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Expanding the phenotypic spectrum associated with ZIC1 variants: a neurodevelopmental disorder with and without craniosynostosis
No full textPurpose: ZIC1 encodes a transcription factor with critical roles in vertebrate neural and skeletal development. Heterozygous deletions encompassing ZIC1 and ZIC4 cause Dandy-Walker malformation, whilst in the final exon heterozygous ZIC1 variants result in a distinct phenotype of craniosynostosis with variable intellectual disability via a gain-of-function mechanism. We describe the largest group of individuals harboring ZIC1 variants to date, significantly expanding the phenotypic spectrum and allowing genotype-phenotype correlation.
Methods: Through international collaboration we identified 18 different heterozygous ZIC1 variants from 22 families, comprising 30 individuals.
Results: Twelve families segregated a phenotype comprising craniosynostosis with facial dysmorphism, structural brain abnormalities and developmental delay, while 10 families had a neurodevelopmental disorder alone without craniosynostosis. Variants associated with craniosynostosis were clustered in the final exon (3) and were predominantly truncating variants predicted to escape nonsense-mediated decay. Variants associated with neurodevelopmental disorder alone included missense substitutions within exons 1 and 2 predicted to disrupt the normal function of the zinc finger domain, leading to loss of ZIC1 function which was confirmed in a functional assay.
Conclusion: This study presents evidence for a ZIC1 genotype-phenotype correlation differentiating variants that cause a neurodevelopmental phenotype with and without craniosynostosis
Associations between autism and self-reported dimensions of interoception
Get PDFDespite a wealth of research on autism and interoception, there is not a clear consensus about which dimensions of interoception (if any) are related to autism. This study explored whether self-reported interoceptive accuracy, attention and evaluation are related to autism diagnosis and autistic traits. We analysed questionnaire responses from 519 participants, including 232 autistic participants. We found that people with an autism diagnosis had more negative interpretations of their bodily signals than people without an autism diagnosis, and increasing autistic traits in a general population sample were associated with higher interoceptive attention, lower interoceptive accuracy, and higher negative interoceptive evaluation. Our findings suggest that interoceptive evaluation should be a priority for future research
Less is more revisited: association with global protocols and multiparty sessions
No full textEnsuring correctness of communication in distributed systems remains challenging. To address this, Multi- party session types (MPST), initially introduced by Honda et al. [52, 53], offer a type discipline in which a programmer or architect specifies an overall view of communication as a global protocol (global type), and each distributed program is locally type-checked against its end-point projection. In practice, the MPST framework has been integrated into over 25 programming languages or tools. Ten years after the emergence of MPST, Scalas and Yoshida [84] discovered that existing proofs of type safety using end-point projection with mergeability are flawed, where the mergeability operator enlarges the typability of MPST end-point programs, admits easy implementation, and is more efficient than alternative approaches, including model checking. Nevertheless, following the result in [84], the soundness of end-point projection (with mergeability) has been interpreted in the literature as problematic. We clarify this concern by proposing a new general proof technique for type soundness (subject reduction) of multiparty session π-calculus, which relies on an association relation between the behavioural semantics of a global type and its end-point projection. With this approach, behavioural properties, namely session fidelity, deadlock freedom, and liveness, are also guar- anteed based on global types. Additionally, we provide detailed comparisons with existing MPST typing systems and discuss their respective proof methods for type soundness
Resilience in late fifth-century Aphrodisias: an archaeological perspective from the Tetrapylon Street
No full textSeverity of intracranial arterial calcification on computed tomography and risk of dementia in patients with stroke or transient ischaemic attack: a population-based study
