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Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.
Methods
We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).
Results
Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.
Conclusions
Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.
Objectives/Goals: This study tests how fiber microstructural integrity and myelination levels within the cingulum connectome are associated with information processing speed (IPS) in relapsing-remitting multiple sclerosis (RRMS). We investigate the functional impact of structural coherence, myelin content, and white matter hyperintensities (WMH) load on IPS. Methods/Study Population: Data from 63 RRMS and 25 healthy controls (HC) were used. We hypothesize that the structural integrity of the cingulum bundle and its structural network – or connectome – is distinctly associated with IPS function in people with RRMS (vs. HC) due to myelin-related plasticity across the wiring. Using diffusion spectrum imaging and high-resolution tract segmentation, we constructed individualized white matter connectomes. Diffusion quantitative anisotropy (QA) and myelin fractions (MWF) were used to quantify structural coherence and myelination. WMH load was measured with T2-FLAIR imaging. Bayesian–Pearson correlations, mixed-linear, and moderation models explored how fiber-specific QA, MWF, and WMH load relate to IPS function in RRMS, as measured by Symbol Digit Modalities Test (SDMT). Results/Anticipated Results: We theorize that (1) QA in the cingulum connectome correlates with SDMT performance dimensionally, indicating that structural coherence in the white matter supports IPS function among both groups; (2) increased myelination will strengthen the positive association between QA and SDMT scores, suggesting that connectome-specific myelin content facilitates IPS; (3) conversely, WMH load within the cingulum connectome is expected to inversely correlate with SDMT scores, reflecting the detrimental impact of lesion burden on IPS function; (4) myelination in specialized tracts within the cingulum connectome play a compensatory role to support IPS function in the RRMS group. These investigations can offer a mechanistic clue to potential neuroplastic targets for cognitive interventions in MS. Discussion/Significance of Impact: By linking white matter integrity to cognitive function at the connectome level, this study can support neuroregenerative strategies to mitigate cognitive burden in RRMS. Our findings may advance understanding of how structural coherence, tract myelination, and WMH affect IPS, shaping personalized prognostic and therapeutic interventions.
Objectives/Goals: Early childhood obesity is a major concern for Latin American children in the U.S., with gut barrier dysfunction as a key risk factor. Diet plays a role in gut development, but few studies have focused on Latin American infants. Our objective is to identify culturally relevant introductory foods that promote in vitro gut barrier development and function. Methods/Study Population: Pooled human milk (2.5 mL) from 6-month postpartum Hispanic mothers was combined with fruit and vegetable baby food products (2.5 g) and subjected to a 3-phase in vitro digestion system that simulates oral, gastric, and intestinal digestion. Digesta products were then anaerobically fermented for 24-hours using human stool inoculum, centrifuged, and filter sterilized. Intestinal epithelial cells (Caco-2, ATCC) were grown to confluence on 0.4 μm polystyrene transwell inserts using a DMEM + 10% FBS medium and allowed to differentiate for 21-days. Highly differentiated monolayers were treated with a 1:4 dilution of fermenta with medium in triplicate. The cell experiment was conducted twice. Cell layer integrity was measured using transepithelial electrical resistance (TEER) 24- and 48-hours after treatment. Results/Anticipated Results: Dietary intake data from the What We Eat in America database indicated that the top 3 fruit and vegetable exposures for infants with Mexican or Hispanic ethnicity were banana, apple, and carrot. Commercial baby food purees of these fruits and vegetables, in addition to baby foods with blueberry and spinach (Natural for Baby, Gerber Products Company) were acquired for digestion and fermentation experiments. Caco-2 cell experiments with these foods are ongoing. We expect Caco-2 monolayer incubated with fermenta from human milk and fruit or vegetables will have greater TEER values due to increased integrity of the cell layer as compared to those with breast milk alone. We also expect that exposure to fruit and vegetable fermenta will increase gene expression of tight junctions compared to exposure to media and human milk. Discussion/Significance of Impact: Using an in vitro digestion and fermentation system coupled with cell culture studies, we are identifying cellular mechanisms that link individual fruits and vegetables to gut barrier function. This will support translational work focused on mitigating obesity development in vulnerable populations.
The addiction syndrome is quite similar across different addictive drug types, reflecting a shared pathway of pathological changes within motivational circuits that increasingly prioritize drug acquisition and use. This neurobiology, and drug addiction symptomatology, overlaps considerably with behavioral addictions (e.g., gambling disorder). However, addiction is distinct from symptoms and mechanisms underpinning intoxication and withdrawal, which are diverse and unique to each drug class. The intoxication phase is followed by some degree of withdrawal, manifesting clinically as opposite to intoxication, reflecting a homeostatic response to it. Withdrawal has a quality, duration, and dangerousness that depends on the individual, the drug type, and drug use history. Heavy/chronic patterns of use in addiction can produce longer, more severe withdrawal phases, but addiction and withdrawal can exist separately. How a drug acts upon different receptors and other downstream brain systems (pharmacodynamics) impacts the strength of its psychoactive (intoxicating) and motivational (addictive effects). Meanwhile, the route and rate of drug intake and its breakdown and elimination (pharmacokinetics) can also impact intoxication, withdrawal, and addiction risk. With addiction, the patient becomes tolerant (insensitive) to the intoxicating profiles of drugs they like, whereas their motivation, craving, and wanting to use the drug sensitizes (grows pathologically).
Addiction is a chronic-progressive disease marked by phases of relapse and recovery. Patients with moderate to severe addictions typically have mental illness of some form (they are dual-diagnosis patients) reflecting how mental illness and addiction are biologically and bidirectionally causally interlinked. Addiction psychiatrists are formally cross-trained in the diagnosis and treatment of both addiction and mental illness. They conduct diagnostic workups that fully embrace complex addiction–mental illness comorbidities while longitudinally tracking illness evolution and recovery trajectories. As implemented in the 2 × 4 model blueprint of integrated addiction psychiatry care, repeated diagnostic evaluations guide individualized treatment planning that attends to patient’s stages of change while integrating psychotherapeutic, experiential, medication, and/or neuromodulator treatments. Multiple mental illness and addiction subtypes are simultaneously or sequentially targeted over the course of detoxification-withdrawal treatments, harm reduction, and full remission strategies. The advancing frontier of addiction psychiatry will involve the growth of inpatient and outpatient teams composed of addiction psychiatrists, nurses, and therapists that reject fragmented/siloed/split-care models that segregate addiction from mental illness treatment and professional training. Addiction psychiatry teams will be important for researching new integrative treatments in full recognition of addiction and mental illness as highly neurobiologically interconnected and clinically interrelated brain diseases.
Addiction is a highly prevalent brain disease. It is a major cause of many secondary forms of medical illness and accidents, and it is a leading root cause of death. The disease attacks the circuits of the brain that govern motivational learning and control. It is defined by increasingly compulsive drug seeking and use, despite the accumulation of negative medical, social, and psychiatric consequences. Because the disease also impacts brain systems governing the exercise of free-will, decision-making, and insight, it is often judged, criminalized, and stigmatized, which are countertherapeutic social responses to the disease. Addiction psychiatry is a field of psychiatry that is uniquely trained to treat the entire spectrum of addictions and mental illness, especially for mainstream dual-diagnosis patients who suffer with combinations of these disorders. The epidemiology of addiction shows that the disease is not evenly distributed in the population. Rather, it tends to concentrate in people with genetic, developmental, and environmental risk factors, many of which overlap with those that also produce mental illness. Advances and growth in addiction psychiatry training, research, and clinical care hold tremendous potential for ending mass incarceration and rendering the healthcare system more efficacious and cost-effective.
As with other diseases, vulnerability to addiction is not evenly distributed in the population. It is concentrated in people that bear higher concentrations of biologically active risk factors. Addiction vulnerability is associated with earlier age of substance use, multiple concurrent addictions, and mental illness. It is determined by complex interactions between many hundreds of genes, and a wide range of environmental–developmental experiences – all of which are biologically active in shaping motivational-behavioral repertoires and cortical–striatal–limbic networks anchored on the NAC. Understanding the developmental neurocircuitry of addiction and its linkage with mental illness informs our understanding of this disease vulnerability. All major forms of mental illness, spanning schizophrenia, bipolar disorder, depression, trauma-spectrum disorders, personality disorders, impulse controls disorders, etc., involve anatomical–functional abnormalities that overlap and interlink with primary motivational circuits involved in addiction. The neurocircuitry of mental illness, involving disrupted inputs from PFC, AMY, HCF, into the NAC, involuntarily alters NAC network responsivity to addictive drugs, allowing their pathological neuroplastic effects to produce more robust and accelerated sensitization of drug-motivated behavior. Similarly, adolescent neurodevelopment is a biological context marked by profound change of motivational-behavioral repertoires – and neural network revision within cortical–striatal–limbic circuits – that increases brain susceptibility to addiction.
