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Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR

Abstract Climate change is causing widespread impacts on seawater pH through ocean acidification (OA). Kelp forests, in some locations can buffer the effects of OA through photosynthesis. However, the factors influencing this variation remain poorly understood. To address this gap, we conducted a literature review and field deployments of pH and dissolved oxygen (DO) loggers within four habitats: intact kelp forest, moderate kelp cover, sparse kelp cover and barrens at one site in Port Phillip Bay, a wind-wave dominated coastal embayment in Victoria, Australia. Additionally, a wave logger was placed directly in front of the intact kelp forest and barrens habitats. Most studies reported that kelp increased seawater pH and DO during the day, compared to controls without kelp. This effect was more pronounced in densely populated forests, particularly in shallow, sheltered conditions. Our field study was broadly consistent with these observations, with intact kelp habitat having higher seawater pH than habitats with less kelp or barrens and higher seawater DO compared to barrens, particularly in the afternoon and during calmer wave conditions. Although kelp forests can provide local refuges to biota from OA, the benefits are variable through time and may be reduced by declines in kelp density and increased wave exposure.

Abstract Background Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

Superdiversity now highlights the complexity of diverse societies. Celebrating and encouraging diverse populations, therefore, remains a priority to ensure fair and equitable treatment for all. Multiculturalism, once seen as part of the solution to diversity issues, is now regarded as problematic, although this is by no means new. Asian contexts have rarely been hospitable milieus for liberal multiculturalism. Although diversity and heterogeneity characterize most Asian societies only responses consistent with 'local values', are allowable. In the West, many scholars (and politicians) have advocated the abandonment of multiculturalism creating a contested agenda for responding to diversity. In the current context there are no commonly agreed attitudinal or behavioral norms capable of responding. Attention needs to be paid to identifying alternatives that can contribute to the development of positive relationships, irrespective of social and political contexts. This paper seeks to do this by considering the role of care ethics.

Active learning approaches to biology teaching, including simulation-based activities, are known to enhance student learning, especially of higher-order skills; nonetheless, there are still many open questions about what features of an activity promote optimal learning. Here we designed three versions of a simulation-based tutorial called Understanding Experimental Design that asks students to design experiments and collect data to test their hypotheses. The three versions vary the experimental design task along the axes of feedback and constraint, where constraint measures how much choice students have in performing a task. Using a variety of assessments, we ask whether each of those features affects student learning of experimental design. We find that feedback has a direct positive effect on learning. We further find that small changes in constraint have only subtle and mostly indirect effects on learning. This work suggests that designers of tools for teaching higher-order skills should strive to include feedback to increase impact and may feel freer to vary the degree of constraint within a range to optimize for other features such as the ability to provide immediate feedback and time-on-task.

BackgroundAflatoxin (AF) exposure is associated with child growth faltering in cross-sectional studies, with limited findings from longitudinal studies.ObjectivesTo evaluate the relationship between maternal AF B1-lysine adduct concentration, child AF B1-lysine adduct concentration, and child growth in the first 30 mo of life.MethodsAF B1-lysine adduct was measured in mother-child dyad plasma samples using isotope dilution mass spectrometry. Using linear regression, we assessed the relationship between AF B1-lysine adduct concentration and child weight, height, and head and mid-upper arm circumferences at 1 wk, 6, 12, 18, 24, and 30 mo of age.ResultsIn adjusted models, maternal prenatal AF B1-lysine adduct (pg/μL) was positively associated with newborn anthropometric outcomes; largest beta coefficients for associations between standardized values were for newborn weight-for-age z-score [β = 0.13; 95% confidence interval (CI): 0.02, 0.24; P < 0.05 and β = 0.11; 95% CI: 0.00, 0.22; P < 0.05 for second and third trimester AF, respectively]. Child AF B1-lysine adduct (pg/μL) at 6 mo was negatively associated with head circumference-for-age z-score at 6, 18, 24, and 30 mo, with beta coefficients ranging from β = -0.15; 95% CI: -0.28, -0.02 to β = -0.17; 95% CI: -0.31, -0.03; P < 0.05); 18-mo AF was negatively associated with anthropometric outcomes at 18, 24, and 30 mo, most consistently with length-for-age z-score (β = -0.18; 95% CI: -0.32, -0.04, β = -0.21; 95% CI: -0.35, -0.07, β = -0.18; 95% CI: -0.32, -0.03 at 18, 24 and 30 mo, respectively).ConclusionsChild AF exposure was associated with impaired child growth, but maternal AF exposure was not. Exposure during infancy was linked to persistent deficit in head circumference, implying reduced brain size lasting beyond the age of 2 years. Exposure at 18 mo was linked to persistent linear growth deficit. Further research should elucidate mechanisms through which AF affects child growth.

Purpose: The optimal management of stage II follicular lymphoma (FL) is unclear. Radiation therapy (RT) alone has been the gold standard treatment, but a proportion of patients relapse. We sought to characterize outcomes and prognostic factors for stage II FL treated with RT alone to identify a high-risk subgroup of patients who may benefit from treatment intensification. Methods: This was a population-based, province-wide, retrospective study. Included patients had grade 1–3A, non-mesenteric, stage IIA or IIAE FL diagnosed between 1986 and 2016 and treated with curative-intent (≥20 Gy) RT alone. Results: 102 patients were included. Median follow-up was 10.4 years (range, 0.3–22.3). Median age was 59 years (range, 33–86). Median greatest disease diameter was 3.6 cm (range, 1.5–11.5). Freedom from progression (FFP) was 60.3% at 5 years and 40.7% at 10 years. Overall survival (OS) was 89.2% at 5 years and 81.8% at 10 years. Greatest disease diameter of >3.6 cm was associated with inferior FFP (10-year FFP 34% vs. 47%, p = 0.013) on univariable analysis and inferior FFP (hazard ratio [HR] 1.87, p = 0.019) and inferior OS (HR 2.12, p = 0.027) on multivariable analysis (MVA). Older age was associated with inferior OS (HR 1.08, unit = 1 year, p 3.6 cm was associated with inferior FFP and OS, representing a novel prognostic indicator in this population that may help in the decision-making process on whether to complement RT with systemic therapy.

Abstract Aims To describe a reflexive account of a mental health nurse as researcher undertaking a mixed methods study as part of a doctoral degree, with women in a secure forensic hospital. Design A discursive paper that draws upon the primary author's experience of dual roles as a mental health nurse and a novice researcher, and relevant literature pertaining to positionality and reflexivity in the context of conducting mixed methods research. Methods A mixed methods study was conducted within a secure forensic hospital in Australia, to identify factors associated with the frequency and duration of seclusion for women and, to explore their experiences of seclusion. Notes and a reflective diary were used to demonstrate the reflexive approach and strategies used throughout the study design and data collection stages of the research. Results Women in the secure forensic hospital setting often have complex histories and experiences and are considered a vulnerable group, which can add additional challenges when undertaking research with this population. As a doctoral student with clinical experience in mental health undertaking research in the forensic hospital setting with women, positionality and the connection with reflexivity requires exploration to understand self and the influence on research. This understanding along with identified strategies to enhance reflexivity, supports the management of the dual nurse as researcher roles to enhance all stages of the research process. Conclusion Doctoral nursing candidates undertaking clinical research in their area of clinical practice and at the location of previous employment, may experience challenges in relation to identity and the dichotomy of roles. Further challenges can be posed when research involves complex populations and/or controversial practices. Support to balance role conflict and maintain reflexivity is critical to understanding the role of self in research and to enhance credibility. Implications for the Profession and/or Clinical Practice Women are a complex, yet minority population in forensic mental health settings, however the numbers of women being admitted to services is increasing. Future research may consider the use of the strategies explored here to enhance the reflexive process, and support future researchers in this field to conduct research that aims to support an often‐misheard population to better support health outcomes. Patient or Public Involvement There was no patient or public contribution to this paper, however the study in which this paper is based on, is grounded in the experience of patients (women).

Post-traumatic stress disorder (PTSD) is a multisystem syndrome. Integration of systems-level multi-modal datasets can provide a molecular understanding of PTSD. Proteomic, metabolomic, and epigenomic assays are conducted on blood samples of two cohorts of well-characterized PTSD cases and controls: 340 veterans and 180 active-duty soldiers. All participants had been deployed to Iraq and/or Afghanistan and exposed to military-service-related criterion A trauma. Molecular signatures are identified from a discovery cohort of 218 veterans (109/109 PTSD+/-). Identified molecular signatures are tested in 122 separate veterans (62/60 PTSD+/-) and in 180 active-duty soldiers (PTSD+/-). Molecular profiles are computationally integrated with upstream regulators (genetic/methylation/microRNAs) and functional units (mRNAs/proteins/metabolites). Reproducible molecular features of PTSD are identified, including activated inflammation, oxidative stress, metabolic dysregulation, and impaired angiogenesis. These processes may play a role in psychiatric and physical comorbidities, including impaired repair/wound healing mechanisms and cardiovascular, metabolic, and psychiatric diseases.

Abstract Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10−7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Abstract High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer’s disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer’s disease, providing mechanistic insight into the biology of neuroinflammation.

ABSTRACTIntroduction: Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates plasticity in brain systems underlying arousal and memory and is associated with posttraumatic stress disorder (PTSD). Research in animal models suggests that PACAP modulates entorhinal cortex (EC) input to the hippocampus, contributing to impaired contextual fear conditioning. In PTSD, PACAP is associated with higher activity of the amygdala to threat stimuli and lower functional connectivity of the amygdala and hippocampus. However, PACAP-affiliated structural alterations of these regions have not been investigated in PTSD. Here, we examined whether peripheral PACAP levels were associated with neuronal morphology of the amygdala and hippocampus (primary analyses), and EC (secondary) using Neurite Orientation Dispersion and Density Imaging.Methods: Sixty-four (44 female) adults (19 to 54 years old) with DSM-5 Criterion A trauma exposure completed the Clinician-Administered PTSD Scale (CAPS-5), a blood draw, and magnetic resonance imaging. PACAP38 radioimmunoassay was performed and T1-weighted and multi-shell diffusion-weighted images were acquired. Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) were quantified in the amygdala, hippocampus, and EC. CAPS-5 total score and anxious arousal score were used to test for clinical associations with brain structure.Results: Higher PACAP levels were associated with greater EC NDI (β = 0.0099, q = 0.032) and lower EC ODI (β = −0.0073, q = 0.047), and not hippocampal or amygdala measures. Neither EC NDI nor ODI was associated with clinical measures.Conclusions: Circulating PACAP levels were associated with altered neuronal density of the EC but not the hippocampus or amygdala. These findings strengthen evidence that PACAP may impact arousal-associated memory circuits in PTSD.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q

Undergraduate chemistry laboratory instruction can be considered from many perspectives and addresses multiple educational aims. We critically assess an inventory of "Cognitive Tasks of Experimental Research" for its applicability to chemistry laboratory teaching, and then apply it to an integrated upper-level laboratory course as an example subject. We note patterns in the prevalence of different cognitive tasks in the course, including: a paucity of tasks related to determining research goals, evaluating experiment feasibility, and experimental design; and differences between cognitive task prevalence in organic chemistry experiments versus those in other subdisciplines of chemistry. We emphasize that this cognitive tasks of experimental research perspective provides multiple ways to consider the chemistry laboratory curriculum, and we discuss implications for practice. The work contributes to the debate about the role and aims of laboratory instruction in chemistry, and provides a tool to chemistry educators with which to reflect upon their practice and curriculum in laboratory education.

The 21st century has ushered in accelerated new technologies, new knowledge and new information and the fourth industrial revolution (4IR) -- causing rapid changes in the way humans live and work and resulting in an outcry for educational reforms globally. Many frameworks and debates centred on rethinking and reshaping the curriculum including what knowledge, skills, values and attitudes should be taught to prepare learners to thrive in the 21st century, have been developed. This study examined the students' conceptions of 21st century education in four diverse schools in Zimbabwe. The study is framed by the powerful theory and the complexity theory. The study used a quantitative non-experimental correlation design to collect data from four secondary schools, three of which follow the ZIMSEC syllabus and the other, a private school that follows a Cambridge syllabus. The questionnaire was adapted from the Partnership for 21st century framework (P21) and (Ravitz, 2014) to fit the Zimbabwean context. A total of 236 students and 93 took part. Exploratory and confirmatory factor analyses and ANOVA were used to analyse the data.The results showed that the students' conception of 21st century skills is defined by three factors: the learning of self-management, learning skills and values and learning process. Students most strongly endorsed self-management.It is envisaged that the proposed model of Zimbabwean students' conceptions of 21st century skills will act as a baseline for theory, policymakers, head teachers, teachers and teacher education colleges to realign the current teaching to fit the 21st century curricula.

Abstract In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction is linked to psychiatric disorders, including opioid use disorder (OUD). Striatal subregions are divided based on neuroanatomy, each with unique roles in OUD. In OUD, the dorsal striatum is involved in altered reward processing, formation of habits, and development of negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) and less abundant cell populations (e.g., interneurons) in human dorsal striatum. Pathways related to neurodegeneration, interferon response, and DNA damage were significantly enriched in striatal neurons of individuals with OUD. DNA damage markers were also elevated in striatal neurons of opioid-exposed rhesus macaques. Sex-specific molecular differences in glial cell subtypes associated with chronic stress were found in OUD, particularly female individuals. Together, we describe different cell types in human dorsal striatum and identify cell type-specific alterations in OUD.

Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N = 525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n = 186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n = 174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N = 888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis-regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis-regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.

Curriculum reform was high on the agenda of South Africa's post-apartheid governments. Yet as time passed, the initial reforms were seen as increasingly problematic, especially when pedagogical realities met policy priorities. There was reluctance on the part of policymakers to give up what was seen as the democratic imperative behind the reforms. Yet as schools struggled, public responses blamed inadequate attention to practical issues as undermining the implementation of the reforms. This perspective on curriculum implementation, blaming teachers for the failure of policy reforms, is not uncommon. This paper argues, however, that such a perspective is very often misinformed because it deflects attention from the specific nature of policies and the role of policymaking in neglecting key issues that might have better facilitated implementation. South Africa's democratic curriculum reforms were essential for dismantling a key aspect of the apartheid state. The paper highlights this point arguing that an understanding of policies rather than a focus on the failure of schools provides a better lens for understanding the trajectory of curriculum reform processes in South Africa.