Get PDFBackground: Coronary arterial calcification is a widely studied risk factor for acute coronary events, but although intracranial arterial calcification on computed tomography brain imaging (CT-IAC) is also a frequent finding, particularly in older individuals, few longitudinal studies have assessed whether its severity or site predict cognitive impairment and dementia. Given the potential clinical and mechanistic importance of any such associations, we did a population-based study in patients with transient ischaemic attack (TIA) or stroke.Methods: In a matched case-control study of patients with minor stroke or TIA nested in the population-based Oxford Vascular Study (OXVASC) cohort, the severity (qualitatively and semi-automated volume) and location (intimal or internal elastic lamina) of CT-IAC in cases who developed dementia on follow-up was compared with that in age/sex-matched controls who did not (logistic regression adjusted for other risk factors).Results: In OXVASC (cases/controls=200/200; mean age/standard deviation=78.0/9.3), dementia was independently associated with severity of internal carotid artery (ICA) CT-IAC on the visual scale (bilateral severe calcification – adjusted OR [aOR]=2.02, 1.26-3.23, p=0.004) and as quantitative volume (top vs. bottom tertile – aOR=2.35, 1.33-4.16, p=0.003), driven mainly by the small number of individuals with very high calcification volumes (≥600 mm^3 vs. 0-299 mm^3 – aOR=6.23, 1.24-31.24, p=0.026). Similar trends were observed for CT-IAC in the ICA and vertebrobasilar artery combined (top vs. bottom tertile – aOR=2.59, 1.43-4.68, p=0.002), including after exclusion of recurrent stroke (aOR=2.60, 1.33-5.08, p=0.005) and of patients with moderate/severe white matter disease (aOR=3.19, 1.54-6.62, p=0.002). ICA CT-IAC of the internal elastic lamina subtype independently predicted dementia after adjusting for qualitative (aOR=1.84, 1.11-3.05, p=0.019) or quantitative (aOR=1.78, 1.06-2.99, p=0.029) CT-IAC severity.Conclusion: Severity of CT-IAC is an independent predictor of future dementia after stroke/TIA. The extent of any non-linearity of the association and any calcification- or dementia-subtype differences should be determined in larger studies
A theoretical model of stakes and their impacts
Get PDFHigh-stakes testing (HST) of entire student cohorts, in which students undertake compulsory tests with an uncertain outcome but a potential benefit, is increasingly used as a policy tool by countries seeking to improve achievement. Long established in the United States, high-stakes testing programs have become prominent features of the accountability landscape in many countries. Researchers have documented the impacts of high stakes testing on schools, teachers, and students (e.g. Polesel et al., Journal of Education Policy, 29(5), 640–657. 2014); (Segool et al., Psychology in the Schools, 50(5), 489–499. 2013); (Baker et al., Education Evaluation and Policy Analysis Archives, 21, 1–71. 2013). Often such research assumes that those involved in testing will value tests and their associated stakes equally and will respond in similar ways. However, different stakeholder groups – students, parents, teachers, school leaders and policymakers – will have different stakes in the outcomes of tests, and within each of these groups, the value placed on the stakes is likely to vary among individuals. How these stakes differ between stakeholders, the role that the value placed on stakes plays, and the effects of these aspects on responses to testing, often remain unexamined. In this paper we propose a theoretical framework of stakeholders and stakes drawing on expectancy-value theory (Wigfield & Eccles, Contemporary Educational Psychology, 25, 68–81. 2000). We theorise that the impact of testing will be influenced by stakeholder motivation and expectations in relation to stakes. We argue that this framework provides a starting point for the development of a more nuanced, multifaceted exploration of the impacts of testing, one that can encompass different stakes and differences in the value stakeholders place on them
A Reanalysis of the FDA's Benefit-Risk Assessment of Moderna's mRNA-1273 COVID Vaccine Based on a Model Incorporating Benefits Derived from Prior COVID Infection
