Chronic Lymphocytic Leukemia IGHV Somatic Hypermutation Detection by Targeted Capture Next-Generation Sequencing.

BACKGROUND: Somatic hypermutation (SHM) status of the immunoglobulin heavy variable (IGHV) gene plays a crucial role in determining the prognosis and treatment of patients with chronic lymphocytic leukemia (CLL). A common approach for determining SHM status is multiplex polymerase chain reaction and Sanger sequencing of the immunoglobin heavy locus; however, this technique is low throughput, is vulnerable to failure, and does not allow multiplexing with other diagnostic assays. METHODS: Here we designed and validated a DNA targeted capture approach to detect immunoglobulin heavy variable somatic hypermutation (IGHV SHM) status as a submodule of a larger next-generation sequencing (NGS) panel that also includes probes for ATM, BIRC3, CHD2, KLHL6, MYD88, NOTCH1, NOTCH2, POT1, SF3B1, TP53, and XPO1. The assay takes as input FASTQ files and outputs a report containing IGHV SHM status and V allele usage following European Research Initiative on CLL guidelines. RESULTS: We validated the approach on 35 CLL patient samples, 34 of which were characterized using Sanger sequencing. The NGS panel identified the IGHV SHM status of 34 of 35 CLL patients. We showed 100% sensitivity and specificity among the 33 CLL samples with both NGS and Sanger sequencing calls. Furthermore, we demonstrated that this panel can be combined with additional targeted capture panels to detect prognostically important CLL single nucleotide variants, insertions/deletions, and copy number variants (TP53 copy number loss). CONCLUSIONS: A targeted capture approach to IGHV SHM detection can be integrated into broader sequencing panels, allowing broad CLL prognostication in a single molecular assay.

Development of a comprehensive approach to adult hereditary cancer testing in Ontario.

BACKGROUND: Genetic testing for hereditary cancer susceptibility has advanced over time due to the discovery of new risk genes, improved technology and decreased cost. In the province of Ontario, testing eligibility criteria were initially developed to include hereditary breast, ovarian and colorectal cancer syndromes. The rapid evolution of genetic technologies has facilitated the ability to interrogate a large number of genes concurrently. This, coupled with new knowledge about risk genes, necessitated a coordinated approach to expanding the scope of genes and indications tested and synchronisation of access and test utilisation across the province as required in a publicly funded universal healthcare system. METHODS: Ontario Health-Cancer Care Ontario convened expert working groups to develop a standardised and comprehensive cancer gene list for adults and accompanying hereditary cancer testing (HCT) criteria using an evidence-based framework and broad laboratory and clinical genetics engagement. RESULTS: A standardised 76-cancer-gene panel, organised into 13 larger disease site panels and 25 single/small gene panels, was developed and endorsed by the working groups. Provincial genetic testing eligibility criteria were updated to align with the new panels and to guide clinical decision-making. In the first year following the implementation of these changes, 10 564 HCT panels were performed with an overall mutation detection rate of 12.2%. CONCLUSION: Using an evidence framework and broad clinical engagement to develop and endorse an updated guidance document, cancer genetic testing for adults in Ontario is now standardised and coordinated across the province.

Increase of Severe Pulmonary Infections in Adults Caused by M1UK Streptococcus pyogenes, Central Scotland, UK.

We characterized the epidemiology, host-pathogen characteristics, and outcomes of severe adult pulmonary Streptococcus pyogenes infections that coincided with a high community caseload in central Scotland, UK. The pulmonary infections had high illness and death rates and were associated with socioeconomic deprivation, influenza A co-infection, and the M1UK lineage of S. pyogenes.

An assessment of the downstream implications of blood culture collection and transit.

