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Temporal information, including information about temporal order and duration, is a fundamental component of event sequence memory. While previous research has demonstrated that aging can have a detrimental effect on memory for temporal order, there has been limited insight into the effect of aging on memory for durations, particularly within the context of sequences. In the current study, neurologically healthy young and older participants were administered two temporal match-mismatch tasks: one in which they were instructed on each trial to compare the temporal order or duration information of stimulus sequences presented first in a study phase and then, after a short delay, in a test phase (event sequence task); and a second in which participants were required to compare single durations or sequences of durations across study and test phases of each trial (pinwheel task). Consistent with the literature, the older participants were significantly poorer compared to their younger counterparts at making temporal order match-mismatch judgments in the event sequence task. In addition to this, data from both tasks suggested that the older adults were also less accurate at match-mismatch judgments based on duration information, with tentative evidence from the pinwheel task to suggest that this age-related effect was most prominent when the duration information was presented within a sequence. We suggest that age-related changes to medial temporal and frontal lobe function may contribute to changes in memory for temporal information in older adults, given the importance of these regions to event sequence memory.

The prefrontal cortex (PFC) has long been associated with arbitrating between approach and avoidance in the face of conflicting and uncertain motivational information, but recent work has also highlighted medial temporal lobe (MTL) involvement. It remains unclear, however, how the contributions of these regions differ in their resolution of conflict information and uncertainty. We designed an fMRI paradigm in which participants approached or avoided object pairs that differed by motivational conflict and outcome uncertainty (complete certainty vs. complete uncertainty). Behavioral data and decision-making parameters estimated using the hierarchical drift diffusion model revealed that participants’ responding was driven by conflict rather than uncertainty. Our neural data suggest that PFC areas contribute to cognitive control during approach-avoidance conflict by potentially adjusting response caution and the strength of evidence generated towards either choice, with differential involvement of anterior cingulate cortex and dorsolateral prefrontal cortex. The MTL, on the other hand, appears to contribute to evidence generation, with the hippocampus linked to evidence accumulation for stimuli. Although findings within perirhinal cortex were comparatively equivocal, some evidence suggests contributions to perceptual representations, particularly under conditions of threat. Our findings provide evidence that MTL and PFC regions may contribute uniquely to arbitrating approach-avoidance conflict.

Neural models of approach-avoidance (AA) conflict behavior and its dysfunction have focused traditionally on the hippocampus, with the assumption that this medial temporal lobe (MTL) structure plays a ubiquitous role in arbitrating AA conflict. We challenge this perspective by using three different AA behavioural tasks in conjunction with optogenetics, to demonstrate that a neighbouring region in rats, perirhinal cortex, is also critically involved but only when conflicting motivational values are associated with objects and not contextual information. The ventral hippocampus, in contrast, was found not to be essential for object-associated AA conflict, suggesting its preferential involvement in context-associated conflict. We propose that stimulus type can impact MTL involvement during AA conflict and that a more nuanced understanding of MTL contributions to impaired AA behaviour (e.g., anxiety) is required. These findings serve to expand upon the established functions of the perirhinal cortex while concurrently presenting innovative behavioural paradigms that permit the assessment of different facets of AA conflict behaviour.

BackgroundImpulsivity is a central symptom of borderline personality disorder (BPD) and its neural basis may be instantiated in a frontoparietal network involved in response inhibition. However, research has yet to determine whether neural activation differences in BPD associated with response inhibition are attributed to attentional saliency, which is subserved by a partially overlapping network of brain regions.MethodsPatients with BPD (n = 45) and 29 healthy controls (HCs; n = 29) underwent functional magnetic resonance imaging while completing a novel go/no-go task with infrequent odd-ball trials to control for attentional saliency. Contrasts reflecting a combination of response inhibition and attentional saliency (no-go > go), saliency processing alone (oddball > go), and response inhibition controlling for attentional saliency (no-go > oddball) were compared between BPD and HC.ResultsCompared to HC, BPD showed less activation in the combined no-go > go contrast in the right posterior inferior and middle-frontal gyri, and less activation for oddball > go in left-hemispheric inferior frontal junction, frontal pole, superior parietal lobe, and supramarginal gyri. Crucially, BPD and HC showed no activation differences for the no-go > oddball contrast. In BPD, higher vlPFC activation for no-go > go was correlated with greater self-rated BPD symptoms, whereas lower vlPFC activation for oddball > go was associated with greater self-rated attentional impulsivity.ConclusionsPatients with BPD show frontoparietal disruptions related to the combination of response inhibition and attentional saliency or saliency alone, but no specific response inhibition neural activation difference when attentional saliency is controlled. The findings suggest a neural dysfunction in BPD underlying attention to salient or infrequent stimuli, which is supported by a negative correlation with self-rated impulsiveness.

Background The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and the Tyrer-Cuzick breast cancer risk prediction models are commonly used in clinical practice and have recently been extended to include polygenic risk scores (PRS). In addition, BOADICEA has also been extended to include reproductive and lifestyle factors, which were already part of Tyrer-Cuzick model. We conducted a comparative prospective validation of these models after incorporating the recently developed 313-variant PRS. Methods Calibration and discrimination of 5-year absolute risk was assessed in a nested case-control sample of 1337 women of European ancestry (619 incident breast cancer cases) aged 23–75 years from the Generations Study. Results The extended BOADICEA model with reproductive/lifestyle factors and PRS was well calibrated across risk deciles; expected-to-observed ratio (E/O) at the highest risk decile :0.97 (95 % CI 0.51 − 1.86) for women younger than 50 years and 1.09 (0.66 − 1.80) for women 50 years or older. Adding reproductive/lifestyle factors and PRS to the BOADICEA model improved discrimination modestly in younger women (area under the curve (AUC) 69.7 % vs. 69.1%) and substantially in older women (AUC 64.6 % vs. 56.8%). The Tyrer-Cuzick model with PRS showed evidence of overestimation at the highest risk decile: E/O = 1.54(0.81 − 2.92) for younger and 1.73 (1.03 − 2.90) for older women. Conclusion The extended BOADICEA model identified women in a European-ancestry population at elevated breast cancer risk more accurately than the Tyrer-Cuzick model with PRS. With the increasing availability of PRS, these analyses can inform choice of risk models incorporating PRS for risk stratified breast cancer prevention among women of European ancestry.

Background Borderline personality disorder (BPD) is associated with subjective reports of forgetfulness and deficits on tests of memory performance. However, it is not yet known whether individuals with BPD show different patterns of activation in the hippocampus during episodic memory encoding, especially for materials that are not emotionally-valenced. Methods Participants with BPD (n = 20) and non-psychiatric controls (n = 21) completed a memory encoding task in which they viewed scenes without emotional content during functional magnetic resonance imaging scans. Subsequently, they completed a recognition memory test outside of the scanner and neural activation during the presentation of successfully remembered scenes was contrasted with scenes that were subsequently forgotten. Results Controls exhibited significant left hippocampal activation during successful memory encoding, displaying greater activity during the presentation of subsequently remembered versus forgotten scenes, and the strength of this activation was related to their recognition memory performance. Although hippocampal activation was observed for the BPD group during successful memory encoding, it did not reach significance when implementing a non-parametric statistical approach. Additionally, individual hippocampal recruitment was not significantly correlated with recognition memory performance in the BPD group. The strength of this correlation, but not the overall magnitude of hippocampal activation, was significantly different between the groups. Limitations Participants with BPD had comorbid psychiatric diagnoses and varied treatment histories. Whether patients and controls differentially perceived emotional content in the neutral scene memoranda was not tested. Conclusions Memory problems in BPD may be partially explained by a disrupted relationship between hippocampal activation and successful memory encoding.

Subjective similarity holds a prominent place in many psychological theories, influencing diverse cognitive processes ranging from attention and categorization to memory and problem solving. Despite the known importance of subjective similarity, there are few resources available to experimenters interested in manipulating the visual similarity of shape, one common type of subjective similarity. Here, across seven validation iterations, we incrementally developed a stimulus space consisting of 360 shapes using a novel image-processing method in conjunction with collected similarity judgments. The result is the Validated Circular Shape space, the first Validated Circular Shape space comparable to the commonly used "color wheel", whereby angular distance along a 2D circle is a proxy for visual similarity. This extensively validated resource is freely available to experimenters wishing to precisely manipulate the visual similarity of shape. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Purpose We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)-associated variants (PRS313) and other, nongenetic risk factors. Methods Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS(313)was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS(313)and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. Results In total, 320 women developed BC. The PRS(313)was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40-1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. Conclusions The effect size of the PRS(313)is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population.

The perirhinal cortex (PRC) is known to support recognition memory, working memory, and perception for objects. Often, information must be maintained in working memory in the face of ongoing visual perception, raising the question of how PRC and other regions supporting object representation deal with this conflict. Here, we used functional MRI to examine the representational content of human ventral visual pathway (VVP) regions, including perirhinal cortex (PRC), during a visual delayed match-to-sample task. Critically, interfering items from a different stimulus category to the target were presented to participants during the maintenance phase, creating conflict between the contents of working memory and ongoing perception. Using representational similarity analysis, we compared information content across study, interference and test phases to models that differed in the extent to which they predicted that information content would be maintained during the delay period and perturbed by interference. This revealed that lateral occipital and fusiform regions are best fit by models that reflect the stimulus content of the item currently being viewed, whereas PRC reflects the information content of the studied item, even when an interfering stimulus is presented during the delay. This division of labor within the VVP sheds light on the specialized nature of representations in VVP regions, including PRC. Our findings support a representational hierarchical understanding of medial temporal lobe function which posits that representations at the most anterior aspect of the VVP are more robust to ongoing perceptual activity.

Funder: Department of Health; FundRef: http://dx.doi.org/10.13039/501100000276, Funder: Ontario Research Fund, Funder: CHU de Quebec Foundation, Funder: Fondation du cancer du sein du Qu��bec; FundRef: http://dx.doi.org/10.13039/100016328, Funder: The Eve Appeal, Background: Epithelial tubo-ovarian cancer (EOC) has high mortality partly due to late diagnosis. Prevention is available but may be associated with adverse effects. A multifactorial risk model based on known genetic and epidemiological risk factors (RFs) for EOC can help identify women at higher risk who could benefit from targeted screening and prevention. Methods: We developed a multifactorial EOC risk model for women of European ancestry incorporating the effects of pathogenic variants (PVs) in BRCA1, BRCA2, RAD51C, RAD51D and BRIP1, a Polygenic Risk Score (PRS) of arbitrary size, the effects of RFs and explicit family history (FH) using a synthetic model approach. The PRS, PV and RFs were assumed to act multiplicatively. Results: Based on a currently available PRS for EOC that explains 5% of the EOC polygenic variance, the estimated lifetime risks under the multifactorial model in the general population vary from 0.5% to 4.6% for the first to 99th percentiles of the EOC risk distribution. The corresponding range for women with an affected first-degree relative is 1.9%���10.3%. Based on the combined risk distribution, 33% of RAD51D PV carriers are expected to have a lifetime EOC risk of less than 10%. RFs provided the widest distribution, followed by the PRS. In an independent partial model validation, absolute and relative 5-year risks were well calibrated in quintiles of predicted risk. Conclusion: This multifactorial risk model can facilitate stratification, in particular among women with FH of cancer and/or moderate-risk and high-risk PVs. The model is available via the CanRisk Tool (www.canrisk.org).

Funder: Genome Canada; doi: https://doi.org/10.13039/http://dx.doi.org/10.13039/100008762, Purpose: Breast cancer risk has conventionally been assessed using family history (FH) and rare high/moderate penetrance pathogenic variants (PVs), notably in BRCA1/2, and more recently PALB2, CHEK2, and ATM. In addition to these PVs, it is now possible to use increasingly predictive polygenic risk scores (PRS) as well. The comparative population-level predictive capability of these three different indicators of genetic risk for risk stratification is, however, unknown. Methods: The Canadian heritable breast cancer risk distribution was estimated using a novel genetic mixing model (GMM). A realistically representative sample of women was synthesized based on empirically observed demographic patterns for appropriately correlated family history, inheritance of rare PVs, PRS, and residual risk from an unknown polygenotype. Risk assessment was simulated using the BOADICEA risk algorithm for 10-year absolute breast cancer incidence, and compared to heritable risks as if the overall polygene, including its measured PRS component, and PV risks were fully known. Results: Generally, the PRS was most predictive for identifying women at high risk, while family history was the weakest. Only the PRS identified any women at low risk of breast cancer. Conclusion: PRS information would be the most important advance in enabling effective risk stratification for population-wide breast cancer screening.

Prospective validation of risk models is needed to assess their clinical utility, particularly over the longer term. We evaluated the performance of six commonly used breast cancer risk models (IBIS, BOADICEA, BRCAPRO, BRCAPRO-BCRAT, BCRAT, and iCARE-lit). 15-year risk scores were estimated using lifestyle factors and family history measures from 7608 women in the Melbourne Collaborative Cohort Study who were aged 50-65 years and unaffected at commencement of follow-up two (conducted in 2003-2007), of whom 351 subsequently developed breast cancer. Risk discrimination was assessed using the C-statistic and calibration using the expected/observed number of incident cases across the spectrum of risk by age group (50-54, 55-59, 60-65 years) and family history of breast cancer. C-statistics were higher for BOADICEA (0.59, 95% confidence interval (CI) 0.56-0.62) and IBIS (0.57, 95% CI 0.54-0.61) than the other models (p-difference ��� 0.04). No model except BOADICEA calibrated well across the spectrum of 15-year risk (p-value < 0.03). The performance of BOADICEA and IBIS was similar across age groups and for women with or without a family history. For middle-aged Australian women, BOADICEA and IBIS had the highest discriminatory accuracy of the six risk models, but apart from BOADICEA, no model was well-calibrated across the risk spectrum., This work was primarily supported by grant 1129136 from the Australian National Health and Medical Research Council (NHMRC) (https://www.nhmrc.gov.au/). MCCS cohort recruitment was funded by Cancer Council Victoria (https://www.cancervic.org.au/) and VicHealth (https://www.vichealth.vic.gov.au/). The MCCS was further supported by Australian NHMRC grants 209057, 396414 and 1074383, and ongoing follow-up and data management has been funded by Cancer Council Victoria since 1995. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database.TN-D is a recipient of a Career Development Fellowship from the National Breast Cancer Foundation (Australia). JLH and MCS are Senior Principal and Senior Research Fellows of the National Health and Medical Research Council (Australia), respectively. ACA and AJL are supported by grants from Cancer Research UK (C12292/A20861 and PPRPGM19 Nov20\100002).

A common challenge in drug design pertains to finding chemical modifications to a ligand that increases its affinity to the target protein. An underutilised advance is the increase in structural biology throughput, which has progressed from an artisanal endeavour to a monthly throughput of up to 100 different ligands against a protein in modern synchrotrons. However, the missing piece is a framework that turns high throughput crystallography data into predictive models for ligand design. Here we designed a simple machine learning approach that predicts protein-ligand affinity from experimental structures of diverse ligands against a single protein paired with biochemical measurements. Our key insight is using physics-based energy descriptors to represent protein-ligand complexes, and a learning-to-rank approach that infers the relevant differences between binding modes. We ran a high throughput crystallography campaign against the SARS-CoV-2 Main Protease (MPro), obtaining parallel measurements of over 200 protein-ligand complexes and the binding activity. This allows us to design a one-step library syntheses which improved the potency of two distinct micromolar hits by over 10-fold, arriving at a non-covalent and non-peptidomimetic inhibitor with 120 nM antiviral efficacy. Crucially, our approach successfully extends ligands to unexplored regions of the binding pocket, executing large and fruitful moves in chemical space with simple chemistry.

In this issue of Neuron, Bonnen et al. (2021) use artificial neural networks to resolve a long-standing controversy surrounding the neurocognitive dichotomy between memory and perception. They show that the perirhinal cortex supports performance on tasks that cannot be solved by the ventral visual stream.

In risk-stratified cancer screening, multiple risk factors are incorporated into the risk assessment. An individual’s estimated absolute cancer risk is linked to risk categories with tailored screening recommendations for each risk category. Absolute risk, expressed as either remaining lifetime risk or shorter-term (five- or ten-year) risk, is estimated from the age at assessment. These risk estimates vary by age, however, some clinical guidelines (e.g., enhanced breast cancer surveillance guidelines) and ongoing personalised breast screening trials, stratify women based on absolute risk thresholds that do not vary by age. We examine an alternative approach in which the risk thresholds used for risk stratification vary by age and consider the implications of using age-independent risk thresholds on risk stratification. We demonstrate that using an age-independent remaining lifetime risk threshold approach could identify high-risk younger women but would miss high-risk older women, whereas an age-independent 5-year or 10-year absolute risk threshold could miss high-risk younger women and classify lower-risk older women as high risk. With risk misclassification, women with an equivalent risk level would be offered a different screening plan. To mitigate these problems, age-dependent absolute risk thresholds should be used to inform risk stratification.

