Early Life Stress Predicts Decreased Total Brain Volume, Cortical Thickness, and Cognitive Functioning in School-Age Children

Severe early life stress (ELS) (e.g., maltreatment/institutionalization) is associated with atypical neurological and cognitive development. Few studies have prospectively examined the neurological mechanisms underlying the cognitive deficits associated with less severe and more common forms of ELS. The current study examined the impact of common forms of ELS assessed during early childhood on children’s brain volume, cortical thickness, and memory and executive functioning assessed three years later in school age children, controlling for current stress. Participants included 63 children (50.8% female) assessed during preschool (Wave 1 age: M=4.23 years, SD=.84) and three years later (Wave 2 age: M=7.19 years, SD=.89). ELS included low socioeconomic status, single parent household, low parental education, child exposure to parental depression, and child exposure to high parental hostility. Children’s current life stress, cognitive abilities, and brain structure were assessed at Wave 2. ELS predicted reduced total gray volume, cortex volume, right inferior parietal thickness, and right superior parietal thickness, controlling for covariates and current stress. ELS also predicted poorer memory and attention shifting, controlling for current stress. Right superior parietal thickness mediated the effects of ELS on story recall memory. Results highlight the possible consequences of less severe forms of ELS on brain volume and cognitive functioning, suggesting potential neural mechanisms to further explore. Early childhood may be a particularly important time for intervention efforts to mitigate the neural and cognitive risks associated with early stress exposure

Consensus and meta-analysis regulatory networks for combining multiple microarray gene expression datasets

Microarray data is a key source of experimental data for modelling gene regulatory interactions from expression levels. With the rapid increase of publicly available microarray data comes the opportunity to produce regulatory network models based on multiple datasets. Such models are potentially more robust with greater confidence, and place less reliance on a single dataset. However, combining datasets directly can be difficult as experiments are often conducted on different microarray platforms, and in different laboratories leading to inherent biases in the data that are not always removed through pre-processing such as normalisation. In this paper we compare two frameworks for combining microarray datasets to model regulatory networks: pre- and post-learning aggregation. In pre-learning approaches, such as using simple scale-normalisation prior to the concatenation of datasets, a model is learnt from a combined dataset, whilst in post-learning aggregation individual models are learnt from each dataset and the models are combined. We present two novel approaches for post-learning aggregation, each based on aggregating high-level features of Bayesian network models that have been generated from different microarray expression datasets. Meta-analysis Bayesian networks are based on combining statistical confidences attached to network edges whilst Consensus Bayesian networks identify consistent network features across all datasets. We apply both approaches to multiple datasets from synthetic and real (Escherichia coli and yeast) networks and demonstrate that both methods can improve on networks learnt from a single dataset or an aggregated dataset formed using a standard scale-normalisation

Enhancing Cancer Care of Rural Dwellers through Telehealth and Engagement (ENCORE): Protocol to Evaluate Effectiveness of a Multi-Level Telehealth-Based Intervention to Improve Rural Cancer Care Delivery

BACKGROUND: Despite lower cancer incidence rates, cancer mortality is higher among rural compared to urban dwellers. Patient, provider, and institutional level factors contribute to these disparities. The overarching objective of this study is to leverage the multidisciplinary, multispecialty oncology team from an academic cancer center in order to provide comprehensive cancer care at both the patient and provider levels in rural healthcare centers. Our specific aims are to: 1) evaluate the clinical effectiveness of a multi-level telehealth-based intervention consisting of provider access to molecular tumor board expertise along with patient access to a supportive care intervention to improve cancer care delivery; and 2) identify the facilitators and barriers to future larger scale dissemination and implementation of the multi-level intervention. METHODS: Coordinated by a National Cancer Institute-designated comprehensive cancer center, this study will include providers and patients across several clinics in two large healthcare systems serving rural communities. Using a telehealth-based molecular tumor board, sequencing results are reviewed, predictive and prognostic markers are discussed, and treatment plans are formulated between expert oncologists and rural providers. Simultaneously, the rural patients will be randomized to receive an evidence-based 6-week self-management supportive care program, Cancer Thriving and Surviving, versus an education attention control. Primary outcomes will be provider uptake of the molecular tumor board recommendation and patient treatment adherence. A mixed methods approach guided by the Consolidated Framework for Implementation Research that combines qualitative key informant interviews and quantitative surveys will be collected from both the patient and provider in order to identify facilitators and barriers to implementing the multi-level intervention. DISCUSSION: The proposed study will leverage information technology-enabled, team-based care delivery models in order to deliver comprehensive, coordinated, and high-quality cancer care to rural and/or underserved populations. Simultaneous attention to institutional, provider, and patient level barriers to quality care will afford the opportunity for us to broadly share oncology expertise and develop dissemination and implementation strategies that will enhance the cancer care delivered to patients residing within underserved rural communities. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04758338 . Registered 17 February 2021 - Retrospectively registered, http://www.clinicaltrials.gov/