The implications of the variables within the pre-analytical phase of blood culture processing are poorly understood. This study aims to explore the effect of transit times (TT) and culture volume, on time to microbiological diagnosis and patient outcomes. Blood cultures received between 1st March and 31st July 2020/21 were identified. TT, time in incubator (TII), and for positive samples, request to positivity times (RPT) were calculated. Demographic details were recorded for all samples, and culture volume, length of stay (LoS), and 30-day mortality for patients with positive samples. Statistical analysis examined how culture volume and TT effected culture positivity and outcome; in the context of the 4-h national TT target. Totally, 14,375 blood culture bottles were received from 7367 patients; 988 (13.4%) were positive for organisms. There was no significant difference between TT of negative and positive samples. The RPT was significantly lower for samples with TT < 4 h (p < 0.001). Culture bottle volume did not affect RPT (p = 0.482) or TII (p = 0.367). A prolonged TT was associated with a longer length-of-stay in those with a bacteraemia with a significant organism (p = 0.001). We found shorter blood culture transportation time was associated with a significantly faster time of positive culture reporting, while optimal blood culture volume did not make a significant impact. Delays in reporting for significant organisms correspond to a prolonged LoS. Laboratory centralisation makes achieving the 4-h target a logistical challenge; however, this data suggests such targets have significant microbiological and clinical impacts.

Bilinguals' inhibitory control and attentional processes in a visual perceptual task.

The aim was to examine theories of bilingual inhibitory control superiority in the visual domain. In an ambiguous figure task, the ability to reverse (switch) interpretations (e.g., duck-rabbit) was examined in 3-5-year-olds bilinguals and monolinguals (N = 67). Bilingualism was no performance predictor in conceptual tasks (Droodle task, false belief task, ambiguous figures production task) that did not pose inhibitory demands. Bilinguals outperformed monolinguals in the ability to reverse, suggesting superior inhibitory capacity per se. Once reversal was experienced there was no difference in the time it took to reverse or reversal frequency between bilinguals and monolinguals. Bayesian analyses confirmed statistical result patterns. Findings support the established view of bilinguals' superior domain-general inhibitory control. This might be brought to bear by attending the environment differently.

Breeding season length predicts duet coordination and consistency in Neotropical wrens (Troglodytidae).

Many animals produce coordinated signals, but few are more striking than the elaborate male-female vocal duets produced by some tropical songbirds. Yet, little is known about the factors driving the extreme levels of vocal coordination between mated pairs in these taxa. We examined evolutionary patterns of duet coordination and their potential evolutionary drivers in Neotropical wrens (Troglodytidae), a songbird family well known for highly coordinated duets. Across 23 wren species, we show that the degree of coordination and precision with which pairs combine their songs into duets varies by species. This includes some species that alternate their song phrases with exceptional coordination to produce rapidly alternating duets that are highly consistent across renditions. These highly coordinated, consistent duets evolved independently in multiple wren species. Duet coordination and consistency are greatest in species with especially long breeding seasons, but neither duet coordination nor consistency are correlated with clutch size, conspecific abundance or vegetation density. These results suggest that tightly coordinated duets play an important role in mediating breeding behaviour, possibly by signalling commitment or coalition of the pair to mates and other conspecifics.

The impact of external facial features on the construction of facial composites.

Witnesses may construct a composite face of a perpetrator using a computerised interface. Police practitioners guide witnesses through this unusual process, the goal being to produce an identifiable image. However, any changes a perpetrator makes to their external facial-features may interfere with this process. In Experiment 1, participants constructed a composite using a holistic interface one day after target encoding. Target faces were unaltered, or had altered external-features: (i) changed hair, (ii) external-features removed or (iii) naturally-concealed external-features (hair, ears, face-shape occluded by a hooded top). These manipulations produced composites with more error-prone internal-features: participants' familiar with a target's unaltered appearance less often provided a correct name. Experiment 2 applied external-feature alterations to composites of unaltered targets; although whole-face composites contained less error-prone internal-features, identification was impaired. Experiment 3 replicated negative effects of changing target hair on construction and tested a practical solution: selectively concealing hair and eyes improved identification. Practitioner Summary: The research indicates that when a target identity disguises or changes hair, this can lead to a witness (or victim) constructing a composite that is less readily identified. We assess a practical method to overcome this forensic issue. Abbreviation: GEE: Generalized Estimating Equations.