The ability to resolve an approach-avoidance conflict is critical to adaptive behavior. The ventral CA3 (vCA3) and CA1 (vCA1) subfields of the ventral hippocampus (vHPC) have been shown to facilitate avoidance and approach behavior, respectively, in the face of motivational conflict, but the neural circuits by which this subfield-specific regulation is implemented is unknown. We demonstrate that two distinct pathways from these subfields to lateral septum (LS) contribute to this divergent control. In Long-Evans rats, chemogenetic inhibition of the vCA3- LS caudodorsal (cd) pathway potentiated approach towards a learned conflict-eliciting stimulus, while inhibition of the vCA1-LS rostroventral (rv) pathway potentiated approach non-specifically. Additionally, vCA3-LScd inhibited animals were less hesitant to explore food during environmental uncertainty, while the vCA1- LSrv inhibited animals took longer to initiate food exploration. These findings suggest that the vHPC influences multiple behavioral systems via differential projections to the LS, which in turn send inhibitory projections to motivational centres of the brain.

Extensive work has demonstrated an age-related decline in face recognition, but the nature and the extent of aging-related alterations in face representations remain unclear. Here, we address these issues using an image reconstruction approach to reveal the content of visual representations. Healthy young and older adults provided similarity judgments for pairs of face images. Facial shape and surface features were subsequently derived and combined into image reconstructions of facial appearance. Both objective and experimental evaluations revealed that reconstructions were successful for every participant. Critically, shape and surface properties, such as eye shape and skin tone, were less accurately represented in older than young individuals. Yet, age-related differences in face representations, though significant, were less pronounced than those due to individual variability. Our results provide novel insights into age-related changes in visual perception and demonstrate the utility of image reconstruction to uncovering internal representations across a variety of populations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The ventral portion of the rodent hippocampus (HPC; anterior in primates) has been implicated in the detection and resolution of approach-avoidance conflict, which arises when an organism encounters a stimulus that predicts both positive and negative outcomes. Previous work has found differential regulation of approach-avoidance conflict behavior by the CA3 and CA1 subfields, with inhibition of ventral CA3 increasing approach toward conflicting stimuli and inhibition of the ventral CA1 potentiating avoidance. Here, we sought to extend these findings by investigating the role of the dentate gyrus (DG), the input region of the HPC, in learned approach-avoidance conflict processing in rats. Animals were first trained to acquire three different visuotactile cue-outcome associations in separate arms of a Y-maze (appetitive, aversive, and neutral). Postacquisition, they were administered a "conflict test," in which they were presented with a choice between exploring an arm in which the appetitive and aversive cues were concurrently presented (conflict stimulus), and another arm containing the neutral stimulus. GABAR-mediated inactivation of the ventral DG, but not dorsal DG, potentiated approach behavior toward the conflict stimulus, similar to the effects of ventral CA3 inactivation. In contrast, dorsal DG, but not ventral DG, inactivation was found to impair performance on a metric spatial discrimination task, which is commonly used as a test of pattern separation. The findings of this study demonstrate a robust double dissociation between the ventral and dorsal aspects of the DG, in line with previous reports of functional differences along the longitudinal axis of the HPC.

BackgroundThe currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2high-risk breast cancer families.Methods101 non-BRCA1/2high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS.ResultsThe mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively.ConclusionOur results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families.

The frontal cortex and temporal lobes together regulate complex learning and memory capabilities. Here, we collected resting-state functional and diffusion-weighted MRI data before and after male rhesus macaque monkeys received extensive training to learn novel visuospatial discriminations (reward-guided learning). We found functional connectivity changes in orbitofrontal, ventromedial prefrontal, inferotemporal, entorhinal, retrosplenial, and anterior cingulate cortices, the subicular complex, and the dorsal, medial thalamus. These corticocortical and thalamocortical changes in functional connectivity were accompanied by related white matter structural alterations in the uncinate fasciculus, fornix, and ventral prefrontal tract: tracts that connect (sub)cortical networks and are implicated in learning and memory processes in monkeys and humans. After the well-trained monkeys received fornix transection, they were impaired in learning new visuospatial discriminations. In addition, the functional connectivity profile that was observed after the training was altered. These changes were accompanied by white matter changes in the ventral prefrontal tract, although the integrity of the uncinate fasciculus remained unchanged. Our experiments highlight the importance of different communication relayed among corticocortical and thalamocortical circuitry for the ability to learn new visuospatial associations (learning-to-learn) and to make reward-guided decisions.SIGNIFICANCE STATEMENTFrontal neural networks and the temporal lobes contribute to reward-guided learning in mammals. Here, we provide novel insight by showing that specific corticocortical and thalamocortical functional connectivity is altered after rhesus monkeys received extensive training to learn novel visuospatial discriminations. Contiguous white matter fiber pathways linking these gray matter structures, namely, the uncinate fasciculus, fornix, and ventral prefrontal tract, showed structural changes after completing training in the visuospatial task. Additionally, different patterns of functional and structural connectivity are reported after removal of subcortical connections within the extended hippocampal system, via fornix transection. These results highlight the importance of both corticocortical and thalamocortical interactions in reward-guided learning in the normal brain and identify brain structures important for memory capabilities after injury.

