Adverse childhood experiences and life opportunities: Shifting the narrative

Substantial research shows that early adversity, including child abuse and neglect, is associated with diminished health across the life course and across generations. Lesswell understood is the relationship between early adversity and adult socioeconomic status, including education, employment, and income. Collectively, these outcomes provide an indication of overall life opportunity. We analyzed data from 10 states and the District of Columbia that used the adverse childhood experiences (ACE) module in the 2010 Behavioral Risk Factor Surveillance System to examine the association between ACEs and adult education, employment, and income. Compared to participants with no ACEs, those with higher ACE scores were more likely to report high school non-completion, unemployment, and living in a household below the federal poverty level. This evidence suggests that preventing early adversity may impact health and life opportunities that reverberate across generations. Current efforts to prevent early adversity might be more successful if they broaden public and professional understanding (i.e., the narrative) of the links between early adversity and poverty. We discuss our findings within the context of structural policies and processes that may further contribute to the intergenerational continuity of child abuse and neglect and poverty

Longitudinal Mediators of Relations Between Family Violence and Adolescent Dating Aggression Perpetration: Family Violence and Adolescent Dating Aggression

Few longitudinal studies have examined the pathways through which family violence leads to dating aggression. In the current study the authors used 3 waves of data obtained from 8th- and 9th-grade adolescents (N = 1,965) to examine the hypotheses that the prospective relationship between witnessing family violence and directly experiencing violence and physical dating aggression perpetration is mediated by 3 constructs: (a) normative beliefs about dating aggression (norms), (b) anger dysregulation, and (c) depression. Results from cross-lagged regression models suggest that the relationship between having been hit by an adult and dating aggression is mediated by changes in norms and anger dysregulation, but not depression. No evidence of indirect effects from witnessing family violence to dating aggression was found through any of the proposed mediators. Taken together, the findings suggest that anger dysregulation and normative beliefs are potential targets for dating abuse prevention efforts aimed at youth who have directly experienced violence

Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer’s disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese–American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia—broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with “frequent” neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer’s disease neuropathology

The Inner-Shelf Dynamics Experiment

17 USC 105 interim-entered record; under review.The article of record as published may be found at http://dx.doi.org/10.1175/BAMS-D-19-0281.1The inner shelf, the transition zone between the surfzone and the midshelf, is a dynamically complex region with the evolution of circulation and stratification driven by multiple physical processes. Cross-shelf exchange through the inner shelf has important implications for coastal water quality, ecological connectivity, and lateral movement of sediment and heat. The Inner-Shelf Dynamics Experiment (ISDE) was an intensive, coordinated, multi-institution field experiment from September–October 2017, conducted from the midshelf, through the inner shelf, and into the surfzone near Point Sal, California. Satellite, airborne, shore- and ship-based remote sensing, in-water moorings and ship-based sampling, and numerical ocean circulation models forced by winds, waves, and tides were used to investigate the dynamics governing the circulation and transport in the inner shelf and the role of coastline variability on regional circulation dynamics. Here, the following physical processes are highlighted: internal wave dynamics from the midshelf to the inner shelf; flow separation and eddy shedding off Point Sal; offshore ejection of surfzone waters from rip currents; and wind-driven subtidal circulation dynamics. The extensive dataset from ISDE allows for unprecedented investigations into the role of physical processes in creating spatial heterogeneity, and nonlinear interactions between various inner-shelf physical processes. Overall, the highly spatially and temporally resolved oceanographic measurements and numerical simulations of ISDE provide a central framework for studies exploring this complex and fascinating region of the ocean.U.S. Office of Naval Research (ONR)ONR Departmental Research Initiative (DRI)Inner-Shelf Dynamics Experiment (ISDE

LATE-NC staging in routine neuropathologic diagnosis : an update

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Recognizing the Cumulative Burden of Childhood Adversities Transforms Science and Practice for Trauma and Resilience

The Adverse Childhood Experiences (ACEs) studies transformed our understanding of the true burden of trauma. Notable elements of Felitti and colleagues’ findings include theinfluence of adversity on many physical as well as psychological problems and the persistenceof impacts decades after the traumas occurred. In this article, we make the case that themost revolutionary finding was the discovery of a strong dose-response effect, with markedincreases in risk observed for individuals who reported four or more adversities. Over the pasttwo decades, our understanding of the cumulative burden of trauma has expanded further,with recognition that experiences outside the family, including peer victimization, communityviolence, and racism, also contribute to trauma dose. Recent research has provided evidencefor the pervasiveness of trauma, which we now realize affects most people, even by the endof adolescence. Extensive scientific evidence has documented that more than 40 biopsychosocialoutcomes, including leading causes of adult morbidity and mortality, are associatedwith adverse childhood experiences, measured by dose. We summarize the state of scienceand explain how ACEs built a movement for uncovering mechanisms responsible for theserelationships. Perhaps unexpectedly, the pervasiveness of trauma also expands our understandingof resilience, which is likewise more common than previously recognized. Emergingresearch on positive childhood experiences and poly-strengths suggests that individual,family, and community strengths may also contribute to outcomes in a dose-responserelationship. We close with an agenda for research, intervention, and policy to reduce thesocietal burden of adversity and promote resilienc