Higher songs of city birds may not be an individual response to noise.

It has been observed in many songbird species that populations in noisy urban areas sing with a higher minimum frequency than do matched populations in quieter, less developed areas. However, why and how this divergence occurs is not yet understood. We experimentally tested whether chronic noise exposure during vocal learning results in songs with higher minimum frequencies in great tits (Parus major), the first species for which a correlation between anthropogenic noise and song frequency was observed. We also tested vocal plasticity of adult great tits in response to changing background noise levels by measuring song frequency and amplitude as we changed noise conditions. We show that noise exposure during ontogeny did not result in songs with higher minimum frequencies. In addition, we found that adult birds did not make any frequency or song usage adjustments when their background noise conditions were changed after song crystallization. These results challenge the common view of vocal adjustments by city birds, as they suggest that either noise itself is not the causal force driving the divergence of song frequency between urban and forest populations, or that noise induces population-wide changes over a time scale of several generations rather than causing changes in individual behaviour.

Fixation patterns, not clinical diagnosis, predict body size over-estimation in eating disordered women and healthy controls.

OBJECTIVE: A core feature of anorexia nervosa (AN) is an over-estimation of body size. Women with AN have a different pattern of eye-movements when judging bodies, but it is unclear whether this is specific to their diagnosis or whether it is found in anyone over-estimating body size. METHOD: To address this question, we compared the eye movement patterns from three participant groups while they carried out a body size estimation task: (i) 20 women with recovering/recovered anorexia (rAN) who had concerns about body shape and weight and who over-estimated body size, (ii) 20 healthy controls who had normative levels of concern about body shape and who estimated body size accurately (iii) 20 healthy controls who had normative levels of concern about body shape but who did over-estimate body size. RESULTS: Comparisons between the three groups showed that: (i) accurate body size estimators tended to look more in the waist region, and this was independent of clinical diagnosis; (ii) there is a pattern of looking at images of bodies, particularly viewing the upper parts of the torso and face, which is specific to participants with rAN but which is independent of accuracy in body size estimation. DISCUSSION: Since the over-estimating controls did not share the same body image concerns that women with rAN report, their over-estimation cannot be explained by attitudinal concerns about body shape and weight. These results suggest that a distributed fixation pattern is associated with over-estimation of body size and should be addressed in treatment programs. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:507-518).

Holistic face processing can inhibit recognition of forensic facial composites.

Facial composite systems help eyewitnesses to show the appearance of criminals. However, likenesses created by unfamiliar witnesses will not be completely accurate, and people familiar with the target can find them difficult to identify. Faces are processed holistically; we explore whether this impairs identification of inaccurate composite images and whether recognition can be improved. In Experiment 1 (n = 64) an imaging technique was used to make composites of celebrity faces more accurate and identification was contrasted with the original composite images. Corrected composites were better recognized, confirming that errors in production of the likenesses impair identification. The influence of holistic face processing was explored by misaligning the top and bottom parts of the composites (cf. Young, Hellawell, & Hay, 1987). Misalignment impaired recognition of corrected composites but identification of the original, inaccurate composites significantly improved. This effect was replicated with facial composites of noncelebrities in Experiment 2 (n = 57). We conclude that, like real faces, facial composites are processed holistically: recognition is impaired because unlike real faces, composites contain inaccuracies and holistic face processing makes it difficult to perceive identifiable features. This effect was consistent across composites of celebrities and composites of people who are personally familiar. Our findings suggest that identification of forensic facial composites can be enhanced by presenting composites in a misaligned format.

Deep venous thrombosis after saphenous endovenous radiofrequency ablation: is it predictable?

