Multimodal Screening Research Articles

Economic value of multimodal cardiovascular screening

Economic value of multimodal cardiovascular screening

Screening for Ovarian Cancer in the General Population: State of Art and Perspectives of Clinical Research.

Screening for ovarian cancer in the general population is a challenging issue. The aim of this review was to analyze both the studies based on serum CA125 assay and ultrasound (US) and the novel perspectives of clinical and biological research on this issue. The trials on the combination of serum CA125 and vaginal/pelvic US as well as the investigations on microRNA (miRNA)s, circulating tumor DNA and tumor protein 53 (TP53) variants in DNA purified from Pap smears have been critically analyzed. Two large randomized trials failed to detect a reduction in ovarian cancer-related deaths in women who underwent serum CA125- and US-based screening compared to those who had no screening. The United Kingdom Collaborative Trial of Ovarian Cancer Screening reported a 39.2% higher incidence of stage I-II and 10.2% lower incidence of stage III-IV disease in women who underwent annual multimodal screening with serum CA125 and vaginal US compared to women who had no screening, but this stage shifting did not translate into a survival benefit. A longitudinal, multiple biomarker algorithm-based strategy might improve ovarian cancer detection compared with serial CA125 alone. The use of serum tumor-associated autoantibodies, circulating tumor DNA and microRNA is still investigational. The identification of TP53 clonal variants in DNA purified from Pap smears can detect early steps of serous ovarian carcinogenesis. The availability of sensitive next-generation sequencing-based approaches for TP53 assessment in PAP smears may allow the reliability of this genetic marker for early detection of ovarian cancer to be verified.

Pentosan Polysulfate Sodium-Associated Maculopathy: Early Detection Using OCT Angiography and Choriocapillaris Flow Deficit Analysis

To compare choriocapillaris flow deficit (CC-FD) analysis using optical coherence tomography angiography (OCTA) in eyes of patients treated with high cumulative dosages of pentosan polysulfate sodium (PPS) but no signs of retinal toxicity versus healthy age-matched controls. Retrospective clinical cohort study. Patients treated with PPS for interstitial cystitis with a cumulative dose of > 1000 g underwent multimodal imaging screening to exclude evidence of PPS maculopathy or other retinal findings. All study patients and age-matched healthy controls completed a 3×3 mm macular volume scan OCTA using the SOLIX full-range OCT. En face OCTA images at the level of the CC were exported and CC-FDs were computed and compared between groups. Fifteen patients treated with PPS and 15 age-matched controls were included. The mean PPS cumulative dose was 1974 ± 666 g over a mean of 17.6 ± 6.8 treatment years. All patients registered a visual acuity of 20/25 or better and normal fundus autofluorescence (FAF), OCT, multicolor, near-infrared reflectance (NIR), and ultra-widefield fundus color and autofluorescence images. The CC-FD was 32.7 ± 3.6% in the PPS group compared with 28.6 ± 4.3% in the control group (P=.023). Patients treated with PPS long enough to accumulate dosages > 1000 g showed significant CC flow impairment before the development of macular toxicity signs with OCT, NIR, and FAF compared with age-matched normal controls. Thus, the choroid may be the earliest manifestation of ocular toxicity, predating the development of clinically evident retinal pigment epithelium (RPE) injury. The subsequent RPE disruption may be the result of choriocapillaris impairment or primary PPS toxicity. Assessment of the CC on OCTA may be a useful tool for early detection of toxicity, although further longitudinal studies are required.

Multimodal screening for dyslexia using anatomical and functional MRI data

Dyslexia is a disability in language and phonetics, with difficulties in learning and reasoning, affecting around 20% of the worldwide population. Detecting dyslexia at an early stage is vital to provide appropriate remedial teaching aid to improve the learning skills of the affected. The key objective of this study is to identify dyslexia based on Anatomical and Functional MRI data. Convolutional Neural Networks and Time Distributed Convolutional Long-Short Term Memory Neural networks are proposed for screening the neuroimaging data. A multimodal fusion technique is proposed to provide a final combined classification based on the anatomical and functional data. Experimental results demonstrate the performance of the multimodal approach over individual modes of MRI data. The result analysis shows that image segmentation has a significant contribution towards improving classifier performance.

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A pilot mixed-methods randomized controlled trial of verbal versus electronic screening for adverse social determinants of health.

