Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations.

BACKGROUND: Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking. METHODS: Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case-control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed. RESULTS: Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V ˙ e, V ˙ O2, V ˙ CO2, V ˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V ˙ e/ V ˙ CO2, PetCO2, O2pulse, work, V ˙ O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1. CONCLUSIONS: Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.

"You need to be super smart to do well in math!" Young children's field-specific ability beliefs.

Success in science, technology, engineering, and mathematics (STEM) fields is often believed to require intellectual talent ("brilliance"). Given that many cultures associate men more than women with brilliance, this belief poses an obstacle to women's STEM pursuits. Here, we investigated the developmental roots of this phenomenon, focusing specifically on young children's beliefs about math (N = 174 U.S. students in Grades 1-4; 93 girls, 81 boys; 52% White, 17% Asian, 13% Hispanic/Latinx). We found that field-specific ability beliefs (FABs) that associate success in math (vs. reading/writing) with brilliance are already present in early elementary school. We also found that brilliance-oriented FABs about math are negatively associated with elementary school students' (and particularly girls') math motivation-specifically, their math self-efficacy and interest. The early emergence of brilliance-oriented FABs about math and the negative relation between FABs and math motivation underscore the need to understand the sources and long-term effects of these beliefs. RESEARCH HIGHLIGHTS: Field-specific ability beliefs (FABs) are beliefs about the extent to which intellectual talent (or "brilliance") is required for success in a particular field or context. Among adults, brilliance-oriented FABs are an obstacle to diversity in science and technology, but the childhood antecedents of these beliefs are not well understood. The present study (N = 174) found that FABs that associate success in math (vs. reading/writing) with brilliance were already present in Grades 1-4. Brilliance-oriented FABs about math were negatively associated with elementary school students' (and particularly girls') math motivation-specifically, their math self-efficacy and interest.

A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is estimated to affect 0.4%-2.5% of the global population. Most cases are unexplained; however, some patients describe an antecedent viral infection or response to antiviral medications. We report here a multicenter study for the presence of viral nucleic acid in blood, feces, and saliva of patients with ME/CFS using polymerase chain reaction and high-throughput sequencing. We found no consistent group-specific differences other than a lower prevalence of anelloviruses in cases compared to healthy controls. Our findings suggest that future investigations into viral infections in ME/CFS should focus on adaptive immune responses rather than surveillance for viral gene products.

Young children interpret number gestures differently than nonsymbolic sets.

Researchers have long been interested in the origins of humans' understanding of symbolic number, focusing primarily on how children learn the meanings of number words (e.g., "one", "two", etc.). However, recent evidence indicates that children learn the meanings of number gestures before learning number words. In the present set of experiments, we ask whether children's early knowledge of number gestures resembles their knowledge of nonsymbolic number. In four experiments, we show that preschool children (n = 139 in total; age M = 4.14 years, SD = 0.71, range = 2.75-6.20) do not view number gestures in the same the way that they view nonsymbolic representations of quantity (i.e., arrays of shapes), which opens the door for the possibility that young children view number gestures as symbolic, as adults and older children do. A video abstract of this article can be viewed at https://youtu.be/WtVziFN1yuI HIGHLIGHTS: Children were more accurate when enumerating briefly-presented number gestures than arrays of shapes, with a shallower decline in accuracy as quantities increased. We replicated this finding with arrays of shapes that were organized into neat, dice-like configurations (compared to the random configurations used in Experiment 1). The advantage in enumerating briefly-presented number gestures was evident before children had learned the cardinal principle. When gestures were digitally altered to pit handshape configuration against number of fingers extended, children overwhelmingly based their responses on handshape configuration.

Longitudinally adaptive assessment and instruction increase numerical skills of preschool children.

Social inequality in mathematical skill is apparent at kindergarten entry and persists during elementary school. To level the playing field, we trained teachers to assess children's numerical and spatial skills every 10 wk. Each assessment provided teachers with information about a child's growth trajectory on each skill, information designed to help them evaluate their students' progress, reflect on past instruction, and strategize for the next phase of instruction. A key constraint is that teachers have limited time to assess individual students. To maximize the information provided by an assessment, we adapted the difficulty of each assessment based on each child's age and accumulated evidence about the child's skills. Children in classrooms of 24 trained teachers scored 0.29 SD higher on numerical skills at posttest than children in 25 randomly assigned control classrooms (P = 0.005). We observed no effect on spatial skills. The intervention also positively influenced children's verbal comprehension skills (0.28 SD higher at posttest, P < 0.001), but did not affect their print-literacy skills. We consider the potential contribution of this approach, in combination with similar regimes of assessment and instruction in elementary schools, to the reduction of social inequality in numerical skill and discuss possible explanations for the absence of an effect on spatial skills.

Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Background and Objectives: Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor. Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET). Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included. SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days. Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001). The range of ME/CFS patient recovery was 1-64 days, while the range in CTL was 1-10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis. Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33). Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET. Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.

Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by unexplained physical fatigue, cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. People with ME/CFS often report a prodrome consistent with infections. Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of plasma from 106 ME/CFS cases and 91 frequency-matched healthy controls. Subjects in the ME/CFS group had significantly decreased levels of plasmalogens and phospholipid ethers (p < 0.001), phosphatidylcholines (p < 0.001) and sphingomyelins (p < 0.001), and elevated levels of dicarboxylic acids (p = 0.013). Using machine learning algorithms, we were able to differentiate ME/CFS or subgroups of ME/CFS from controls with area under the receiver operating characteristic curve (AUC) values up to 0.873. Our findings provide the first metabolomic evidence of peroxisomal dysfunction, and are consistent with dysregulation of lipid remodeling and the tricarboxylic acid cycle. These findings, if validated in other cohorts, could provide new insights into the pathogenesis of ME/CFS and highlight the potential use of the plasma metabolome as a source of biomarkers for the disease.

Elementary school teachers' math anxiety and students' math learning: A large-scale replication.

A solid foundation in math is important for children's long-term academic success. Many factors influence children's math learning-including the math content students are taught in school, the quality of their instruction, and the math attitudes of students' teachers. Using a large and diverse sample of first-grade students (n = 551), we conducted a large-scale replication of a previous study (Proceedings of the National Academy of Sciences of the USA, 2010, 1860; n = 117), which found that girls in classes with highly math anxious teachers learned less math during the school year, as compared to girls whose math teachers were less anxious about math. With a larger sample, we found a negative relation between teachers' math anxiety and students' math achievement for both girls and boys, even after accounting for teachers' math ability and children's beginning of year math knowledge, replicating and extending those previous results. Our findings strengthen the support for the hypothesis that teachers' math anxiety is one factor that undermines children's math learning and could push students off-track during their initial exposure to math in early elementary school.

Facilitating young children's numeracy talk in play: The role of parent prompts.

Previous research has demonstrated the contribution of parents' number language to children's own engagement with numbers and later mathematical achievement. Although there is evidence that both the quantity and complexity of parent number talk contribute to children's math learning, it is unclear whether different forms of parents' number talk-statements versus prompts-offer unique contributions to how children engage in math. We examined parent number talk among 50 dyads of parents and 2- to 4-year-olds during pretend play, coding parents' provisions of informative number statements and prompts inviting children to engage in number talk. The total amount (tokens) and diversity (types) of children's number words were analyzed separately. Parents' number utterances, particularly prompts about number, were infrequent. Both parents' number statements and their prompts were uniquely related to children's number word tokens. Only prompts were associated with children's number word types. Follow-up analyses indicated that prompts were associated with lengthier parent-child conversations about number than parent statements and that children used larger number words when responding to parent prompts than when they themselves initiated number talk. These findings highlight the importance of parents' prompts for enhancing the quality of parent-child math exchanges by providing opportunities for children to advance their current use of numerical language. Consequently, parents' use of number-related prompts may play an important role in children's early math engagement.

PROXEMICS, COVID-19, AND THE ETHICS OF CARE IN SOUTH AFRICA.

In South Africa, lockdown and its excesses have opened up questions on the limits of an ethics of care, whose ethics are privileged, how care is delivered, and what care means. We show how an ethics of proxemics and its operationalization as distance highlight everyday inequalities and limit the provision of care. Constraints on physical distancing in line with public health measures intended to limit the spread of the coronavirus echo the controls enforced under apartheid, showing how inequality is both embodied and legally entrenched.

Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of unknown etiology lasting for a minimum of 6 months but usually for many years, with features including fatigue, cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Dysregulation of cytokine signaling could give rise to many of these symptoms. Cytokines are present in both plasma and extracellular vesicles, but little investigation of EVs in ME/CFS has been reported. Therefore, we aimed to characterize the content of extracellular vesicles (EVs) isolated from plasma (including circulating cytokine/chemokine profiling) from individuals with ME/CFS and healthy controls. METHODS: We included 35 ME/CFS patients and 35 controls matched for age, sex and BMI. EVs were enriched from plasma by using a polymer-based precipitation method and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and immunoblotting. A 45-plex immunoassay was used to determine cytokine levels in both plasma and isolated EVs from a subset of 19 patients and controls. Linear regression, principal component analysis and inter-cytokine correlations were analyzed. RESULTS: ME/CFS individuals had significantly higher levels of EVs that ranged from 30 to 130 nm in size as compared to controls, but the mean size for total extracellular vesicles did not differ between groups. The enrichment of typical EV markers CD63, CD81, TSG101 and HSP70 was confirmed by Western blot analysis and the morphology assessed by TEM showed a homogeneous population of vesicles in both groups. Comparison of cytokine concentrations in plasma and isolated EVs of cases and controls yielded no significant differences. Cytokine-cytokine correlations in plasma revealed a significant higher number of interactions in ME/CFS cases along with 13 inverse correlations that were mainly driven by the Interferon gamma-induced protein 10 (IP-10), whereas in the plasma of controls, no inverse relationships were found across any of the cytokines. Network analysis in EVs from controls showed 2.5 times more significant inter-cytokine interactions than in the ME/CFS group, and both groups presented a unique negative association. CONCLUSIONS: Elevated levels of 30-130 nm EVs were found in plasma from ME/CFS patients and inter-cytokine correlations revealed unusual regulatory relationships among cytokines in the ME/CFS group that were different from the control group in both plasma and EVs. These disturbances in cytokine networks are further evidence of immune dysregulation in ME/CFS.

