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Abstract Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.

Abstract Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.

Abstract Introduction Rural placements are an important component of rural medical education programs seeking to develop rural practice pathways for medical students. These placements are usually domestic, but James Cook University in Australia developed an international rural placement program in the first half of the medical course that was funded through bursaries. This study explores how the international rural placement helped to shape the lives (personal development and learning) of the participants, using Transformational Learning Theory as a framework for identifying and describing the transformational elements, process and impact of the program. Methods Sixty-five students received a bursary for an international rural placement between 2001–2019. All were contacted by email and invited to participate in a short survey and a follow-up interview. Fifteen participants agreed and twelve were able to participate in individual semi-structured interviews which were recorded, transcribed and analysed using inductive thematic analysis. Results Participants reported that the bursary provided a “once in a lifetime opportunity” to “experience eye-opening and culturally rich difference”. Nonetheless, some elements of the placement experience presented disorientating dilemmas that triggered deep reflections and shifts in perceptions. The bursary recipients realised that “being open-minded” allowed them “enjoy good company”. They were also able to assume “outsider view which allowed reassessment of their own country” and the “isolation experiences gingered desire to right health wrongs”. The triggers and mental shifts had significant impact on the bursary recipients and fostered the development of “inspirational new horizons” based on an appreciation of the “value of rural practice” and “role-modelling for life-long learning.” These findings are consistent with Transformational Learning Theory. Conclusion Participants in this study reported meaningful and strongly positive impacts from the experiences gained during an international rural clinical placement early in their course. They described transformative experiences which appear to contribute strongly to personal development. This finding supports maintaining opportunities for international experiences during rurally-oriented medical programs as these may impact longer term career choice.

Alzheimer’s disease is associated with changes in astrocytes. Here the authors investigated the astrocyte translatome associated with amyloid-ß and tau pathology.

The study of microglia isolated from adult human brain tissue provides unique insight into the physiology of these brain immune cells and their role in adult human brain disorders. Reports of microglia in post-mortem adult human brain tissue show regional differences in microglial populations, however, these differences have not been fully explored in living microglia. In this study biopsy tissue was obtained from epileptic patients undergoing surgery and consisted of both cortical areas and neurogenic ventricular and hippocampal (Hp) areas. Microglia were concurrently isolated from both regions and compared by immunochemistry. Our initial observation was that a greater number of microglia resulted from isolation and culture of ventricular/Hp tissue than cortical tissue. This was found to be due to a greater proliferative capacity of microglia from ventricular/Hp regions compared to the cortex. Additionally, ventricular/Hp microglia had a greater proliferative response to the microglial mitogen Macrophage Colony-Stimulating Factor (M-CSF). This enhanced response was found to be associated with higher M-CSF receptor expression and higher expression of proteins involved in M-CSF signalling DAP12 and C/EBPβ. Microglia from the ventricular/Hp region also displayed higher expression of the receptor for Insulin-like Growth Factor-1, a molecule with some functional similarity to M-CSF. Compared to microglia isolated from the cortex, ventricular/Hp microglia showed increased HLA-DP, DQ, DR antigen presentation protein expression and a rounded morphology. These findings show that microglia from adult human brain neurogenic regions are more proliferative than cortical microglia and have a distinct protein expression profile. The data present a case for differential microglial phenotype and function in different regions of the adult human brain and suggest that microglia in adult neurogenic regions are “primed” to an activated state by their unique tissue environment.

