frailty, in relation to these more commonly used frailty assessments (FP and FI).

Setting/methods: A total of 143 older (age 50+) PWH (mean age 57 years; 88% male) seen at the Southern Alberta Clinic underwent both frailty screening with the FP, CFS, and FI and neuropsychological testing. Mixed-effects regressions examined the associations between frailty status and cognition.

Results: Concordance with the FP was slightly superior for the CFS than the FI. The FP and CFS had similar associations with domain-specific cognitive performance with frail PWH performing worse than nonfrail individuals on tests requiring manual dexterity (Trail Making Part A and B; Symbol Digit; and Grooved Pegboard; P values <0.05). Neither were associated with executive function, learning, or memory performance. The FI was associated with worse fluency, fine motor skills (Grooved Pegboard), and Trail Making Part A.

Conclusion: The CFS is a simple screening tool with good construct and criterion-related validity. It was associated with a similar pattern of cognitive deficits as the FP. If confirmed and the associations are extended to other clinically significant characteristics and outcomes, the CFS can be considered as an alternative to the FP and FI in assessing frailty in older PWH.
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http://dx.doi.org/10.1097/QAI.0000000000002736DOI Listing
September 2021

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

Copy number aberrations drive kinase rewiring, leading to genetic vulnerabilities in cancer.

Cell Rep 2021 May;35(7):109155

European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Electronic address:

Somatic DNA copy number variations (CNVs) are prevalent in cancer and can drive cancer progression, albeit with often uncharacterized roles in altering cell signaling states. Here, we integrate genomic and proteomic data for 5,598 tumor samples to identify CNVs leading to aberrant signal transduction. The resulting associations recapitulate known kinase-substrate relationships, and further network analysis prioritizes likely causal genes. Of the 303 significant associations we identify from the pan-tumor analysis, 43% are replicated in cancer cell lines, including 44 robust gene-phosphosite associations identified across multiple tumor types. Several predicted regulators of hippo signaling are experimentally validated. Using RNAi, CRISPR, and drug screening data, we find evidence of kinase addiction in cancer cell lines, identifying inhibitors for targeting of kinase-dependent cell lines. We propose copy number status of genes as a useful predictor of differential impact of kinase inhibition, a strategy that may be of use in the future for anticancer therapies.
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http://dx.doi.org/10.1016/j.celrep.2021.109155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149807PMC
May 2021

Real-world comparison of curative open, laparoscopic and robotic resections for sigmoid and rectal cancer-single center experience.

J Robot Surg 2021 Apr 19. Epub 2021 Apr 19.

Department of Surgery, Level 3, Royal Blackburn Hospital, East Lancashire University Hospitals NHS Trust, Blackburn, BB2 3HH, UK.

There has been an increase in the utilization of robotic surgery in addition to traditional open or laparoscopic approaches. Aim of this study is to compare the short-term outcomes for open, laparoscopic, and robotic surgery for rectal and sigmoid cancer. One hundred and forty-seven patients (open n = 48, laparoscopic n = 49, robotic n = 50) undergoing curative resections by two surgeons between 2013 and 2020 were included. Data analyzed included patient demographics, tumor characteristics, length of stay, post-operative outcomes, and pathologic surrogates of oncologic results, including total mesorectal excision (TME) quality, circumferential resection margin (CRM) involvement and lymph node (LN) yield. Median age of population was 68 years (IQR 59-73), majority (68%) were males. Median distance from anal verge in the robotic surgery group was 8 cm, compared to 15 and 14.5 cm in the open and laparoscopic groups, respectively, p = 0.029, (laparoscopic vs robotic, p = 0.005 and open vs robotic, p = 0.027). Proportion of patients who received neoadjuvant radiotherapy in robotic surgery group was higher, p = 0.04. In sub-group of tumors between 3 and 7 cm from anal verge more patients in the robotic surgery group had sphincter preservation, p = 0.006. Length of stay, maximum C-reactive protein, and white blood cell rise favored minimally invasive approaches compared to open surgery. There were no differences in post-operative complications, lymph node yield or CRM positivity rate between the three groups. Robotic surgery approach is safe and allows sphincter preservation without compromising TME quality in rectal cancer surgery.
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http://dx.doi.org/10.1007/s11701-021-01239-yDOI Listing
April 2021

COVID-19 Crisis Reduces Free Tropospheric Ozone Across the Northern Hemisphere.