The front door to addiction pathophysiology is through the nucleus accumbens (NAC) (aka, ventral striatum) – the brain’s primary neural network for representing, storing, and modifying motivational information. NAC motivational codes are informed and altered by converging axonal inputs from prefrontal cortex (PFC), hippocampal formation (HCF), and amygdala (AMY) that import cognitive and emotional information carried by glutamate (GLU) neurotransmission. Relaying motivational codes from NAC into the caudate-putamen (CA-PU; aka, dorsal striatum) influences the prioritization, sequencing, automaticity, and execution of complex, goal-directed motor programs. Four classes of stimuli increase dopamine (DA) neurotransmitter release into the NAC – events that are (1) rewarding, (2) unexpected, (3) stressful/painful, and (4) addictive drugs. The three classes of natural salient events promote DA discharge into the NAC to optimize flow of motivational information while operating as a learning signal for the creation and modification of new motivational codes and motor program sequences. In addiction pathogenesis, repeated drug delivery exploits the DA learning signal, causing abnormal changes in neuronal DNA expression, phenotypes, and axodendritic connections within the NAC network. This change in connectivity alters motivational codes managed and stored by the NAC network, so that motivated behavior driving drug use is involuntarily prioritized over other healthy motivations.
This essential, concept-oriented book provides a highly integrative and translational approach to addiction, offering a deep understanding of the condition and its close biological-causal-developmental linkage with mental illness. The book explains addiction around five fundamental components that define disease: 1) Population Impact; 2) Symptom Sets; 3) Disorder of Anatomical Structure and Function; 4) Biological Risk Amplification; and 5) Diagnosis and Treatment. Key evidence and concepts from basic neuroscience are translated to epidemiological, clinical-observational, and treatment levels. The book discusses the broad reach and potent clinical capabilities of addiction psychiatry teams using integrative diagnostics and multi-dimensional treatment plans for patients across the entire addiction-mental illness spectrum. It introduces science-based psychotherapies, therapeutic experiences, medication and neurostimulatory treatments used by addiction psychiatrists in different settings to advance patients through all stages of recovery. An illustrated foundation for advanced undergraduates, physicians, allied clinicians, and scientists entering brain-behavioural health fields.
Starting in late September 1872, horses started falling ill with a severe respiratory complaint in the countryside about a dozen miles north of Toronto, Ontario. Veterinary experts swiftly diagnosed the malady, which paralyzed street transportation, commerce, and everyday life in Toronto itself during the first weeks of October, as influenza. Over the next year, an equine plague that most contemporaries referred to as the epizootic—and which I call the Great Horse Flu in the book I am completing on this outbreak—spread throughout southern Canada, every reach of the United States, and parts of Cuba, Mexico, and Central America. The novel influenza virus responsible for this outbreak sickened between ninety and ninety-nine percent of horses, donkeys, and mules across this vast swath of the northern Americas.1 Our best guess is that the Great Horse Flu killed between one and four percent of the equines it afflicted—a case fatality rate roughly not unlike those recorded by the Great Influenza Pandemic of 1918–1920 and the COVID Pandemic. In less than a year, an estimated 112,500 to 554,000 horses and ponies perished alongside tens or hundreds of thousands of mules and donkeys.2
The nature and extent of interactions between the distant regions and cultures of Mesoamerica remain open to much debate. Close economic and political ties developed between Teotihuacan and the lowland Maya during the Early Classic period (AD 250–550), yet the relationship between these cultures continues to perplex scholars. This article presents an elaborately painted altar from an elite residential group at the lowland Maya centre of Tikal, Guatemala. Dating to the fifth century AD, the altar is unique in its display of Teotihuacan architectural and artistic forms, adding to evidence not only for cultural influence during this period, but also for an active Teotihuacan presence at Tikal.
We provide an assessment of the Infinity Two Fusion Pilot Plant (FPP) baseline plasma physics design. Infinity Two is a four-field period, aspect ratio A = 10, quasi-isodynamic stellarator with improved confinement appealing to a max-J approach, elevated plasma density and high magnetic fields (⟨B⟩ = 9 T). At the envisioned operating point [800 MW deuterium-tritium (DT) fusion], the configuration has robust magnetic surfaces based on magnetohydrodynamic (MHD) equilibrium calculations and is stable to both local and global MHD instabilities. The configuration has excellent confinement properties with small neoclassical transport and low bootstrap current (|Ibootstrap| ∼ 2 kA). Calculations of collisional alpha particle confinement in a DT FPP scenario show small energy losses to the first wall (< 1.5%) and stable energetic particle/Alfvén eigenmodes at high ion density. Low turbulent transport is produced using a combination of density profile control consistent with pellet fueling and reduced stiffness to turbulent transport via three-dimensional shaping. Transport simulations with the T3D-GX-SFINCS code suite with self-consistent turbulent and neoclassical transport predict that the Pfus = 800 MW operating point is attainable with high fusion gain (Q = 40) at volume-averaged electron densities ne ≈ 2×1020 m−3, below the Sudo density limit. Additional transport calculations show that an ignited (Q = ∞) solution is available at slightly higher density (2.2×1020 m−3) with Pfus = 1.5 GW. The magnetic configuration is defined by a magnetic coil set with sufficient room for an island divertor, shielding and blanket solutions with tritium breeding ratios (TBR) above unity. An optimistic estimate for the gas-cooled solid breeder designed Helium Cooled Pebble Bed is TBR ∼ 1.3. Infinity Two satisfies the physics requirements of a stellarator fusion pilot plant.
