The Nested States Model: An Empirical Framework for Integrating Brain and Mind.

Philosophy of mind has made substantial progress on biologically-rooted approaches to understanding the mind and subjectivity through the enactivist perspective, but research on subjectivity within neuroscience has not kept apace. Indeed, we possess no principled means of relating experiential phenomena to neurophysiological processes. Here, we present the Nested States Model as a framework to guide empirical investigation into the relationship between subjectivity and neurobiology. Building on recent work in phenomenology and philosophy of mind, we develop an account of experiential states as layered, or nested. We argue that this nested structure is also apparent in brain activity. The recognition of this structural homology - that both experiential and brain states can be characterized as systems of nested states - brings our views of subjective mental states into broad alignment with our understanding of general principles and properties of brain activity. This alignment enables a more systematic approach to formulating specific hypotheses and predictions about how the two domains relate to one another.

From chemistry to genomics: A concise history of the porphyrias.

We describe developments in understanding of the porphyrias associated with each step in the haem biosynthesis pathway and the role of individuals whose contributions led to major advances over the past 150 years. The first case of erythropoietic porphyria was reported in 1870, and the first with acute porphyria in 1889. Photosensitisation by porphyrin was confirmed by Meyer-Betz, who self-injected haematoporphyrin. Günther classified porphyrias into haematoporphyria acuta, acuta toxica, congenita and chronica. This was revised by Waldenström into porphyria congenita, acuta and cutanea tarda, with the latter describing those with late-onset skin lesions. Waldenström was the first to recognise porphobilinogen's association with acute porphyria, although its structure was not solved until 1953. Hans Fischer was awarded the Nobel prize in 1930 for solving the structure of porphyrins and the synthesis of haemin. After 1945, research by several groups elucidated the pathway of haem biosynthesis and its negative feedback regulation by haem. By 1961, following the work of Watson, Schmid, Rimington, Goldberg, Dean, Magnus and others, aided by the availability of modern techniques of porphyrin separation, six of the porphyrias were identified and classified as erythropoietic or hepatic. The seventh, 5-aminolaevulinate dehydratase deficiency porphyria, was described by Doss in 1979. The discovery of increased hepatic 5-aminolaevulinate synthase activity in acute porphyria led to development of haematin as a treatment for acute attacks. By 2000, all the haem biosynthesis genes were cloned, sequenced and assigned to chromosomes and disease-specific mutations identified in all inherited porphyrias. These advances have allowed definitive family studies and development of new treatments.

Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.

BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

Global LEADR pivotal trial results.

BACKGROUND: Implantable cardioverter-defibrillators last longer, and interest in reliable leads with targeted lead placement is growing. The OmniaSecure™ defibrillation lead is a novel small-diameter, catheter-delivered lead designed for targeted placement, based on the established SelectSecure SureScan MRI Model 3830 lumenless pacing lead platform. OBJECTIVE: This trial assessed safety and efficacy of the OmniaSecure defibrillation lead. METHODS: The worldwide LEADR pivotal clinical trial enrolled patients indicated for de novo implantation of a primary or secondary prevention implantable cardioverter-defibrillator/cardiac resynchronization therapy defibrillator, all of whom received the study lead. The primary efficacy end point was successful defibrillation at implantation per protocol. The primary safety end point was freedom from study lead-related major complications at 6 months. The primary efficacy and safety objectives were met if the lower bound of the 2-sided 95% credible interval was >88% and >90%, respectively. RESULTS: In total, 643 patients successfully received the study lead, and 505 patients have completed 12-month follow-up. The lead was placed in the desired right ventricular location in 99.5% of patients. Defibrillation testing at implantation was completed in 119 patients, with success in 97.5%. The Kaplan-Meier estimated freedom from study lead-related major complications was 97.1% at 6 and 12 months. The trial exceeded the primary efficacy and safety objective thresholds. There were zero study lead fractures and electrical performance was stable throughout the mean follow-up of 12.7 ± 4.8 months (mean ± SD). CONCLUSION: The OmniaSecure lead exceeded prespecified primary end point performance goals for safety and efficacy, demonstrating high defibrillation success and a low occurrence of lead-related major complications with zero lead fractures.

A mixed-method evaluation of implementation determinants for chaplain intervention in a hospital setting.

Healthcare chaplains address broad social and emotional dimensions of care within a pluralistic religious landscape. Although the development and evaluation of chaplaincy interventions has advanced the field, little research has investigated factors influencing the implementation of new chaplain interventions. In this mixed-method study, we examined attitudes about evidence-based interventions held by chaplain residents (n = 39) at the outset of an ACPE-accredited residency program in the southeast United States. We also used semi-structured interviews (n = 9) to examine residents' attitudes, beliefs, and decision-making processes after they trained in the delivery of a novel manualized intervention, Compassion-Centered Spiritual Health (CCSH). Most residents reported favorable attitudes toward manualized approaches prior to training. Interviews revealed complex decision-making processes and highlighted personal motivations and challenges to learning and implementing CCSH. Implementation science can reveal factors related to motivation, intention, and training that may be optimized to improve the implementation of healthcare chaplaincy interventions.

Neuropeptides affecting social behavior in mammals: Oxytocin.

Oxytocin (OXT), a neuropeptide consisting of only nine amino acids, is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Although OXT is best known for its role in lactation and parturition, recent research has shown that it also has a significant impact on social behaviors in mammals. However, a comprehensive review of this topic is still lacking. In this paper, we systematically reviewed the effects of OXT on social behavior in mammals. These effects of OXT from the perspective of five key behavioral dimensions were summarized: parental behavior, anxiety, aggression, attachment, and empathy. To date, researchers have agreed that OXT plays a positive regulatory role in a wide range of social behaviors, but there have been controversially reported results. In this review, we have provided a detailed panorama of the role of OXT in social behavior and, for the first time, delved into the underlying regulatory mechanisms, which may help better understand the multifaceted role of OXT. Levels of OXT in previous human studies were also summarized to provide insights for diagnosis of mental disorders.

Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function.

Hyperpolarized 129Xe gas MRI is an emerging technique to evaluate and measure regional lung function including pulmonary gas distribution and gas exchange. Chest computed tomography (CT) still remains the clinical gold standard for imaging of the lungs, though, in part due to the rapid CT protocols that acquire high-resolution images in seconds and the widespread availability of CT scanners. Quantitative approaches have enabled the extraction of structural lung parenchymal, airway and vascular measurements from chest CT that have been evaluated in many clinical research studies. Together, CT and 129Xe MRI provide complementary information that can be used to evaluate regional lung structure and function, resulting in new insights into lung health and disease. 129Xe MR-CT image registration can be performed to measure regional lung structure-function to better understand lung disease pathophysiology, and to perform image-guided pulmonary interventions. Here, a method for 129Xe MRI-CT registration is outlined to support implementation in research or clinical settings. Registration methods and applications that have been employed to date in the literature are also summarized, and suggestions are provided for future directions that may further overcome technical challenges related to 129Xe MR-CT image registration and facilitate broader implementation of regional lung structure-function evaluation.

Recurrence After Atrial Fibrillation Ablation and Investigational Biomarkers of Cardiac Remodeling.

BACKGROUND: Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model. METHODS AND RESULTS: Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein-10, angiopoietin-2, fibroblast growth factor-23, insulin-like growth factor-binding protein-7, myosin-binding protein C3, growth differentiation factor-15, interleukin-6, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [<60 ml/min/1.73m2], LA diameter ≥43 mm, EF <50%; which includes age, left atrial diameter, left ventricular ejection fraction, persistent atrial fibrillation, and estimated glomerular filtration rate), preablation rhythm, sex, height, body mass index, presence of an implanted continuous monitor, year of ablation, and additional linear ablation. A total of 1873 participants were included. A multivariable logistic regression showed an association between recurrence and levels of angiopoietin-2 (odds ratio, 1.08 [95% CI, 1.02-1.15], P=0.007) and interleukin-6 (odds ratio, 1.02 [95% CI, 1.003-1.03]; P=0.02). The area under the receiver operating characteristic curve of a model that only contained clinical predictors was 0.711. The addition of any of the 9 studied biomarkers to the predictive model did not result in a statistically significant improvement in the area under the receiver operating characteristic curve. CONCLUSIONS: Higher angiopoietin-2 and interleukin-6 levels were associated with recurrence after atrial fibrillation ablation in multivariable modeling. However, the addition of biomarkers to a clinical prediction model did not significantly improve recurrence prediction.

Rigorous Screened Interactions for Realistic Correlated Electron Systems.

We derive a widely applicable first-principles approach for determining two-body, static effective interactions for low-energy Hamiltonians with quantitative accuracy. The algebraic construction rigorously conserves all instantaneous two-point correlation functions in a chosen model space at the level of the random phase approximation, improving upon the traditional uncontrolled static approximations. Applied to screened interactions within a quantum embedding framework, we demonstrate these faithfully describe the relaxation of local subspaces via downfolding high-energy physics in molecular systems, as well as enabling a systematically improvable description of the long-range plasmonic contributions in extended graphene.

Lowest instrumented vertebrae in early onset scoliosis: is there a role for a more selective approach?

PURPOSE: This purpose of this study was to assess the impact of patient and implant characteristics on LIV selection in ambulatory children with EOS and to assess the relationship between the touched vertebrae (TV), the last substantially touched vertebrae (LSTV), the stable vertebrae (SV), the sagittal stable vertebrae (SSV), and the LIV. METHODS: A multicenter pediatric spine database was queried for patients ages 2-10 years treated by growth friendly instrumentation with at least 2-year follow up. The relationship between the LIV and preoperative spinal height, curve magnitude, and implant type were assessed. The relationships between the TV, LSTV, SV, SSV, and the LIV were also evaluated. RESULTS: Overall, 281 patients met inclusion criteria. The LIV was at L3 or below in most patients with a lumbar LIV: L1 (9.2%), L2 (20.2%), L3 (40.9%), L4 (29.5%). Smaller T1 - T12 length was associated with more caudal LIV selection (p = 0.001). Larger curve magnitudes were similarly associated with more caudal LIV selection (p = < 0.0001). Implant type was not associated with LIV selection (p = 0.32) including MCGR actuator length (p = 0.829). The LIV was caudal to the TV in 78% of patients with a TV at L2 or above compared to only 17% of patients with a TV at L3 or below (p < 0.0001). CONCLUSIONS: Most EOS patients have an LIV of L3 or below and display TV-LIV and LSTV-LIV incongruence. These findings suggest that at the end of treatment, EOS patients rarely have the potential for selective thoracic fusion. Further work is necessary to assess the potential for a more selective approach to LIV selection in EOS. LEVEL OF EVIDENCE: III.

Serum binding folate receptor autoantibodies lower in autistic boys and positively-correlated with folate.

Folate receptor autoantibody (FRAA) has caught increasing attention since its discovery in biological fluids of patients with autism spectrum disorder (ASD), but quantification and understanding of its function are still in their infancy. In this study, we aimed to quantify serum binding-FRAA and explore its relation with serum folate, vitamin B12 (VB12) and ferritin. We quantitated serum binding-FRAA in 132 ASD children and 132 typically-developing (TD) children, as well as serum levels of folate, VB12 and ferritin. The results showed that serum binding-FRAA in the ASD group was significantly lower than that in the TD group (p < 0.0001). Further analysis showed that the difference between these two groups was attributed to boys in each group, not girls. There was no statistically significant difference in folate levels between the ASD and TD groups (p > 0.05). However, there was significant difference in boys between these two groups, not girls. Additionally, the combination of nitrite and binding-FRAA showed potential diagnostic value in patients with ASD (AUC > 0.7). Moreover, in the ASD group, the level of folate was consistent with that of binding-FRAA, whereas in the TD group, the binding-FRAA level was high when the folate level was low. Altogether, these differences revealed that the low serum FRAA in autistic children was mediated by multiple factors, which deserves more comprehensive investigation with larger population and mechanistic studies.

Covalent bicyclization of protein complexes yields durable quaternary structures.

Proteins are essential biomolecules and central to biotechnological applications. In many cases, assembly into higher-order structures is a prerequisite for protein function. Under conditions relevant for applications, protein integrity is often challenged, resulting in disassembly, aggregation, and loss of function. The stabilization of quaternary structure has proven challenging, particularly for trimeric and higher-order complexes, given the complexity of involved inter- and intramolecular interaction networks. Here, we describe the chemical bicyclization of homotrimeric protein complexes, thereby increasing protein resistance toward thermal and chemical stress. This approach involves the structure-based selection of cross-linking sites, their variation to cysteine, and a subsequent reaction with a triselectrophilic agent to form a protein assembly with bicyclic topology. Besides overall increased stability, we observe resistance toward aggregation and greatly prolonged shelf life. This bicyclization strategy gives rise to unprecedented protein chain topologies and can enable new biotechnological and biomedical applications.

Implication of M2 macrophage on NLRP3 inflammasome signaling in mediating the neuroprotective effect of Canagliflozin against methotrexate-induced cognitive impairment.

Methotrexate (MTX), a chemotherapeutic antimetabolite, has been linked to cognitive impairment in cancer patients. MTX-induced metabolic pathway disruption may result in decreased antioxidant activity and increased oxidative stress, influencing hippocampal neurogenesis and microglial activation. Nuclear factor-kappa B (NF-κB), an oxidative stress byproduct, has been linked to MTX toxicity via the activation of NLRP3 inflammasome signaling. Macrophage activation and polarization plays an important role in tissue injury. This differentiation may be mediated via either the Toll-like receptor 4 (TLR4) or NLRP3 inflammasome. Interestingly, Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor has been recently reported to exert anti-inflammatory effects by modulating macrophage polarization balance. This study aimed to investigate CANA's protective effect against MTX-induced cognitive impairment, highlighting the possible involvement of TLR4/ NF-κB crosstalk with NLRP3 inflammasome activation and macrophage polarization. Forty-eight Male Wistar rats were divided into 4 groups; (1) received saline orally for 30 days and intravenously on days 8 and 15. (2) received Canagliflozin (CANA; 20 mg/kg/day; p.o.) for 30 days. (3) received MTX (75 mg/kg, i.v.) on day 8 and 15, then they were injected with four i.p. injections of leucovorin (LCV): the first dose was 6 mg/ kg after 18 h, and the remaining doses were 3 mg/kg after 26, 42, and 50 h of MTX administration. (4) received MTX and LCV as in group 3 in addition to CANA as in group 2. MTX-treated rats showed cognitive deficits in spatial and learning memory as evidenced in the novel object recognition and Morris water maze tests. MTX exerted an oxidative effect which was evident by the increase in MDA and decline in SOD, GSH and GPx. Moreover, it exerted an inflammatory effect via elevated caspase-1, IL-1ß and IL-8. CANA treatment restored cognitive ability, reduced MTX-induced oxidative stress and neuroinflammation via attenuation of TLR4/NF-κB/NLRP3 signaling, and rebalanced macrophage polarization by promoting the M2 phenotype. Hence, targeting molecular mechanisms manipulating macrophage polarization may offer novel neuroprotective strategies for preventing or treating MTX-induced immune modulation and its detrimental sequel.

Gender-Affirming Mastectomy: Psychosocial and Surgical Outcomes in Transgender Adults.

BACKGROUND: Limited literature exists examining the effects of gender-affirming mastectomy on transmasculine and nonbinary patients that is prospective and uses validated survey instruments. STUDY DESIGN: The psychosocial functioning of transmasculine and nonbinary patients was compared between patients who underwent gender-affirming mastectomy and those who had not yet undergone surgery. Participants were enrolled in a single-site, combined study of surgical and psychosocial outcomes, including a cross-sectional cohort of preoperative and postoperative patients, as well as separate prospective cohort. Participants completed the BREAST-Q psychosocial and sexual well-being modules, the BODY-Q satisfaction with chest and nipples modules, the Body Image Quality of Life Inventory, the Transgender Congruence Scale, the Patient Health Questionnaire-9, and the Generalized Anxiety Disorder-7 scale before and after surgery. We also examined how patient demographic factors correlated with postoperative surgical and psychosocial outcomes. RESULTS: A total of 111 transmasculine and nonbinary patients 18 to 63 years of age (mean ± SD 26.5 ± 8) underwent mastectomy and were included in the study. All were included in the cross-sectional cohort, and 20 were enrolled in the prospective cohort. More than one-third (34.2%) of patients were nonbinary. After surgery, psychosocial and sexual well-being, satisfaction, body image-related quality of life, and gender congruence were increased (p < 0.001) in both cohorts, and depression (p < 0.009 cross-sectional), and anxiety (p < 0.001 cross-sectional) were decreased. The most common adverse event was hypertrophic scarring, which occurred in 41 (36.9%) participants. CONCLUSIONS: In this study of transmasculine and nonbinary adults, gender-affirming mastectomy was followed by substantial improvements in psychosocial functioning.

Spiritual health practitioners' contributions to psychedelic assisted therapy: A qualitative analysis.

BACKGROUND: Psychedelic-assisted therapies hold early promise for treating multiple psychiatric conditions. However, absent standards for the care, teams providing psychedelic-assisted therapy pose a major roadblock to safe administration. Psychedelics often produce spiritually and existentially meaningful experiences, and spiritual health practitioners have been involved in administering psychedelic-assisted therapies in multiple settings, suggesting important qualifications for delivering these therapies. However, the roles and competencies of spiritual health practitioners in psychedelic-assisted therapies have not been described in research. METHOD: This study examined interviews with 15 spiritual health practitioners who have facilitated psychedelic-assisted therapy. Thematic analyses focused on their contributions, application of expertise and professional background, and roles in administering these therapies. RESULTS: Seven themes emerged, comprising two domains: unique and general contributions. Unique contributions included: competency to work with spiritual material, awareness of power dynamics, familiarity with non-ordinary states of consciousness, holding space, and offer a counterbalance to biomedical perspectives. General contributions included use of generalizable therapeutic repertoire when conducting PAT, and contributing to interdisciplinary collaboration. IMPLICATIONS: Spiritual health practitioners bring unique and specific expertise to psychedelic-assisted therapy based on their training and professional experience. They are skilled at interprofessional collaboration in a way that complements other clinical team members. Psychedelic-assisted therapy teams may benefit from including spiritual health practitioners. In order to ensure rigorous standards and quality care, further efforts to delineate the roles and necessary qualifications and training of spiritual health clinicians for psychedelic-assisted therapy are needed.

Population genomic structure of a widespread, urban-dwelling mammal: The eastern grey squirrel (Sciurus carolinensis).

Urbanization is a persistent and widespread driver of global environmental change, potentially shaping evolutionary processes due to genetic drift and reduced gene flow in cities induced by habitat fragmentation and small population sizes. We tested this prediction for the eastern grey squirrel (Sciurus carolinensis), a common and conspicuous forest-dwelling rodent, by obtaining 44K SNPs using reduced representation sequencing (ddRAD) for 403 individuals sampled across the species' native range in eastern North America. We observed moderate levels of genetic diversity, low levels of inbreeding, and only a modest signal of isolation-by-distance. Clustering and migration analyses show that estimated levels of migration and genetic connectivity were higher than expected across cities and forested areas, specifically within the eastern portion of the species' range dominated by urbanization, and genetic connectivity was less than expected within the western range where the landscape is fragmented by agriculture. Landscape genetic methods revealed greater gene flow among individual squirrels in forested regions, which likely provide abundant food and shelter for squirrels. Although gene flow appears to be higher in areas with more tree cover, only slight discontinuities in gene flow suggest eastern grey squirrels have maintained connected populations across urban areas in all but the most heavily fragmented agricultural landscapes. Our results suggest urbanization shapes biological evolution in wildlife species depending strongly on the composition and habitability of the landscape matrix surrounding urban areas.

Associations of religious and existential variables with psychosocial factors and biomarkers of cardiovascular risk in bereavement.

Bereavement increases in prevalence as people age and is associated with multiple psychological and health risks, including cardiovascular risk. Religious and existential variables may play an important role in the health impacts of bereavement. Theorized pathways linking religious and existential variables with health have suggested these associations are due to intermediary psychosocial variables, but have not been tested in bereavement. This research empirically tested these pathways in a bereaved population. In N = 73 adults within 1 year of bereavement (mean age = 64.36), this study examined associations between (1) religious and existential characteristics (religious and spiritual struggles, intrinsic religiosity, and existential quest) and intermediary psychosocial variables (depression, loneliness, and difficulties in emotion regulation), and between (2) intermediary psychosocial variables and bereavement-relevant health outcomes (self-reported health, change in health since last year, grief severity, and cardiovascular biomarkers). Cardiovascular biomarkers (heart rate, heart rate variability, and blood pressure) were collected before, during, and after a laboratory grief recall emotion elicitation. Anticipated associations between self-reported religious and existential characteristics and intermediary variables, and between intermediary variables and self-reported bereavement-relevant outcomes, were consistently observed. However, associations between intermediary variables and cardiovascular biomarkers were largely unobserved. This study examined the role of religious and existential variables in whole-person health after bereavement and is among the first to include biomarkers of cardiovascular risk. Results suggest that although religious and existential variables are associated with important bereavement-related outcomes, these associations may be "skin-deep," and extensions to cardiovascular functioning should be re-examined.