Geophys Res Lett 2021 Mar 26;48(5):e2020GL091987. Epub 2021 Feb 26.

NOAA ESRL Global Monitoring Laboratory Boulder CO USA.

Throughout spring and summer 2020, ozone stations in the northern extratropics recorded unusually low ozone in the free troposphere. From April to August, and from 1 to 8 kilometers altitude, ozone was on average 7% (≈4 nmol/mol) below the 2000-2020 climatological mean. Such low ozone, over several months, and at so many stations, has not been observed in any previous year since at least 2000. Atmospheric composition analyses from the Copernicus Atmosphere Monitoring Service and simulations from the NASA GMI model indicate that the large 2020 springtime ozone depletion in the Arctic stratosphere contributed less than one-quarter of the observed tropospheric anomaly. The observed anomaly is consistent with recent chemistry-climate model simulations, which assume emissions reductions similar to those caused by the COVID-19 crisis. COVID-19 related emissions reductions appear to be the major cause for the observed reduced free tropospheric ozone in 2020.
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http://dx.doi.org/10.1029/2020GL091987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995013PMC
March 2021

Endorsement of the domains of knee and hip osteoarthritis (OA) flare: A report from the OMERACT 2020 inaugural virtual consensus vote from the flares in OA working group.

Semin Arthritis Rheum 2021 06 20;51(3):618-622. Epub 2021 Mar 20.

Department of Physical Therapy, The University of British Columbia, Arthritis Research Canada, Canada.

Objective: Towards developing an instrument to measure knee and hip osteoarthritis (KHOA) flare, the Outcome Measures in Rheumatology (OMERACT) Flares in OA Working Group first sought to identify and define relevant domains of flare in KHOA.

Methods: Guided by OMERACT Filter 2.1, candidate domains were identified from data generated in interviews, in English or French, with persons with KHOA and health professionals (HPs) who treat OA. The first and second rounds of an online Delphi process with patients and HPs, including researchers, selected relevant domains. The third round provided agreement on the selected domains and their definitions. At the virtual OMERACT 2020 workshop, the proposed domains and their definitions were discussed in facilitated breakout groups with patients and HPs. Participants then voted, with consensus set at ≥70%.

Results: Qualitative interviews characterizing OA flare were completed with 29 persons with KHOA and 16 HPs. Content was analyzed and grouped into nine clusters. These candidate domains were included in two Delphi rounds, completed by 91 patients and 165 HPs then 50 patients and 116 HPs, per round, respectively. This resulted in selecting five relevant domains. A final Delphi round, completed by 38 patients and 89 HPs, provided agreement on these domains and their definitions. The OMERACT virtual vote included 27 patients and 106 HPs. The domains and their definitions were endorsed with ≥98% agreement. Domains include: Pain, Swelling, Stiffness, Psychological aspects, and Impact of symptoms, all defined "during flare".

Conclusion: Using OMERACT methodology, we have developed five domains of KHOA flare that were highly endorsed by patients and HPs.
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http://dx.doi.org/10.1016/j.semarthrit.2021.03.010DOI Listing
June 2021

Exercise and chronic health conditions in the community: A qualitative Study of Patients and Fitness instructors.

Health Soc Care Community 2021 Mar 11. Epub 2021 Mar 11.

School of Medicine, Trinity College Dublin, Dublin, Ireland.

