School Readiness in Preschool-Age Children with Critical Congenital Heart Disease.

This study examined the nature, variability, and predictors of school readiness difficulties in young children with critical congenital heart disease (CCHD). We hypothesized that, compared to a community control (CC) group, children with CCHD would score less well on measures of readiness and that readiness would be associated with CCHD-related risk factors. Children (60 CCHD and 60 CC) were 4 to 5 years of age and not yet attending kindergarten. Readiness measures included tests of cognition, executive function, motor ability, and pre-academic skills. Caregivers provided child behavior ratings. Analyses examined group differences in readiness, readiness profiles, and associations of readiness with CCHD-related medical risk factors. The CCHD group had lower scores than the CC group on testing and higher caregiver ratings of problems in social communication, as well as higher rates of deficits on several of the measures. Latent class analysis provided evidence for different readiness profiles, with more children with CCHD displaying profiles characterized by weaknesses in readiness. CCHD-related medical risk factors associated with readiness problems in the CCHD group included a co-morbid genetic disorder, postnatal diagnosis of CCHD, major perioperative complication, and longer periods of hospitalizations, cardiopulmonary bypass, and aortic cross-clamp placements. Findings document multiple problems in school readiness in young children with CCHD. Deficits vary across individuals and are associated with higher medical risk. Results confirm the importance of screening for school readiness in these children and suggest areas to target in designing screening measures and providing early childhood interventions.

The presence of intratumoral Porphyromonas gingivalis correlates with a previously defined pancreatic adenocarcinoma, immune cell expression phenotype and with tumor resident, adaptive immune receptor features.

The association between pancreatic adenocarcinoma (PAAD) and the pancreatic microbiome is not fully understood, although bacteria may decrease the effectiveness of chemotherapy and lead to anti-apoptotic, pro-inflammatory microenvironments. To better understand the relationship between the PAAD microbiome and the microenvironment, we identified Porphyromonas gingivalis-positive PAAD samples and found a strong association between intratumoral P. gingivalis and: (i) an immune cell gene expression phenotype previously defined by others as gene program 7; and (ii) recovery of immunoglobulin recombination, sequencing reads. We applied a novel chemical complementarity scoring algorithm, suitable for a big data setting, and determined that the previously established P. gingivalis antigen, rpgB had a reduced chemical complementarity with T-cell receptor (TCR) complementarity-determining region-3 amino acid sequences recovered from PAAD samples with P. gingivalis in comparison to TCR-rpgB chemical complementarity represented by the PAAD samples that lacked P. gingivalis. This finding strengthens the existing body of evidence correlating P. gingivalis with PAAD, which may have implications for the treatment and prognosis of patients. Furthermore, demonstrating the correlation of P. gingivalis and gene program 7 raises the question of whether P. gingivalis infection is responsible for the gene program 7 subdivision of PAAD?

High Level Immunoglobulin Gene Expression and Reduced Intra-tumoral Bacteria Associated With the Transition from Initial to Progressive Diffuse Intrinsic Pontine Glioma.

BACKGROUND/AIM: In the past decade, diffuse intrinsic pontine glioma (DIPG), the most common childhood brainstem glioma, has benefitted from an increase in tissue-based research because of improved biopsy collection techniques. However, the adaptive immune receptor (IR) features represented by tumor material and tumor infiltrating lymphocytes have remained poorly understood. MATERIALS AND METHODS: Herein, we characterized the adaptive immune parameters of DIPG through the recovery of IR recombination reads from RNAseq files representing initial and progressive DIPG samples. RESULTS: An elevated level of immunoglobulin gene expression in the progressive DIPG sample files and a reduced number of bacterial sequencing read recoveries in comparison to RNAseq files representing the initial form of DIPG, was found. Furthermore, the RNAseq files representing both initial and progressive DIPG samples had significant numbers of reads representing Cutibacterium acnes, a bacterium previously linked to prostate cancer development. Results also indicated an opportunity to distinguish overall survival probabilities based on IGL complementarity determining region-3 amino acid sequence physicochemical parameters. CONCLUSION: Genomics analyses allow for a better understanding of adaptive IR features and bacterial infections in the DIPG setting.

School Readiness Predictors of Early Academic Achievement in Children Born Very Preterm.