Background Many individuals with borderline personality disorder (BPD) perceive emotional expressions in faces intended to convey no emotion and display a heightened sensitivity to facial expressions conveying threat, such as fear. In BPD, the amygdala activates in response to ambiguous and threatening facial expressions, although the differential sensitivity of this brain region to higher and lower intensities of fearful expressions and the relationship of this neural activity to personality impairments have not yet been investigated. Methods In the present study, we examined brain activation during an implicit facial emotion task with neutral faces and fearful expressions displayed at 50% and 100% intensity in patients with BPD (n=45) and healthy controls (HC; n=25). Results On neutral faces, higher brain activation was found in BPD compared to HC in the right temporal pole, amygdala, hippocampus, pallidum, and orbitofrontal cortex, whereas no significant whole-brain group differences were observed for either intensity of fearful expressions. A region-of-interest analysis focused on the amygdala-hippocampal complex showed greater activation for neutral and 50%-intensity fearful faces in BPD. Severity of personality impairment in the domains of empathy and identity were associated with higher precuneus activity during neutral and 100%-fearful face processing. Limitations Brain activation differences of this naturalistic severely ill inpatient sample may be influenced by comorbid Axis-I disorders often seen in samples of BPD. Conclusions: These findings suggest a heightened amygdala-hippocampal response to neutral faces and moderate-intensity fearful expressions in BPD, while self and interpersonal impairments are associated with task-based activations in regions implicated in self-referential processes.

Recent research has demonstrated that neural and behavioral data acquired in response to viewing face images can be used to reconstruct the images themselves. However, the theoretical implications, promises, and challenges of this direction of research remain unclear. Here, we evaluate the potential of this research for elucidating the visual representations underlying face recognition. Specifically, we outline complementary and converging accounts of the visual content, the representational structure, and the neural dynamics of face processing. We illustrate how this research addresses fundamental questions in the study of normal and impaired face recognition, and how image reconstruction provides a powerful framework for uncovering face representations, for unifying multiple types of empirical data, and for facilitating both theoretical and methodological progress.

Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Extensive work has demonstrated a decline in face recognition abilities associated with healthy aging. To date, however, there has been limited insight into the nature and the extent of aging-related alterations in internal face representations. Here, we sought to address these issues by using an image reconstruction approach that capitalizes on the structure of behavioral data to reveal the pictorial content of visual representations. To this end, healthy young and older adults provided similarity judgments with pairs of face images. Facial shape and surface features were subsequently derived from the structure of the data for each participant and combined into image reconstructions of facial appearance. Our findings revealed that image reconstruction was successful for every participant, irrespective of age. However, reconstruction accuracies of shape and surface information were lower for older individuals than young individuals. Specifically, facial features diagnostic for face perception, such as eye shape and skin tone, were reconstructed poorly in older adults relative to young adults. At the same time, we found that age-related effects only accounted for a relatively small proportion of individual variability in face representations. Thus, our results provide novel insight into age-related changes in visual perception, they account for the decline in facial recognition occurring with age and they demonstrate the utility of image reconstruction to uncovering internal representations across a variety of populations.

Recent investigations have focused on the spatiotemporal dynamics of visual recognition by appealing to pattern analysis of EEG signals. While this work has established the ability to decode identity-level information (such as the identity of a face or of a word) from neural signals, much less is known about the precise nature of the signals that support such feats, their robustness across visual categories, or their consistency across human participants. Here, we address these questions through the use of EEG-based decoding and multivariate feature selection as applied to three visual categories: words, faces and face ensembles (i.e., crowds of faces). Specifically, we use recursive feature elimination to estimate the diagnosticity of time and frequency-based EEG features for identity-level decoding across three datasets targeting each of the three categories. We then relate feature diagnosticity across categories and across participants while, also, aiming to increase decoding performance and reliability. Our investigation shows that word and face processing are similar in their reliance on spatiotemporal information provided by occipitotemporal channels. In contrast, ensemble processing appears to also rely on central channels and exhibits a similar profile with word processing in the frequency domain. Further, we find that feature diagnosticity is stable across participants and is even capable of supporting cross-participant feature selection, as demonstrated by systematic boosts in decoding accuracy and feature reduction. Thus, our investigation sheds new light on the nature and the structure of the information underlying identity-level visual processing as well as on its generality across categories and participants.

Recent interest in the role of the hippocampus in temporal aspects of cognition has been fueled, in part, by the observation of “time” cells in the rodent hippocampus—that is, cells that have differential firing patterns depending on how long ago an event occurred. Such cells are thought to provide an internal representation of elapsed time. Yet, the hippocampus is not needed for processing temporal duration information per se, at least on the order of seconds, as evidenced by intact duration judgments in rodents and humans with hippocampal damage. Rather, it has been proposed that the hippocampus may be essential for coding higher order aspects of temporal mnemonic processing, such as those needed to temporally organize a sequence of events that form an episode. To examine whether (1) the hippocampus uses duration information in the service of establishing temporal relations among events and (2) its role in memory for duration is unique to sequences, we tested amnesic patients with medial-temporal lobe damage (including the hippocampus). We hypothesized that medial-temporal lobe damage should impair the ability to remember sequential duration information but leave intact judgments about duration devoid of a sequential demand. We found that amnesics were impaired in making judgments about durations within a sequence but not in judging single durations. This impairment was not due to higher cognitive load associated with duration judgments about sequences. In convergence with rodent and human fMRI work, these findings shed light on how time coding in the hippocampus may contribute to temporal cognition.