BACKGROUND: Endovenous radiofrequency ablation (RFA) is a safe and effective treatment for varicose veins caused by saphenous reflux. Deep venous thrombosis (DVT) is a known complication of this procedure. The purpose of this study is to describe the frequency of DVT after RFA and the associated predisposing factors. METHODS: A retrospective analysis was performed using prospectively collected data from December 2008 to December 2011; a total of 277 consecutive office-based RFA procedures were performed at a single institution using the VNUS ClosureFast catheter (VNUS Medical Technologies, San Jose, CA). Duplex ultrasonography scans were completed 2 weeks postprocedure in all patients. Risk factors assessed for the development of DVT included: great versus small saphenous vein (SSV) treated, right versus left side treated, number of radiofrequency cycles used, hypercoagulable state, history of DVT, tobacco use, medications (i.e., oral contraceptives, aspirin, warfarin, and clopidogrel), and vein diameter at the junction of the superficial and deep systems. RESULTS: Seventy-two percent of the patients were women, 56% were treated on the right side, and 86% were performed on the great saphenous vein (GSV). The mean age was 54 ± 14 years (range: 23-88 years). Three percent of patients had a preprocedure diagnosis of hypercoagulable state, and 8% had a history of previous DVT. On postprocedural ultrasound, thrombus protrusion into the deep system without occlusion (endovenous heat-induced thrombosis) was present in 11 patients (4%). DVT, as defined by thrombus protrusion with complete occlusion of the femoral or popliteal vein, was identified in 2 patients (0.7%). Previous DVT was the only factor associated with postprocedural DVT (P = 0.018). Although not statistically significant, there was a trend toward a higher risk of DVT in SSV-treated patients. Factors associated with endovascular heat-induced thrombosis alone were male sex (P = 0.02), SSV treatment (P = 0.05), aspirin use (P = 0.008), and factor V Leiden deficiency (P = 0.01). CONCLUSIONS: The use of RFA to treat patients with symptoms caused by saphenous reflux involves a small but definite risk of DVT. This study shows that the risk of post-RFA DVT is greater in patients with previous DVT, with a trend toward an increased risk in patients having treatment of the SSV. Periprocedural anticoagulation may be considered in this subset to reduce the risk of DVT after RFA. Thrombus protrusion without DVT was found to be more likely in patients with hypercoagulability, male sex, SSV treatment, and aspirin use. Additional prospective studies are required to analyze these and other factors that may predict thrombotic events after endovenous RFA.

That looks familiar: attention allocation to familiar and unfamiliar faces in children with autism spectrum disorder.

INTRODUCTION: Existing eye-tracking literature has shown that both adults and children with autism spectrum disorders (ASD) show fewer and slower fixations on faces. Despite this reduced saliency and processing of other faces, recognition of their own face is reported to be more "typical" in nature. This study uses eye-tracking to explore the typicality of gaze patterns when children with ASD attend their own faces compared to other familiar and unfamiliar faces. METHODS: Eye-tracking methodology was used to explore fixation duration and time taken to fixate on the Eye and Mouth regions of familiar, unfamiliar and Self Faces. Twenty-one children with ASD (9-16 years) were compared to typically developing matched groups. RESULTS: There were no significant differences between children with ASD and typically matched groups for fixation patterns to the Eye and Mouth areas of all face types (familiar, unfamiliar and self). Correlational analyses showed that attention to the Eye area of unfamiliar and Self Faces was related to socio-communicative ability in children with ASD. CONCLUSIONS: Levels of socio-communicative ability in children with ASD were related to gaze patterns on unfamiliar and Self Faces, but not familiar faces. This lack of relationship between ability and attention to familiar faces may indicate that children across the autism spectrum are able to fixate these faces in a similar way. The implications for these findings are discussed.

Configural and featural information in facial-composite images.