OBJECTIVE: This study examined associations of school readiness measures obtained before school entry with academic achievement at early school age in children born very preterm (VPT, gestational age ≤ 30 weeks) and children born full term (FT, GA ≥ 37 weeks). METHOD: The sample included 38 children born VPT and 30 born FT recruited at age 4 years and followed to early school age. Measures of readiness included tests of global cognition, executive function, motor abilities, and preacademic skills, as well as caregiver behavior ratings. Tests of math, reading, and spelling were administered to assess school-age achievement. Analyses that controlled for socioeconomic status and accounted for inclusion of siblings compared the groups on the achievement tests and identified measures of readiness related to school-age achievement. RESULTS: Achievement difficulties were more pronounced in the VPT group and associated with problems in multiple readiness domains. Effect sizes for these associations were largest for measures of spatial ability, executive function, and preacademic skills. Some associations remained significant when controlling for global cognitive ability at age 4 years, and others were significant only for the VPT group. CONCLUSION: Findings suggest that deficits on tests in multiple readiness domains assessed before school entry in children born VPT or FT are associated with early school-age achievement. The most pronounced readiness deficits in the VPT group at age 4 years were also among those most closely associated with later difficulties in achievement. Further research is needed to refine assessment of school readiness in children born VPT.

Hypoxic transcriptomes predict survival and tumor-infiltrating immune cell composition in cutaneous melanoma.

Hypoxia has established associations with aggressive tumor phenotypes in many cancers. However, it is not currently understood whether tumor hypoxia levels map to distinct immune infiltrates in cutaneous melanoma, potentially unveiling novel therapeutic targets. To this end, we leveraged a previously identified seven-gene hypoxia signature to grade hypoxia levels of 460 cutaneous melanomas obtained from the Broad Institute GDAC Firehose portal. CIBERSORTx ( https://cibersortx.stanford.edu/ ) was employed to calculate the relative abundance of 22 mature human hematopoietic populations. Clinical outcomes and immune cell associations were assessed by computational means. Results indicated that patients with high-hypoxia tumors reported significantly worse overall survival and correlated with greater Breslow depth, validating the in-silico methodology. High-hypoxia tumors demonstrated increased infiltration of activated and resting dendritic cells, resting mast cells, neutrophils, and resting NK cells, but lower infiltration of gamma-delta T cells. These data suggest that high tumor hypoxia correlates with lower survival probability and distinct population differences of several tumor-infiltrating leukocytes in cutaneous melanomas.

Factors affecting African postdoctoral researcher capacity development within 'learn-by-doing' international research partnerships: findings from the 'Partnership for Increasing the Impact of Vector Control (PIIVeC)'.

INTRODUCTION: The Partnership to Increase the Impact of Vector Control sought to develop the research and leadership capacity of 10 African postdoctoral vectorborne disease scientists via a 'learn-by-doing' approach. We identified factors that either supported or hindered their development and, drawing on this information, determined key lessons for future programmes with similar objectives. METHODS: A longitudinal qualitative study encompassing focus group discussions and semistructured interviews conducted with the cohort of African postdoctoral fellows, programme leadership, supervisory and research support staff (N=28). Data analysis was informed by a general inductive approach. RESULTS: Numerous supportive and hindering factors were identified. Supportive factors were primarily structural or attitudinal in nature, whereas hindering factors were primarily operational or contextual. None of the supporting or hindering factors were specific to vectorborne disease research. Four key lessons for future programme implementation emerged, including: the value in exposing postdoctoral fellows to a diverse work-mix and training-mix to improve understanding of the broad skillset needed for scientific career advancement; recognising and managing the potentially competing interests of different partnership members to ensure everyone benefits from participation; ensuring equity of opportunity and rewarding engagement; and ensuring flexibility in support provision. CONCLUSION: Our study highlights numerous factors that may be readily incorporated into early career researcher capacity strengthening initiatives based on a learn-by-doing approach. Many of these factors are supported by a growing weight of evidence and would be appropriate to research capacity strengthening programmes both within and outside of a vectorborne disease context.

Specific Intratumor Bacteria Genera and TRG Recombinations Associated with Greater Survival Probability in Alimentary Tract Cancers.

INTRODUCTION: There remains a lack of knowledge regarding the effects of the intratumor microbiome on the tumor immune milieu. We aimed to investigate whether intratumoral bacterial RNA sequence abundance in gastric and esophageal cancers is associated with T-cell infiltrate features. METHODS: We assessed cases representing the stomach adenocarcinoma (STAD) and esophageal cancer (ESCA) databases of The Cancer Genome Atlas. RNA-seq data estimating intratumoral bacterial abundance was obtained from publicly available sources. TCR recombination reads were mined from exome files. Survival models were generated using the lifelines python package. RESULTS: Increasing levels of the Klebsiella genus were associated with a better OS probability (hazard ratio, 0.5), via a Cox proportional hazards model. The higher Klebsiella abundance was associated with a significantly increased overall (p = 0.0001) and disease-specific survival (p = 0.0289) probability for the STAD dataset. Cases representing the upper 50th percentile of Klebsiella abundance also represented a significantly increased recovery of TRG and TRD recombination reads (p = 0.00192). Analogous results were found for the Aquincola genus in ESCA. CONCLUSIONS: This is the first report of associations between low biomass bacterial samples from primary tumor samples with patient survival and with an increased gamma-delta T cell infiltrate. Results indicate that the gamma-delta T cells potentially play a role in the dynamics of the bacterial infiltration of primary tumors of the alimentary tract.

Bacterial Sequencing Reads in Blood Exome Files from Melanoma and Cervical Cancer Patients are Associated with Cancer Recurrence.

Bacteremia poses great risk for morbidity and mortality for immunocompromised cancer patients. Although the presence of bacteria within solid tumors is gaining greater attention, few studies have analyzed species of bacteria in the blood and their effect on cancer clinical outcomes. Using the Kraken 2 taxonomic profiling tool, we classified bacteria present in blood and primary tumors of cervical cancer and melanoma cases. The Cancer Genome Atlas (TCGA) melanoma blood exome files with Pseudomonas species were found to represent a worse disease-free survival (DFS) probability, while a worse overall survival (OS) result was evidenced for both the TCGA and Moffitt Cancer Center melanoma datasets. Cervical cancer cases with reads representing the Bradyrhizobium genus and Bradyrhizobium sp. BTAi1 found in blood and tumor exome files were found to have lower DFS. Additionally, reduced DFS and OS were observed for cervical cancer cases positive for Bacteroides species including Bacteroides fragilis. This study provides novel evidence and a novel approach for indicating that bacteria in blood is associated with cancer recurrence. These findings may guide the development of more efficient prognostic and screening tools related to bacterial blood infections of melanoma and cervical cancer patients.

Knowledge translation and evidence generation to increase the impact of vector control in Burkina Faso, Cameroon and Malawi.

Lack of context-specific evidence and inadequate evidence-use for decision-making contribute to poor health. This paper reports on our work aimed at addressing the knowledge translation (KT) gap between evidence generators and users. We present our experiences of strengthening KT via technical advisory groups (TAGs) in parallel with increasing evidence generation through research fellowships and operational research. Vectorborne diseases (VBDs) impose substantial health and economic burdens in sub-Saharan Africa despite being preventable with vector control. The Partnership for Increasing the Impact of Vector Control aimed to reduce the burden of VBDs in Burkina Faso, Cameroon, Malawi and at regional and global levels. TAGs can promote evidence-use in policy and practice by engaging relevant stakeholders in both research and policy processes. TAGs and related activities are best facilitated by a coordinator with skills in research and policy. Contextual factors should influence the design and governance of TAGs, which will likely evolve over time. Relevant national stakeholders should be included in TAGs and be actively involved in developing research agendas to increase the relevance and acceptability of research findings for decision-making. The countries present three differing contexts with longer-term research and evaluation necessary to draw lessons on impact.

Guidance and conceptual tools to inform the design, selection and evaluation of research capacity strengthening interventions.

This practice note presents four conceptual tools intended to support the design, selection and evaluation of research capacity strengthening (RCS) programmes in low-income and middle-income country settings. The tools may be used by a wide range of RCS stakeholders, including funders, implementing parties and programme evaluators, to guide decision-making in lieu of largely as yet unavailable empirical evidence. The first conceptual tool guides decision-making regarding RCS intervention design, focusing specifically on the combination and integration of potential intervention activities. The second conceptual tool provides a framework for assessing the implementation challenges of potential RCS interventions in terms of: (1) the overall cost of implementing the proposed intervention in a given context; (2) the length of time required to complete full implementation of the proposed intervention in a given context and (3) the level of control the implementing partners would have over the proposed intervention in a given context. The third conceptual tool provides a means to consider the anticipated impact of potential RCS interventions in order to inform selection decisions (ie, which out of a number of potential RCS intervention options may be most impactful in a given setting given the intervention design and implementation challenges). The fourth and final tool is designed to support the evaluation of a collective RCS effort, whether that be multiple RCS interventions delivered within the context of a single or continuous programme or multiple RCS programmes delivered in a common setting.