Introduction: Relapsed SCLC is characterized by therapeutic resistance and high mortality rate. Despite decades of research, mechanisms responsible for therapeutic resistance have remained elusive owing to limited tissues available for molecular studies. Thus, an unmet need remains for molecular characterization of relapsed SCLC to facilitate development of effective therapies. Methods: We performed whole-exome and transcriptome sequencing of metastatic tumor samples procured from research autopsies of five patients with relapsed SCLC. We implemented bioinformatics tools to infer subclonal phylogeny and identify recurrent genomic alterations. We implemented immune cell signature and single-sample gene set enrichment analyses on tumor and normal transcriptome data from autopsy and additional primary and relapsed SCLC data sets. Furthermore, we evaluated T cell-inflamed gene expression profiles in neuroendocrine (ASCL1, NEUROD1) and non-neuroendocrine (YAP1, POU2F3) SCLC subtypes. Results: Exome sequencing revealed clonal heterogeneity (intertumor and intratumor) arising from branched evolution and identified resistance-associated truncal and subclonal alterations in relapsed SCLC. Transcriptome analyses further revealed a noninflamed phenotype in neuroendocrine SCLC subtypes (ASCL1, NEUROD1) associated with decreased expression of genes involved in adaptive antitumor immunity whereas non-neuroendocrine subtypes (YAP1, POU2F3) revealed a more inflamed phenotype. Conclusions: Our results reveal substantial tumor heterogeneity and complex clonal evolution in relapsed SCLC. Furthermore, we report that neuroendocrine SCLC subtypes are immunologically cold, thus explaining decreased responsiveness to immune checkpoint blockade. These results suggest that the mechanisms of innate and acquired therapeutic resistances are subtype-specific in SCLC and highlight the need for continued investigation to bolster therapy selection and development for this cancer.

Numerous studies have documented the detrimental impact of age-based stereotype threat (ABST) on older adults' cognitive performance and especially on veridical memory. However, far fewer studies have investigated the impact of ABST on older adults' memory distortion. Here, we review the subset of research examining memory distortion and provide evidence for the role of stereotype threat as a powerful socio-emotional factor that impacts age-related susceptibility to memory distortion. In this review we define memory distortion as errors in memory that are associated with gist-based errors or source misattributions. Whereas, some of the reviewed experiments support the conclusion that ABST should be considered in the context of age-related differences in memory distortion, others reported little or no impact of stereotype threat. These discrepancies suggest that the role of ABST, and socio-emotional processes generally, in age-related changes in memory distortion are less clear. In this review, we argue that ABST does play an important role in age-related changes in memory distortion. We present evidence suggesting that discrepancies in the reviewed literature may be reconciled when evaluated in the context of the leading theories about stereotype threat: the Executive Resource Depletion hypothesis and the Regulatory Focus theory. We also discuss how differences in methodology and participant characteristics can account for a priori contradictory results in the literature. Finally, we propose some recommendations for researchers and practitioners when assessing memory in older adults.

Abstract Background Microglia play critical roles in the brain during homeostasis and pathological conditions. Understanding the molecular events underpinning microglial functions and activation states will further enable us to target these cells for the treatment of neurological disorders. The transcription factor PU.1 is critical in the development of myeloid cells and a major regulator of microglial gene expression. In the brain, PU.1 is specifically expressed in microglia and recent evidence from genome-wide association studies suggests that reductions in PU.1 contribute to a delayed onset of Alzheimer’s disease (AD), possibly through limiting neuroinflammatory responses. Methods To investigate how PU.1 contributes to immune activation in human microglia, microarray analysis was performed on primary human mixed glial cultures subjected to siRNA-mediated knockdown of PU.1. Microarray hits were confirmed by qRT-PCR and immunocytochemistry in both mixed glial cultures and isolated microglia following PU.1 knockdown. To identify attenuators of PU.1 expression in microglia, high throughput drug screening was undertaken using a compound library containing FDA-approved drugs. NanoString and immunohistochemistry was utilised to investigate the expression of PU.1 itself and PU.1-regulated mediators in primary human brain tissue derived from neurologically normal and clinically and pathologically confirmed cases of AD. Results Bioinformatic analysis of gene expression upon PU.1 silencing in mixed glial cultures revealed a network of modified AD-associated microglial genes involved in the innate and adaptive immune systems, particularly those involved in antigen presentation and phagocytosis. These gene changes were confirmed using isolated microglial cultures. Utilising high throughput screening of FDA-approved compounds in mixed glial cultures we identified the histone deacetylase inhibitor vorinostat as an effective attenuator of PU.1 expression in human microglia. Further characterisation of vorinostat in isolated microglial cultures revealed gene and protein changes partially recapitulating those seen following siRNA-mediated PU.1 knockdown. Lastly, we demonstrate that several of these PU.1-regulated genes are expressed by microglia in the human AD brain in situ. Conclusions Collectively, these results suggest that attenuating PU.1 may be a valid therapeutic approach to limit microglial-mediated inflammatory responses in AD and demonstrate utility of vorinostat for this purpose.