Eyewitnesses are often invited to construct a facial composite, an image created of the person they saw commit a crime that is used by law enforcement to locate criminal suspects. In the current paper, the effectiveness of composite images was investigated from traditional feature systems (E-FIT and PRO-fit), where participants (face constructors) selected individual features to build the face, and a more recent holistic system (EvoFIT), where they 'evolved' a composite by repeatedly selecting from arrays of complete faces. Further participants attempted to name these composites when seen as an unaltered image, or when blurred, rotated, linearly stretched or converted to a photographic negative. All of the manipulations tested reduced correct naming of the composites overall except (i) for a low level of blur, for which naming improved for holistic composites but reduced for feature composites, and (ii) for 100% linear stretch, for which a substantial naming advantage was observed. Results also indicated that both featural (facial elements) and configural (feature spacing) information were useful for recognition in both types of composite system, but highly-detailed information was more accurate in the feature-based than in the holistic method. The naming advantage of linear stretch was replicated using a forensically more-practical procedure with observers viewing an unaltered composite sideways. The work is valuable to police practitioners and designers of facial-composite systems.

A new way of classifying developmental prosopagnosia: Balanced Integration Score.

Despite severe everyday problems recognising faces, some individuals with developmental prosopagnosia (DP) can achieve typical accuracy scores on laboratory face recognition tests. To address this, studies sometimes also examine response times (RTs), which tend to be longer in DPs relative to control participants. In the present study, 24 potential (according to self-report) DPs and 110 age-matched controls completed the Cambridge Face and Bicycle Memory Tests, old new faces task, and a famous faces test. We used accuracy and the Balanced Integration Score (BIS), a measure that adjusts accuracy for RTs, to classify our sample at the group and individual levels. Subjective face recognition ability was assessed using the PI20 questionnaire and semi structured interviews. Fifteen DPs showed a major impairment using BIS compared with only five using accuracy alone. Logistic regression showed that a model incorporating the BIS measures was the most sensitive for classifying DP and showed highest area under the curve (AUC). Furthermore, larger between-group effect sizes were observed for a derived global (averaged) memory measure calculated using BIS versus accuracy alone. BIS is thus an extremely sensitive novel measure for attenuating speed-accuracy trade-offs that can otherwise mask impairment measured only by accuracy in DP.

Trust in automation and the accuracy of human-algorithm teams performing one-to-one face matching tasks.

The human face is commonly used for identity verification. While this task was once exclusively performed by humans, technological advancements have seen automated facial recognition systems (AFRS) integrated into many identification scenarios. Although many state-of-the-art AFRS are exceptionally accurate, they often require human oversight or involvement, such that a human operator actions the final decision. Previously, we have shown that on average, humans assisted by a simulated AFRS (sAFRS) failed to reach the level of accuracy achieved by the same sAFRS alone, due to overturning the system's correct decisions and/or failing to correct sAFRS errors. The aim of the current study was to investigate whether participants' trust in automation was related to their performance on a one-to-one face matching task when assisted by a sAFRS. Participants (n = 160) completed a standard face matching task in two phases: an unassisted baseline phase, and an assisted phase where they were shown the identification decision (95% accurate) made by a sAFRS prior to submitting their own decision. While most participants improved with sAFRS assistance, those with greater relative trust in automation achieved larger gains in performance. However, the average aided performance of participants still failed to reach that of the sAFRS alone, regardless of trust status. Nonetheless, further analysis revealed a small sample of participants who achieved 100% accuracy when aided by the sAFRS. Our results speak to the importance of considering individual differences when selecting employees for roles requiring human-algorithm interaction, including identity verification tasks that incorporate facial recognition technologies.

Low-grade follicular lymphoma with interferon regulatory factor-4 rearrangement: Expanding the spectrum of interferon regulatory factor-4-rearranged lymphomas.