Causal Effects of Parent Number Talk on Preschoolers' Number Knowledge.

Individual differences in children's number knowledge arise early and are associated with variation in parents' number talk. However, there exists little experimental evidence of a causal link between parent number talk and children's number knowledge. Parent number talk was manipulated by creating picture books which parents were asked to read with their children every day for 4 weeks. N = 100 two- to four-year olds and their parents were randomly assigned to read either Small Number (1-3), Large Number (4-6), or Control (non-numerical) books. Small Number books were particularly effective in promoting number knowledge relative to the Control books. However, children who began the study further along in their number development also benefited from reading the Large Number Books with their parents.

Parents' perceptions of functional abilities in people with Down syndrome.

A realistic assessment of the range of functional abilities found in people with Down syndrome (DS) may assist in counseling expectant parents. This study asked parents from the United States and the Netherlands to assess 11 functional skills of their sons and daughters with DS: walking, eating, speaking, grooming/personal hygiene, reading, writing, preparing meals, working at a job, going on dates, traveling independently, and living independently. We analyzed responses from 2,658 parents who have sons/daughters with DS of all ages. The majority of people with DS in the United States could walk by 25 months of age, speak reasonably well by 12 years, maintain their own personal hygiene by 13 years, and work independently by 20 years. By 31 years of age, 49% were reading reasonably well, and 46% were writing reasonably well. Approximately 30% could travel independently, and 34% were living independently. The results from parents in the Netherlands were similar for most measures. This normative data on function may contribute to anticipatory guidance and decision-making. Furthermore, as parents and clinicians seek to assess the relative strengths and weakness of people with DS, resources and supports can be marshaled for those not meeting milestones at expected times.

Number gestures predict learning of number words.

When asked to explain their solutions to a problem, children often gesture and, at times, these gestures convey information that is different from the information conveyed in speech. Children who produce these gesture-speech "mismatches" on a particular task have been found to profit from instruction on that task. We have recently found that some children produce gesture-speech mismatches when identifying numbers at the cusp of their knowledge, for example, a child incorrectly labels a set of two objects with the word "three" and simultaneously holds up two fingers. These mismatches differ from previously studied mismatches (where the information conveyed in gesture has the potential to be integrated with the information conveyed in speech) in that the gestured response contradicts the spoken response. Here, we ask whether these contradictory number mismatches predict which learners will profit from number-word instruction. We used the Give-a-Number task to measure number knowledge in 47 children (Mage  = 4.1 years, SD = 0.58), and used the What's on this Card task to assess whether children produced gesture-speech mismatches above their knower level. Children who were early in their number learning trajectories ("one-knowers" and "two-knowers") were then randomly assigned, within knower level, to one of two training conditions: a Counting condition in which children practiced counting objects; or an Enriched Number Talk condition containing counting, labeling set sizes, spatial alignment of neighboring sets, and comparison of these sets. Controlling for counting ability, we found that children were more likely to learn the meaning of new number words in the Enriched Number Talk condition than in the Counting condition, but only if they had produced gesture-speech mismatches at pretest. The findings suggest that numerical gesture-speech mismatches are a reliable signal that a child is ready to profit from rich number instruction and provide evidence, for the first time, that cardinal number gestures have a role to play in number-learning.

Parents' early book reading to children: Relation to children's later language and literacy outcomes controlling for other parent language input.

It is widely believed that reading to preschool children promotes their language and literacy skills. Yet, whether early parent-child book reading is an index of generally rich linguistic input or a unique predictor of later outcomes remains unclear. To address this question, we asked whether naturally occurring parent-child book reading interactions between 1 and 2.5 years-of-age predict elementary school language and literacy outcomes, controlling for the quantity of other talk parents provide their children, family socioeconomic status, and children's own early language skill. We find that the quantity of parent-child book reading interactions predicts children's later receptive vocabulary, reading comprehension, and internal motivation to read (but not decoding, external motivation to read, or math skill), controlling for these other factors. Importantly, we also find that parent language that occurs during book reading interactions is more sophisticated than parent language outside book reading interactions in terms of vocabulary diversity and syntactic complexity.

Children's Early Decontextualized Talk Predicts Academic Language Proficiency in Midadolescence.

This study examines whether children's decontextualized talk-talk about nonpresent events, explanations, or pretend-at 30 months predicts seventh-grade academic language proficiency (age 12). Academic language (AL) refers to the language of school texts. AL proficiency has been identified as an important predictor of adolescent text comprehension. Yet research on precursors to AL proficiency is scarce. Child decontextualized talk is known to be a predictor of early discourse development, but its relation to later language outcomes remains unclear. Forty-two children and their caregivers participated in this study. The proportion of child talk that was decontextualized emerged as a significant predictor of seventh-grade AL proficiency, even after controlling for socioeconomic status, parent decontextualized talk, child total words, child vocabulary, and child syntactic comprehension.

Toxic layering through three disciplinary lenses: childhood poisoning and street pesticide use in Cape Town, South Africa.

This article focuses on the devastating hidden perils of agricultural pesticides repurposed by informal sellers in urban South African townships to kill rats and other unwanted pests. Drawing on collaborative research techniques, we investigate the causal relationship between child poisoning episodes and the household use of illegal street pesticides. Such pesticides are used to safeguard homes from pests in an attempt to protect children from the harmful consequences of rodent bites and vectorborne diseases. Here, we consider the social injustice and economic inequality of episodes of child pesticide poisoning in the Western Cape from three disciplinary perspectives: public health, medical anthropology and fine art. We ultimately seek to demonstrate the complex relationship between the political economy of sanitation, waste removal and insecure housing, and the proliferation of rodents and other pests in urban townships. As a contribution to the medical humanities, the paper leans into different disciplines to highlight the toxic layering at play in a child pesticide poisoning event. The public health perspective focuses on the circulation of illegal street pesticides, the anthropologists focus on the experiences of the children and caregivers who are victims of poisoning, and the fine artist centres the rat within a broader environmental context. While non-toxic methods to eliminate rats and household pests are critical, longer term structural changes, through environmental and human rights activism, are necessary to ameliorate the suffering caused by poisoning. The medical and health humanities is well poised to highlight creative ways to draw public attention to these challenges, as well as to bridge the divide between science and the humanities through collaborative research efforts. With this paper we set the stage for discussing and balancing perspectives when addressing pest control in poor urban communities.

Parents' Spatial Language Mediates a Sex Difference in Preschoolers' Spatial-Language Use.

Do boys produce more terms than girls to describe the spatial world-that is, dimensional adjectives (e.g., big, little, tall, short), shape terms (e.g., circle, square), and words describing spatial features and properties (e.g., bent, curvy, edge)? If a sex difference in children's spatial-language use exists, is it related to the spatial language that parents use when interacting with children? We longitudinally tracked the development of spatial-language production in children between the ages of 14 and 46 months in a diverse sample of 58 parent-child dyads interacting in their homes. Boys produced and heard more of these three categories of spatial words, which we call "what" spatial types (i.e., unique "what" spatial words), but not more of all other word types, than girls. Mediation analysis revealed that sex differences in children's spatial talk at 34 to 46 months of age were fully mediated by parents' earlier spatial-language use, when children were 14 to 26 months old, time points at which there was no sex difference in children's spatial-language use.

How do generic statements impact performance? Evidence for entity beliefs.

Generic statements about the abilities of children's social groups (e.g. 'Girls/Boys are good at this game') negatively impact children's performance - even if the statements are favorable towards children's own social groups. We explored the mechanism by which generic language impairs children's performance. Across three studies, our findings suggest that generic statements influence children's performance by creating an entity belief (i.e. a belief that a fixed ability determines performance). Children who were exposed to a generic statement about their social group's ability performed worse than children in control conditions. This effect hurt children's performance even when the person who made the generic statement was no longer present and a new person not privy to the statement replaced them. However, when children heard a generic statement paired with an effort explanation (i.e. 'Girls/Boys are good at this game because they try really hard when they draw') they performed better than children who heard the generic statement with no explanation (i.e. just 'Girls/Boys are good at this game') and children who heard the generic statement paired with a trait explanation (i.e. 'Girls/Boys are good at this game because they are smart and really good at drawing'). This work uncovers when and how generic statements that refer to the ability of one's social group hinder performance, informing the development of practices to improve student motivation and learning.

Commentary on Leibovich et al.: What next?

The conclusions reached by Leibovich et al. urge the field to regroup and consider new ways of conceptualizing quantitative development. We suggest three potential directions for new research that follow from the authors' extensive review, as well as building on the common ground we can take from decades of research in this area.