Further information is needed on how community exercise facilities can be effectively utilised to engage people living with chronic health conditions in exercise. The aim of this study was to identify the exercise barriers, facilitators and needs of patients with chronic disease in the community; and to provide recommendations to support the transition from hospital-based to community-based exercise. Using a qualitative approach, four focus groups were conducted with patients who had completed hospital-based exercise programmes (n = 11) and fitness instructors (n = 10). Data were audio recorded, member checked and transcribed verbatim for thematic analysis using NVivo. The side effects of chronic health conditions, the gym environment and a need for support when joining/attending a gym were perceived as barriers to exercising in the community. In contrast, the presence of supportive staff was perceived by patients as a facilitator to engaging in exercise in the community. A total of three themes emerged from participants views on exercise needs in the community; the referral and induction process in community gyms, fitness instructor training and experience and creating a supportive exercise environment. Themes informed eight key recommendations to support patients to exercise in the community, including supportive gym referral and induction processes for patients with chronic conditions, increased professional training for fitness instructors in the area of chronic disease management and exercise prescription, and exercise support at regular intervals for those with chronic conditions attending community gyms. This study found that there is potential for community gyms to play a key role in promoting health among people with chronic conditions. However, more can be done to foster an inclusive atmosphere in this space. Patients living with chronic conditions need information and advice on exercising in their communities. Community gyms require further support to ensure that facilities meet the exercise needs of people with chronic conditions.
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http://dx.doi.org/10.1111/hsc.13288DOI Listing
March 2021

Rare Copy Number Variants Are Associated With Poorer Cognition in Schizophrenia.

Biol Psychiatry 2021 07 19;90(1):28-34. Epub 2020 Dec 19.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. Electronic address:

Background: Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia.

Methods: General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment.

Results: A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = -0.66, 95% confidence interval [CI] = -1.31 to -0.01) and replication samples (β = -0.91, 95% CI = -1.71 to -0.11) and after meta-analysis (β = -0.76, 95% CI = -1.26 to -0.25, p = .003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = -0.15, 95% CI = -0.29 to -0.001, p = .048).

Conclusions: In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5-1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs.
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http://dx.doi.org/10.1016/j.biopsych.2020.11.025DOI Listing
July 2021

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

Elife 2021 Feb 26;10. Epub 2021 Feb 26.

Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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http://dx.doi.org/10.7554/eLife.58430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009672PMC
February 2021

Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity.

J Biol Chem 2021 Jan-Jun;296:100469. Epub 2021 Feb 25.

Gladstone Institute of Neurological Disease, San Francisco, California, USA; Department of Neurology, University of California, San Francisco, San Francisco, California, USA; Graduate Programs in Neuroscience and Biomedical Sciences, University of California, San Francisco, San Francisco, California, USA. Electronic address:

Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer's disease (AD). However, we understand very little about the normal functions of fission or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca (mitoCa) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca. This mitoCa overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.
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http://dx.doi.org/10.1016/j.jbc.2021.100469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042169PMC
August 2021

Those who ignore the past are doomed…to be heartless: Lay historicist theory is associated with humane responses to the struggles and transgressions of others.

PLoS One 2021 19;16(2):e0246882. Epub 2021 Feb 19.

Department of Psychology, Lehigh University, Bethlehem, PA, United States of America.

When one learns that current struggles or transgressions of an individual or group are rooted in an unfortunate history, one experiences compassion and reduced blame. Prior research has demonstrated this by having participants receive (or not) a concrete historicist narrative regarding the particular individual or group under consideration. Here, we take a different approach. We explore the possibility that everyday people show meaningful variation in a broad lay theory that we call lay historicism. Lay historicists believe that-as a general fact-people's psychological characteristics and life outcomes are powerfully molded by their life histories. We present eight studies linking lay historicism to broad tendencies toward compassion and non-blaming. Collectively, Studies 1-5 suggest that lay historicism affects compassion and blame, respectively, via distinct mechanisms: (1) Lay historicism is associated with compassion because it creates a sense that-as a general fact-past suffering lies behind present difficulties, and (2) lay historicism is associated with blame mitigation because historicists reject the idea that-as a general fact-people freely and autonomously create their moral character. Thus, lay historicism increases compassion and decreases blame via distinct mechanisms. The remaining studies diversify our evidence base. Study 6 examines criminal justice philosophies rather than broad moral traits (as in the earlier studies) and shows that lay historicism is associated with preference for humane criminal justice philosophies. Study 7 moves from abstract beliefs to concrete situations and shows that lay historicism predicts reduced blaming of an irresponsible peer who is encountered face-to-face. One additional study-in our Supplemental Materials-shows that lay historicism predicts lower levels of blaming on implicit measures, although only among those who also reject lay controllability theories. Overall, these studies provide consistent support for the possibility that lay historicism is broadly associated with humane responding to the struggles and transgressions of others.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246882PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894831PMC
August 2021

Covid-19: Self-isolation is the weakest link in stopping transmission.