Get PDFBackgroundThe U.S. Food and Drug Administration (FDA) conducted a benefit-risk assessment for Moderna's COVID vaccine mRNA-1273 prior to its full approval, announced 31 January 2022. The FDA's assessment focused on males 18-64 years old because its risk analysis was limited to vaccine-attributable myocarditis/pericarditis (VAM/P), given the excess risk among males. The FDA's analysis concluded that vaccine benefits outweighed risks, even for 18-25-year-old males (those at highest VAM/P risk). We reanalyze the FDA's benefit-risk assessment using information available through the third week of January 2022 and focusing on 18-25-year-old males.MethodsWe develop a benefit-risk model, extending the FDA's, that can stratify benefits and risks of vaccination by prior-infection and comorbidity status. We use the FDA's framework but apply our model to account for benefits derived from prior COVID infection, while also accounting for finer age stratification in COVID-hospitalization rates, incidental hospitalizations (those of patients who test positive for COVID but receive treatment for something else), more realistic projections of Omicron-infection rates, and more accurate VAM/P rates.ResultsWith hospitalizations as the principal endpoint of the analysis (those prevented by vaccination vs. those caused by VAM/P), our model finds vaccine risks outweighed benefits for 18-25-year-old males, except in scenarios projecting implausibly high Omicron-infection prevalence. Our assessment suggests that mRNA-1273 vaccination of 18-25-year-old males generated between 8% and 52% more hospitalizations for VAM/P compared to COVID hospitalizations prevented (over a five-month period of vaccine protection assumed by the FDA). The preceding assessment uses model inputs based on data available at the time of the FDA's mRNA-1273 assessment. Moreover, these inputs as well as model outputs are validated by subsequently available data.ConclusionsThe outcome of a vaccine benefit-risk assessment may be dramatically impacted by accounting for the benefits derived from prior infection by the vaccine-targeted disease. To increase public confidence in vaccines and thereby reduce vaccine hesitancy, public-health agencies should employ benefit-risk models capable of supporting stratification of vaccination recommendations not only based on age and sex but also on prior-infection and comorbidity status
Biocompatible ligand balancing in transition metal coordination enables benign in-cell protein arylation
Get PDFMetal-mediated chemistries now find increasing application in in vitro biomolecule modification. However, the perceived and potential toxicity of some metals has limited the application of organometallic reagents in more complex biological settings such as inside living cells. Ligands play a crucial role in modulating both the reactivity and availability of transition metals. Here we reveal that organonickel-mediated S-arylation tolerates flexible chelation with biocompatible ligands without destroying the chemical reactivity of corresponding aryl-nickel reagents, enabling the creation of safe, site-selective C–S-bond-forming arylation manifolds. These balanced systems prove sufficiently benign for use on diverse protein substrates in vitro and in living prokaryotic and eukaryotic cells. This, in turn, enables deep chemical surveys of reactive cysteines in human cells with sensitivity sufficient to detect covalently targetable proteins from emerging intracellular viral and bacterial pathogens. Biocompatible ligand balancing thus offers a path to the broader use of transition metals in living systems
Chronicity moderates the impact of severity on central executive-default mode network functional interactions in depression
Get PDFNeuroimaging has revealed that major depression is underpinned by dysfunctional brain networks, with symptom variability stemming from altered interactions within and between brain regions. While the effect of depression severity is well-studied, the effect of depression duration (chronicity) is relatively neglected, despite its clinical significance. This study examined how severity, chronicity, and their interaction affect brain network connectivity and grey matter volume. Forty-six patients (31 females, mean age 40.5) were assessed using whole-brain network modeling and voxel-based morphometry (VBM). Severity was measured via the Hamilton Depression Rating Scale, and chronicity was defined as an episode lasting over 24 months. The key finding was that chronicity moderated the impact of severity on functional connectivity between the Central Executive Network (CEN) and the precuneus (part of the Default Mode Network, DMN). Chronic versus non-chronic patients showed opposite patterns. Non-chronic patients showed stronger CEN-Default Mode Precuneus connectivity at low severity and weaker at high severity; chronic patients showed the reverse. This study reveals a novel impact of chronicity on CEN-DMN interactions, a neglected moderator of brain-symptom severity correlations in depression