ObjectivesExamining the social risks that influence the health of patients accessing emergency care can inform future efforts to improve health outcomes. The optimal modality for screening in the emergency department (ED) has not yet been identified. We conducted a mixed methods evaluation of the impact of screening modality on patient satisfaction with the screening process.MethodsPatients were enrolled at a large urban academic ED and randomized to verbal versus electronic modalities following informed consent. Participants completed a short demographic survey, a brief validated health literacy test, and a social need and risk screening tool. Participants were purposively sampled to complete qualitative interviews balanced across 4 groups defined by health literacy scores (high vs limited) and screening modality. Quantitative outcomes included screening results and satisfaction with the screening process; qualitative questions focused on experience with the screening process, barriers, and facilitators to screening.ResultsOf 554 patients assessed, 236 were randomized (115 verbal, 121 electronic). Participants were 23% Hispanic, 6% non‐Hispanic Black, 58% non‐Hispanic White, 38% publicly insured, and 57% privately insured. Two‐thirds (67%) identified social needs and risks and the majority (81%) reported satisfaction with the screening. Screening modality was not associated with satisfaction with screening process after adjustment for language, health literacy, and social risk (adjusted odds ratio, 0.74; 95% confidence interval, 0.32, 1.71).ConclusionScreening modality was not associated with overall satisfaction with screening process. Future strategies can consider the advantage of multimodal screening options, including the use of electronic tools to streamline screening and expand scalability and sustainability.

Genomics of Pulmonary Hypertension

Background -Pulmonary hypertension (PH), defined by mean pulmonary artery pressure &amp;gt;20 mmHg, is a common physiologic manifestation of many diseases. Pulmonary arterial hypertension (PAH) represents a smaller subgroup of patients who have PH, and PAH causes significant cardiorespiratory morbidity and premature mortality. PH can manifest across the lifespan, with similar incidence for both pediatric- and adult-onset disease. However, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung and heart developmental anomalies. For PH Group 1/pulmonary arterial hypertension, causal genetic variants can be identified in ~13% of adults and ~43% of children.Clinical implications –Education about the option for genetic testing is strongly recommended for all pediatric and adult HPAH/IPAH patients. Both gene panel and exome/genome sequencing tests can be useful in diagnosis, but exome/genome sequencing provides a comprehensive dataset for reanalysis over time for cases without an initial diagnosis. Knowledge of genetic diagnoses can immediately impact clinical management of PH, including multimodal medical treatment, surgical intervention, transplantation decisions, and screening for associated conditions.Conclusions -There is a need for large, diverse, international consortia with ever-improving analytical pipelines to confirm previously implicated genes, identify additional genes/variants, assess penetrance, and clinically characterize each genetic subtype for natural history, prognosis and response to therapies to inform more precise clinical management.

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

How to predict a difficult airway

According to The American Society of Anaesthesiologists Task Force, a difficult airway is defined as a clinical situation in which a conventionally– trained anaesthesiologist experiences difficulty with face mask ventilation and/or difficulty with tracheal intubation. Failing at efficient airway management is a source of major apprehension for physicians. Predicting difficult airway management is a mandatory part of clinical practice for paediatric and adult patients so as to avoid unexpected difficult airway management and adverse outcomes. Predicting a difficult airway is based on a focused medical history, review of prior medical records, physical examination, and specific tests for airway assessment. Each feature or airway test has its own sensitivity and specificity for the prediction of a difficult airway. All airway assessment tests are characterised by low sensitivity, reasonable specificity, and a low positive predictive value. Several scoring system models have been developed by multivariate analysis with multiple different integrated tests or risk factors to improve the prediction of a difficult airway, but with considerably different effectiveness to predict a difficult airway. According to the European Society of Anaesthesiology, systematic multimodal screening before airway management should include the Mallampati classification and thyromental distance, mouth opening or interincisor distance, range of motion of head and neck, compliance of the mandibular space, and the upper lip bite test.

Multimodal Identification by Transcriptomics and Multiscale Bioassays of Active Components in Xuanfeibaidu Formula to Suppress Macrophage-Mediated Immune Response.

Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 104 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide I, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.

Co-existing of craniofacial fibrous dysplasia and cerebrovascular diseases: a series of 22 cases and review of the literature

BackgroundCraniofacial fibrous dysplasia is a fairly rare condition. Some literature have reported a few patients with craniofacial fibrous dysplasia suffering from vascular abnormalities. This study aimed to describe the possible coexistence of craniofacial fibrous dysplasia and cerebrovascular diseases for the first time.MethodWe retrospectively reviewed the 1175 patients with craniofacial fibrous dysplasia in Beijing Tiantan Hospital and the information of the 22 patients coexisted with cerebrovascular diseases were described. In addition, we performed a systematic review for cases of craniofacial fibrous dysplasia with vascular abnormalities.Result22 out of 1175 patients (1.9%) were diagnosed with craniofacial fibrous dysplasia and cerebrovascular diseases including 9 intracranial aneurysms, 4 venous malformations, 2 arteriovenous malformations, 1 moyamoya disease, 2 intracranial venous stenosis and 4 cerebral ischemia with a mean age of 38.18 years old. Only 2 patients were managed surgically for craniofacial fibrous dysplasia and 6 patients were treated with neurosurgery for cerebrovascular diseases. 8 patients were closely followed and only 1 patient’s symptoms worsened.ConclusionCraniofacial fibrous dysplasia might cause constriction of the intracranial vessels and alteration of the overall hemodynamics of the intracranial vasculature resulting in various cerebrovascular diseases. Multimodal screening and examinations seems reasonable for patients with craniofacial fibrous dysplasia for throughout treatment and prognosis evaluations.

S130 Multimodal Circulating Tumor DNA (ctDNA) Blood-Based Colorectal Cancer (CRC) Screening Test Demonstrates Clinically Meaningful Sensitivity Across Multiple Clinical Parameters

Introduction: Blood-based CRC screening holds potential to improve screening compliance due to ease of use and high patient and provider acceptability. A blood-based screening test must detect CRC across multiple clinical parameters in order to prove clinically meaningful in a screen-relevant population. We aimed to describe the performance of a multimodal ctDNA blood-based CRC screening test in a cohort of patients (pts) with newly diagnosed CRC. Methods: A consecutive, unselected series of pts with newly diagnosed CRC were consented to a study permitting use of clinical data and biospecimens for research. Consented pts provided a blood sample (10mL collected in EDTA) prior to surgical resection. Isolated plasma (median 3mL) from a cohort of pts with Stage I – III CRC was analyzed with a 500kb next-generation sequencing based panel and bioinformatic platform incorporating cell-free DNA (cfDNA) methylation-based partitioning to identify cancer related genomic alterations and epigenomic modifications (methylation and modifications in chromatin state). The output is a “ctDNA detected” or “ctDNA not detected” result. Final results were correlated with clinical features. Results: ctDNA results were available for 699 pts; 43% female, median age 63 years (range 20 - 89), 90% of pts were age 45 - 84. Overall sensitivity was 96% (671 / 699). The assay demonstrated sensitivity in the 88 – 100% range across cancer stage and presentation, primary tumor location, histology and grade, degree of tumor invasion, and microsatellite instability status (Table). Sensitivity in 138 pts with Stage I / II well-differentiated (low grade) CRC was 93%. CRC presentation status was known in 83% of pts with Stage I / II CRC (N = 344). Sensitivity was 90% in the 44% (N = 152) of pts who were asymptomatic at presentation. Sensitivity was 96% in the 56% (N = 192) of pts with Stage I / II disease who presented symptomatically. Specificity in age-matched cancer-free controls was 94%. Conclusion: This multimodal ctDNA CRC screening test has clinically meaningful sensitivity across multiple clinical parameters, most notably in those with early-stage asymptomatic disease and early-stage low-grade tumors. The data suggest this test will have clinically meaningful performance in an average risk screening population presenting with varying cancer stages and tumor histologic features. A prospective registrational study to evaluate the test in an average risk, screen-relevant cohort is ongoing (NCT04136002).Table 1.: Sensitivity of blood-based CRC screening test.

In postmenopausal women, multimodal or US screening for ovarian cancer did not reduce ovarian cancer mortality.

Menon U, Gentry-Maharaj A, Burnell M, et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2021;397:2182-93. 33991479.

Circulating maternal placental growth factor responses to low-molecular-weight heparin in pregnant patients at risk of placental dysfunction

Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain. Because low-molecular-weight heparin augments the production and release of placental growth factor invitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating placental growth factor in the early second trimester. This study aimed to define a gestational age-specific reference range for placental growth factor and to test the hypothesis that prophylactic low-molecular-weight heparin administered in the early second trimester may restore deficient circulating placental growth factor levels and thereby prolong pregnancy. Centile curves for circulating placental growth factor levels from 12 to 36 weeks' gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, United Kingdom, at 4 sampling time points (12, 20, 28, and 36 weeks' gestation) and the White majority (n=531) of a healthy nulliparous cohort in Toronto, Canada, at 16 weeks' gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of 7 patients with a circulating placental growth factor at the <10th centile in the early second trimester received daily prophylactic low-molecular-weight heparin (enoxaparin; 40 mg subcutaneously) and were followed up until delivery (group 1). Their baseline characteristics, delivery details, and placental pathologies were compared with 5 similar patients who did not receive low-molecular-weight heparin during the observation period (group 2) and further with 21 patients who delivered with severe preeclampsia (group 3) in the same institution. A gestational age-specific reference range for placental growth factor levels at weekly intervals between 12 and 36 weeks was established for White women with singleton pregnancies. Within group 1, 5 of 7 patients demonstrated a sustained increase in circulating placental growth factor levels, whereas placental growth factor levels did not increase in group 2 or group 3 patients who did not receive low-molecular-weight heparin. Group 1 patients receiving low-molecular-weight heparin therapy exhibited a later gestation at delivery, relative to groups 2 and 3 (36 weeks [33-37] vs 23 weeks [22-26] and 28 weeks [27-31], respectively), and consequently had higher birthweights (1.93 kg [1.1-2.7] vs 0.32 kg [0.19-0.39] and 0.73 kg [0.52-1.03], respectively). The incidence of stillbirth was lowest in group 1 (14% [1 of 7]), relative to groups 2 and 3 (80% [4 of 5] and 29% [6 of 21], respectively). Maternal vascular malperfusion was the most common placental pathology found in association with abnormal uterine artery Doppler. In patients at high risk of a serious adverse pregnancy outcome owing to placental disease, the addition of low-molecular-weight heparin to aspirin prophylaxis in the early second trimester may restore deficient circulating placental growth factor to mediate an improved perinatal outcome. These data support the implementation of a multicenter pilot randomized control trial where patients are recruited primarily based on the assessment of placental function in the early second trimester.

Identifying falls remotely in people with multiple sclerosis

BackgroundFalling is common in people with multiple sclerosis (MS) but tends to be under-ascertained and under-treated.ObjectiveTo evaluate fall risk in people with MS.MethodsNinety-four people with MS, able to walk > 2 min with or without an assistive device (Expanded Disability Status Scale (EDSS ≤ 6.5) were recruited. Clinic-based measures were recorded at baseline and 1 year. Patient-reported outcomes (PROs), including a fall survey and the MS Walking Scale (MSWS-12), were completed at baseline, 1.5, 3, 6, 9, and 12 months. Average daily step counts (STEPS) were recorded using a wrist-worn accelerometer.Results50/94 participants (53.2%) reported falling at least once. Only 56% of participants who reported a fall on research questionnaires had medical-record documented falls. Fallers had greater disability [median EDSS 5.5 (IQR 4.0–6.0) versus 2.5 (IQR 1.5–4.0), p < 0.001], were more likely to have progressive MS (p = 0.003), and took fewer STEPS (mean difference − 1,979, p = 0.007) than Non-Fallers. Stepwise regression revealed MSWS-12 as a major predictor of future falls.ConclusionsFalling is common in people with MS, under-reported, and under-ascertained by neurologists in clinic. Multimodal fall screening in clinic and remotely may help improve patient care by identifying those at greatest risk, allowing for timely intervention and referral to specialized physical rehabilitation.

Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

SummaryBackgroundOvarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS.MethodsIn this randomised controlled trial, postmenopausal women aged 50–74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032.FindingsBetween April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1–17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (−41·8 to –2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (−21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group.InterpretationThe reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended.FundingNational Institute for Health Research, Cancer Research UK, and The Eve Appeal.

Multimodal Neurocognitive Screening of Military Personnel With a History of Mild Traumatic Brain Injury Using the Bethesda Eye & Attention Measure.

To evaluate a neurocognitive eye tracking task, the Bethesda Eye & Attention Measure (BEAM), for use in cognitive screening of patients with a history of mild traumatic brain injury (TBI). US military TBI rehabilitation clinic. Cross-sectional study of 191 military personnel receiving outpatient services related to history of mild TBI. Main measures: BEAM; neuropsychological screening measures of attention, processing speed, executive function, and memory. Medium effect sizes were found for partial correlations (controlling for age) between key BEAM metrics and neuropsychological screening tests. Linear regression analyses demonstrated that BEAM saccadic eye movements and manual (button press) metrics each provided complementary value in measurement of cognitive performance, above and beyond effects of demographic factors and clinical characteristics. This study provides initial support for the use of BEAM neurocognitive eye tracking in cognitive screening of adults with a history of mild TBI. BEAM saccadic metrics appear to be particularly well-suited for the assessment of visual attention. Study findings also highlight opportunities for greater cognitive sensitivity or testing efficiency that may be missed by tests measuring only one response modality at a time.

A Novel Cell-Based Intracellular Protein–Protein Interaction Detection Platform (SOLIS) for Multimodality Screening

Intervention in protein-protein interactions (PPIs) has tremendous effects in the molecular therapy of many diseases. To fulfill the requirements for targeting intracellular proteins, here we develop SOS-localization-based interaction screening (SOLIS), which elaborately mimics signaling via the Ras-mitogen-activated protein kinase pathway. SOLIS employs two chimeric proteins in which a membrane localization motif (CaaX) is fused at the C-terminus of a protein of interest and the catalytic domain of SOS is fused at the C-terminus of another protein of interest. Interaction between the two proteins of interest induces membrane localization of the SOS chimera and cell proliferation. Thus, the SOLIS system enables enrichment of superior binders based on cell proliferation in an intracellular PPI-dependent manner. This was verified by three major modalities against intracellular PPIs (small molecules, peptide aptamers, and intrabodies). The system worked over a broad range of affinities (KD = 0.32-140 nM). In a screening of a site-directed randomized library, novel intrabody clones were selected on the basis of the potency of cell proliferation. Three other PPI detection methods (NanoBiT, SPR, and pull-down assays) were employed to characterize the SOLIS system, and several intrabody clones were judged as false negatives in these assays. SOLIS signals would be less sensitive to the orientation/conformation of the chimeric proteins, and this feature emerges as the advantage of SOLIS as a mammalian cytosolic PPI detection system with few false negatives.

Zebrafish Cancer Predisposition Models.

Cancer predisposition syndromes are rare, typically monogenic disorders that result from germline mutations that increase the likelihood of developing cancer. Although these disorders are individually rare, resulting cancers collectively represent 5–10% of all malignancies. In addition to a greater incidence of cancer, affected individuals have an earlier tumor onset and are frequently subjected to long-term multi-modal cancer screening protocols for earlier detection and initiation of treatment. In vivo models are needed to better understand tumor-driving mechanisms, tailor patient screening approaches and develop targeted therapies to improve patient care and disease prognosis. The zebrafish (Danio rerio) has emerged as a robust model for cancer research due to its high fecundity, time- and cost-efficient genetic manipulation and real-time high-resolution imaging. Tumors developing in zebrafish cancer models are histologically and molecularly similar to their human counterparts, confirming the validity of these models. The zebrafish platform supports both large-scale random mutagenesis screens to identify potential candidate/modifier genes and recently optimized genome editing strategies. These techniques have greatly increased our ability to investigate the impact of certain mutations and how these lesions impact tumorigenesis and disease phenotype. These unique characteristics position the zebrafish as a powerful in vivo tool to model cancer predisposition syndromes and as such, several have already been created, including those recapitulating Li-Fraumeni syndrome, familial adenomatous polyposis, RASopathies, inherited bone marrow failure syndromes, and several other pathogenic mutations in cancer predisposition genes. In addition, the zebrafish platform supports medium- to high-throughput preclinical drug screening to identify compounds that may represent novel treatment paradigms or even prevent cancer evolution. This review will highlight and synthesize the findings from zebrafish cancer predisposition models created to date. We will discuss emerging trends in how these zebrafish cancer models can improve our understanding of the genetic mechanisms driving cancer predisposition and their potential to discover therapeutic and/or preventative compounds that change the natural history of disease for these vulnerable children, youth and adults.

The voice, text, and the visual as semiotic companions: an analysis of the materiality and meaning potential of multimodal screen feedback

The gap between how learners interpret and act upon feedback has been widely documented in the research literature. What is less certain is the extent to which the modality and materiality of the feedback influence students’ and teachers’ perceptions. This article explores the semiotic potential of multimodal screen feedback to enhance written feedback. Guided by an “Inquiry Graphics” approach, situated within a semiotic theory of learning edusemiotic conceptual framework, constructions of meaning in relation to screencasting feedback were analysed to determine how and whether it could be incorporated into existing feedback practices. Semi-structured video elicitation interviews with student teachers were used to incorporate both micro and macro levels of analysis. The findings suggested that the relationship between the auditory, visual and textual elements in multimodal screen feedback enriched the feedback process, highlighting the importance of form in addition to content to aid understanding of written feedback. The constitutive role of design and material artefacts in feedback practices in initial teacher training pertinent to these findings is also discussed.