Triheptanoin Did Not Show Benefit versus Placebo for the Treatment of Paroxysmal Movement Disorders in Glut1 Deficiency Syndrome: Results of a Randomized Phase 3 Study.

BACKGROUND: Paroxysmal movement disorders are common in Glut1 deficiency syndrome (Glut1DS). Not all patients respond to or tolerate ketogenic diets. OBJECTIVES: The objective was to evaluate the effectiveness and safety of triheptanoin in reducing the frequency of disabling movement disorders in patients with Glut1DS not receiving a ketogenic diet. METHODS: UX007G-CL301 was a randomized, double-blind, placebo-controlled, phase 3 crossover study. After a 6-week run-in, eligible patients were randomized 1:1 to the first sequence (triheptanoin/placebo or placebo/triheptanoin) titration plus maintenance, followed by washout and the opposite sequence titration plus maintenance. The placebo (safflower oil) matched the appearance, taste, and smell of triheptanoin. Open-label triheptanoin was administered in the extension. The frequency of disabling paroxysmal movement disorder events per 4 weeks (recorded by diary during maintenance; primary endpoint) was assessed by Wilcoxon rank-sum test. RESULTS: Forty-three patients (children, n = 16; adults, n = 27) were randomized and treated. There was no difference between triheptanoin and placebo in the mean (interquartile range) number of disabling paroxysmal movement disorder events (14.3 [4.7-38.3] vs. 11.8; [3.2-28.7]; Hodges-Lehmann estimated median difference: 1.46; 95% confidence interval, -1.12 to 4.36; P = 0.2684). Treatment-emergent adverse events were mild/moderate in severity and included diarrhea, vomiting, upper abdominal pain, headache, and nausea. Two patients discontinued the study because of non-serious adverse events that were predominantly gastrointestinal. The study was closed early during the open-label extension because of lack of effectiveness. Seven patients continued to receive triheptanoin compassionately. CONCLUSION: There were no significant differences between the triheptanoin and placebo groups in the frequency of disabling movement disorder events during the double-blind maintenance period. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interactive transcriptome analyses of Northern Wild Rice (Zizania palustris L.) and Bipolaris oryzae show convoluted communications during the early stages of fungal brown spot development.

Fungal diseases, caused mainly by Bipolaris spp., are past and current threats to Northern Wild Rice (NWR) grain production and germplasm preservation in both natural and cultivated settings. Genetic resistance against the pathogen is scarce. Toward expanding our understanding of the global gene communications of NWR and Bipolaris oryzae interaction, we designed an RNA sequencing study encompassing the first 12 h and 48 h of their encounter. NWR activated numerous plant recognition receptors after pathogen infection, followed by active transcriptional reprogramming of signaling mechanisms driven by Ca2+ and its sensors, mitogen-activated protein kinase cascades, activation of an oxidative burst, and phytohormone signaling-bound mechanisms. Several transcription factors associated with plant defense were found to be expressed. Importantly, evidence of diterpenoid phytoalexins, especially phytocassane biosynthesis, among expression of other defense genes was found. In B. oryzae, predicted genes associated with pathogenicity including secreted effectors that could target plant defense mechanisms were expressed. This study uncovered the early molecular communication between the NWR-B. oryzae pathosystem, which could guide selection for allele-specific genes to boost NWR defenses, and overall aid in the development of more efficient selection methods in NWR breeding through the use of the most virulent fungal isolates.

Mitigation of CXCL10 secretion by metabolic disorder drugs in microglial-mediated neuroinflammation.

Metabolic disorders are associated with several neurodegenerative diseases. We previously identified C-X-C motif chemokine ligand 10 (CXCL10), also known as interferon gamma-induced protein 10 (IP-10), as a major contributor to the type I interferon response in microglial-mediated neuroinflammation. Therefore, we hypothesized FDA-approved metabolic disorder drugs that attenuate CXCL10 secretion may be repurposed as a treatment for neurodegenerative diseases. Screening, dose curves, and cytotoxicity assays in LPS-stimulated microglia yielded treprostinil (hypertension), pitavastatin (hyperlipidemia), and eplerenone (hypertension) as candidates that significantly reduced CXCL10 secretion (in addition to other pro-inflammatory mediators) without impacting cell viability. Altogether, these data suggest metabolic disorder drugs that attenuate CXCL10 as potential treatments for neurodegenerative disease through mitigating microglial-mediated neuroinflammation.

The use of virtual reality as a perspective-taking manipulation to improve self-awareness in Alzheimer's disease.

Lack of awareness of symptoms or having a condition referred to as anosognosia is a common feature of individuals with Alzheimer's Disease (AD). Previous literature on AD reported difficulties in evaluating self-abilities, often showing underestimation of limitations. There is increasing evidence that the perspective through which information is presented may moderate the performance appraisal and that anosognosia in AD might be a consequence of a deficit in assuming a third-person perspective. In this context, some studies showed that subjects may better recognize self-and other-difficulties when exposed to a third-person perspective. Considering the variety of approaches aiming to investigate the lack of awareness, there is still a scarcity of methods that provide great ecological validity and consider more than one facet of awareness, thus failing to offer more accurate evaluations of daily experiences. The present paper primarily addresses the theme of the multidimensional character of awareness of abilities in AD and the effect of perspective-taking on its trajectories. The focus turns to virtual reality as a promising tool for a greater evaluation of perspective-taking and self-awareness. Particularly, these systems offer the possibility to involve users in cognitive and sensorimotor tasks that simulate daily life conditions within immersive and realistic environments, and a great sense of embodiment. We propose that virtual reality might allow a great level of complexity, veracity, and safety that is needed for individuals with AD to behave according to their actual abilities and enable to explore the liaison between the subject's viewpoint, performance, and self-evaluation. In addition, we suggest promising clinical implications of virtual reality-based methods for individualized assessments, investigating specific impacts on subjects' life and possible improvements in their awareness.

Do Hounsfield Units From Intraoperative CT Scans Correlate With Preoperative Values?

BACKGROUND: There is increasing interest in forecasting postoperative complications using bone density metrics. Vertebral Hounsfield unit measurements obtained from CT scans performed for surgical planning or other purposes, known as opportunistic CTs, have shown promise for their ease of measurement and the ability to target density measurement to a particular region of interest. Concomitant with the rising interest in prognostic bone density measurement use has been the increasing adoption of intraoperative advanced imaging techniques. Despite the interest in both outcome prognostication and intraoperative advanced imaging, there is little information regarding the use of CT-based intraoperative imaging as a means to measure bone density. QUESTIONS/PURPOSES: (1) Can vertebral Hounsfield units be reliably measured by physician reviewers from CT scans obtained intraoperatively? (2) Do Hounsfield units measured from intraoperative studies correlate with values measured from preoperative CT scans? METHODS: To be eligible for this retrospective study, patients had to have been treated with the use of an intraoperative CT scan for instrumented spinal fusion for either degenerative conditions or traumatic injuries between January 2015 and December 2022. Importantly, patients without a preoperative CT scan of the fused levels within 180 days before surgery or who were indicated for surgery because of infection, metastatic disease, or who were having revision surgery after prior instrumentation were excluded from the query. Of the 285 patients meeting these inclusion criteria, 53% (151) were initially excluded for the following reasons: 36% (102) had intraoperative CT scans obtained after placement of instrumentation, 16% (47) had undergone intraoperative CT scans but the studies were not accessible for Hounsfield unit measurement, and 0.7% (2) had prior kyphoplasty wherein the cement prevented Hounsfield unit measurement. Finally, an additional 19% (53) of patients were excluded because the preoperative CT and intraoperative CT were obtained at different peak voltages, which can influence Hounsfield unit measurement. This yielded a final population of 81 patients from whom 276 preoperative and 276 intraoperative vertebral Hounsfield unit measurements were taken. Hounsfield unit data were abstracted from the same vertebra(e) from both preoperative and intraoperative studies by two physician reviewers (one PGY3 and one PGY5 orthopaedic surgery resident, both pursuing spine surgery fellowships). For a small, representative subset of patients, measurements were taken by both reviewers. The feasibility and reliability of Hounsfield unit measurement were then assessed with interrater reliability of values measured from the same vertebra by the two different reviewers. To compare Hounsfield unit values from intraoperative CT scans with preoperative CT studies, an intraclass correlation using a two-way random effects, absolute agreement testing technique was employed. Because the data were formatted as multiple measurements from the same vertebra at different times, a repeated measures correlation was used to assess the relationship between preoperative and intraoperative Hounsfield unit values. Finally, a linear mixed model with patients handled as a random effect was used to control for different patient and clinical factors (age, BMI, use of bone density modifying agents, American Society of Anesthesiologists [ASA] classification, smoking status, and total Charlson comorbidity index [CCI] score). RESULTS: We found that Hounsfield units can be reliably measured from intraoperative CT scans by human raters with good concordance. Hounsfield unit measurements of 31 vertebrae from a representative sample of 10 patients, measured by both reviewers, demonstrated a correlation value of 0.82 (95% CI 0.66 to 0.91), indicating good correlation. With regard to the relationship between preoperative and intraoperative measurements of the same vertebra, repeated measures correlation testing demonstrated no correlation between preoperative and intraoperative measurements (r = 0.01 [95% CI -0.13 to 0.15]; p = 0.84). When controlling for patient and clinical factors, we continued to observe no relationship between preoperative and intraoperative Hounsfield unit measurements. CONCLUSION: As intraoperative CT and measurement of vertebral Hounsfield units both become increasingly popular, it would be a natural extension for spine surgeons to try to extract Hounsfield unit data from intraoperative CTs. However, we found that although it is feasible to measure Hounsfield data from intraoperative CT scans, the obtained values do not have any predictable relationship with values obtained from preoperative studies, and thus, these values should not be used interchangeably. With this knowledge, future studies should explore the prognostic value of intraoperative Hounsfield unit measurements as a distinct entity from preoperative measurements. LEVEL OF EVIDENCE: Level III, diagnostic study.

Palliative care integration and end-of-life care intensity for patients with NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) without oncogenic driver mutations is considered to have a poor prognosis, although recent therapeutic progress. This study aims to assess the real-life integration of palliative care (PC) and the intensity of end-of-life (EOL) care for this population. METHODS: This was an observational cohort study of decedent patients from metastatic NSCLC without oncogenic driver mutations over the period 01/2018 to 12/2022, treated in first line with immunotherapy +/- chemotherapy. We analysed PC integration and aggressiveness criteria of EOL care in the last month before death: systemic anti-cancer treatment administration, emergency room visits, intensive care unit admission, hospitalization, hospitalization duration > 14 days, and hospital death. RESULTS: Among 149 patients, 75 (50 %) met the PC team at least once, and the median time from the first encounter to death was 2.3 months. In the last month before death, at least one criterion of aggressive EOL care was present for 97 patients (70 %). For patients with PC use < 30 days and for patients with PC use < 90 days before death, there were significant changes: increase in the frequency of systemic anti-cancer treatment (respectively 51.1 % vs 20 %; p < 0.001 and 58.7 % vs 6.2 %; p < 0.001); decrease in hospitalization lasting > 14 days (respectively 30 % vs 7 %; p = 0.001 and 36 % vs 6.2 %; p = 0.018) and in death hospitalisation (respectively 66 % and 18 %; p < 0.001 and 58.7 % and 10.3 %; p < 0.001). After adjusting for the factors tested, patients with no PC or late PC use in the last month before death or in the last three month before death, the odds ratio (OR) remained significantly greater than 1 (respectively OR = 3.97 [1.70; 9.98]; p = 0.001 and OR = 23.1 [5.21-177.0], p < 0.0001). CONCLUSION: PC is still insufficiently integrated for patients with NSCL cancer. Cancer centres should monitor key indicators such as PC use and aggressiveness criteria of EOL care.

Local gun violence, mental health, and sleep: A neighborhood analysis in one hundred US Cities.

RATIONALE: Community gun violence significantly shapes public health and collective well-being. Understanding how gun violence is associated with community health outcomes like mental health and sleep is crucial for developing interventions to mitigate disparities exacerbated by violence exposure. OBJECTIVE: This study examines the associations between community gun violence , insufficient sleep, and poor mental health across neighborhoods in the United States. METHODS: We utilized a novel database covering nearly 16,000 neighborhoods in 100 US cities from 2014 through 2019. Correlated trait fixed-effects models were employed to conduct all analyses while considering various neighborhood covariates such as concentrated disadvantage, demographic composition, population density, and proximity to trauma centers. RESULTS: Our analysis revealed that greater gun violence is associated with both insufficient sleep and poor mental health in subsequent years. There is a reciprocal relationship between poor mental health and insufficient sleep, with each partially mediating the other's association with community gun violence. Notably, gun violence exhibits the strongest direct association with poor sleep rather than with poor mental health. We found a consistent reciprocal relationship between sleep and mental health at the community level. CONCLUSIONS: The findings highlight a complex interplay between community violence, sleep, and mental health, underlining the importance of reducing community violence through numerous long-term interventions to address health disparities across the US.

Noncanonical Microprotein Regulation of Immunity.

The immune system is highly regulated, but when dysregulated, suboptimal protective or overly robust immune responses can lead to immune-mediated disorders. The genetic and molecular mechanisms of immune regulation are incompletely understood, impeding the development of more precise diagnostics and therapeutics for immune-mediated disorders. Recently, thousands of previously unrecognized noncanonical microprotein genes encoded by small open reading frames have been identified. Many of these microproteins perform critical functions, often in a cell- and context-specific manner. Several microproteins are now known to regulate immunity; however, the vast majority are uncharacterized. Therefore, illuminating what is often referred to as the "dark proteome," may present opportunities to tune immune responses more precisely. Here, we review noncanonical microprotein biology, highlight recently discovered examples regulating immunity, and discuss the potential and challenges of modulating dysregulated immune responses by targeting microproteins.

Gut-Initiated Alpha Synuclein Fibrils Drive Parkinson's Disease Phenotypes: Temporal Mapping of non-Motor Symptoms and REM Sleep Behavior Disorder.

Parkinson's disease (PD) is characterized by progressive motor as well as less recognized non-motor symptoms that arise often years before motor manifestation, including sleep and gastrointestinal disturbances. Despite the heavy burden on the patient's quality of life, these non-motor manifestations are poorly understood. To elucidate the temporal dynamics of the disease, we employed a mouse model involving injection of alpha-synuclein (αSyn) pre-formed fibrils (PFF) in the duodenum and antrum as a gut-brain model of Parkinsonism. Using anatomical mapping of αSyn-PFF propagation and behavioral and physiological characterizations, we unveil a correlation between post-injection time the temporal dynamics of αSyn propagation and non-motor/motor manifestations of the disease. We highlight the concurrent presence of αSyn aggregates in key brain regions, expressing acetylcholine or dopamine, involved in sleep duration, wakefulness, and particularly REM-associated atonia corresponding to REM behavioral disorder-like symptoms. This study presents a novel and in-depth exploration into the multifaceted nature of PD, unraveling the complex connections between α-synucleinopathies, gut-brain connectivity, and the emergence of non-motor phenotypes.

New CNS tumor classification: The importance in pediatric neurosurgical practice.

Background: The management of the central nervous system (CNS) tumors in the pediatric population is crucial in neurosurgical practice. The World Health Organization (WHO) has evolved its classification of CNS tumors from the 19th century to the 5th edition, published in 2021, incorporating molecular advancements. This transition from morphology to molecular characterization is ongoing. Methods: This manuscript analyzes the modifications introduced in the 5th edition of WHO's CNS tumor classification, particularly focusing on pediatric tumor families. The paper integrates clinical, morphological, and molecular information, aiming to guide pediatric neurosurgeons in their daily practice and interdisciplinary discussions. Results: The 5th edition of the WHO classification introduces a hybrid taxonomy that incorporates both molecular and histological components. The terminology shifts from "entity" to "type" and "subtype," aiming to standardize terminology. Tumor grading experiences changes, integrating molecular biomarkers for prognosis. The concept of integrated layered diagnosis is emphasized, where molecular and histological information is combined systematically. Conclusion: The 5th edition of the WHO CNS classification signifies a paradigm shift toward molecular characterization. The incorporation of molecular advances, the layered diagnostic approach, and the inclusion of clinical, morphological, and molecular information aim to provide comprehensive insights into pediatric CNS tumors. This classification offers valuable guidance for pediatric neurosurgeons, aiding in precise diagnosis and treatment planning for these complex neoplasms.

Cell Simulation as Cell Segmentation.

Single-cell spatial transcriptomics promises a highly detailed view of a cell's transcriptional state and microenvironment, yet inaccurate cell segmentation can render this data murky by misattributing large numbers of transcripts to nearby cells or conjuring nonexistent cells. We adopt methods from ab initio cell simulation to rapidly infer morphologically plausible cell boundaries that preserve cell type heterogeneity. Benchmarking applied to datasets generated by three commercial platforms show superior performance and computational efficiency of this approach compared with existing methods. We show that improved accuracy in cell segmentation aids greatly in detection of difficult to accurately segment tumor infiltrating immune cells such as neutrophils and T cells. Lastly, through improvements in our ability to delineate subsets of tumor infiltrating T cells, we show that CXCL13-expressing CD8+ T cells tend to be more closely associated with tumor cells than their CXCL13-negative counterparts in data generated from renal cell carcinoma patient samples. Proseg is available under at open source license at https://github.com/dcjones/proseg.