The authors wish to make the following change to their paper (Akosah-Twumasi et al [...]

Universal school-based social and emotional learning (SEL) programs have been shown to have a range of benefits for students. However, these programs tend to focus on students, not involving parents, which may limit their impact outside the school context. We conducted focus groups and interviews with 118 parents, 58 teachers, and 6 school administrators at six public elementary schools across the United States implementing the Second Step SEL program to determine (a) what parents want to know about SEL in their children's schools and why, (b) what parents actually know about SEL in their children's schools, and (c) educators' perspectives on SEL communication with parents. The findings suggest that school staff underestimate parents' interest in knowing what their children are learning in SEL at school and perceive logistical barriers to SEL communication with parents. Accordingly, many parents report lacking knowledge about SEL despite valuing that knowledge and wishing to support their children's SEL development. These findings point to ways SEL programs can be designed to better communicate with parents, and importantly, to facilitate parental engagement in the development of their children's SEL skills.

This study describes the development of a 12-item inventory of school supports for military-connected (MC) children. Participants were 444 students (grades 3 or 5) with an active-duty military parent (48% female; 57.3% White, 10.7% Black, 6.2% Native American, 5% Asian, 3.3% Pacific Islander, 17.5% bi/multiracial; 19% Latinx). Youth completed the Inventory of School Supports--Youth Report (ISS-YR) and measures of academic efficacy, parental involvement in school, school connectedness, and whether they had a non-parental supportive adult in their life. Parents reported on parent-teacher relationship quality. Confirmatory factor analyses supported a two-factor model (functional and relational support). Results psychometrically supported the ISS-YR. Scores demonstrated adequate internal consistency reliability. Results also supported the measure's convergent and criterion validity as evidenced by positive associations with school connectedness, academic efficacy, parental school involvement, and parent-teacher relationship quality. Youth with a supportive adult in their life at and outside of school had the highest ISS-YR scores. Implications of these findings for schools' efforts to support MC students are discussed.

Tools that assess school supports for highly mobile, military-connected students are lacking. This study describes the development and preliminary validation of the Inventory of School Supports-Parent Report (ISS-PR). Participants were 433 parents (74% female; 62.5% White, 12% Black, 6.5% Asian, 5.5% Pacific Islander, 4% Native American, and 9.5% bi/multiracial; 19% Latinx) of students (grades 3-5) from families with an active-duty military parent. Parents completed the ISS-PR and rated: (a) how welcoming schools were toward military-connected families; (b) parent-teacher relationship quality; and (c) satisfaction with their child's school. We created three proportional index composite scores: a 26-item school supports score, a 13-item parent-focused supports score, and a 13-item child-focused supports score. Results supported the ISS-PR's psychometric properties: summary scores were positively linked to parent-teacher relationship quality, school welcoming, and parent satisfaction with the school. We also found evidence for test-retest reliability for parents completing the inventory with students who had either moved schools or remained in their previous schools. Future studies could use the ISS-PR to assess whether parents' perceptions of the availability and importance of school supports for military-connected families are related to other constructs such as overall school climate, student academic performance, and socioemotional functioning. Schools could use the inventory to determine which supports could potentially have the greatest impact for military-connected families and to what extent parents are aware of the supports schools offer.

If high-conflict family environments are cariogenic across cultures, and can be studied in cultures where both these environments and cariogenic dental practices are particularly prevalent, this would afford the opportunity to examine how these two pathways of risk might interact, laying the stage for culturally competent, integrated prevention efforts. The first investigation involved qualitative data about perceptions of oral health and family stressors in Grenadian families with school-aged children. The second study used a questionnaire and observational data to assess relations among oral health behaviors, relationship satisfaction, parenting, and child behavior; it also included a pilot study of Motivational Interviewing. Most of the themes discussed in focus groups suggested overlap between U.S. and Grenadian parents; possible culture-specific issues were high prevalence of single-parent homes, normativity of physical discipline, less preventive dental care, and more fatalistic view of oral health outcomes. Significant associations were found between parent and child oral health behaviors, between child externalizing and internalizing behaviors, and between family variables (e.g., relationship satisfaction, child behavior) and oral health behaviors (e.g., parent flossing, child brush time). The results strongly support the need for research on the relations between family functioning and oral health to be embedded within culture.

Pre-existing acculturation models have focused on individual orientation and may not be fully applicable to African migrants due to their strong connection to family. In this study, we utilised qualitative semi-structured interviews to explore how 22 migrant families from eight sub-Saharan African representative countries: Congo, Eritrea, Kenya, Nigeria, Rwanda, Sierra Leone, Uganda and Zimbabwe, who now reside in Townsville, Australia experienced the acculturation process. Data were analysed at the family unit level using the three steps of grounded theory method: open, axial and selective coding. The theory derived illustrates that the acculturation process involves two major phases (maintaining core moral values and attaining a sense of belonging) within which six categories were identified. Three of the categories were related to deeply held heritage values and beliefs (family relationships, societal expectations and cultural norms), while the other three (religious beliefs, socio-economic gains and educational values) indicated integration with the host culture. These categories constitute central concerns for the participants and demonstrate what matters to them as a family unit and not as individuals. We conclude that a selective process of “prioritising family needs” determines the acculturation strategy of sub-Saharan African migrant families, aiding the fulfilment of their migration goals, ensuring effective functioning of the family unit, and enabling them to be productive members of their local community.

Valproic acid (VPA) is widely used for the treatment of mood disorders and epilepsy, but its mechanism of action is unclear. In vivo and in vitro studies using rodent models have demonstrated that VPA has both neuroprotective and neurotrophic effects. These beneficial effects are, in part, through modulation of glial cell function. Recently, we and others have shown that VPA selectively induces caspase-3 mediated apoptosis in rodent microglial cells. However, the effect of VPA on human microglia has not been tested. In this study, using microglia derived from adult human brains, we demonstrate that VPA does not induce microglial apoptosis as determined by the absence of caspase-3 cleavage. However, VPA does partially decrease the expression of the microglial markers PU.1 and CD45, as well as dramatically reducing microglial phagocytosis. Due to the many roles of microglia in the brain, these VPA-induced alterations in microglial phenotype could potentially have major effects on physiological and pathological actions of these cells.

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Introduction The Office of the Secretary of Defense and each of the services have made an unprecedented commitment to the prevention of sexual assault and related behavioral health phenomena. Indeed, the Department of Air Force has selected, in some cases tailored, and disseminated a wide array of evidence-based preventative programs, policies, and practices (EBPs) over the last few decades. However, many of these efforts seem to follow a predictable life course. EBPs are initially implemented with great enthusiasm, supported for a few years, then fall out of favor, and are replaced by a different effort. This research effort aims to build on the existing civilian implementation science research to (1) offer a military-specific model of sustained, high-quality implementation and (2) test this model in a series of interconnected studies. Materials and Methods New York University's Institutional Review Board approved the study protocols, and the Army's Human Research Protection Office provided permission to collect data. We conducted interviews first with prevention leaders in the services and at the Office of the Secretary of Defense level regarding factors that they thought helped or hurt the sustainment of EBPs. We used these interviews to identify EBPs currently implemented in Department of Air Force and selected four EBPs out of the 25 identified for intensive study. We then interviewed implementers of those four EBPs regarding what they thought helped or hurt the sustainment of that EBP. We also gathered information about the 25 currently implemented EBPs themselves and gathered policy and guidance, as well as leadership communication about those EBPs and the target problems they focus on. We coded this information to allow us to test EBP parameters and policy and leader communication that predict sustained high-quality implementation. We conducted over 100 observations of the 4 EBPs we are studying intensively and have collected quantitative data from implementers and participants to help us test factors related to sustained high-quality implementation within each of those 4 EBPs and across the EBPs. Results Several military-specific factors were nominated for inclusion in the military-specific model of implementation sustainment. The implementation of even highly standardized EBPs varies greatly. Implementers and participants are generally highly engaged, but implementers vary in the extent to which they understand the mechanisms of action for the EBP they are implementing. Conclusions We recommend training implementers in the mechanisms of action in the EBPs they are expected to implement and including quality assurance as a component of prevention efforts in a manner more similar to how the military addresses aspects of the operational mission. By moving beyond counting classes and attendance, and specifying how to engage participants in the EBPs in the manner that produces the key outcomes, it is likely that EBPs will have more robust implementations that can be better sustained over time. [ABSTRACT FROM AUTHOR]

Understanding the extent to which youth and families experienced COVID-related stress requires accounting for prior levels of stress and other associated factors. This is especially important for military families, which experience unique stressors and may be reluctant to seek outside help. In this prospective study, we examined the role of pre-pandemic family factors in predicting parent and youth stress during the COVID-19 pandemic. Participants were 234 families with at least one active-duty parent and a 3rd or 5th-grade child. Findings revealed that preexisting factors predicted youth and family COVID-related stress. Specifically, heightened pre-pandemic parental stress and youth internalizing symptoms were significant predictors of COVID-related stress. Implications for mental health professionals and other organizations supporting military parents and families during the COVID-19 pandemic as well as other times of upheaval are discussed. [ABSTRACT FROM AUTHOR]

Despite evidence that parents' physical aggression abuse has long-lasting negative consequences, information about the true population prevalence of aggression and physical abuse is limited. We have even less information about how parental aggression and abuse vary by child age, parent gender, and how that aggression and abuse might be clustered within families. To address these gaps, an anonymous, computer-based assessment was administered to nearly 40,000 parents of more than 60,000 children in the United States Air Force, which included a detailed assessment on up to four minor children of aggression and its impact. The survey was the largest of its type ever conducted in the United States, allowing for stable, crossvalidated estimation of rates of both corporal punishment and physical abuse. Approximately 39% of children experienced corporal punishment, peaking at three years of age, and 7% experienced physical abuse, peaking at age six. About 45% of parents reported perpetrating corporal punishment and 8% abuse; these rates were higher in multi-child families and most often involved more than one child. Parent gender was not associated with physical aggression or abuse. [ABSTRACT FROM AUTHOR]

Objectives: U.S. and global estimates indicate that over 30% of adults fear receiving dental care, including over 20% who have visited a dentist in the last year, leading to avoidance and degraded oral and systemic health. Although evidence‐based cognitive‐behavioral treatments for dental fear (CBT‐DF) exist, they have little impact on the millions who seek dental care annually because they are not disseminable (6 h of in‐chair time, delivered only in person at a few sites). We developed a disseminable CBT‐DF stepped‐care treatment comprising (Step 1) a mobile‐health application and, for those who remain fearful, (Step 2) a 1‐h, one‐on‐one psychological treatment session that allows practice during exposure to the patient's most‐feared stimuli. We hypothesized that the treatment would (a) be rated highly on usability and credibility and (b) result in clinically consequential (i.e., lowering fear into the 0–3 "no/low fear" zone) and statistically significant changes in global dental fear. Method: Racially/ethnically diverse patients (N = 48) with moderate to severe dental fear were recruited; all completed Step 1, and n = 16 completed Step 2. Results: As hypothesized, users found the stepped‐care treatment highly usable, credible, and helpful. Critically, this stepped‐care approach produced reductions in patients' dental fear that were both clinically consequential (with half no longer fearful) and statistically significant (d = 1.11). Conclusions: This usable, credible, stepped‐care approach to dental fear treatment holds promise for liberating evidence‐based CBT‐DF from specialty clinics, allowing broad dissemination. [ABSTRACT FROM AUTHOR]

In the present investigation we focused on 2 broad sets of questions: Do parental overreactivity, laxness, and corporal punishment show evidence of normative change in early to middle childhood? Are persistently elevated child conduct problems (CPs) associated with deviations from normative changes in, as well as high initial levels of, discipline practices? Four hundred fifty-three couples with 3- to 7-year-old children were recruited via random digit dialing and studied at 3 annual assessments. Parents completed questionnaire measures of all study constructs. Normative declines were found in maternal corporal punishment and laxness. Maternal overreactivity showed a normative increase. For fathers, only corporal punishment showed evidence of a normative decline. The declines in mothers' corporal punishment and laxness, and in fathers' corporal punishment, exhibited little variability. In contrast, the trajectories of maternal overreactivity were significantly variable. High-increasing CPs were more common than low-stable CPs in families with greater increases in maternal overreactivity. High-increasing CPs were also more common in families with greater initial maternal overreactivity and corporal punishment. Yet in no case did discipline practices significantly distinguish children on high-increasing versus high-decreasing CPs trajectories. In tests of alternative models, child effects were found for all parenting variables, suggesting reciprocal causation. The findings are discussed relative to etiological models of CPs and implications for preventive intervention.

This study investigates associations between (a) relationship satisfaction and intimate partner violence (IPV: psychological, physical, and sexual) and (b) observed couple communication behavior. Mixed-sex couples (N = 291) were recruited via random digit dialing. Partners completed the Quality of Marriage Index (Norton, 1983), the Revised Conflict Tactics Scale (Straus et al., 1996), and one female-initiated and one male-initiated 10-min conflict conversations. Discussions were coded with Rapid Marital Interaction Coding System, 2nd Generation (Heyman et al., 2015). As hypothesized, lower satisfaction was associated with more hostility (p =.018) and less positivity (p <.001); more extensive IPV was associated with more hostility (p <.001). For negative reciprocity, there was a dissatisfaction × IPV extent × conversation-initiator interaction (p <.006). Results showed that conflict behaviors of mixed-sex couples are related to the interplay among gender, satisfaction, and the severity of couple-level IPV. Theoretical and clinical implications are discussed. [ABSTRACT FROM AUTHOR]

For decades, researchers, interventionists, and the lay public have subscribed to the notion that couples low in relationship satisfaction and/or experiencing psychological, physical, or sexual intimate partner violence (IPV) have communication skills deficits. In contrast, experimental studies of communication have concluded that differences were more likely due to partners' "ill will than poor skill." We revisited this debate by recruiting a fairly generalizable sample of couples (N = 291) via random‐digit dialing and asking them to discuss two top conflict areas ("at your best" and "as you typically do"), thus measuring will—conscious inhibition of hostility and negative reciprocity and production of positivity (i.e., the "conflict triad"). The conflict triad was observed with the Rapid Marital Interaction Coding System, Second Generation. We found partial support for the hypotheses grounded in Finkel's I3 meta‐model. Frequency of hostility was associated with a complicated satisfaction × IPV‐extent × conversation type × gender interaction, indicating that couples' communication skills are multi‐determined. Unhappier couples showed almost no change in positivity when at their best, whereas happier couples nearly doubled their positivity despite their considerably higher typical positivity mean. Negative reciprocity was associated with satisfaction and IPV‐extent but not conversation type, implying that immediate instigation combined with risk factors overwhelms conscious inhibition. Intervention implications are discussed. [ABSTRACT FROM AUTHOR]