Does self-monitoring reduce blood pressure? Meta-analysis with meta-regression of randomized controlled trials

Introduction. Self-monitoring of blood pressure (BP) is an increasingly common part of hypertension management. The objectives of this systematic review were to evaluate the systolic and diastolic BP reduction, and achievement of target BP, associated with self-monitoring. Methods. MEDLINE, Embase, Cochrane database of systematic reviews, database of abstracts of clinical effectiveness, the health technology assessment database, the NHS economic evaluation database, and the TRIP database were searched for studies where the intervention included self-monitoring of BP and the outcome was change in office/ambulatory BP or proportion with controlled BP. Two reviewers independently extracted data. Meta-analysis using a random effects model was combined with meta-regression to investigate heterogeneity in effect sizes. Results. A total of 25 eligible randomized controlled trials (RCTs) (27 comparisons) were identified. Office systolic BP (20 RCTs, 21 comparisons, 5,898 patients) and diastolic BP (23 RCTs, 25 comparisons, 6,038 patients) were significantly reduced in those who self-monitored compared to usual care (weighted mean difference (WMD) systolic −3.82 mmHg (95% confidence interval −5.61 to −2.03), diastolic −1.45 mmHg (−1.95 to −0.94)). Self-monitoring increased the chance of meeting office BP targets (12 RCTs, 13 comparisons, 2,260 patients, relative risk = 1.09 (1.02 to 1.16)). There was significant heterogeneity between studies for all three comparisons, which could be partially accounted for by the use of additional co-interventions. Conclusion. Self-monitoring reduces blood pressure by a small but significant amount. Meta-regression could only account for part of the observed heterogeneity

Elucidating the aetiology of human Campylobacter coli infections

Peer reviewedPublisher PD

Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3

Background Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. Methods Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. Results As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8+ T cells, T cell factor 1 (TCF1)+ T cells and CD69− T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3Kδ and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3Kδ inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3Kδ inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies. Conclusions These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies

Gut Homing Receptors on CD8 T Cells Are Retinoic Acid Dependent and Not Maintained by Liver Dendritic or Stellate Cells

BACKGROUND & AIMS: Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and α4β7, which recognize CCL25 and mucosal addressin cell-adhesion molecule-1 in the intestine promoting the development of regional immunity. In mice, imprinting of CCR9 and α4β7 is dependent on retinoic acid during T-cell activation. Tissue specificity is lost in primary sclerosing cholangitis (PSC), an extraintestinal manifestation of inflammatory bowel disease, when ectopic expression of mucosal addressin cell-adhesion molecule-1 and CCL25 in the liver promotes recruitment of CCR9+α4β7+ T cells to the liver. We investigated the processes that control enterohepatic T-cell migration and whether the ability to imprint CCR9 and α4β7 is restricted to intestinal DCs or can under some circumstances be acquired by hepatic DCs in diseases such as PSC. METHODS: Human and murine DCs from gut, liver, or portal lymph nodes and hepatic stellate cells were used to activate CD8 T cells. Imprinting of CCR9 and α4β7 and functional migration responses were determined. Crossover activation protocols assessed plasticity of gut homing. RESULTS: Activation by gut DCs imprinted high levels of functional CCR9 and α4β7 on naïve CD8 T cells, whereas hepatic DCs and stellate cells proved inferior. Imprinting was RA dependent and demonstrated plasticity. CONCLUSIONS: Imprinting and plasticity of gut-homing human CD8 T cells requires primary activation or reactivation by gut DCs and is retinoic acid dependent. The inability of liver DCs to imprint gut tropism implies that α4β7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut