Summary Survivors of childhood cancer treated with anthracycline chemotherapy or chest radiation are at an increased risk of developing congestive heart failure. In this population, congestive heart ...failure is well recognised as a progressive disorder, with a variable period of asymptomatic cardiomyopathy that precedes signs and symptoms. As a result, several clinical practice guidelines have been developed independently to help with detection and treatment of asymptomatic cardiomyopathy. These guidelines differ with regards to definitions of at-risk populations, surveillance modality and frequency, and recommendations for interventions. Differences between these guidelines could hinder the effective implementation of these recommendations. We report on the results of an international collaboration to harmonise existing cardiomyopathy surveillance recommendations using an evidence-based approach that relied on standardised definitions for outcomes of interest and transparent presentation of the quality of the evidence. The resultant recommendations were graded according to the quality of the evidence and the potential benefit gained from early detection and intervention.
Among patients in whom childhood cancer was diagnosed in the 1970s and 1980s, 18% of those who survived for 5 years died within the subsequent 25 years. In recent decades, cancer treatments have been ...modified with the goal of reducing life-threatening late effects.
We evaluated late mortality among 34,033 patients in the Childhood Cancer Survivor Study cohort who survived at least 5 years after childhood cancer (i.e., cancer diagnosed before the age of 21 years) for which treatment was initiated during the period from 1970 through 1999. The median follow-up was 21 years (range, 5 to 38). We evaluated demographic and disease factors that were associated with death from health-related causes (i.e., conditions that exclude recurrence or progression of the original cancer and external causes but include the late effects of cancer therapy) using cumulative incidence and piecewise exponential models to estimate relative rates and 95% confidence intervals.
Of the 3958 deaths that occurred during the study period, 1618 (41%) were attributable to health-related causes, including 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes. A reduction in 15-year mortality was observed for death from any cause (from 12.4% in the early 1970s to 6.0% in the 1990s, P<0.001 for trend) and from health-related causes (from 3.5% to 2.1%, P<0.001 for trend). These reductions were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04). Changes in therapy according to decade included reduced rates of cranial radiotherapy for acute lymphoblastic leukemia (85% in the 1970s, 51% in the 1980s, and 19% in the 1990s), of abdominal radiotherapy for Wilms' tumor (78%, 53%, and 43%, respectively), of chest radiotherapy for Hodgkin's lymphoma (87%, 79%, and 61%, respectively), and of anthracycline exposure. Reduction in treatment exposure was associated with reduced late mortality among survivors of acute lymphoblastic leukemia and Wilms' tumor.
The strategy of lowering therapeutic exposure has contributed to an observed decline in late mortality among 5-year survivors of childhood cancer. (Funded by the National Cancer Institute and the American Lebanese-Syrian Associated Charities.).
Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While gamma ...amino-butyric acid Type A (GABAA) receptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites. Using middle-down mass spectrometry (MS), we identified three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human α1β3 GABAA receptor. Novel intrasubunit binding sites were identified within the transmembrane helical bundles of both the α1 (labeled residues α1-N408, Y415) and β3 (labeled residue β3-Y442) subunits, adjacent to the extracellular domains (ECDs). An intersubunit site (labeled residues β3-L294 and G308) in the interface between the β3(+) and α1(-) subunits of the GABAA receptor pentamer was also identified. Computational docking studies of neurosteroid to the three sites predicted critical residues contributing to neurosteroid interaction with the GABAA receptors. Electrophysiological studies of receptors with mutations based on these predictions (α1-V227W, N408A/Y411F, and Q242L) indicate that both the α1 intrasubunit and β3-α1 intersubunit sites are critical for neurosteroid action.
Young children with limited knowledge of formal mathematics can intuitively perform basic arithmetic‐like operations over nonsymbolic, approximate representations of quantity. However, the ...algorithmic rules that guide such nonsymbolic operations are not entirely clear. We asked whether nonsymbolic arithmetic operations have a function‐like structure, like symbolic arithmetic. Children (n = 74 4‐ to ‐8‐year‐olds in Experiment 1; n = 52 7‐ to 8‐year‐olds in Experiment 2) first solved two nonsymbolic arithmetic problems. We then showed children two unequal sets of objects, and asked children which of the two derived solutions should be added to the smaller of the two sets to make them “about the same.” We hypothesized that, if nonsymbolic arithmetic follows similar function rules to symbolic arithmetic, then children should be able to use the solutions of nonsymbolic computations as inputs into another nonsymbolic problem. Contrary to this hypothesis, we found that children were unable to reliably do so, suggesting that these solutions may not operate as independent representations that can be used inputs into other nonsymbolic computations. These results suggest that nonsymbolic and symbolic arithmetic computations are algorithmically distinct, which may limit the extent to which children can leverage nonsymbolic arithmetic intuitions to acquire formal mathematics knowledge.
Vaccination-associated adenopathy is a frequent imaging finding after administration of COVID-19 vaccines that may lead to a diagnostic conundrum in patients with manifest or suspected cancer, in ...whom it may be indistinguishable from malignant nodal involvement. To help the medical community address this concern in the absence of studies and evidence-based guidelines, this special report offers recommendations developed by a multidisciplinary panel of experts from three of the leading tertiary care cancer centers in the United States. According to these recommendations, some routine imaging examinations, such as those for screening, should be scheduled before or at least 6 weeks after the final vaccination dose to allow for any reactive adenopathy to resolve. However, there should be no delay of other clinically indicated imaging (eg, for acute symptoms, short-interval treatment monitoring, urgent treatment planning or complications) due to prior vaccination. The vaccine should be administered on the side contralateral to the primary or suspected cancer, and both doses should be administered in the same arm. Vaccination information-date(s) administered, injection site(s), laterality, and type of vaccine-should be included in every preimaging patient questionnaire, and this information should be made readily available to interpreting radiologists. Clear and effective communication between patients, radiologists, referring physician teams, and the general public should be considered of the highest priority when managing adenopathy in the setting of COVID-19 vaccination.
Children live in a dynamic environment, in which objects continually change locations and move into and out of occlusion. Children must therefore rely on working memory to store information from the ...environment and to update those stored representations as the environment changes. Previous work suggests that the ability to store information in working memory increases through infancy and childhood. However, less is known about the development of the ability to update stored information. Participants were 63 4-7-year-old children (37 girls; 34 caregivers completed optional demographic forms, and those children were reported as Asian one, Asian/White four, Black one, Middle East/Arab one, or White 27; two were Hispanic/Latinx). We asked children to keep track of arrays of hidden items that either remained where they were hidden (static trials) or swapped locations (swap trials) and then to identify from two alternatives which item was hidden in a particular location. We manipulated the number of items in the arrays and the number of times the items swapped locations in order to investigate how increasing storage and updating load impacted children's performance. We found that children's ability to update working memory developed significantly across our age range. Updating appeared to impose a significant one-time cost to working memory performance, regardless of the number of times items swapped. Our results yield new insights into the developmental trajectories of storage and updating in working memory across early childhood.
•Children can reason by exclusion to infer unknown identities in working memory.•The use of reasoning by exclusion also poses additional cognitive demands.•The cognitive cost of reasoning by ...exclusion eases with development.
Reasoning by exclusion allows us to form more complete representations of our environments, “filling in” inaccessible information by ruling out known alternatives. In two experiments (Experiment 1: N = 34 4- to 6-year-olds; Experiment 2: N = 85 4- to 8-year-olds), we examined children’s ability to use reasoning by exclusion to infer the identity of an unknown object and investigated the role of working memory in this ability. Children were asked to encode a set of objects that were then hidden, and after a brief retention interval children were asked to select the identity of the object hidden in one of the locations from two alternatives. On some trials, all the images were visible during encoding, so selecting the correct identity when probed required successful working memory storage and retrieval. On other trials, all but one of the images was visible during encoding, so selecting the correct identity when probed also required maintaining a representation of an unknown object in working memory and then using reasoning by exclusion to fill in the missing information retroactively to complete that representation by ruling out known alternatives. To investigate the working memory cost of exclusive reasoning, we manipulated the working memory demands of the task. Our results suggest that children can use reasoning by exclusion to retroactively assign an identity to an incomplete object representation at least by 4 years of age but that this ability incurs some cognitive cost, which eases with development. These results provide new insights into children’s representational capacities and on the foundational building blocks of fully developed exclusive reasoning.
Children can represent the approximate quantity of sets of items using the Approximate Number System (ANS), and can perform arithmetic-like operations over ANS representations. Previous work has ...shown that the representational precision of the ANS develops substantially during childhood. However, less is known about the development of the
operational
precision of the ANS. We examined developmental change in the precision of the solutions to two non-symbolic arithmetic operations in 4-6-year-old U.S. children. We asked children to represent the quantity of an occluded set (Baseline condition), to compute the sum of two sequentially occluded arrays (Addition condition), or to infer the quantity of an addend after observing an initial array and then the array incremented by the unknown addend (Unknown-addend condition). We measured the precision of the solutions of these operations by asking children to compare their solutions to visible arrays, manipulating the ratio between the true quantity of the solution and the comparison array. We found that the precision of ANS representations that were not the result of operations (in the Baseline condition) was higher than the precision of solutions to ANS operations (in the Addition and Unknown-addend conditions). Further, we found that precision in the Baseline and Addition conditions improved significantly between 4 and 6 years, while precision in the Unknown-Addend condition did not. Our results suggest that ANS operations may inject “noise” into the representations they operate over, and that the development of the precision of different operations may follow different trajectories in childhood.
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