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There is evidence that aerobic exercise improves brain health. Benefits may be modulated by acute physiological responses to exercise, but this has not been well characterized in older or cognitively impaired adults. The randomized controlled trial 'AEROBIC' (NCT04299308) enrolled 60 older adults who were cognitively healthy (n = 30) or cognitively impaired (n = 30) to characterize the acute brain responses to moderate [45-55% heart rate reserve (HRR)] and higher (65-75% HRR) intensity acute exercise. Each participant received two fluorodeoxyglucose positron emission tomography (FDG-PET) scans, one at rest and one following acute exercise. Change in cerebral glucose metabolism from rest to exercise was the primary outcome. Blood biomarker responses were also characterized as secondary outcomes. Whole grey matter FDG-PET standardized uptake value ratio (SUVR) differed between exercise (1.045 ± 0.082) and rest (0.985 ± 0.077) across subjects [Diff = -0.060, t(58) = 13.8, P < 0.001] regardless of diagnosis. Exercise increased lactate area under the curve (AUC) [F(1,56) = 161.99, P < 0.001] more in the higher intensity group [mean difference (MD) = 97.0 ± 50.8] than the moderate intensity group (MD = 40.3 ± 27.5; t = -5.252, P < 0.001). Change in lactate AUC and FDG-PET SUVR correlated significantly (R2 = 0.179, P < 0.001). Acute exercise decreased whole grey matter cerebral glucose metabolism. This effect tracked with the systemic lactate response, suggesting that lactate may serve as a key brain fuel during exercise. Direct measurements of brain lactate metabolism in response to exercise are warranted. KEY POINTS: Acute exercise is associated with a drop in global brain glucose metabolism in both cognitively healthy older adults and those with Alzheimer's disease. Blood lactate levels increase following acute exercise. Change in brain metabolism tracks with blood lactate, suggesting it may be an important brain fuel. Acute exercise stimulates changes in brain-derived neurotrophic factor and other blood biomarkers.

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We lack the fundamental information needed to understand how DNA damage in the brain is generated and how it is controlled over a lifetime in the absence of replication check points. To address these questions, here, we integrate cell-type and region-specific features of DNA repair activity in the normal brain. The brain has the same repair proteins as other tissues, but normal, canonical repair activity is unequal and is characterized by high base excision repair (BER) and low double strand break repair (DSBR). The natural imbalance creates conditions where single strand breaks (SSBs) can convert to double strand breaks (DSBs) and reversibly switch between states in response to oxidation both in vivo and in vitro. Our data suggest that, in a normal background of repair, SSBs and DSBs are in an equilibrium which is pushed or pulled by metabolic state. Interconversion of SSB to DSBs provides a physiological check point, which would allow the formation of unrepaired DSBs for productive functions, but would also restrict them from exceeding tolerable limits.

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Current state-of-the-art (SOTA) LiDAR-only detectors perform well for 3D object detection tasks, but point cloud data are typically sparse and lacks semantic information. Detailed semantic information obtained from camera images can be added with existing LiDAR-based detectors to create a robust 3D detection pipeline. With two different data types, a major challenge in developing multi-modal sensor fusion networks is to achieve effective data fusion while managing computational resources. With separate 2D and 3D feature extraction backbones, feature fusion can become more challenging as these modes generate different gradients, leading to gradient conflicts and suboptimal convergence during network optimization. To this end, we propose a 3D object detection method, Attention-Enabled Point Fusion (AEPF). AEPF uses images and voxelized point cloud data as inputs and estimates the 3D bounding boxes of object locations as outputs. An attention mechanism is introduced to an existing feature fusion strategy to improve 3D detection accuracy and two variants are proposed. These two variants, AEPF-Small and AEPF-Large, address different needs. AEPF-Small, with a lightweight attention module and fewer parameters, offers fast inference. AEPF-Large, with a more complex attention module and increased parameters, provides higher accuracy than baseline models. Experimental results on the KITTI validation set show that AEPF-Small maintains SOTA 3D detection accuracy while inferencing at higher speeds. AEPF-Large achieves mean average precision scores of 91.13, 79.06, and 76.15 for the car class's easy, medium, and hard targets, respectively, in the KITTI validation set. Results from ablation experiments are also presented to support the choice of model architecture.

