A mutually exclusive stem-loop arrangement in roX2 RNA is essential for X-chromosome regulation in Drosophila.

The X chromosome provides an ideal model system to study the contribution of RNA-protein interactions in epigenetic regulation. In male flies, roX long noncoding RNAs (lncRNAs) harbor several redundant domains to interact with the ubiquitin ligase male-specific lethal 2 (MSL2) and the RNA helicase Maleless (MLE) for X-chromosomal regulation. However, how these interactions provide the mechanics of spreading remains unknown. By using the uvCLAP (UV cross-linking and affinity purification) methodology, which provides unprecedented information about RNA secondary structures in vivo, we identified the minimal functional unit of roX2 RNA. By using wild-type and various MLE mutant derivatives, including a catalytically inactive MLE derivative, MLEGET, we show that the minimal roX RNA contains two mutually exclusive stem-loops that exist in a peculiar structural arrangement: When one stem-loop is unwound by MLE, an alternate structure can form, likely trapping MLE in this perpetually structured region. We show that this functional unit is necessary for dosage compensation, as mutations that disrupt this formation lead to male lethality. Thus, we propose that roX2 lncRNA contains an MLE-dependent affinity switch to enable reversible interactions of the MSL complex to allow dosage compensation of the X chromosome.

The efficacy of manipulatives versus fingers in supporting young children's addition skills.

Recent empirical investigations have revealed that finger counting is a strategy associated with good arithmetic performance in young children. Fingers could have a special status during development because they operate as external support that provide sensory-motor and kinesthetic affordances in addition to visual input. However, it was unknown whether fingers are more helpful than manipulatives such as tokens during arithmetic problem solving. To address this question, we conducted a study with 93 Vietnamese children (48 girls) aged 4 and 5 years (mean = 58 months, range = 47-63) with high arithmetic and counting skills from families with relatively high socioeconomic status. Their behaviors were observed as they solved addition problems with manipulatives at their disposal. We found that children spontaneously used both manipulatives and fingers to solve the problems. Crucially, their performance was not higher when fingers rather than manipulatives were used (i.e., 70% vs. 81% correct answers, respectively). Therefore, at the beginning of learning, it is possible that, at least for children with high numerical skills, fingers are not the only gateway to efficient arithmetic development and manipulatives might also lead to proficient arithmetic.

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.

BACKGROUND: Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis). METHODS: In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non-subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov. FINDINGS: 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7·4 years [IQR 3·1-9·4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12·6 years [2·2-16·6]). 641 (5·1%) of 12 469 participants carried cancer predisposing variants (294 [6·7%] in the SJLIFE cohort and 347 [4·3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade ≥4 vs grade <4: odds ratio 2·15, 95% CI 1·18-4·19, p=0·0085). 263 (2·1%) subsequent malignant neoplasm-related deaths (44 [1·0%] in the SJLIFE cohort; and 219 [2·7%] in the CCSS cohort) and 426 (3·4%) other-cause deaths (103 [2·3%] in SJLIFE; and 323 [4·0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3·7% (95% CI 1·2-8·5) in SJLIFE and 6·9% (4·1-10·7) in CCSS versus 1·5% (1·0-2·1) in SJLIFE and 2·1% (1·7-2·5) in CCSS in non-carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3·40 [95% CI 1·37-8·43]; p=0·0082; CCSS: 3·58 [2·27-5·63]; p<0·0001). INTERPRETATION: Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden. FUNDING: American Lebanese Syrian Associated Charities and US National Institutes of Health.

Sediment Spatial Distribution and Quality Assessment of Metals in Chinook Salmon and Resident Killer Whale Marine Habitat in British Columbia, Canada.