The magneto-hydrodynamic equilibrium and stability properties of the Infinity Two Fusion Pilot Plant baseline plasma physics design are presented. The configuration is a four field period, aspect ratio A = 10 quasi-isodynamic stellarator optimized for excellent confinement at elevated density and high magnetic field B = 9 T. Magnetic surfaces exist in the plasma core in vacuum and retain good equilibrium surface integrity from vacuum to an operational β = 1.6%, the ratio of the volume average of the plasma and magnetic pressures, corresponding to 800 MW Deuterium-Tritium fusion operation. Neoclassical calculations show that a selfconsistent bootstrap current on the order of ∼ 1 kA slightly increases the rotational transform profile by less than 0.001. The configuration has a magnetic well across its entire radius. From vacuum to the operating point, the configuration exhibits good ballooning stability characteristics, exhibits good Mercier stability across most of its minor radius, and it is stable against global low-n MHD instabilities up to β = 3.2%.
This work presents visual morphological and dynamical classifications for 637 spatially resolved galaxies, most of which are at intermediate redshift (z ∼ 0.3), in the Middle-Ages Galaxy Properties with Integral field spectroscopy (MAGPI) Survey. For each galaxy, we obtain a minimum of 11 independent visual classifications by knowledgeable classifiers. We use an extension of the standard Dawid-Skene Bayesian model introducing classifier-specific confidence parameters and galaxy-specific difficulty parameters to quantify classifier confidence and infer reliable statistical confidence estimates. Selecting sub-samples of 86 bright (r < 20 mag) high-confidence (> 0.98) morphological classifications at redshifts (0.2 ≤ z ≤ 0.4), we confirm the full range of morphological types is represented in MAGPI as intended in the survey design. Similarly, with a sub-sample of 82 bright high-confidence stellar kinematic classifications, we find that the rotating and non-rotating galaxies seen at low redshift are already in place at intermediate redshifts. We do not find evidence that the kinematic morphology-density relation seen at z ∼ 0 is established at z ∼ 0.3. We suggest that galaxies without obvious stellar rotation are dynamically pre-processed sometime before z ∼ 0.3 within lower mass groups before joining denser environments.
To improve early intervention and personalise treatment for individuals early on the psychosis continuum, a greater understanding of symptom dynamics is required. We address this by identifying and evaluating the movement between empirically derived attenuated psychotic symptomatic substates—clusters of symptoms that occur within individuals over time.
Methods
Data came from a 90-day daily diary study evaluating attenuated psychotic and affective symptoms. The sample included 96 individuals aged 18–35 on the psychosis continuum, divided into four subgroups of increasing severity based on their psychometric risk of psychosis, with the fourth meeting ultra-high risk (UHR) criteria. A multilevel hidden Markov modelling (HMM) approach was used to characterise and determine the probability of switching between symptomatic substates. Individual substate trajectories and time spent in each substate were subsequently assessed.
Results
Four substates of increasing psychopathological severity were identified: (1) low-grade affective symptoms with negligible psychotic symptoms; (2) low levels of nonbizarre ideas with moderate affective symptoms; (3) low levels of nonbizarre ideas and unusual thought content, with moderate affective symptoms; and (4) moderate levels of nonbizarre ideas, unusual thought content, and affective symptoms. Perceptual disturbances predominantly occurred within the third and fourth substates. UHR individuals had a reduced probability of switching out of the two most severe substates.
Conclusions
Findings suggest that individuals reporting unusual thought content, rather than nonbizarre ideas in isolation, may exhibit symptom dynamics with greater psychopathological severity. Individuals at a higher risk of psychosis exhibited persistently severe symptom dynamics, indicating a potential reduction in psychological flexibility.