Being recovered: a qualitative study of parents' experience of their child's recovery up to a year after a displaced distal radius fracture.

Aims: The aim of this study was to explore parents' experience of their child's recovery, and their thoughts about their decision to enrol their child in a randomized controlled trial (RCT) of surgery versus non-surgical casting for a displaced distal radius fracture. Methods: A total of 20 parents of children from 13 hospitals participating in the RCT took part in an interview five to 11 months after injury. Interviews were informed by phenomenology and analyzed using thematic analysis. Results: Analysis of the findings identified the theme "being recovered", which conveyed: 1) parents' acceptance and belief that their child received the best treatment for them; 2) their memory of the psychological impact of the injury for their child; and 3) their pride in how their child coped with their cast and returned to activities. The process of recovery was underpinned by three elements of experience: accepting the treatment, supporting their child through challenges during recovery, and appreciating their child's resilience. These findings extend our framework that highlights parents' desire to protect their child during early recovery from injury, by making the right decision, worrying about recovery, and comforting their child. Conclusion: By one year after injury, parents in both treatment groups considered their child "recovered". They had overcome early concerns about healing, the appearance of the wrist, and coping after cast removal. Greater educational support for families during recovery would enable parents and their child to cope with the uncertainty of recovery, particularly addressing the loss of confidence, worry about reinjury, and the appearance of their wrist.

Clinical outcomes of the light adjustable lens in eyes with a history of prior corneal refractive surgery.

PURPOSE: This study aimed to evaluate the visual and refractive outcomes in eyes with a history of laser corneal refractive surgery implanted with the second-generation light-adjustable lens (LAL). SETTING: Private Practice, Sioux Falls, South Dakota, US. DESIGN: Retrospective, consecutive case series. METHODS: Eyes with a history of prior corneal refractive surgery that underwent cataract surgery with implantation of the LAL and were targeted for plano were included. Data on the type and number of prior refractive surgeries were collected, in addition to the timing and number of postoperative adjustments. The primary outcome measures were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and the percentage (%) of eyes within ±0.25 diopter (D), ±0.50D, and ±1.00 D of their refractive target. RESULTS: 76 eyes from 70 patients were included. A total of 45 eyes with a history of one prior refractive surgery and 31 eyes with a history of ≥2 refractive surgeries were included. 74% (n=56) of all eyes achieved UDVA of 20/20 or better, 88% (n=67) achieved 20/25 UDVA or better and 93% (n=71) were correctable to 20/20 or better postoperatively. For refractive outcomes, 66% of eyes (n=50) were within ±0.25 D and 86% (n=65) were within ±0.50 D of refractive target. CONCLUSIONS: Patients with a history of laser corneal refractive surgery achieved favorable visual and refractive outcomes with the LAL. This intraocular lens (IOL), which affords postoperative adjustability, is a promising option for patients with a history of corneal refractive surgery who maintain high expectations for functional uncorrected acuity following cataract surgery.

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Drivers and implications of alternative routes to fuels decarbonization in net-zero energy systems.

Energy transition scenarios are characterized by increasing electrification and improving efficiency of energy end uses, rapid decarbonization of the electric power sector, and deployment of carbon dioxide removal (CDR) technologies to offset remaining emissions. Although hydrocarbon fuels typically decline in such scenarios, significant volumes remain in many scenarios even at the time of net-zero emissions. While scenarios rely on different approaches for decarbonizing remaining fuels, the underlying drivers for these differences are unclear. Here we develop several illustrative net-zero systems in a simple structural energy model and show that, for a given set of final energy demands, assumptions about the use of biomass and CO2 sequestration drive key differences in how emissions from remaining fuels are mitigated. Limiting one resource may increase reliance on another, implying that decisions about using or restricting resources in pursuit of net-zero objectives could have significant tradeoffs that will need to be evaluated and managed.

A mouse model of wildfire smoke-induced health effects: sex differences in acute and sustained effects of inhalation exposures.