In recent years, the recognition of distinct lymphoma entities has expanded with advancements in molecular characterization. Large B-cell Lymphoma with interferon regulatory factor-4 (IRF4) rearrangement (LBCL-IRF4-R) is one such entity. We present a case of classic low-grade follicular lymphoma with IRF4 rearrangement in a 50-year-old male, demonstrating an unusual immunophenotypic and genetic profile reminiscent of LBCL-IRF4-R. Molecular analysis revealed mutations in CREBBP, KMT2D, IRF4, and CARD11, with previously unreported variants identified in IRF4 and CREBBP. This case broadens the spectrum of B-cell lymphomas associated with IRF4 rearrangement by demonstrating a small B-cell lymphoma with this genetic feature.

Benchmarking automation-aided performance in a forensic face matching task.

Carragher and Hancock (2023) investigated how individuals performed in a one-to-one face matching task when assisted by an Automated Facial Recognition System (AFRS). Across five pre-registered experiments they found evidence of suboptimal aided performance, with AFRS-assisted individuals consistently failing to reach the level of performance the AFRS achieved alone. The current study reanalyses these data (Carragher and Hancock, 2023), to benchmark automation-aided performance against a series of statistical models of collaborative decision making, spanning a range of efficiency levels. Analyses using a Bayesian hierarchical signal detection model revealed that collaborative performance was highly inefficient, falling closest to the most suboptimal models of automation dependence tested. This pattern of results generalises previous reports of suboptimal human-automation interaction across a range of visual search, target detection, sensory discrimination, and numeric estimation decision-making tasks. The current study is the first to provide benchmarks of automation-aided performance in the one-to-one face matching task.

Face masks and fake masks: the effect of real and superimposed masks on face matching with super-recognisers, typical observers, and algorithms.

Mask wearing has been required in various settings since the outbreak of COVID-19, and research has shown that identity judgements are difficult for faces wearing masks. To date, however, the majority of experiments on face identification with masked faces tested humans and computer algorithms using images with superimposed masks rather than images of people wearing real face coverings. In three experiments we test humans (control participants and super-recognisers) and algorithms with images showing different types of face coverings. In all experiments we tested matching concealed or unconcealed faces to an unconcealed reference image, and we found a consistent decrease in face matching accuracy with masked compared to unconcealed faces. In Experiment 1, typical human observers were most accurate at face matching with unconcealed images, and poorer for three different types of superimposed mask conditions. In Experiment 2, we tested both typical observers and super-recognisers with superimposed and real face masks, and found that performance was poorer for real compared to superimposed masks. The same pattern was observed in Experiment 3 with algorithms. Our results highlight the importance of testing both humans and algorithms with real face masks, as using only superimposed masks may underestimate their detrimental effect on face identification.

Multisite clinical cross-validation and variant interpretation of a next generation sequencing panel for lymphoid cancer prognostication.

AIMS: Genomic sequencing of lymphomas is under-represented in routine clinical testing despite having prognostic and predictive value. Clinical implementation is challenging due to a lack of consensus on reportable targets and a paucity of reference samples. We organised a cross-validation study of a lymphoma-tailored next-generation sequencing panel between two College of American Pathologists (CAP)-accredited clinical laboratories to mitigate these challenges. METHODS: A consensus for the genomic targets was discussed between the two institutes based on recurrence in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and T-cell lymphomas. Using the same genomic targets, each laboratory ordered libraries independently and a cross-validation study was designed to exchange samples (8 cell lines and 22 clinical samples) and their FASTQ files. RESULTS: The sensitivity of the panel when comparing different library preparation and bioinformatic workflows was between 97% and 99% and specificity was 100% when a 5% limit of detection cut-off was applied. To evaluate how the current standards for variant classification of tumours apply to lymphomas, the Association for Molecular Pathology/American Society of Clinical Oncology/CAP and OncoKB classification systems were applied to the panel. The majority of variants were assigned a possibly actionable class or likely pathogenic due to more limited evidence in the literature. CONCLUSIONS: The cross-validation study highlights the benefits of sample and data exchange for clinical validation and provided a framework for reporting the findings in lymphoid malignancies.