Leveraging the Science of Early Life Predictability to Inform Policies Promoting Child Health

Addressing the tremendous burden of early-life adversity requires constructive dialogues between scientists and policy makers to improve population health. Whereas dialogues focused on several aspects of early-life adversity have been initiated, discussion of an underrecognized form of adversity that has been observed across multiple contexts and cultures is only now emerging. Here we provide evidence for “why unpredictability?”, including: 1. Evidence that exposures to unpredictability affect child neurodevelopment, with influences that persist into adulthood. 2. The existence of a translational non-human animal model of exposure to early life unpredictability that can be capitalized upon to causally probe neurobiological mechanisms. 3. Evidence that patterns of signals in the early environment promote brain maturation across species. 4. The uneven distribution of unpredictability across demographic populations that illuminates a possible focal point for enhancing health equity. We then outline the potential of unpredictability in terms of the “what”; that is, how might the concept of unpredictability be leveraged to inform policy? We emphasize the importance of interdisciplinary and community partnerships to the success of this work and describe our community-engaged research project. Finally, we highlight opportunities for the science of unpredictability to inform policies in areas such as screening, immigration, criminal justice, education, childcare, child welfare, employment, healthcare and housing

Female philopatry in smalltooth sawfish Pristis pectinata: conservation and management implications

Populations are more effectively managed with information on breeding and dispersal behavior, making the evaluation of these characteristics essential for effective conservation of a species. In the USA, 2 critical habitat units were designated in 2009 for the federally endangered smalltooth sawfish Pristis pectinata. Previous research in the Charlotte Harbor Estuary Unit (CHEU) of critical habitat shows that female smalltooth sawfish are polyandrous and highly philopatric to nursery grounds. However, these characteristics have not yet been examined in a larger area of designated critical habitat: the Ten Thousand Islands/Everglades Unit (TTIEU). We used microsatellite genotypes from 214 juvenile smalltooth sawfish to examine mating and dispersal behavior via sibship analyses and reconstruction of parental genotypes with the program COLONY. Parental reconstruction yielded 71 female and 117 male genotypes. Many females returned to the same region within TTIEU for parturition on a biennial cycle; however, at least 1 female switched parturition sites within TTIEU and at least 2 females produced litters in both TTIEU and CHEU over the study period. The maximum number of pups genetically assigned to 1 female was 12, a number that is consistent with that found for CHEU (8 pups), and within the litter size range reported (7 to 14) for the species. Confirmation of these mating behaviors and reproductive characteristics is important for understanding how the present population uses these protected habitats at different life stages, and for determining future habitat protection and population expansion strategies to restore smalltooth sawfish to previously occupied areas of their range

Immune genotypes, immune responses, and survival in a wild bird population

ACKNOWLEDGEMENTS We thank the Tsawout and Tseycum bands for allowing us to conduct research on Mandarte Island, and to the many contributors to long-term monitoring, especially L. Keller, P. Nietlisbach, and J. Krippel. We also thank C. Ritland, A. Miscampbell, and G. Huber for their assistance in the laboratory. All work was conducted under permit of the Canadian Wildlife Service and UBC Animal Care Committee. Funding Information: This study was generously supported by the Natural Sciences and Engineering Research Council of Canada via a Post‐doctoral Fellowship award to MJNF (PDF‐2014–454522) and a Discovery Grant to EAMS.Peer reviewedPublisher PD

Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins

Given the clinical impact of LMNA cardiomyopathies, understanding lamin function will fulfill a clinical need and will lead to advancement in the treatment of heart failure. A multidisciplinary approach combining cell biology, atomic force microscopy (AFM) and molecular modeling was used to analyze the biomechanical properties of human lamin A/C gene (LMNA) mutations (E161K, D192G, N195K) using an in vitro neonatal rat ventricular myocyte (NRVM) model

Efficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM

Walking slowly after stroke reduces health and quality of life. This multi-site, prospective, interventional, 2-arm randomized controlled trial (NCT04121754) evaluated the safety and efficacy of an autonomous neurorehabilitation system (InTandemTM) designed to use auditory-motor entrainment to improve post-stroke walking. 87 individuals were randomized to 5-week walking interventions with InTandem or Active Control (i.e., walking without InTandem). The primary endpoints were change in walking speed, measured by the 10-meter walk test pre-vs-post each 5-week intervention, and safety, measured as the frequency of adverse events (AEs). Clinical responder rates were also compared. The trial met its primary endpoints. InTandem was associated with a 2x larger increase in speed (Δ: 0.14 ± 0.03 m/s versus Δ: 0.06 ± 0.02 m/s, F(1,49) = 6.58, p = 0.013), 3x more responders (40% versus 13%, χ2(1) ≥ 6.47, p = 0.01), and similar safety (both groups experienced the same number of AEs). The auditory-motor intervention autonomously delivered by InTandem is safe and effective in improving walking in the chronic phase of stroke

Innovation Contests with Entry Auction

We consider procurement of an innovation from heterogeneous sellers. Innovations are random but depend on unobservable effort and private information. We compare two procurement mechanisms where potential sellers first bid in an auction for admission to an innovation contest. After the contest, an innovation is procured employing either a fixed prize or a first-price auction. We characterize Bayesian Nash equilibria such that both mechanisms are payoff-equivalent and induce the same efforts and innovations. In these equilibria, signaling in the entry auction does not occur since contestants play a simple strategy that does not depend on rivals' private information