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BACKGROUND: There is evidence that chronic exercise can benefit the brain, but the effects vary markedly between studies. One potential mechanism for exercise-related benefit is the increase in systemic lactate concentration that is well-characterized to occur during exercise. Lactate is known to cross the blood brain barrier and can be used readily as a fuel for neurons. This may be particularly important in Alzheimer's Disease, which is characterized by cerebral hypometabolism. However, little is known about how whole-body lactate metabolism differs between older adults and individuals with cognitive impairment. This information is critical when considering potential differences in responses to exercise in various cognitive diagnosis groups. METHODS: Here we describe the use of a "lactate clamp" procedure to adjust blood lactate levels to approximate those achieved during exercise, but while at rest. This trial will compare lactate oxidation between cognitively healthy older adults and cognitively impaired participants. We will further evaluate the effect of acute lactate infusion on cognitive performance. DISCUSSION: The findings of the study described here, the Lactate for Energy and Neurocognition trial (clinicaltrials.gov # NCT05207397) will add to our understanding of systemic lactate mechanics in cognitively healthy older adults and individuals with Alzheimer's Disease. These findings will be applicable to ongoing exercise trials and to future studies aimed at modulating systemic bioenergetic function in aging and Alzheimer's Disease.

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Our objective is to test a single dose of the phosphoinositide-3-kinase (PI3K) inhibitor alpelisib as a tool for acute modeling of insulin resistance in healthy volunteers. This single-center, double-blind, phase 1 clinical trial randomized healthy adults to take a single oral dose of alpelisib 300 mg (n = 5) or placebo (n = 6) at bedtime, followed by measurement of glucose, insulin, and C-peptide levels after an overnight fast and during a 3-hour, 75-g oral glucose tolerance test. Fasting plasma glucose trended higher with alpelisib (mean ± S.D.: 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL), while mean fasting serum insulin increased nearly fivefold (23 ± 12 µU/mL vs. 5 ± 3 µU/mL, respectively) and Homeostasis Model Assessment of Insulin Resistance scored 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was over fourfold greater with alpelisib (22 ± 15 mU/mL x min) than placebo (5 ± 2 mU/mL x min); glucose AUC trended higher with alpelisib. Single-dose alpelisib was well tolerated and produced metabolic alterations consistent with acute induction of IR, validating its use for mechanistic study of insulin action in humans. (ClinicalTrials.gov registration: NCT05733455).

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BACKGROUND: Mucosal barrier injury central line-associated bloodstream infections (MBI-CLABSIs) remain a challenge among the pediatric cancer population. These infections commonly occur by oral or gastrointestinal (GI) bacteria translocating through impaired gut or oral mucosa. Although strategies to prevent gut MBI-CLABSIs are well characterized, oral pathogen prevention strategies are lacking. METHODS: The authors' oncodental collaboration quality improvement project, which included two Plan-Do-Study-Act (PDSA) cycles, aimed to improve MBI-CLABSI rates and oral care adherence on a pediatric hematopoietic stem cell transplant (HSCT) unit. PDSA cycle 1 integrated dental residents into existing rounds every third week to screen for dental, gum, and mucosal disease and provide targeted education to patients and families. PDSA cycle 2 implemented a novel oral health educator (OHE) role in which a trained dental hygienist rounded four days per week. Monthly MBI-CLABSI rates and oral care adherence were followed from December 2020 to May 2021 (baseline), June 2021 to March 2022 (PDSA cycle 1), and April 2022 to December 2022 (PDSA cycle 2). Qualitative surveys captured patient and family perception, and a cost savings analysis was completed. RESULTS: A 58.8% reduction in MBI-CLABSI rate (events per 1,000 central venous line days) was detected (baseline: 5.1; PDSA cycle 2: 2.1), oral care adherence improved 41.7% (baseline: 60.9%; PDSA cycle 2: 86.3%), 100% of patients found it beneficial to receive oral care demonstrations, and an annual cost savings of $541,000 was estimated. CONCLUSION: Direct patient outcomes have measurably improved. This project suggests the implementation of an OHE in pediatric HSCT inpatient units may be valuable to patients and families and may be a cost-effective way to reduce MBI-CLABSIs resulting from oral pathogens.

