Visual mismatch negativity in Parkinson's psychosis and potential for testing treatment mechanisms.

Psychosis and visual hallucinations are a prevalent non-motor symptom of Parkinson's disease, negatively affecting patients' quality of life and constituting a greater risk for dementia. Understanding neural mechanisms associated to these symptoms is instrumental for treatment development. The mismatch negativity is an event-related potential evoked by a violation in a sequence of sensory events. It is widely considered an index of sensory change-detection. Reduced mismatch negativity response is one of the most replicated results in schizophrenia and has been suggested to be a superior psychosis marker. To understand whether this event-related potential component could be a similarly robust marker for Parkinson's psychosis, we used electroencephalography with a change-detection task to study the mismatch negativity in the visual modality in 20 participants with Parkinson's and visual hallucinations and 18 matched Parkinson's participants without hallucinations. We find that visual mismatch negativity is clearly present in participants with Parkinson's disease without hallucinations at both parieto-occipital and frontal sites, whereas participants with Parkinson's and visual hallucinations show reduced or no differences in the two waveforms, confirming the sensitivity of mismatch negativity to psychosis, even within the same diagnostic group. We also explored the relationship between hallucination severity and visual mismatch negativity amplitude, finding a negative correlation between visual hallucinations severity scores and visual mismatch negativity amplitude at a central frontal and a parieto-occipital electrodes, whereby the more severe or complex (illusions, formed visual hallucinations) the symptoms the smaller the amplitude. We have also tested the potential role of the serotonergic 5-HT2A cascade in visual hallucinations in Parkinson's with these symptoms, following the receptor trafficking hypothesis. We did so with a pilot study in healthy controls (N = 18) providing support for the role of the Gi/o-dependent pathway in the psychedelic effect and a case series in participants with Parkinson's and visual hallucinations (N = 5) using a double-blind crossover design. Positive results on psychosis scores and mismatch amplitude add further to the potential role of serotonergic modulation of visual hallucinations in Parkinson's disease.

Action of Molybdate Anion on d-Glucosone: Catalytic Conversion to Aldonates Involving C1-C2 Transposition.

Treatment of the osone (aldos-2-ulose), d-[1-13C]glucosone (1 1), with sodium molybdate at 90° for 30 h gave a mixture of d-[2-13C]gluconate (2 2) and d-[2-13C]mannonate (3 2) in an 85:15 ratio, indicating that the reaction proceeds with C1-C2 transposition similar to that observed previously with aldoses. Reactions with several singly and doubly 13C-labeled isotopomers of 1 confirmed this transposition. In contrast to the aldose reaction, the reaction with 1 is irreversible, presumably due to electrostatic repulsion between the negatively charged catalytically active bimolybdate species and the negatively charged aldonate product. The production of 2 and 3 is mediated by the formation of two structurally distinct bimolybdate complexes, one producing the gluco isomer and the other producing the manno isomer. Reaction byproducts were also observed, specifically d-[1-13C]arabinose (4 1) and [13C]formate (5), when 1 1 was used as the reactant. These byproducts appear to form from the breakdown of bimolybdate complexes via alternative pathways that compete with those responsible for aldonate formation.

Epigenetic Regulation in Psychosomatics and Psychotherapy.

Epigenetic modifications play a pivotal role in the regulation of gene expression and cell function, offering potential markers of disease states and therapeutic outcomes. Recent advancements in neuroscience have spurred interest in studying the epigenetic underpinnings of psychosomatic medicine. This review presents a new perspective on the role of epigenetic regulation in the realms of psychosomatics and psychotherapy. The authors first highlight epigenetic patterns associated with prevalent psychosomatic disorders, including irritable bowel syndrome, fibromyalgia, psoriasis, and lichen planus. For these conditions, psychotherapy serves as a treatment modality and can be conceptualized as an epigenetic intervention that beneficially affects the epigenome as part of the therapeutic process. Focusing on cognitive-behavioral and mindfulness-based therapies, the authors highlight evidence on psychotherapy-associated epigenetic signatures occurring at genes that are involved in stress response, inflammation, neurotransmission, neuroplasticity, and aging. Educating patients about the potential of psychotherapy to affect the epigenome may enhance patient engagement with and adherence to treatment, and psychotherapy-induced epigenetic changes have the potential to promote transgenerational disease prevention, underscoring the far-reaching implications of this therapeutic approach. Challenges persist in epigenetic studies, and this review aimed to catalyze further research in this burgeoning field, with the goal of enhancing patient care.

MA'AT analysis of the O-glycosidic linkages of oligosaccharides using nonconventional NMR J-couplings: MA'AT and MD models of phi.

MA'AT analysis (Meredith et al., J. Chem. Inf. Model. 2022, 62, 3135-3141) is a new NMR-based method to treat ensembles of redundant NMR spin-coupling constants (J-couplings) to obtain experiment-based probability distributions of molecular torsion angles in solution. Work reported to date on modeling the conformations of O-glycosidic linkages of oligosaccharides using three conventional J-coupling constraints (2 J COC, 3 J COCH, 3 J COCC) has shown that the method gives mean torsion angles and circular standard deviations (CSDs) for psi in very good agreement with those obtained by MD simulation. On the other hand, CSDs for phi determined by MA'AT analysis have consistently been much larger than those determined by MD, calling into question either the reliability of MA'AT analysis or MD to accurately predict this behavior. Prior work has shown that this discrepancy does not stem from the limitations of DFT-based J-coupling equation parameterization where secondary conformational dependencies can introduce uncertainties. The present work re-visits this problem by incorporating a new nonconventional J-coupling constraint into MA'AT analyses of phi, namely, a geminal (two-bond) 2 J CCH J-value that exhibits a strong primary dependence on phi. The latter property pertains explicitly to linkages contributed by GlcNAc pyranosyl rings and pyranosyl rings devoid of substituents at C2 (i.e., deoxy residues) where known secondary contributions to 2 J CCH magnitude caused by C-O bond rotation involving the coupled carbon are negligible or absent. The results show that when 2 J CCH values are added to the analysis, phi CSDs reduce considerably, bringing them into better alignment with those obtained by MD simulation. The cause of the discrepancy when only three conventional J-couplings are used to treat phi appears to be associated with the two-bond 2 J COC, which has properties that make it less effective than the non-conventional 2 J CCH as a discriminator of different conformational models of phi.

Community-Based Medications First for Opioid Use Disorder - Care Utilization and Mortality Outcomes.

Purpose: A large treatment gap exists for people who could benefit from medications for opioid use disorder (MOUD). People OUD accessing services in harm reduction and community-based organizations often have difficulty engaging in MOUD at opioid treatment programs and traditional health care settings. We conducted a study to test the impacts of a community-based medications first model of care in six Washington (WA) State communities that provided drop-in MOUD access. Participants and Methods: Participants included people newly prescribed MOUD. Settings included harm reduction and homeless services programs. A prospective cohort analysis tested the impacts of the intervention on MOUD and care utilization. Intervention impacts on mortality were tested via a synthetic comparison group analysis matching on demographics, MOUD history, and geography using WA State agency administrative data. Results: 825 people were enrolled in the study of whom 813 were matched to state records for care utilization and outcomes. Cohort analyses indicated significant increases for days' supply of buprenorphine, months with any MOUD, and months with any buprenorphine for people previously on buprenorphine (all results p<0.05). Months with an emergency department overdose did not change. Months with an inpatient hospital stay increased (p<0.05). The annual death rate in the first year for the intervention group was 0.45% (3 out of 664) versus 2.2% (222 out of 9893) in the comparison group in the 12 months; a relative risk of 0.323 (95% CI 0.11-0.94). Conclusion: Findings indicated a significant increase in MOUD for the intervention group and a lower mortality rate relative to the comparison group. The COVID-19 epidemic and rapid increase in non-pharmaceutical-fentanyl may have lessened the intervention impact as measured in the cohort analysis. Study findings support expanding access to a third model of low barrier MOUD care alongside opioid treatment programs and traditional health care settings.

Post-hospitalisation COVID-19 cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers, and reduced anterior cingulate cortex volume one year after COVID-19. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

Geographic Access to High-Volume Mechanical Thrombectomy Centers in Florida, 2019.

Background and Objectives: Mechanical thrombectomy (MT) improves outcomes for acute ischemic stroke (AIS) due to large vessel occlusion, but is time sensitive and requires specialized infrastructure. Professional organizations and certification bodies have promulgated minimum procedural volume standards for centers and for individual proceduralists but it is unclear whether enforcing these requirements would decrease geographic access to MT. Therefore, we sought to evaluate the potential impact of applying a minimum procedural volume threshold on geographic access to MT. Methods: We identified all hospital discharges for stroke where an MT procedure was performed at any nonfederal hospital in Florida in 2019 using statewide hospital discharge data. We then generated geographic service area maps based on prespecified ground transport distances for the subset of hospitals that performed at least 1 MT and for those that performed at least 15 MTs that year, the minimum volume threshold required for thrombectomy capable and comprehensive stroke centers by the Joint Commission. Then, using zip code centroids and patient-level discharge hospital data, we computed the proportion of patients with AIS who lived within each of the generated service areas. Results: A total of 105 of 297 hospitals performed MT; of those, 51 (17%) were low-volume centers (1-14 MTs/year) and 54 (18%) were high-volume centers (≥15 MTs/year). High-volume centers accounted for nearly 95% of all MTs performed in the state. Most patients hospitalized with AIS (87%) lived within 20 miles (or an estimated as a 1-hour driving time) of a hospital that performed at least 1 MT, and all (100%) lived within 115 miles (or estimated as 3-hour driving time). Setting a minimum MT volume threshold of 15 would decrease the proportion of stroke patients living within 1-hour driving time of an MT center from 87% to 77%. Discussion: In 2019, most Florida stroke patients lived within a 1-hour ground transport time to a center that performed at least 1 MT and all lived within 3-hour driving time of an MT center, irrespective of whether a minimum procedural volume threshold of 15 cases per year was applied or not.

Mesenchymal Stromal Cell Implants for Chronic Motor Deficits After Traumatic Brain Injury: Post Hoc Analysis of a Randomized Trial.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.

Ethnic Diversity and Distinctive Features of Familial Versus Multifactorial Chylomicronemia Syndrome: Insights From the UK FCS National Registry.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS). METHODS: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project. RESULTS: FCS was relatively common in non-Europeans and those with parental consanguinity (P<0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P=0.001), recurrent pancreatitis (92% versus 63%; P<0.001), unexplained abdominal pain (84% versus 52%; P<0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P<0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P<0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS (P<0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS (P=0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS. CONCLUSIONS: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS.

The researcher's guide to selecting biomarkers in mental health studies.

Clinical mental health researchers may understandably struggle with how to incorporate biological assessments in clinical research. The options are numerous and are described in a vast and complex body of literature. Here we provide guidelines to assist mental health researchers seeking to include biological measures in their studies. Apart from a focus on behavioral outcomes as measured via interviews or questionnaires, we advocate for a focus on biological pathways in clinical trials and epidemiological studies that may help clarify pathophysiology and mechanisms of action, delineate biological subgroups of participants, mediate treatment effects, and inform personalized treatment strategies. With this paper we aim to bridge the gap between clinical and biological mental health research by (1) discussing the clinical relevance, measurement reliability, and feasibility of relevant peripheral biomarkers; (2) addressing five types of biological tissues, namely blood, saliva, urine, stool and hair; and (3) providing information on how to control sources of measurement variability.

Clearing the air: A systematic review of studies on air pollution and childhood brain outcomes to mobilize policy change.

Climate change, wildfires, and environmental justice concerns have drawn increased attention to the impact of air pollution on children's health and development. Children are especially vulnerable to air pollution exposure, as their brains and bodies are still developing. The objective of this systematic review was to synthesize available empirical evidence on the associations between air pollution exposure and brain outcomes in developmental samples (ages 0-18 years old). Studies were identified by searching the PubMed and Web of Science Core Collection databases and underwent a two-phase screening process before inclusion. 40 studies were included in the review, which included measures of air pollution and brain outcomes at various points in development. Results linked air pollution to varied brain outcomes, including structural volumetric and cortical thickness differences, alterations in white matter microstructure, functional network changes, metabolic and molecular effects, as well as tumor incidence. Few studies included longitudinal changes in brain outcomes. This review also suggests methodologies for incorporating air pollution measures in developmental cognitive neuroscience studies and provides specific policy recommendations to reduce air pollution exposure and promote healthy brain development by improving access to clean air.

Oligodendroglial fatty acid metabolism as a central nervous system energy reserve.

Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts. In the isolated optic nerve from young adult mice of both sexes, oligodendrocytes survive glucose deprivation better than astrocytes. Under low glucose, both axonal ATP levels and action potentials become dependent on fatty acid ß-oxidation. Importantly, ongoing oligodendroglial lipid degradation feeds rapidly into white matter energy metabolism. Although not supporting high-frequency spiking, fatty acid ß-oxidation in mitochondria and oligodendroglial peroxisomes protects axons from conduction blocks when glucose is limiting. Disruption of the glucose transporter GLUT1 expression in oligodendrocytes of adult mice perturbs myelin homeostasis in vivo and causes gradual demyelination without behavioral signs. This further suggests that the imbalance of myelin synthesis and degradation can underlie myelin thinning in aging and disease.

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

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 < 0.001) predictive power for post-deployment PTSD. CONCLUSION: The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts.

Designing Nanoporous Polymer Films for High-Performance Passive Daytime Radiative Cooling.

Energy-free passive daytime radiative cooling (PDRC) technology makes it an attractive solution to both the building energy crisis and global warming. Spectrally selective porous polymers have great potential for practical PDRC applications owing to their cooling performance and scalability. A fundamental understanding of the relationship between the cooling performance and pore properties is crucial for guiding future structural designs of high-performance PDRC materials. However, one of the key challenges is achieving uniform nanopores and tailorable pore morphologies in the PDRC coating films. Here we demonstrate a strategy to use advanced metal-organic framework (MOF) nanocrystals as a sacrificial template creating a nanoporous poly(vinylidene fluoride) (PVDF) coating film with uniform-sized nanopores for highly daytime passive radiative cooling. The experimental evidence indicates that nanopores around 400 nm in size, comparable to the wavelength within the ultraviolet and visible spectra, along with an appropriate porosity of 37%, contribute to excellent solar reflectance (94.9 ± 0.8%) and high long-wave infrared emission (92.8 ± 1.4%) in the resulting porous PVDF films. This leads to subambient cooling of ≈9.5 °C and a promising net cooling power of 137 W/m2 at midday under solar intensities of ∼1275 and ∼1320 W/m2. The performance equals or exceeds that of state-of-the-art polymeric PDRC designs, and this general strategy of tailing nanostructures is expected to open a new avenue toward high-performance radiative cooling materials for PDRC applications.

Regional Differences in Vascular Graft Degradation and Regeneration Contribute to Dilation.

Severe coronary artery disease is often treated with a coronary artery bypass graft using an autologous blood vessel. When this is not available, a commercially available synthetic graft can be used as an alternative but is associated with high failure rates and complications. Therefore, the research focus has shifted toward the development of biodegradable, regenerative vascular grafts that can convert into neoarteries. We previously developed an electrospun tropoelastin (TE)-polyglycerol sebacate (PGS) vascular graft that rapidly regenerated into a neoartery, with a cellular composition and extracellular matrix approximating the native aorta. We noted, however, that the TE-PGS graft underwent dilation until sufficient neotissue had been regenerated. This study investigated the mechanisms behind the observed dilation following TE-PGS vascular graft implantation in mice. We saw more pronounced dilation at the graft middle compared with the graft proximal and graft distal regions at 8 weeks postimplantation. Histological analysis revealed less degradation at the graft middle, although the remaining graft material appeared pitted, suggesting compromised structural and mechanical integrity. We also observed delayed cellular infiltration and extracellular matrix (ECM) deposition at the graft middle, corresponding with the area's reduced ability to resist dilation. In contrast, the graft proximal region exhibited greater degradation and significantly enhanced cellular infiltration and ECM regeneration. The nonuniform dilation was attributed to the combined effect of the regional differences in graft degradation and arterial regeneration. Consideration of these findings is crucial for graft optimization prior to its use in clinical applications.

Impact of obesity on clinical outcomes of methicillin-susceptible Staphylococcus aureus bloodstream infections.

Obesity affects over one-third of U.S. adults and complicates the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSI). A study at the University of Florida Health Centers compared clinical outcomes between 233 obese and non-obese patients receiving cefazolin for MSSA BSI. No significant differences were found in clinical success (81.9% vs 82.7%), mortality (7.2% vs 5.3%), or adverse events (3.6% vs 3.3%). However, obese patients took longer to clear blood cultures (4.62 vs 4.01 days, P = 0.017).