Authors:
Michael Gill

BMJ 2021 02 17;372:n455. Epub 2021 Feb 17.

London NW6 4DG, UK.

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http://dx.doi.org/10.1136/bmj.n455DOI Listing
February 2021

Ensuring effective implementation of the post-2020 global biodiversity targets.

Nat Ecol Evol 2021 04 25;5(4):411-418. Epub 2021 Jan 25.

German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany.

Biodiversity underpins the fundamental elements for human well-being including food security, human health and access to clean water. In 2010, the Aichi Targets were adopted by world leaders to address the crisis of biodiversity loss. Despite conservation efforts, none of the Aichi Targets have been fully met. However, comprehensive analysis of the reasons for failure in terms of implementation mechanisms is, to date, rare and limited in scope. Here, we demonstrate that most parties did not set effective national targets in accordance with the Aichi Targets, and investments, knowledge and accountability for biodiversity conservation have been inadequate to enable effective implementation. We recommend that the new global targets under the post-2020 Global Biodiversity Framework should be adopted by parties as the minimum national targets to achieve the 2050 Vision. We propose that financial resources for biodiversity conservation are substantially increased through a variety of sources, including the deployment of new economic instruments such as payments for ecosystem services. In addition, science-policy interfaces at all levels need to be strengthened to integrate scientific, Indigenous and local knowledge to support decision-making. We suggest that a compliance and accountability mechanism, based on monitoring systems, is created to provide transparent and credible review of parties' implementation of the new global targets.
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http://dx.doi.org/10.1038/s41559-020-01375-yDOI Listing
April 2021

The : Assessing the Propensity to Blame Harshly and Its Unique Capacity to Predict Malicious Satisfaction From Offender Victimization.

Pers Soc Psychol Bull 2021 Jan 10:146167220985362. Epub 2021 Jan 10.

Lehigh University, Bethlehem, PA, USA.

Blame permeates our social lives. When done properly, blame can facilitate the upholding of moral norms. When done with excessive intensity or harshness, however, blame can have significant negative impacts. Here, we develop and validate a scale-the Blame Intensity Inventory-to measure individual differences in the propensity for intense blame responses. First, we present evidence for its convergent and divergent validity by examining relations with existing scales. In addition, in two studies, we show that the Blame Intensity Inventory-rooted in an affective conception of blame-predicts hostile responses to offenders better than do measures focused on blame-related cognitive appraisals (e.g., free will, intentionality). Finally, in three studies, we show that Blame Intensity uniquely predicts malicious satisfaction, or gratification upon learning that an offender has suffered gratuitous harm. Results are discussed in terms of important research questions that could be addressed using the Blame Intensity Inventory.
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http://dx.doi.org/10.1177/0146167220985362DOI Listing
January 2021

Long-term consequences of interpersonal violence experiences on treatment engagement and health status in people living with HIV.

AIDS 2021 04;35(5):801-809

Department of Psychiatry.

Objective: To examine the impact of previous interpersonal violence (IPersV) experiences on long-term healthcare engagement and health outcomes in a large Canadian HIV-cohort.

Design: People living with HIV (PLHIV) were screened for IPersV, and their healthcare outcomes over the nine subsequent years were analyzed.

Methods: A total of 1064 PLHIV were screened for past and present IPersV experiences through semistructured interviews. Follow-up included core treatment engagement (e.g. clinic visits) and health-status variables (HIV viral load, CD4+ T-cell count, mortality, comorbidities), analyzed descriptively and with longitudinal Cox regressions.