'You want to deal with power while riding on power': global perspectives on power in participatory health research and co-production approaches.

INTRODUCTION: Power relations permeate research partnerships and compromise the ability of participatory research approaches to bring about transformational and sustainable change. This study aimed to explore how participatory health researchers engaged in co-production research perceive and experience 'power', and how it is discussed and addressed within the context of research partnerships. METHODS: Five online workshops were carried out with participatory health researchers working in different global contexts. Transcripts of the workshops were analysed thematically against the 'Social Ecology of Power' framework and mapped at the micro (individual), meso (interpersonal) or macro (structural) level. RESULTS: A total of 59 participants, with participatory experience in 24 different countries, attended the workshops. At the micro level, key findings included the rarity of explicit discussions on the meaning and impact of power, the use of reflexivity for examining assumptions and power differentials, and the perceived importance of strengthening co-researcher capacity to shift power. At the meso level, participants emphasised the need to manage co-researcher expectations, create spaces for trusted dialogue, and consider the potential risks faced by empowered community partners. Participants were divided over whether gatekeeper engagement aided the research process or acted to exclude marginalised groups from participating. At the macro level, colonial and 'traditional' research legacies were acknowledged to have generated and maintained power inequities within research partnerships. CONCLUSIONS: The 'Social Ecology of Power' framework is a useful tool for engaging with power inequities that cut across the social ecology, highlighting how they can operate at the micro, meso and macro level. This study reiterates that power is pervasive, and that while many researchers are intentional about engaging with power, actions and available tools must be used more systematically to identify and address power imbalances in participatory research partnerships, in order to contribute to improved equity and social justice outcomes.

Measuring the outcome and impact of research capacity strengthening initiatives: A review of indicators used or described in the published and grey literature.

Background: Development partners and research councils are increasingly investing in research capacity strengthening initiatives in low- and middle-income countries to support sustainable research systems. However, there are few reported evaluations of research capacity strengthening initiatives and no agreed evaluation metrics. Methods: To advance progress towards a standardised set of outcome and impact indicators, this paper presents a structured review of research capacity strengthening indicators described in the published and grey literature. Results: We identified a total of 668 indicators of which 40% measured output, 59.5% outcome and 0.5% impact. Only 1% of outcome and impact indicators met all four quality criteria applied. A majority (63%) of reported outcome indicators clustered in four focal areas, including: research management and support (97/400), the attainment and application of new research skills and knowledge (62/400), research collaboration (53/400), and knowledge transfer (39/400). Conclusions: Whilst this review identified few examples of quality research capacity strengthening indicators, it has identified priority focal areas in which outcome and impact indicators could be developed as well as a small set of 'candidate' indicators that could form the basis of development efforts.

Strengthening research management and support services in sub-Saharan African universities and research institutions.

Background: International development partners and research councils are increasingly funding research management and support (RMS) capacity strengthening initiatives in sub-Saharan Africa (SSA) as part of a broader investment in strengthening national and regional research systems.  However, the evidence-base to inform RMS capacity strengthening initiatives is limited at present. This research note presents a synthesis of 28 RMS capacity assessments completed in 25 universities/research institutions from across 15 SSA countries between 2014 and 2018.  Methods: All 28 capacity assessments were completed following a standardised methodology consisting of semi-structured interviews conducted with research and research support staff at the respective institution as well as document reviews and observation of onsite facilities. Data were extracted from the 28 reports detailing the findings of each assessment according to a framework synthesis approach. Results: In total, 13 distinct capacity gap categories emerged from across the 28 RMS capacity assessment reports.  Almost all the institutions assessed faced significant gaps in RMS capacity within and across each of these 13 categories. The 13 categories were not independent of each other and were often closely inter-connected. Commonalities were also evident across multiple categories, the two most obvious of which were severe fiscal constraints and the often-complex bureaucracy of the institutional operating environment. Conclusions: The synthesis findings reveal multiple, commonly shared RMS capacity gaps in universities and research institutions across SSA. No single intervention type, or focus, would be sufficient to strengthen capacity across all 13 areas; rather, what is needed to facilitate a significant shift in RMS capacity within such SSA universities and research institutions is a combination of interventions, consisting of differing levels of cost and complexity, variously led (or supported) by both internal and external actors.