There has been much interest in how the hippocampus codes time in support of episodic memory. Notably, while rodent hippocampal neurons, including populations in subfield CA1, have been shown to represent the passage of time in the order of seconds between events, there is limited support for a similar mechanism in humans. Specifically, there is no clear evidence that human hippocampal activity during long-term memory processing is sensitive to temporal duration information that spans seconds. To address this gap, we asked participants to first learn short event sequences that varied in image content and interval durations. During fMRI, participants then completed a recognition memory task, as well as a recall phase in which they were required to mentally replay each sequence in as much detail as possible. We found that individual sequences could be classified using activity patterns in the anterior hippocampus during recognition memory. Critically, successful classification was dependent on the conjunction of event content and temporal structure information (with unsuccessful classification of image content or interval duration alone), and further analyses suggested that the most informative voxels resided in the anterior CA1. Additionally, a classifier trained on anterior CA1 recognition data could successfully identify individual sequences from the mental replay data, suggesting that similar activity patterns supported participants' recognition and recall memory. Our findings complement recent rodent hippocampal research, and provide evidence that long-term sequence memory representations in the human hippocampus can reflect duration information in the order of seconds.

Although we can all agree that interference induces forgetting, there is surprisingly little consensus regarding what type of interference most likely disrupts memory. We previously proposed that the similarity of interference differentially impacts the representational detail of color memory. Here, we extend this work by applying the Validated Circular Shape Space (Li et al., 2020) for the first time to a continuous retrieval task, in which we quantified both the visual similarity of distracting information as well as the representational detail of shape memory. We found that the representational detail of memory was systematically and differentially altered by the similarity of distracting information. Dissimilar distractors disrupted both fine- and coarse-grained information about the target, akin to memory erasure. In contrast, similar distractors disrupted fine-grained target information but increased reliance on coarse-grained information about the target, akin to memory blurring. Notably, these effects were consistent across two mixture models that each implemented a different scaling metric (either angular distance or perceived target similarity), as well as a parameter-free analysis that did not fit the mixture model. These findings suggest that similar distractors will help memory in cases where coarse-grained information is sufficient to identify the target. In other cases where precise fine-grained information is needed to identify the target, similar distractors will impair memory. As these effects have now been observed across both stimulus domains of shape and color, and were robust across multiple scaling metrics and methods of analyses, we suggest that these results provide a general set of principles governing how the nature of interference impacts forgetting.

Issue Online: 23 October 2019 Investigations into the neural basis of reading have shed light on the cortical locus and the functional role of visual-orthographic processing. Yet, the fine-grained structure of neural representations subserving reading remains to be clarified. Here, we capitalize on the spatiotemporal structure of electroencephalography (EEG) data to examine if and how EEG patterns can serve to decode and reconstruct the internal representation of visually presented words in healthy adults. Our results show that word classification and image reconstruction were accurate well above chance, that their temporal profile exhibited an early onset, soon after 100 ms, and peaked around 170 ms. Further, reconstruction results were well explained by a combination of visual-orthographic word properties. Last, systematic individual differences were detected in orthographic representations across participants. Collectively, our results establish the feasibility of EEG-based word decoding and image reconstruction. More generally, they help to elucidate the specific features, dynamics, and neurocomputational principles underlying word recognition. This research was supported by the Natural Sciences and Engineering Research Council of Canada (to A.N., A.C.H.L., and B. C. A.).

Surprisingly little is known about how the brain combines spatial elements to form a coherent percept. Regions that may underlie this process include the hippocampus (HC) and parahippocampal place area (PPA), regions central to spatial perception but whose role in spatial coherency has not been explored. Participants were scanned with functional MRI while they judged whether Escher-like scenes were possible or impossible. Univariate analyses revealed differential HC and PPA involvement, with greater HC activity during spatial incoherency detection and more PPA activity during spatial coherency detection. Recognition and eye-tracking data ruled out long- or short-term memory confounds. Multivariate statistics demonstrated spatial coherency-dependent functional connectivity for the HC, but not PPA, with greater HC connectivity to various brain regions including lateral occipital complex during spatial incoherency detection. We suggest the PPA is preferentially involved during the perception of spatially coherent scenes, whereas the HC binds distinct features to create coherent representations. © 2016 Wiley Periodicals, Inc.

There is an ongoing debate regarding the nature of memory deficits that occur in the early stages of mild cognitive impairment (MCI). MCI has been associated with atrophy to regions that process objects, namely perirhinal and lateral entorhinal cortices. However, it is currently unclear whether older adults with early MCI will show memory deficits that are specific to objects, or whether they will also show memory deficits for other stimulus classes, such as scenes. We tested 75 older adults using an object and scene recognition task with stimulus-specific interference (i.e., exposure to irrelevant object or scene stimuli). We found an interaction (P = 0.05) whereby scores on the Montreal Cognitive Assessment, a neuropsychological test with high sensitivity to MCI, shared a stronger relationship with object recognition than with scene recognition performance. Interestingly, this relationship was not modulated by the stimulus category of interfering items. To further explore these findings, we also tested an amnesic patient (DA) with known medial temporal lobe damage. Like older adults with early signs of MCI, DA showed poorer object recognition than scene recognition performance. Additionally, his performance was not modulated by the stimulus category of interfering material. By demonstrating that object memory is more predictive of cognitive decline than scene memory, these findings support the notion of perirhinal and lateral entorhinal cortex dysfunction in the early stages of MCI. © 2016 Wiley Periodicals, Inc.

There has been growing recognition of the contribution of medial and anterior temporal lobe structures to non-mnemonic functions, such as perception. To evaluate the nature of this contribution, we contrast the perceptual performance of three patient groups, all of whom have a perturbation of these temporal lobe structures. Specifically, we compare the profile of patients with focal hippocampal (HC) lesions, those with more extensive lesions to the medial temporal lobe (MTL) that include HC and perirhinal cortex (PrC), and those with congenital prosopagnosia (CP), whose deficit has been attributed to the disconnection of the anterior temporal lobe from more posterior structures. All participants completed a range of'oddity' tasks in which, on each trial, they determined which of four visual stimuli in a display was the'odd-one-out'. There were five stimulus categories including faces, scenes, objects (high and low ambiguity) and squares of different sizes. Comparisons were conducted separately for the HC, MTL and CP groups against their matched control groups and then the group data were compared to each other directly. The group profiles were easily differentiable. Whereas the HC group stood out for its difficulty in discriminating scenes and the CP group stood out for its disproportionate difficulty in discriminating faces with milder effects for scenes and high ambiguity objects, the MTL group evinced a more general discrimination deficit for faces, scenes and high ambiguity objects. The group differences highlight distinct profiles for each of the three groups and distinguish the signature perceptual impairments following more extended temporal lobe alterations. In the recent reconsideration of the role of the hippocampus and neocortex, Moscovitch and colleagues (Moscovitch et al., 2016) note that the medial temporal lobe structures play a role in non-mnemonic functions, such as perception, problem solving, decision-making and language. Here, we address this exact issue, specifically with respect to perception, and we dedicate this paper to Morris Moscovitch in recognition of his profound contribution to science, to his students and to his colleagues.

Although a large body of research has implicated the hippocampus in the processing of memory for temporal duration, there is an exigent degree of inconsistency across studies that obfuscates the precise contributions of this structure. To shed light on this issue, the present review article surveys both historical and recent cross-species evidence emanating from a wide variety of experimental paradigms, identifying areas of convergence and divergence. We suggest that while factors such as time-scale (e.g. the length of durations involved) and the nature of memory processing (e.g. prospective vs. retrospective memory) are very helpful in the interpretation of existing data, an additional important consideration is the context in which the duration information is experienced and processed, with the hippocampus being preferentially involved in memory for durations that are embedded within a sequence of events. We consider the mechanisms that may underpin temporal duration memory and how the same mechanisms may contribute to memory for other aspects of event sequences such as temporal order.

Fundamental to the understanding of the functions of spatial cognition and attention is to clarify the underlying neural mechanisms. It is clear that relatively right-dominant activity in ventral and dorsal parieto-frontal cortex is associated with attentional reorienting, certain forms of mental imagery and spatial working memory for higher loads, while lesions mostly to right ventral areas cause spatial neglect with pathological attentional biases to the right side. In contrast, complementary leftward biases in healthy people, called pseudoneglect, have been associated with varying patterns of cortical activity. Notably, this inconsistency may be explained, at least in part, by the fact that pseudoneglect studies have often employed experimental paradigms that do not control sufficiently for cognitive processes unrelated to pseudoneglect. To address this issue, here we administered a carefully designed continuum of pseudoneglect and control tasks in healthy adults while using functional magnetic resonance imaging (fMRI). Data submitted to partial least square (PLS) imaging analysis yielded a significant latent variable that identified a right-dominant network of brain regions along the intra-occipital and -parietal sulci, frontal eye fields and right ventral cortex in association with perceptual pseudoneglect. Our results shed new light on the interplay of attentional and cognitive systems in pseudoneglect.

BACKGROUND. Differences in regional brain volumes as a function of family history (FH) of alcohol use disorder (AUD) have been reported, and it has been suggested that these differences might index genetic risk for AUD. However, results have been inconsistent. The aims of the current study were 1) to provide an updated descriptive review of the existing literature; and 2) to examine the association of FH with indices of subcortical volumes and cortical thickness in a sample of youth recruited based on FH status. METHODS. To address aim 1, a literature search located fifteen published studies comprising 1735 participants. Studies were characterized according to population, analytic methods, regions of interest (ROIs), and primary findings. To address the second aim, we examined volumetric and cortical thickness in a sample of 69 youth (mean age = 19.71 years, SD = 0.79) recruited based on FH status and matched on drinking variables. Associations of sex and alcohol use with volumetric outcomes were also examined. RESULTS. Our descriptive review revealed an inconsistent pattern of results with respect to the presence, direction, and regional specificity of volumetric differences across FH groups. The most consistent finding, significantly smaller amygdala volumes in FH+ participants, was not replicated in all studies. In the current sample of youth, measures of subcortical volumes and cortical thickness did not significantly differ as a function of FH, sex, or their interaction. CONCLUSIONS. Evidence for FH group differences in regional brain volumes is inconsistent, and the current study failed to detect any group differences. Further research is needed to confirm the reproducibility of FH group differences and implications for AUD risk.

Recent rodent work suggests the hippocampus may provide a temporal representation of event sequences, in which the order of events and the interval durations between them are encoded. There is, however, limited human evidence for the latter, in particular whether the hippocampus processes duration information pertaining to the passage of time rather than qualitative or quantitative changes in event content. We scanned participants while they made match-mismatch judgements on each trial between a study sequence of events and a subsequent test sequence. Participants explicitly remembered event order or interval duration information (Experiment 1), or monitored order only, with duration being manipulated implicitly (Experiment 2). Hippocampal study-test pattern similarity was significantly reduced by changes to order or duration in mismatch trials, even when duration was processed implicitly. Our findings suggest the human hippocampus processes short intervals within sequences and support the idea that duration information is integrated into hippocampal mnemonic representations.

Recent work has demonstrated that the perirhinal cortex (PRC) supports conjunctive object representations that aid object recognition memory following visual object interference. It is unclear, however, how these representations interact with other brain regions implicated in mnemonic retrieval and how congruent and incongruent interference influences the processing of targets and foils during object recognition. To address this, multivariate partial least squares was applied to fMRI data acquired during an interference match-to-sample task, in which participants made object or scene recognition judgments after object or scene interference. This revealed a pattern of activity sensitive to object recognition following congruent (i.e., object) interference that included PRC, prefrontal, and parietal regions. Moreover, functional connectivity analysis revealed a common pattern of PRC connectivity across interference and recognition conditions. Examination of eye movements during the same task in a separate study revealed that participants gazed more at targets than foils during correct object recognition decisions, regardless of interference congruency. By contrast, participants viewed foils more than targets for incorrect object memory judgments, but only after congruent interference. Our findings suggest that congruent interference makes object foils appear familiar and that a network of regions, including PRC, is recruited to overcome the effects of interference.

Prostate cancer is the second most common cancer in men worldwide and a leading cause of mortality. Incidences continues to rise and vary substantially between populations. Although the prevalence of prostate cancer is relatively low in Vietnam, some hospital-based reports have shown an upward trend in recent years. While certain non-modifiable factors such as age, race and genetics are known to be mainly responsible, the literature has also suggested that environmental exposures can delay the onset of this disease. The present study provides a review of the epidemiology of prostate cancer in Vietnam by systematically searching several electronic databases. The results confirm an increasing trend of prostate cancer over the past decade, with age-standardised rate more than doubled from 2.2 per 100,000 men in 2000 to 4.7 per 100,000 men in 2010. However, no study has been found on modifiable risk factors, with the exception of one in vitro experiment that showed the inhibitory effect of garlic on the growth of prostate cancer cells. The lack of epidemiological information poses a difficulty to develop public health interventions to prevent this emerging malignant disease in Vietnam.

The ventral hippocampus is thought to play a key role in the resolution of approach-avoidance conflict, a scenario that arises when stimuli with opposing valences are present simultaneously. Little is known, however, about the contributions of specific hippocampal sub-regions in this process, a critical issue given the functional and anatomical heterogeneity of this structure. Using a non-spatial cue-based paradigm in rats, we found that transient pharmacological inactivation of ventral CA1 produced an avoidance of a conflict cue imbued with both learned positive and negative outcomes, whereas inactivation of the ventral CA3 resulted in the opposite pattern of behavior, with significant preference for the conflict cue. In contrast, dorsal CA1- and CA3- inactivated rats showed no change in conflict behavior. Our findings provide important insight into the functions and circuitry of the ventral hippocampus by demonstrating that the ventral CA1 and CA3 subserve distinct and opposing roles in approach-avoidance conflict processing.Grant sponsorNatural Science and Engineering Research Council (N.S.E.R.C) of Canada awarded to RI (402642) and ACHL (402651).

Background: The cost-effectiveness of population-based panel testing for high- and moderate-penetrance ovarian cancer (OC)/breast cancer (BC) gene mutations is unknown. We evaluate the cost-effectiveness of population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutation testing compared with clinical criteria/family history (FH) testing in unselected general population women. Methods: A decision-analytic model comparing lifetime costs and effects of criteria/FH-based BRCA1/BRCA2 testing is compared with BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing in those fulfilling clinical criteria/strong FH of cancer (≥10% BRCA1/BRCA2 probability) and all women age 30 years or older. Analyses are presented for UK and US populations. Identified carriers undergo risk-reducing salpingo-oophorectomy. BRCA1/BRCA2/PALB2 carriers can opt for magnetic resonance imaging/mammography, chemoprevention, or risk-reducing mastectomy. One-way and probabilistic sensitivity analysis (PSA) enabled model uncertainty evaluation. Outcomes include OC, BC, and additional heart disease deaths. Quality-adjusted life-years (QALYs), OC incidence, BC incidence, and incremental cost-effectiveness ratio (ICER) were calculated. The time horizon is lifetime and perspective is payer. Results: Compared with clinical criteria/FH-based BRCA1/BRCA2 testing, clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is cost-effective (ICER = £7629.65/QALY or $49 282.19/QALY; 0.04 days' life-expectancy gained). Population-based testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutations is the most cost-effective strategy compared with current policy: ICER = £21 599.96/QALY or $54 769.78/QALY (9.34 or 7.57 days' life-expectancy gained). At £30 000/QALY and $100 000/QALY willingness-to-pay thresholds, population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 panel testing is the preferred strategy in 83.7% and 92.7% of PSA simulations; criteria/FH-based panel testing is preferred in 16.2% and 5.8% of simulations, respectively. Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing can prevent 1.86%/1.91% of BC and 3.2%/4.88% of OC in UK/US women: 657/655 OC cases and 2420/2386 BC cases prevented per million. Conclusions: Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than any clinical criteria/FH-based strategy. Clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than BRCA1/BRCA2 testing alone.

Visual memory for faces has been extensively researched, especially regarding the main factors that influence face memorability. However, what we remember exactly about a face, namely, the pictorial content of visual memory, remains largely unclear. The current work aims to elucidate this issue by reconstructing face images from both perceptual and memory-based behavioural data. Specifically, our work builds upon and further validates the hypothesis that visual memory and perception share a common representational basis underlying facial identity recognition. To this end, we derived facial features directly from perceptual data and then used such features for image reconstruction separately from perception and memory data. Successful levels of reconstruction were achieved in both cases for newly-learned faces as well as for familiar faces retrieved from long-term memory. Theoretically, this work provides insights into the content of memory-based representations while, practically, it may open the path to novel applications, such as computer-based ‘sketch artists’.

Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component. Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer. Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404–12. ©2016 AACR.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P