Results: At intake, 385 (36%) PLHIV reported past or present IPersV including childhood (n = 224, 21%) or adulthood experiences (n = 161, 15%) and were offered conventional social work support. Over 9 years, individuals with any IPersV experiences were 36% more likely to discontinue care, 81% more likely to experience viremia, 47% more likely to experience a drop in CD4+ cell counts below 200/μl, and 65% more likely to die compared with patients not reporting IPersV (P < 0.05). Outcomes were similar when adjusted for sociodemographic factors. Childhood IPersV in particular was linked to several of the outcomes, with higher rates of discontinuation of care, viremia, and mortality related to mental health/addiction or HIV-related complications.

Conclusion: IPersV is associated with an increased risk over time of healthcare discontinuation, poorer long-term HIV-related health outcomes, and increased mortality, especially for patients victimized in childhood. Apart from targeted IPersV screening to initiate conventional supports (e.g. through social work), increased efforts to engage vulnerable populations in their long-term care seems warranted.
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http://dx.doi.org/10.1097/QAD.0000000000002798DOI Listing
April 2021

No Effect of Coenzyme Q10 on Cognitive Function, Psychological Symptoms, and Health-related Outcomes in Schizophrenia and Schizoaffective Disorder: Results of a Randomized, Placebo-Controlled Trial.

J Clin Psychopharmacol 2021 Jan/Feb 01;41(1):53-57

From the Department of Psychiatry, School of Medicine, Trinity College Dublin.

Background: Cognitive impairments, negative symptoms, affective symptoms, and low energy are highly prevalent features of schizophrenia. Mitochondrial dysfunction has been hypothesized as one of the numerous factors to underlie the manifestation of these symptoms. The objective of this study was to evaluate whether Coenzyme Q10 (CoQ10) has a role in the treatment of schizophrenia and schizoaffective disorder.

Methods: A double-blind, randomized, placebo-controlled trial was conducted to assess the effects of CoQ10 supplementation (300 mg/day) on the co-primary outcomes of attention and working memory performance after 3 and 6 months. Secondary outcomes included plasma CoQ10 levels, mitochondrial function, energy, depression, anxiety, negative symptoms, and quality oflife.

Findings: In total, 72 patients were randomized to intervention groups. Overall, there was no effect of CoQ10 supplementation on the primary outcome measures at 3 or 6 months. Further, with the exception of plasma CoQ10 levels, CoQ10 supplementation also had no effect on the secondary outcomes. At 3 months, CoQ10 concentration was significantly higher in the CoQ10 group (3.85 μg/mL) compared with placebo (1.13 μg/mL); this difference was not present at 6 months.

Conclusions: The results of the study suggest that CoQ10 supplementation at 300 mg/day for 6 months is unlikely to be beneficial for cognitive, psychological and health-related outcomes in schizophrenia and schizoaffective disorder. However, a number of limitations including low adherence, modest sample size, and attrition, likely reduce estimates of effects. As such, results should be considered preliminary.
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http://dx.doi.org/10.1097/JCP.0000000000001330DOI Listing
September 2021

Malocclusion Classification on 3D Cone-Beam CT Craniofacial Images Using Multi-Channel Deep Learning Models

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:1294-1298

Analyzing and interpreting cone-beam computed tomography (CBCT) images is a complicated and often time-consuming process. In this study, we present two different architectures of multi-channel deep learning (DL) models: "Ensemble" and "Synchronized multi-channel", to automatically identify and classify skeletal malocclusions from 3D CBCT craniofacial images. These multi-channel models combine three individual single-channel base models using a voting scheme and a two-step learning process, respectively, to simultaneously extract and learn a visual representation from three different directional views of 2D images generated from a single 3D CBCT image. We also employ a visualization method called "Class-selective Relevance Mapping" (CRM) to explain the learned behavior of our DL models by localizing and highlighting a discriminative area within an input image. Our multi-channel models achieve significantly better performance overall (accuracy exceeding 93%), compared to single-channel DL models that only take one specific directional view of 2D projected image as an input. In addition, CRM visually demonstrates that a DL model based on the sagittal-left view of 2D images outperforms those based on other directional 2D images.Clinical Relevance- the proposed method aims at assisting orthodontist to determine the best treatment path for the patient be it orthodontic or surgical treatment or a combination of both.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176672DOI Listing
July 2020

Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer's disease mutations but not by inhibition of BACE1.

Mol Neurodegener 2020 09 14;15(1):53. Epub 2020 Sep 14.

Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA, 94158, USA.

Background: Alzheimer's disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement.

Methods: To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence.

Results: Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable.

Conclusions: hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.
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http://dx.doi.org/10.1186/s13024-020-00393-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489007PMC
September 2020

Effects of complement gene-set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls.

Am J Med Genet B Neuropsychiatr Genet 2020 12 12;183(8):445-453. Epub 2020 Sep 12.

Cognitive Genetics & Cognitive Therapy Group, The Centre for Neuroimaging, Cognition and Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the "complement" system would be broadly associated with memory function and associated brain structure. We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R change = 0.016, p = .015). However, after correcting for further testing of association with the more general indices of cortical thickness, surface area or total brain volume, none of which were associated with complement, the association with hippocampal volume became non-significant. A post-hoc analysis of hippocampal subfields suggested an association between complement PRS and several hippocampal subfields, findings that appeared to be particularly driven by the patient sample. In conclusion, our study yielded suggestive evidence of association between complement-based schizophrenia PRS and variation in memory function and hippocampal volume.
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http://dx.doi.org/10.1002/ajmg.b.32820DOI Listing
December 2020

Long-term potentiation is independent of the C-tail of the GluA1 AMPA receptor subunit.

Elife 2020 08 24;9. Epub 2020 Aug 24.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.

We tested the proposal that the C-terminal domain (CTD) of the AMPAR subunit GluA1 is required for LTP. We found that a knock-in mouse lacking the CTD of GluA1 expresses normal LTP and spatial memory, assayed by the Morris water maze. Our results support a model in which LTP generates synaptic slots, which capture passively diffusing AMPARs.
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http://dx.doi.org/10.7554/eLife.58042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500950PMC
August 2020

Childhood trauma, parental bonding, and social cognition in patients with schizophrenia and healthy adults.

J Clin Psychol 2021 01 12;77(1):241-253. Epub 2020 Aug 12.

School of Psychology, National University of Ireland Galway, Galway, Ireland.

Objective: This study investigated associations between childhood trauma, parental bonding, and social cognition (i.e., Theory of Mind and emotion recognition) in patients with schizophrenia and healthy adults.

Methods: Using cross-sectional data, we examined the recollections of childhood trauma experiences and social cognitive abilities in 74 patients with schizophrenia and 116 healthy adults.

Results: Patients had significantly higher scores compared with healthy participants on childhood trauma, and lower scores on parental bonding and social cognitive measures. Physical neglect was found to be the strongest predictor of emotion recognition impairments in both groups. Optimal parental bonding attenuated the impact of childhood trauma on emotion recognition.

Conclusion: The present study provides evidence of an association between physical neglect and emotion recognition in patients with schizophrenia and healthy individuals and shows that both childhood trauma and parental bonding may influence social cognitive development. Psychosocial interventions should be developed to prevent and mitigate the long-term effects of childhood adversities.
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http://dx.doi.org/10.1002/jclp.23023DOI Listing
January 2021

Comorbidities in Older Persons with Controlled HIV Infection: Correlations with Frailty Index Subtypes.

AIDS Patient Care STDS 2020 07;34(7):284-294

Department of Neurology and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Frailty is prevalent in persons with human immunodeficiency virus (PWH), but factors predisposing older PWH to frailty remain uncertain. We examined factors associated with frailty and determined whether there were multiple frailty subtypes in older adults with controlled HIV infection. This was a cross-sectional outpatient study in an urban HIV clinic. Twenty-nine clinical indicators were extracted from medical records to compute a Frailty Index (FI) for 389 older (age 50+) PWH (range = 50-93; mean = 61.1, standard deviation = 7.2; 85% men) receiving HIV treatment in Calgary, Canada. We used regressions to identify factors associated with FI values. Latent class analysis was used to identify FI subtypes. Age, employment status, and duration of known HIV infection were the strongest predictors of FI (s < 0.05). Four FI subtypes were identified. Subtype 1 (severe metabolic dysfunction+polypharmacy) had the highest mean FI (0.30). Subtype 2 (less severe metabolic dysfunction+polypharmacy) and Subtype 3 (lung and liver dysfunction+polypharmacy) had lower but equivalent mean FIs (0.20 for each). Subtype 4 (least severe metabolic dysfunction) had the lowest mean FI (0.13; s < 0.001). Sociodemographic and behavioral characteristics differed among the subtypes. Individuals with Subtype 1 were older and more frequently unemployed/retired, whereas those with Subtype 3 were more likely to smoke, use crack/cocaine, have heavy alcohol use, and live in temporary/unstable housing. The clinical presentation of frailty in older PWH is heterogeneous. The metabolic syndrome, hepatitis C virus coinfection, cirrhosis, lung disease, and polypharmacy were associated with frailty as were unemployment/retirement, unstable housing, and substance use.
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http://dx.doi.org/10.1089/apc.2020.0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106245PMC
July 2020

Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19.

Elife 2020 06 19;9. Epub 2020 Jun 19.

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

Previously, we showed that 3% (31/1032)of asymptomatic healthcare workers (HCWs) from a large teaching hospital in Cambridge, UK, tested positive for SARS-CoV-2 in April 2020. About 15% (26/169) HCWs with symptoms of coronavirus disease 2019 (COVID-19) also tested positive for SARS-CoV-2 (Rivett et al., 2020). Here, we show that the proportion of both asymptomatic and symptomatic HCWs testing positive for SARS-CoV-2 rapidly declined to near-zero between 25th April and 24th May 2020, corresponding to a decline in patient admissions with COVID-19 during the ongoing UK 'lockdown'. These data demonstrate how infection prevention and control measures including staff testing may help prevent hospitals from becoming independent 'hubs' of SARS-CoV-2 transmission, and illustrate how, with appropriate precautions, organizations in other sectors may be able to resume on-site work safely.
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http://dx.doi.org/10.7554/eLife.59391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326489PMC
June 2020

Prevalence of N-Methyl-d-Aspartate Receptor antibody (NMDAR-Ab) encephalitis in patients with first episode psychosis and treatment resistant schizophrenia on clozapine, a population based study.

Schizophr Res 2020 08 1;222:455-461. Epub 2020 Jun 1.

Department of Psychiatry, Trinity College Dublin, Ireland; Department of Psychiatry, St James's Hospital, Dublin, Ireland.

Introduction: N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis consensus criteria has recently been defined. We aimed to examine the prevalence of NMDAR-Ab encephalitis in patients with first episode psychosis (FEP) and treatment resistant schizophrenia (TRS) on clozapine, using clinical investigations, antibody testing and to retrospectively apply diagnostic consensus criteria.

Methods: Adult (18-65 years old) cases of FEP meeting inclusion criteria were recruited over three years and assessed using the Structured Clinical Interview for DSM-IV disorders (SCID). NMDAR-Ab was identified using a live cell-based assay (L-CBA). Seropositive cases were clinically investigated for features of encephalitis including neuro-imaging, EEG and CSF where possible. Serum was retested using immunohistochemistry (IHC) as part of diagnostic criteria guidelines. A cohort of patients with TRS was also recruited.

Results: 112 FEP patients were recruited over 3 years. NMDAR-Ab seroprevalence was 4/112 (3.5%) cases. One case (<1%) was diagnosed with definite NMDAR-Ab encephalitis and treated with immunotherapy. One of the three other seropositive cases met criteria for probable encephalitis. However all three were ultimately diagnosed with mood disorders with psychotic features. None have developed neurological features at three year follow up. 1/100 (1%) of patients with TRS was 100 patients with TRS were recruited. One case (1%) seropositive for NMDAR-Ab but did not meet criteria for encephalitis.

Conclusions: NMDAR-Ab encephalitis as defined by consensus guidelines occured rarely in psychiatric services in this study. Further studies are needed to establish pathogenicity of serum NMDAR-Ab antibodies. Psychiatric services should be aware of the clinical features of encephalitis.
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http://dx.doi.org/10.1016/j.schres.2019.11.023DOI Listing
August 2020

Data on Indicators used in Southeast Asian nations' 4th and 5th National Reports to the Convention on Biological Diversity.

Data Brief 2020 Aug 15;31:105705. Epub 2020 May 15.

ASEAN Centre for Biodiversity, Domingo M. Lantican Avenue, Los Baños, Laguna 4031, Philippines.

The data presented in this article are related to the research article entitled "Progress on National Biodiversity Indicator Reporting and Prospects for Filling Indicator Gaps in Southeast Asia " (Han et al., 2020). We examined quantifiable information about biodiversity indicators from the most recent two national reports (i.e., 4th in 2010 and 5th in 2015) to the United Nation's Convention on Biological Diversity (CBD) by the 10-member countries of the Association of Southeast Asian Nations (ASEAN): Brunei Darussalam, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand and Vietnam. This article presents the number of indicators, their level of development, and detailed lists of indicators for each country, and demonstrates general improvement in indicator use by the highest level of government reporting about implementation of the CBD at the national scale.
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http://dx.doi.org/10.1016/j.dib.2020.105705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262426PMC
August 2020

Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy.

Nat Genet 2020 06 1;52(6):582-593. Epub 2020 Jun 1.

Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.
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http://dx.doi.org/10.1038/s41588-020-0630-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353209PMC
June 2020

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

Cell 2020 02 23;180(3):568-584.e23. Epub 2020 Jan 23.

Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
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http://dx.doi.org/10.1016/j.cell.2019.12.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250485PMC
February 2020

Identifying schizophrenia patients who carry pathogenic genetic copy number variants using standard clinical assessment: retrospective cohort study.

Br J Psychiatry 2020 05;216(5):275-279

Professor, Head of Discipline, Neuropsychiatric Genetics Research Group, Department of Psychiatry, School of Medicine, Trinity College Dublin, Ireland.

Background: Copy number variants (CNVs) play a significant role in disease pathogenesis in a small subset of individuals with schizophrenia (~2.5%). Chromosomal microarray testing is a first-tier genetic test for many neurodevelopmental disorders. Similar testing could be useful in schizophrenia.

Aims: To determine whether clinically identifiable phenotypic features could be used to successfully model schizophrenia-associated (SCZ-associated) CNV carrier status in a large schizophrenia cohort.

Method: Logistic regression and receiver operating characteristic (ROC) curves tested the accuracy of readily identifiable phenotypic features in modelling SCZ-associated CNV status in a discovery data-set of 1215 individuals with psychosis. A replication analysis was undertaken in a second psychosis data-set (n = 479).

Results: In the discovery cohort, specific learning disorder (OR = 8.12; 95% CI 1.16-34.88, P = 0.012), developmental delay (OR = 5.19; 95% CI 1.58-14.76, P = 0.003) and comorbid neurodevelopmental disorder (OR = 5.87; 95% CI 1.28-19.69, P = 0.009) were significant independent variables in modelling positive carrier status for a SCZ-associated CNV, with an area under the ROC (AUROC) of 74.2% (95% CI 61.9-86.4%). A model constructed from the discovery cohort including developmental delay and comorbid neurodevelopmental disorder variables resulted in an AUROC of 83% (95% CI 52.0-100.0%) for the replication cohort.

Conclusions: These findings suggest that careful clinical history taking to document specific neurodevelopmental features may be informative in screening for individuals with schizophrenia who are at higher risk of carrying known SCZ-associated CNVs. Identification of genomic disorders in these individuals is likely to have clinical benefits similar to those demonstrated for other neurodevelopmental disorders.
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http://dx.doi.org/10.1192/bjp.2019.262DOI Listing
May 2020
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