HTLV-1 clonality during chronic infection and BLV clonality during primary infection

peer reviewedaudience: researcherHTLV-1 clonality during chronic infection and BLV clonality during primary infection Nicolas A Gillet1,2*, Carol Hlela1, Tine Verdonck3, Eduardo Gotuzzo3, Daniel Clark3, Sabrina Rodriguez2, Nirav Malani4, Anat Melamed1, Niall Gormley5, Richard Carter5, David Bentley5, Charles Berry6, Frederic D Bushman4, Graham P Taylor7, Luc Willems2, Charles R M Bangham1 1Department of Immunology, Wright-Fleming Institute, Imperial College London, London, W2 1PG, UK. 2Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège (ULg), Liège, 4000, Belgium. 3Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru. 4Department of Microbiology, University of Pennsylvania School of Medicine, Pennsylvania, Philadelphia, PA, 19104, USA. 5Illumina, Chesterford Research Park, Essex, Little Chesterford, CB10 1XL, UK. 6University of California, California, La Jolla San Diego, CA, 92093-0901, USA. 7Department of Genitourinary Medicine and Communicable Diseases, Wright-Fleming Institute, Imperial College London, London, W2 1PG, UK. HTLV-1 persists by driving clonal proliferation of infected T-lymphocytes. A high proviral load predisposes to the inflammatory and malignant diseases associated with HTLV-1. Yet the reasons for the remarkable variation within and between individuals in the abundance of HTLV-1-infected clones remain unknown. We demonstrate that negative selection dominates during chronic infection, favouring establishment of proviruses integrated in transcriptionally silenced DNA: this selection is significantly stronger in asymptomatic carriers. We postulated that this selection occurred mainly during the primary infection. We are testing this hypothesis in an animal model by studying the BLV clonality during the primary infection in cows. By measuring the proviral load, the anti-BLV immune response and the BLV clonality we aim to quantify the impact of the immune response on the rate of infectious spread and on the selection of proviruses inserted in a particular genomic environment. Co-infection with Strongyloides stercoralis or Staphylococcus appears to be another risk factor for the development of HTLV-1 associated diseases. We observed that HTLV-1 clonality is altered by co-infection with these pathogens with an increase of both the number and the abundance of the infected T-cell clones. The genomic characteristics of the proviral integration sites in the most abundant clones differ significantly between co-infected individuals and those with HTLV-1 alone, implying the existence of different selection forces in co-infected patients. The rate of appearance of new clones in patients co-infected with Strongyloides stercoralis is higher than in patients with HTLV-1 alone. By comparing skin lesions and blood samples from patients with Infective Dermatitis associated with HTLV-1 (IDH), we observed a significant proportion of distinct infected clones between the two compartments. The skin lesions seem to be a site for HTLV-1 infectious spread

Pathological Computed Tomography Features Associated with Adverse Outcomes after Mild Traumatic Brain Injury:A TRACK-TBI Study with External Validation in CENTER-TBI

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood. Objective: To identify pathological CT features associated with adverse outcomes after mTBI. Design, Setting, and Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021. Exposures: Acute nonpenetrating head trauma. Main Outcomes and Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months. Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI.98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study. Conclusions and Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up

Genomics, social media and mobile phone data enable mapping of SARS-CoV-2 lineages to inform health policy in Bangladesh.

Genomics, combined with population mobility data, used to map importation and spatial spread of SARS-CoV-2 in high-income countries has enabled the implementation of local control measures. Here, to track the spread of SARS-CoV-2 lineages in Bangladesh at the national level, we analysed outbreak trajectory and variant emergence using genomics, Facebook 'Data for Good' and data from three mobile phone operators. We sequenced the complete genomes of 67 SARS-CoV-2 samples (collected by the IEDCR in Bangladesh between March and July 2020) and combined these data with 324 publicly available Global Initiative on Sharing All Influenza Data (GISAID) SARS-CoV-2 genomes from Bangladesh at that time. We found that most (85%) of the sequenced isolates were Pango lineage B.1.1.25 (58%), B.1.1 (19%) or B.1.36 (8%) in early-mid 2020. Bayesian time-scaled phylogenetic analysis predicted that SARS-CoV-2 first emerged during mid-February in Bangladesh, from abroad, with the first case of coronavirus disease 2019 (COVID-19) reported on 8 March 2020. At the end of March 2020, three discrete lineages expanded and spread clonally across Bangladesh. The shifting pattern of viral diversity in Bangladesh, combined with the mobility data, revealed that the mass migration of people from cities to rural areas at the end of March, followed by frequent travel between Dhaka (the capital of Bangladesh) and the rest of the country, disseminated three dominant viral lineages. Further analysis of an additional 85 genomes (November 2020 to April 2021) found that importation of variant of concern Beta (B.1.351) had occurred and that Beta had become dominant in Dhaka. Our interpretation that population mobility out of Dhaka, and travel from urban hotspots to rural areas, disseminated lineages in Bangladesh in the first wave continues to inform government policies to control national case numbers by limiting within-country travel