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BACKGROUND: Despite being recognized as a safe procedure with minimal reported complications, injecting autologous bone marrow aspirate concentrate (BMAC) as an adjuvant to arthroscopic partial meniscectomy (APM) for symptomatic patients with meniscal tears and concomitant knee osteoarthritis (OA) has not been studied in randomized controlled trials. PURPOSE: To compare patient-reported outcome measure (PROM) scores and radiographic outcomes in symptomatic patients with meniscal tears and concomitant mild knee OA who underwent APM with and without an autologous BMAC injection administered at the time of surgery. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Enrolled patients aged ≥18 years determined to have a symptomatic meniscal tear with concomitant mild knee OA suitable for APM and meeting inclusion and exclusion criteria were randomized into 2 groups: BMAC and control (no BMAC). The primary endpoint of the study was the International Knee Documentation Committee (IKDC) score at 1 year postoperatively. Secondary endpoints included radiographic outcomes (Kellgren-Lawrence grade) at 1 year postoperatively and various PROM scores, including those for the IKDC, Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale, and Veterans RAND 12-Item Health Survey, at 3 months, 6 months, 1 year, and 2 years after meniscectomy. RESULTS: Of the 95 enrolled patients, 83 (87.4%) were included for final analysis. No significant differences were found between the groups with regard to patient characteristics, intraoperative variables, concomitant procedures, preoperative PROM scores, or preoperative radiographic findings. At 1 year postoperatively, the BMAC group failed to demonstrate significantly better IKDC scores (P = .687) or radiographic outcomes (P > .05 for all radiographic measures) compared with the control group. Secondary PROM scores also did not significantly differ between the groups (P > .05 for all PROMs). However, there were higher achievement rates of the minimal clinically important difference for the KOOS Sport (100.0% vs 80.0%, respectively; P = .023) and KOOS Symptoms (92.3% vs 68.0%, respectively; P = .038) at 1 year postoperatively in the BMAC group than in the control group. All PROMs, excluding the VR-12 mental score, showed significant improvements compared with baseline at all postoperative time points for both the BMAC and control groups. CONCLUSION: The addition of an autologous BMAC injection during APM did not result in significant changes in IKDC scores or radiographic outcomes at the 1-year postoperative mark. Secondary PROM scores were generally comparable between the 2 groups, but there was higher minimal clinically important difference achievement for the KOOS Sport and KOOS Symptoms at 1 year postoperatively in the BMAC group. In patients with symptoms consistent with a meniscal tear who had concomitant mild OA, the addition of BMAC to arthroscopic debridement did not affect the outcome. REGISTRATION: NCT02582489 (ClinicalTrials.gov).

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INTRODUCTION: Patients with triple-class refractory (TCR) multiple myeloma (MM) often need cytoreductive chemotherapy for rapid disease control. Bendamustine is an outpatient-administered, bifunctional alkylator and isatuximab is an anti-CD38 monoclonal antibody with unique cytotoxicity characteristics. We hypothesized that isatuximab-bendamustine-prednisone would be well-tolerated regimen in TCR MM, and conducted single-center, phase Ib, investigator-initiated study. PATIENTS/METHODS: Patients had TCR MM and last daratumumab exposure ≥ 6 weeks. This study was conducted as a 3 + 3 design to establish the maximally tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Isatuximab 10 mg/kg IV was administered weekly (cycle 1), and every 2 weeks thereafter. Bendamustine was administered on days 1 and 2 at 3 dose levels (DL): 50, 75, and 100 mg/m2. Methylprednisolone was administered as 125 mg on day 1 and prednisone 60 mg days 2-4. Common definitions were used for DLTs, adverse events (CTCAE v 5.0), and disease response. RESULTS: Fifteen patients were treated (3 DL1, 6 DL2, 6 DL3). Median age was 71, 53% had high-risk cytogenetics, and 34% had prior BCMA-targeting therapy. One DLT was observed at DL2 (Grade 3 thrombocytopenia plus bleeding). There were no Grade 5 treatment-related AEs. The MTD was not reached. The overall response rate was 20% (3/15) including one stringent complete response. The median PFS was 2.5 months (95% CI 0.9-4.1 months). CONCLUSION: We demonstrated the safety and tolerability of isatuximab-bendamustine-prednisone. Toxicities were mild and manageable with limited intervention. The study was discontinued due to slow accrual. However, we observed responses even among highly refractory patients. CLINICAL TRIAL REGISTRATION: This study was registered on clinicaltrials.gov as NCT04083898 on 9/6/2019.