At-risk resident killer whale (Orcinus orca) populations of the northeastern Pacific, Canada, and their main prey, Chinook Salmon (Oncorhynchus tshawytscha), are exposed to a variety of contaminants including chemical elements from both natural and anthropogenic sources, which may be constraining their recovery. Concentrations of 36 chemical elements in subtidal surface sediments (1-435 m depth) collected from 98 sites along the British Columbia coast were used to characterize coast-wide patterns, and a subset of metals (mercury (Hg), cadmium (Cd), arsenic (As), nickel (Ni), copper (Cu), and lead (Pb)) were selected to assess Chinook Salmon and resident killer whale marine habitat quality. Principal component analysis (PCA) showed a dominance of Hg, antimony (Sb), Pb, Cu, and zinc (Zn) for Prince Rupert Harbour, Victoria Harbour, and Burrard Inlet, suggesting local sources. Based on the PCA, geochemical properties such as total organic carbon (TOC), acid volatile sulfide (AVS), and pH explained the spatial distribution of all elements in sediment (p < 0.001). Mercury, Cd, As, Ni, Cu, and Pb hotspots were identified along the coast of Vancouver Island, the central and north coast, in the Strait of Georgia, and Haida Gwaii. Bischof Island of Haida Gwaii and Ardmillan Bay on the central coast were most contaminated and enriched by Cd, determined by geoaccumulation index (Igeo) and enrichment factor (EF), respectively. Marine habitat quality was assessed by comparing metal concentrations to Canadian Sediment Quality Guidelines (SQGs). Chinook Salmon populations may be indirectly affected by metal toxicity (As > Cd and Cu > Ni > Hg > Pb) to lower trophic level prey species. Toxicity related impacts to benthic organisms as a result of exposure to elevated Cd and As concentrations in Northern Resident Killer Whale critical habitat and to Hg, Cd, As, Ni, Cu, and Pb concentrations in Southern Resident Killer Whale critical habitat may indirectly pose a threat to resident killer whale populations, highlighting a need for management actions to reduce risks associated with these metals.

A theory-based behavioural change communication intervention to decrease the provision of water to infants under 6 months of age in the Republic of Guinea.

OBJECTIVE: In many countries, the provision of water in the early months of a baby's life jeopardises exclusive breast-feeding (EBF). Using a behavioural theory, this study assessed the impact of a behaviour change intervention on mothers' intention to act and, in turn, on the water provision in addition to breast milk to their infants under 6 months of age (IU6M) in two regions of Guinea. DESIGN: A quasi-experimental design. Data on individual and environmental factors of the theoretical framework, sociodemographic and outcomes were collected using validated questionnaires before and after the intervention. The outcomes examined were the intention to provide water to IU6M, the provision of water and EBF. Path analyses were performed to investigate pathways by which psychosocial and environmental factors influenced the water provision in addition to breast milk. SETTING: Four health centres were assigned randomly to each study's arm (one control/CG and one intervention group/IG per region). PARTICIPANTS: The sample included 300 mothers of IU6M: 150 per group. RESULTS: In IG, the proportion of mothers providing water decreased from 61 % to 29 % before and after the intervention (P < 0·001), while no difference was observed in CG (P = 0·097). The EBF rate increased in IG (from 24·0 % to 53·8 %, P < 0·001) as opposed to CG (36·7 % to 45·9 %, P = 0·107). An association (P < 0·001) between the intention and the behaviour was observed in both groups. CONCLUSIONS: An intervention developed using a sound framework reduces the provision of water among IU6M and improves EBF.

Acceptance and challenges of the introduction of the routine community-based vitamin A supplementation strategy: the case of Burkina Faso.

OBJECTIVES: With the phase-out of the polio campaigns, Burkina Faso has developed a new strategy for routine community-based vitamin A supplementation (VAS) by institutionalising community-based health workers (CBHW) to sustain the gain of two decades of successful programming. Formative research was conducted soon after the strategy was introduced to solicit feedback on the acceptability of the new approach by the implementing actors while identifying the main implementation challenges for improving its effectiveness and sustainability. DESIGN: This qualitative study was conducted in 2018 through (i) document review, (ii) individual interviews with key informants at the central, regional and district levels, and (iii) focus groups with CBHW and caregivers. SETTING: Data collection was carried out at six levels of sites covering the entire country and selected based on VAS coverage rates with the community routine. A total of six health districts were selected. PARTICIPANTS: We conducted 46 individual interviews with health workers and 20 focus groups with 59 CBHW and 108 caregivers. RESULTS: The study showed good acceptability of the strategy by all stakeholders. In the first 2 years of implementation, the national coverage of VAS was maintained at a high level (above 90 %) and there was a reduction in operational costs. The main challenges included delayed CBHW remuneration and weak communication and supervision. CONCLUSIONS: The acceptability of the community-based routine VAS was good and was perceived to have a high potential for sustainability. Addressing identified challenges will allow us to better manage the expectations of community stakeholders and maintain the initial results.

A tool to assess underlying factors to water provision among Guinean children.

In many countries, water is provided to children under 6 months of age (CU6M) in addition to breast milk (BM), hence increasing the risk of child mortality and morbidity. Factors related to this practice have not been thoroughly investigated either a tool to assess them. Based on the extended theory of planned behaviour (eTPB), we aim to develop and validate a questionnaire to assess psychosocial and environmental factors that may contribute/limit the water provision in addition to BM by mothers of CU6M in the Republic of Guinea. A three-step process was used. Ten focus group discussions (FGDs) were held to identify salient beliefs related to each of the four constructs of the eTPB. Data from FGDs were used to develop a questionnaire composed of 88 items administered to 428 mothers. Exploratory factor analyses were conducted to identify latent factors for each construct. A shorter version of the questionnaire was administered to another sample of 300 mothers. Confirmatory factor analyses (CFAs) were performed. Hancock and Mueller's H reliability indices were computed on final models to assess the tool's validity and reliability. The final questionnaire included 57 items. For all four final models, most criteria for fit indices of CFA were generally met. Reliability coefficients were all equal to or above 0.90 for each construct. This research offers a tool that could be used to investigate determinants of water provision besides BM among mothers of CU6M. Further validation in other contexts is warranted.

Explaining Pathogenicity of Congenital Zika and Guillain-Barré Syndromes: Does Dysregulation of RNA Editing Play a Role?

Previous studies of Zika virus (ZIKV) pathogenesis have focused primarily on virus-driven pathology and neurotoxicity, as well as host-related changes in cell proliferation, autophagy, immunity, and uterine function. It is now hypothesized that ZIKV pathogenesis arises instead as an (unintended) consequence of host innate immunity, specifically, as the side effect of an otherwise well-functioning machine. The hypothesis presented here suggests a new way of thinking about the role of host immune mechanisms in disease pathogenesis, focusing on dysregulation of post-transcriptional RNA editing as a candidate driver of a broad range of observed neurodevelopmental defects and neurodegenerative clinical symptoms in both infants and adults linked with ZIKV infections. The authors collect and synthesize existing evidence of ZIKV-mediated changes in the expression of adenosine deaminases acting on RNA (ADARs), known links between abnormal RNA editing and pathogenesis, as well as ideas for future research directions, including potential treatment strategies.

Facilitating factors and challenges of the implementation of multisectoral nutrition programmes at the community level to improve optimal infant and young child feeding practices: a qualitative study in Burkina Faso.

OBJECTIVES: To identify the drivers and challenges of successful nutrition programme implementation in a multisectoral, community-level approach to improve infant and young child feeding (IYCF) practices in northern Burkina Faso. DESIGN: A qualitative study was conducted in 2019 through (i) individual interviews with key informants from five different sectors (health, agriculture, environment, livestock and education) and association staff, agents and community leaders and (ii) focus groups with mothers of children under the age of 2 years. SETTING: Three health districts in the northern region of Burkina Faso implemented a multisectoral community nutrition programme to improve IYCF practices. PARTICIPANTS: Forty-seven implementing actors and twenty-four beneficiary mothers. RESULTS: Factors influencing successful implementation include community participation; sector commitment and involvement; the existence of nutrition champions; capacity building; the integration of interventions; micronutrient powder distribution; the introduction of nutrition-sensitive interventions, such as the promotion of the consumption of orange-fleshed sweet potatoes; improved food production and small livestock rearing and the effective coordination of actors and complementary funding. The main challenges of the implementation of multisectorality are low participation among nutrition-sensitive sectors, a tendency for siloed work among sectors, scheduling conflicts, high actor mobility, differences in the target population by sector, a lack of technical skills among community workers, insufficient financial resources, low geographic convergence and coverage of beneficiaries, a lack of a multisectoral monitoring mechanism and accountability and insecurity. CONCLUSIONS: Strengthening sector participation, identifying a common targeting strategy and mobilising financial resources have the potential to significantly reduce barriers and improve the quality of implementation.

Preschoolers' mastery of advanced counting: The best predictor of addition skills 2 years later.

The current study addressed the following question: Among preschoolers' basic numerical abilities, what are the best predictors for the later addition skills? We measured numerical abilities at preschool age and used dominance analysis to determine the dominant predictor for addition skills 2 years later. We tested seven numerical specific predictors (counting, advanced counting, enumeration, Give-N, collection comparison, number-word comparison, and approximate addition). Both quantitative and qualitative aspects (accuracy, strategy choice, and fluency) of addition skills were measured. The results show that the predictor weights for addition skills were 39% (counting), 37% (advanced counting), and 25% (collection comparison). We concluded that counting ability and especially advanced counting measured in early preschool is the most robust predictor of addition skills 2 years later (even after controlling for global cognitive abilities). This study generalized the previous findings found for Western children to Vietnamese preschoolers (N = 157, Mage = 4.8 years); extended and highlighted the role of advanced counting (count from a number other than 1) to later addition performance, mature strategy, and calculation fluency; and suggested further implications.

Automated Isoform Diversity Detector (AIDD): a pipeline for investigating transcriptome diversity of RNA-seq data.

BACKGROUND: As the number of RNA-seq datasets that become available to explore transcriptome diversity increases, so does the need for easy-to-use comprehensive computational workflows. Many available tools facilitate analyses of one of the two major mechanisms of transcriptome diversity, namely, differential expression of isoforms due to alternative splicing, while the second major mechanism-RNA editing due to post-transcriptional changes of individual nucleotides-remains under-appreciated. Both these mechanisms play an essential role in physiological and diseases processes, including cancer and neurological disorders. However, elucidation of RNA editing events at transcriptome-wide level requires increasingly complex computational tools, in turn resulting in a steep entrance barrier for labs who are interested in high-throughput variant calling applications on a large scale but lack the manpower and/or computational expertise. RESULTS: Here we present an easy-to-use, fully automated, computational pipeline (Automated Isoform Diversity Detector, AIDD) that contains open source tools for various tasks needed to map transcriptome diversity, including RNA editing events. To facilitate reproducibility and avoid system dependencies, the pipeline is contained within a pre-configured VirtualBox environment. The analytical tasks and format conversions are accomplished via a set of automated scripts that enable the user to go from a set of raw data, such as fastq files, to publication-ready results and figures in one step. A publicly available dataset of Zika virus-infected neural progenitor cells is used to illustrate AIDD's capabilities. CONCLUSIONS: AIDD pipeline offers a user-friendly interface for comprehensive and reproducible RNA-seq analyses. Among unique features of AIDD are its ability to infer RNA editing patterns, including ADAR editing, and inclusion of Guttman scale patterns for time series analysis of such editing landscapes. AIDD-based results show importance of diversity of ADAR isoforms, key RNA editing enzymes linked with the innate immune system and viral infections. These findings offer insights into the potential role of ADAR editing dysregulation in the disease mechanisms, including those of congenital Zika syndrome. Because of its automated all-inclusive features, AIDD pipeline enables even a novice user to easily explore common mechanisms of transcriptome diversity, including RNA editing landscapes.

Investigating the respective contribution of sensory modalities and spatial disposition in numerical training.

Recent studies have suggested that multisensory redundancy may improve cognitive learning. According to this view, information simultaneously available across two or more modalities is highly salient and, therefore, may be learned and remembered better than the same information presented to only one modality. In the current study, we wanted to evaluate whether training arithmetic with a multisensory intervention could induce larger learning improvements than a visual intervention alone. Moreover, because a left-to-right-oriented mental number line was for a long time considered as a core feature of numerical representation, we also wanted to compare left-to-right-organized and randomly organized arithmetic training. Therefore, five training programs were created and called (a) multisensory linear, (b) multisensory random, (c) visual linear, (d) visual random, and (e) control. A total of 85 preschoolers were randomly assigned to one of these five training conditions. Whereas children were trained to solve simple addition and subtraction operations in the first four training conditions, story understanding was the focus of the control training. Several numerical tasks (arithmetic, number-to-position, number comparison, counting, and subitizing) were used as pre- and post-test measures. Although the effect of spatial disposition was not significant, results demonstrated that the multisensory training condition led to a significantly larger performance improvement than the visual training and control conditions. This result was specific to the trained ability (arithmetic) and is discussed in light of the multisensory redundancy hypothesis.

Policy overview of the multisectoral nutrition planning process: The progress, challenges, and lessons learned from Burkina Faso.

INTRODUCTION: Malnutrition is a multifactorial problem, and multisectoral planning is an indispensable tool. The objective of this study was (a) to evaluate the extent to which nutrition is integrated into policies and (b) to describe the process used by the government of Burkina Faso to reform its policy frameworks and multisectoral nutrition planning. METHODS: This was a qualitative study, and data were collected in two key steps: first, through a policy overview conducted in 2015 and, second, in November 2017, through a document review and individual stakeholder interviews with 32 key actors involved in national nutrition planning. RESULTS: The extent to which nutrition is integrated into development policies varied from one sector to another. Since 2014, Burkina Faso has initiated nutrition planning through a multisectoral approach involving six sectors. This process was implemented in three key stages. Progress includes revision of national nutrition policy towards multisectoral perspective, formulation of a consensual and quality multisectoral nutrition strategic plan, creation of nutrition budget line, and establishment of nutrition technical secretariat. CONCLUSION: To improve the anchoring of multisectoral coordination bodies at the supra-ministerial level, mobilizing resources and promoting sector accountability are key next steps that would contribute to the success of the implementation.

Recruitment of the occipital cortex by arithmetic processing follows computational bias in the congenitally blind.

Arithmetic reasoning activates the occipital cortex of congenitally blind people (CB). This activation of visual areas may highlight the functional flexibility of occipital regions deprived of their dominant inputs or relate to the intrinsic computational role of specific occipital regions. We contrasted these competing hypotheses by characterizing the brain activity of CB and sighted participants while performing subtraction, multiplication and a control letter task. In both groups, subtraction selectively activated a bilateral dorsal network commonly activated during spatial processing. Multiplication triggered activity in temporal regions thought to participate in memory retrieval. No between-group difference was observed for the multiplication task whereas subtraction induced enhanced activity in the right dorsal occipital cortex of the blind individuals only. As this area overlaps with regions showing selective tuning to auditory spatial processing and exhibits increased functional connectivity with a dorsal "spatial" network, our results suggest that the recruitment of occipital regions during high-level cognition in the blind actually relates to the intrinsic computational role of the activated regions.

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.

STOP second generation (2G)-tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval [CI], 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.

Clozapine-Related Myocarditis and Rechallenge: A Case Series and Clinical Review.

PURPOSE/BACKGROUND: That clozapine is the only agent with an indication for treatment-resistant schizophrenia presents real challenges if clozapine-related myocarditis (CIM) occurs. Clinicians have chosen to rechallenge with a second trial of clozapine in the face of CIM. However, there is very limited literature of this topic. METHODS/PROCEDURES: Three cases who underwent clozapine rechallenge after CIM are reviewed and discussed in the context of existing literature and current recommendations. FINDINGS/RESULTS: We present 3 young male patients with schizophrenia and schizoaffective disorder who developed CIM during a first clozapine trial, stopped treatment, and subsequently underwent a second clozapine trial. In all cases, the rechallenge was discontinued owing to suspected CIM. A review of the literature includes reports of both successful and unsuccessful clozapine rechallenges after CIM and suggests certain risk factors. Clozapine rechallenge after CIM may be undertaken, as now occurs on occasion with agranulocytosis, although rates of success may be lower. Any such undertaking calls for education, careful monitoring, cautious titration, and a multidisciplinary approach. The balance of risk versus benefits must be considered, and strategies may include a drug holiday, more frequent monitoring upon reinitiation, and slower titration. IMPLICATIONS/CONCLUSIONS: Pressure to undertake a rechallenge reflects clozapine's unique role in treatment-resistant schizophrenia and absence of other comparable options. However, it is not without risk, and more research is needed to understand those at increased risk, as well as established strategies that diminish this.

Relapse after severe acute malnutrition: A systematic literature review and secondary data analysis.

The objectives of most treatment programs for severe acute malnutrition (SAM) in children focus on initial recovery only, leaving post-discharge outcomes, such as relapse, poorly understood and undefined. This study aimed to systematically review current literature and conduct secondary data analyses of studies that captured relapse rates, up to 18-month post-discharge, in children following recovery from SAM treatment. The literature search (including PubMed and Google Scholar) built upon two recent reviews to identify a variety of up-to-date published studies and grey literature. This search yielded 26 articles and programme reports that provided information on relapse. The proportion of children who relapsed after SAM treatment varied greatly from 0% to 37% across varying lengths of time following discharge. The lack of a standard definition of relapse limited comparability even among the few studies that have quantified post-discharge relapse. Inconsistent treatment protocols and poor adherence to protocols likely add to the wide range of relapse reported. Secondary analysis of a database from Malawi found no significant association between potential individual risk factors at admission and discharge, except being an orphan, which resulted in five times greater odds of relapse at 6 months post-discharge (95% CI [1.7, 12.4], P = 0.003). The development of a standard definition of relapse is needed for programme implementers and researchers. This will allow for assessment of programme quality regarding sustained recovery and better understanding of the contribution of relapse to local and global burden of SAM.

The effect of visual arrangement on visuospatial short-term memory: Insights from children with 22q11.2 deletion syndrome.

Recent models of visuospatial (VSSP) short-term memory postulate the existence of two dissociable mechanisms depending on whether VSSP information is presented simultaneously or sequentially. However, they do not specify to what extent VSSP short-term memory is under the influence of general VSSP processing. This issue was examined in people with 22q11.2 deletion syndrome, a genetic condition involving a VSSP deficit. The configuration of VSSP information was manipulated (structured vs. unstructured) to explore the impact of arrangement on VSSP short-term memory. Two presentation modes were used to see whether the VSSP arrangement has the same impact on simultaneous and sequential short-term memory. Compared to children matched on chronological age, children with 22q11.2 deletion syndrome showed impaired performance only for structured arrangement, regardless of the presentation mode, suggesting an influence of VSSP processing on VSSP short-term memory abilities. A revised cognitive architecture for a model of VSSP short-term memory is proposed.

Executive Function, Chaos and Temperament: Specificities in Preschoolers with Externalizing Behaviors.

Various factors may contribute to the emergence of externalizing behavior (EB) problems in the preschool period. At the child level, temperament and executive function (EF) seem to play an important role, as well as environmental variables such as household chaos. In this study, we examined the profiles of 49 EB preschoolers compared to 49 typically developing (TD) preschoolers matched on age and gender. To evaluate the behavioral aspect of EB, we asked teachers and parents to fill out questionnaires, but we also used an observational paradigm. We assessed executive functions using attention, inhibition, flexibility and working memory tests. Finally, we used questionnaires to assess household chaos and child temperament. Results showed that children rated by parents as presenting EB were also assessed so by teachers and exhibited more agitation in our observational paradigm. As expected, EB children also presented weaker performance than the TD children in all EF tasks, except those measuring attention, and showed a larger reaction-time variability. Parents of the EB group reported a more chaotic environment at home. Finally, we found that child temperament (i.e., emotionality) also plays a role in group belonging. This study shows that EB children already exhibit specific characteristics by the time they are of preschool age, not only in the behavioral sphere, but also in the cognitive and environmental areas. However, despite all the differences between the two groups, a discriminant analysis showed that EF capacities have a weak power for EB diagnosis.

Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia.

BACKGROUND: Several studies have demonstrated that approximately one-half of patients with chronic myeloid leukemia (CML) who receive treatment with tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. In patients who have a molecular relapse, a DMR is rapidly regained upon treatment re-initiation. METHODS: The authors report the results from RE-STIM, a French observational, multicenter study that evaluated treatment-free remission (TFR) in 70 patients who re-attempted TKI discontinuation after a first unsuccessful attempt. After the second TKI discontinuation attempt, the trigger for treatment re-introduction was the loss of a major molecular response in all patients. RESULTS: The median follow-up was 38.3 months (range, 4.7-117 months), and 45 patients (64.3%) lost a major molecular response after a median time off therapy of 5.3 months (range, 2-42 months). TFR rates at 12, 24, and 36 months were 48% (95% confidence interval [CI], 37.6%-61.5%), 42% (95% CI, 31.5%-55.4%), and 35% (95% CI, 24.4%-49.4%), respectively. No progression toward advanced-phase CML occurred, and no efficacy issue was observed upon TKI re-introduction. In univariate analysis, the speed of molecular relapse after the first TKI discontinuation attempt was the only factor significantly associated with outcome. The TFR rate at 24 months was 72% (95% CI, 48.8%-100%) in patients who remained in DMR within the first 3 months after the first TKI discontinuation and 36% (95% CI, 25.8%-51.3%) for others. CONCLUSIONS: This study is the first to demonstrate that a second TKI discontinuation attempt is safe and that a first failed attempt at discontinuing TKI does not preclude a second successful attempt. Cancer 2017;123:4403-10. © 2017 American Cancer Society.