Due to climate change, wildfires have increased in intensity and duration. While wildfires threaten lives directly, the smoke has more far-reaching adverse health impacts. During an extreme 2017 wildfire event, residents of Seeley Lake, Montana were exposed to unusually high levels of wood smoke (WS) causing sustained effects on lung function (decreased FEV1/FVC). Objective: The present study utilized an animal model of WS exposure to research cellular and molecular mechanisms of the resulting health effects. Methods: Mice were exposed to inhaled WS utilizing locally harvested wood to recapitulate community exposures. WS was generated at a rate resulting in a 5 mg/m3 PM2.5 exposure for five days. Results: This exposure resulted in a similar 0.28 mg/m2 particle deposition (lung surface area) in mice that was calculated for human exposure. As with the community observations, there was a significant effect on lung function, increased resistance, and decreased compliance, that was more pronounced in males at an extended (2 months) timepoint and males were more affected than females: ex vivo assays illustrated changes to alveolar macrophage functions (increased TNFα secretion and decreased efferocytosis). Female mice had significantly elevated IL-33 levels in lungs, however, pretreatment of male mice with IL-33 resulted in an abrogation of the observed WS effects, suggesting a dose-dependent role of IL-33. Additionally, there were greater immunotoxic effects in male mice. Discussion: These findings replicated the outcomes in humans and suggest that IL-33 is involved in a mechanism of the adverse effects of WS exposures that inform on potential sex differences.

Escherichia coli non-coding regulatory regions are highly conserved.

Microbial genome sequences are rapidly accumulating, enabling large-scale studies of sequence variation. Existing studies primarily focus on coding regions to study amino acid substitution patterns in proteins. However, non-coding regulatory regions also play a distinct role in determining physiologic responses. To investigate intergenic sequence variation on a large-scale, we identified non-coding regulatory region alleles across 2350 Escherichia coli strains. This 'alleleome' consists of 117 781 unique alleles for 1169 reference regulatory regions (transcribing 1975 genes) at single base-pair resolution. We find that 64% of nucleotide positions are invariant, and variant positions vary in a median of just 0.6% of strains. Additionally, non-coding alleles are sufficient to recover E. coli phylogroups. We find that core promoter elements and transcription factor binding sites are significantly conserved, especially those located upstream of essential or highly-expressed genes. However, variability in conservation of transcription factor binding sites is significant both within and across regulons. Finally, we contrast mutations acquired during adaptive laboratory evolution with wild-type variation, finding that the former preferentially alter positions that the latter conserves. Overall, this analysis elucidates the wealth of information found in E. coli non-coding sequence variation and expands pangenomic studies to non-coding regulatory regions at single-nucleotide resolution.

Mapping genotypes to chromatin accessibility profiles in single cells.

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from patients with myeloproliferative neoplasms with JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.

Mood regulation as a shared basis for creativity and curiosity.

We extend the work of Ivancovsky et al. by proposing that in addition to novelty seeking, mood regulation goals - including enhancing positive mood and repairing negative mood - motivate both creativity and curiosity. Additionally, we discuss how the effects of mood on state of mind are context-dependent (not fixed), and how such flexibility may impact creativity and curiosity.

Police Contact, Non-Suicidal Self-Injury, and Suicidal Ideation: Findings From a National Sample of Canadian Adolescents and Young Adults.

BACKGROUND AND OBJECTIVES: The purpose of this research is to investigate associations between police contact, non-suicidal self-injury (NSSI), and suicidal ideation (SI) among a national sample of Canadian adolescents and young adults (ages 16-30). METHODS: Data used in this study were obtained from the Canadian Study of Adolescent Health Behaviors (N = 940), a national survey of Canadians ages 16-30. RESULTS: Police contact was associated with higher odds of NSSI (OR = 1.98, 95% CI = 1.37, 2.86). Those who reported police contact with intrusion (OR = 2.39, 95% CI = 1.49, 3.38) and police contact with harassment (OR = 3.98, 95% CI = 2.30, 6.88) had higher odds of NSSI relative to respondents with no contact. Finally, any police contact was associated with higher odds of SI (OR = 1.56, 95% CI = 1.04, 2.34) and respondents experiencing police stops with harassment had higher odds of SI compared to those who had never been stopped (OR = 2.48, 95% CI = 1.45, 4.24). CONCLUSIONS: Distressing police contact heightens the risk of NSSI and SI among young people. Rigorous evaluation of trauma-informed, developmentally appropriate strategies for identifying and intervening on NSSI and SI following adverse police encounters should be prioritized.