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Thiol dioxygenases (TDOs) are non­heme Fe(II)­dependent enzymes that catalyze the O2-dependent oxidation of thiol substrates to their corresponding sulfinic acids. Six classes of TDOs have thus far been identified and two, cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO), are found in eukaryotes. All TDOs belong to the cupin superfamily of enzymes, which share a common ß­barrel fold and two cupin motifs: G(X)5HXH(X)3-6E(X)6G and G(X)5-7PXG(X)2H(X)3N. Crystal structures of TDOs revealed that these enzymes contain a relatively rare, neutral 3­His iron­binding facial triad. Despite this shared metal-binding site, TDOs vary greatly in their secondary coordination spheres. Site­directed mutagenesis has been used extensively to explore the impact of changes in secondary sphere residues on substrate specificity and enzymatic efficiency. This chapter summarizes site-directed mutagenesis studies of eukaryotic TDOs, focusing on the tools and practicality of non­standard amino acid incorporation.

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Visitors to Colter Bay Village in Grand Teton National Park were surveyed to elicit their evaluations of experimental outdoor lighting conditions. Luminaires capable of dimming and switching between two LED modules (white, blended red-white) were installed in street and parking areas. The blended red-white lamps consisted of 30 narrowband LED with a peak wavelength 623 nm and two 3000 K white LEDs. Similar "red" lamps were previously shown to reduce impacts to bats and insects. The white and red lamps were closely matched for luminance. Measured horizontal illuminance at survey locations had an interquartile range from 0.63 to 3.82 lx. The red lamps produced lower perceived brightness (VB2(λ)), even after reflection off asphalt, yet survey participants expressed higher ratings for visual comfort and safety under red lighting. Surveys conducted earlier in the evening, with higher levels of predicted solar and measured horizontal illuminance, rated higher on visual comfort and safety, though these correlations were not as strong as the effect of lamp color. Streetlight ratings and support for lighting that protected natural resources were not contingent upon age or gender. Survey participants assessed red lighting as more protective of the environment. These results demonstrate that outdoor lighting designed to reduce ecological impacts can yield superior nocturnal experience for pedestrians.

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Tree-mycorrhizal associations are associated with patterns in nitrogen (N) availability and soil organic matter storage; however, we still lack a mechanistic understanding of what tree and fungal traits drive these patterns and how they will respond to global changes in soil N availability. To address this knowledge gap, we investigated how arbuscular mycorrhizal (AM)- and ectomycorrhizal (EcM)-associated seedlings alter rhizodeposition in response to increased seedling inorganic N acquisition. We grew four species each of EcM and AM seedlings from forests of the eastern United States in a continuously 13C-labeled atmosphere within an environmentally controlled chamber and subjected to three levels of 15N-labeled fertilizer. We traced seedling 15N uptake from, and 13C-labeled inputs (net rhizodeposition) into, root-excluded or -included soil over a 5-month growing season. N uptake by seedlings was positively related to rhizodeposition for EcM- but not AM-associated seedlings in root-included soils. Despite this contrast in rhizodeposition, there was no difference in soil C storage between mycorrhizal types over the course of the experiment. Instead root-inclusive soils lost C, while root-exclusive soils gained C. Our findings suggest that mycorrhizal associations mediate tree belowground C investment in response to inorganic N availability, but these differences do not affect C storage. Continued soil warming and N deposition under global change will increase soil inorganic N availability and our seedling results indicate this could lead to greater belowground C investment by EcM-associated trees. This potential for less efficient N uptake by EcM-trees could contribute to AM-tree success and a shift toward more AM-dominated temperate forests.

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Rift Valley fever (RVF) is an emerging arboviral disease affecting both humans and livestock. In humans, RVF displays a spectrum of clinical manifestations, including encephalitis. To date, there are no FDA-approved vaccines or therapeutics for human use, although several are in pre-clinical development. Few small animal models of RVF encephalitis exist, further complicating countermeasure assessment. Human mAbs RVFV-140, RVFV-268 and RVFV-379 are recombinant potently neutralizing antibodies that prevent infection by binding the RVFV surface glycoproteins. Previous studies showed that both RVFV-268 and RVFV-140 improve survival in a lethal mouse model of disease, and RVFV-268 has prevented vertical transmission in a pregnant rat model of infection. Despite these successes, evaluation of mAbs in the context of brain disease has been limited. This is the first study to assess neutralizing antibodies for prevention of RVF neurologic disease using a rat model. Administration of RVFV-140, RVFV-268, or RVFV-379 twenty-four hours prior to aerosol exposure to the virulent ZH501 strain of RVFV results in substantially enhanced survival and lack of neurological signs of disease. These results using a stringent and highly lethal aerosol infection model supports the potential use of human mAbs to prevent the development of RVF encephalitis.

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Collaborative care management (CoCM) is an evidenced based approach to psychiatric treatment in primary care, yet literature examining factors associated with program adherence is lacking. This study analyzed predictors of adherence to a CoCM model of psychopharmacological treatment of depression and anxiety in primary care by conducting a retrospective cohort analysis on Veterans referred to a large VA Medical Center's CoCM program over an 18-month period. Baseline characteristics, symptomatic assessments, and covariates of interest were collected. For the primary outcome, the association between covariates and programmatic completion were analyzed. Secondary analyses assessed improvements in psychiatric symptoms. A total of 757 Veterans with depressive or anxiety disorders were included, and 256 completed the CoCM program. Baseline covariates associated with differences in completion rates included the following: age, contact with psychology prior to referral, baseline PHQ-9, baseline GAD-7, and a number of comorbid psychiatric/substance abuse covariates. After controlling for baseline differences, age remained a significant positive predictor of completion (OR 1.019, 95% CI 1.008‒1.030) and cannabis use a significant negative predictor (OR 0.507, 95% CI 0.275‒0.934). Both early improvement in PHQ-9 (OR 1.864, 95% CI 1.210‒2.872) and GAD-7 (OR 1.762, 95% CI 1.154‒2.691) scores were positive predictors. Secondary analyses showed that programmatic completion was associated with greater reductions in psychiatric symptoms. Results identified a number of modifiable parameters associated with differences in completion rates and greater symptomatic reduction for those who complete the program. Additional studies should be conducted examining interventions to optimize CoCM programs by supporting positive predictors while minimizing negative predictors.

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INTRODUCTION: Precision in surgical documentation is essential to avoid miscommunication and errors in patient care. Synoptic operative reports are more precise than narrative operative reports, however they have not been widely implemented in pediatric surgical oncology. To assess the need for implementation of synoptic operative reports in pediatric surgical oncology, we examined the completeness of narrative operative reports in patients undergoing resection of Wilms tumor. METHODS: We conducted a retrospective review of narrative operative reports for resection of Wilms tumor at a single pediatric oncology center from January 2022 through July 2023. Primary outcomes were the presence or absence of 11 key operative report components. Inclusion rates were calculated as simple percentages. Unilateral and bilateral operations were considered. RESULTS: Thirty-five narrative reports for Wilms tumor resection were included. The most consistently documented operative report components were estimated blood loss, indication for surgery, intraoperative complications, and specimen naming (100% documentation rates). Documentation of lymph node sampling was present in 94.3% of reports. The least consistently documented components were assessment of intraoperative tumor spillage, completeness of resection, metastatic disease, and assessment of vascular involvement (each ≤40% documentation rate). All 11 key components were documented in three reports. CONCLUSIONS: Even at a large tertiary pediatric oncology referral center, narrative operative reports for pediatric Wilms tumor resection were found to be frequently missing important components of surgical documentation. Often, these were omissions of negative findings. Utilization of synoptic operative reports may be able to reduce these gaps.

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External human-machine interfaces (eHMIs) serve as communication bridges between autonomous vehicles (AVs) and road users, ensuring that vehicles convey information clearly to those around them. While their potential has been explored in one-to-one contexts, the effectiveness of eHMIs in complex, real-world scenarios with multiple pedestrians remains relatively unexplored. Addressing this gap, our study provides an in-depth evaluation of how various eHMI displays affect pedestrian behavior. The research aimed to identify eHMI configurations that most effectively convey an AV's information, thereby enhancing pedestrian safety. Incorporating a mixed-methods approach, our study combined controlled outdoor experiments, involving 31 participants initially and 14 in a follow-up session, supplemented by an intercept survey involving 171 additional individuals. The participants were exposed to various eHMI displays in crossing scenarios to measure their impact on pedestrian perception and crossing behavior. Our findings reveal that the integration of a flashing green LED, robotic sign, and countdown timer constitutes the most effective eHMI display. This configuration notably increased pedestrians' willingness to cross and decreased their response times, indicating a strong preference and enhanced concept understanding. These findings lay the groundwork for future developments in AV technology and traffic safety, potentially guiding policymakers and manufacturers in creating safer urban environments.

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Extracellular beta-amyloid (Aß) is thought to cause impairments in brain-wide functional connectivity, although mechanisms linking Aß to broader functional network processing remain elusive. In the present study, we evaluated the effects of Aß on fear memory and functional connectome measures in male and female mice. Middle-aged (9-11mo) double transgenic APP-PS1 mice and age and sex-matched controls were tested on a fear conditioning protocol and then imaged at 11.1 Tesla. Brains were harvested and processed for analysis of Aß plaques and Iba1 immunolabeling in neocortical areas, hippocampus, and basolateral amygdala. Additional RNA sequencing data from separate age, strain, and sex-matched mice were analyzed for differentially expressed genes (DEGs) and weighted gene co-expression networks. In both male and female mice, we observed increased functional connectivity in a dorsal striatal/amygdala network as a result of Aß. Increased functional connectivity within this network was matched by increases in APP gene expression, Aß and Iba1 immunolabeling, and an upregulated cluster of DEGs involved in the immune response. Conversely, the network measure representing node hubness, eigenvector centrality, was increased in prefrontal cortical brain regions, but only in female APP-PS1 mice. This female-specific effect of amyloid was associated with down-regulation of a cluster of DEGs involved in cortical and striatal GABA transmission, anxiogenic responses, and motor activity, in female APP-PS1 mice, but not males. Our results contribute to a growing literature linking between Aß, immune activation, and functional network connectivity. Furthermore, our results reveal outcomes of Aß on gene expression patterns in female mice that may contribute to amyloidosis-induced dysregulation of non-cognitive circuitry.

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Passive smartphone measures hold significant potential and are increasingly employed in psychological and biomedical research to capture an individual's behavior. These measures involve the near-continuous and unobtrusive collection of data from smartphones without requiring active input from participants. For example, GPS sensors are used to determine the (social) context of a person, and accelerometers to measure movement. However, utilizing passive smartphone measures presents methodological challenges during data collection and analysis. Researchers must make multiple decisions when working with such measures, which can result in different conclusions. Unfortunately, the transparency of these decision-making processes is often lacking. The implementation of open science practices is only beginning to emerge in digital phenotyping studies and varies widely across studies. Well-intentioned researchers may fail to report on some decisions due to the variety of choices that must be made. To address this issue and enhance reproducibility in digital phenotyping studies, we propose the adoption of preregistration as a way forward. Although there have been some attempts to preregister digital phenotyping studies, a template for registering such studies is currently missing. This could be problematic due to the high level of complexity that requires a well-structured template. Therefore, our objective was to develop a preregistration template that is easy to use and understandable for researchers. Additionally, we explain this template and provide resources to assist researchers in making informed decisions regarding data collection, cleaning, and analysis. Overall, we aim to make researchers' choices explicit, enhance transparency, and elevate the standards for studies utilizing passive smartphone measures.

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OBJECTIVE: To test the hypothesis that conductive hearing loss (CHL) is associated with dementia, and that middle ear reconstruction (MER) associates with improved outcomes for these measures in a multinational electronic health records database. STUDY DESIGN: Retrospective cohort study with propensity-score matching (PSM). SETTING: TriNetX is a research database representing about 110 million patients from the United States, Taiwan, Brazil, and India. PATIENTS: Subjects older than 50 years with no HL and any CHL (ICD-10: H90.0-2). Subjects of any age with and without any MER (CPT: 1010174). MAIN OUTCOME MEASURES: Odds ratios (ORs) and hazard ratios with 95% confidence intervals (95% CIs) for incident dementia (ICD-10: F01, F03, G30). RESULTS: Of 103,609 patients older than 50 years experiencing any CHL, 2.74% developed dementia compared with 1.22% of 38,216,019 patients with no HL (OR, 95% CI: 2.29, 2.20-2.37). Of patients experiencing CHL, there were 39,850 who received MER. The average age was 31.3 years, with 51% female patients. A total of 343,876 control patients with CHL were identified; 39,900 patients remained in each cohort after 1:1 PSM for HL- and dementia-related risk factors. Matched risk for developing dementia among MER recipients was 0.33% compared with 0.58% in controls (OR: 0.58, 0.46-0.72). CONCLUSIONS: CHL increases the odds for dementia, and MER improves the odds for incident dementia. This study represents the first population study on the topic of CHL, MER, and dementia.

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The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype.