Assessment of clinical outcomes in patients with inflammatory arthritis: analysis from the UK Medical Cannabis Registry.

The aim of this study was to assess changes in validated patient-reported outcome measures after initiation of cannabis-based medicinal products (CBMPs) and the safety of CBMPs in patients with inflammatory arthritis. A prospective case series from the UK Medical Cannabis Registry was analyzed. The primary outcomes changes were in Brief Pain Inventory, McGill Pain Questionnaire, EuroQol 5-dimension 5-level (EQ-5D-5L), Generalised Anxiety Disorder-7 questionnaire, and Single-Item Sleep Quality Scale at 1, 3, 6, and 12 months of follow-up compared with baseline. Adverse events were analyzed in accordance with Common Terminology Criteria for Adverse Events, v.4.0. Statistical significance was defined as a P-value less than 0.050. Eighty-two patients met the inclusion criteria. Initiation of CBMP treatment was associated with improvements in Brief Pain Inventory, McGill Pain Questionnaire, EQ-5D-5L, Generalised Anxiety Disorder-7 questionnaire, and Single-Item Sleep Quality Scale at 1, 3, 6, and 12 months compared with baseline (P < 0.050). There were 102 (44.35%) mild adverse events, 97 (42.17%) moderate adverse events, and 31 (13.48%) severe adverse events recorded by 21 (25.61%) participants. This study suggests that CBMP treatment is associated with pain improvement and increased health-related quality of life for inflammatory arthritis patients. While causality cannot be inferred in this observational study, the results support the development of randomized control trials for inflammatory arthritis pain management with CBMPs.

Decomposing loss aversion from a single neural signal.

People often display stronger aversion to losses than appetite for equivalent gains, a widespread phenomenon known as loss aversion. The prevailing theory attributes loss aversion to a valuation bias that amplifies losses relative to gains. An alternative account attributes loss aversion to a response bias that avoids choices that might result in loss. By modeling the temporal dynamics of scalp electrical activity during decisions to accept or reject gambles within a sequential sampling framework, we decomposed valuation bias and response bias from a single event-related neural signal, the P3. Specifically, we found valuation bias manifested as larger sensitivity of P3 to losses than gains, which was localizable to reward-related brain regions. By contrast, response bias manifested as larger P3 preceding gamble acceptance than rejection and was localizable to motor cortex. Our study reveals the dissociable neural biomarkers of response bias and valuation bias underpinning loss-averse decisions.

Immune gene regulation is associated with age and environmental adversity in a nonhuman primate.

Phenotypic aging is ubiquitous across mammalian species, suggesting shared underlying mechanisms of aging. Aging is linked to molecular changes to DNA methylation and gene expression, and environmental factors, such as severe external challenges or adversities, can moderate these age-related changes. Yet, it remains unclear whether environmental adversities affect gene regulation via the same molecular pathways as chronological, or 'primary', aging. Investigating molecular aging in naturalistic animal populations can fill this gap by providing insight into shared molecular mechanisms of aging and the effects of a greater diversity of environmental adversities - particularly those that can be challenging to study in humans or laboratory organisms. Here, we characterised molecular aging - specifically, CpG methylation - in a sample of free-ranging rhesus macaques living off the coast of Puerto Rico (n samples = 571, n individuals = 499), which endured a major hurricane during our study. Age was associated with methylation at 78,661 sites (31% of all sites tested). Age-associated hypermethylation occurred more frequently in areas of active gene regulation, while hypomethylation was enriched in regions that show less activity in immune cells, suggesting these regions may become de-repressed in older individuals. Age-associated hypomethylation also co-occurred with increased chromatin accessibility while hypermethylation showed the opposite trend, hinting at a coordinated, multi-level loss of epigenetic stability during aging. We detected 32,048 CpG sites significantly associated with exposure to a hurricane, and these sites overlapped age-associated sites, most strongly in regulatory regions and most weakly in quiescent regions. Together, our results suggest that environmental adversity may contribute to aging-related molecular phenotypes in regions of active gene transcription, but that primary aging has specific signatures in non-regulatory regions.

Multi-organ imaging-derived polygenic indexes for brain and body health.

The UK Biobank (UKB) imaging project is a crucial resource for biomedical research, but is limited to 100,000 participants due to cost and accessibility barriers. Here we used genetic data to predict heritable imaging-derived phenotypes (IDPs) for a larger cohort. We developed and evaluated 4,375 IDP genetic scores (IGS) derived from UKB brain and body images. When applied to UKB participants who were not imaged, IGS revealed links to numerous phenotypes and stratified participants at increased risk for both brain and somatic diseases. For example, IGS identified individuals at higher risk for Alzheimer's disease and multiple sclerosis, offering additional insights beyond traditional polygenic risk scores of these diseases. When applied to independent external cohorts, IGS also stratified those at high disease risk in the All of Us Research Program and the Alzheimer's Disease Neuroimaging Initiative study. Our results demonstrate that, while the UKB imaging cohort is largely healthy and may not be the most enriched for disease risk management, it holds immense potential for stratifying the risk of various brain and body diseases in broader external genetic cohorts.

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome.

Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest multi-brain-region bulk transcriptional datasets for the rhesus macaque and characterized sex-biased gene expression patterns to investigate the translatability of this species for sex-biased neurological conditions. We identify patterns similar to those in humans, which are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and support the rhesus macaque model for the translational study of these conditions.

Interpersonal heart rate synchrony predicts effective information processing in a naturalistic group decision-making task.

Groups often outperform individuals in problem-solving. Nevertheless, failure to critically evaluate ideas risks suboptimal outcomes through so-called groupthink. Prior studies have shown that people who hold shared goals, perspectives, or understanding of the environment show similar patterns of brain activity, which itself can be enhanced by consensus-building discussions. Whether shared arousal alone can predict collective decision-making outcomes, however, remains unknown. To address this gap, we computed interpersonal heart rate synchrony, a peripheral index of shared arousal associated with joint attention, empathic accuracy, and group cohesion, in 44 groups (n = 204) performing a collective decision-making task. The task required critical examination of all available information to override inferior, default options and make the right choice. Using multidimensional recurrence quantification analysis (MdRQA) and machine learning, we found that heart rate synchrony predicted the probability of groups reaching the correct consensus decision with >70% cross-validation accuracy-significantly higher than that predicted by the duration of discussions, subjective assessment of team function or baseline heart rates alone. We propose that heart rate synchrony during group discussion provides a biomarker of interpersonal engagement that facilitates adaptive learning and effective information sharing during collective decision-making.

Assessment of Clinical Outcomes in Patients With Osteoarthritis: Analysis From the UK Medical Cannabis Registry.

Osteoarthritis accounts for 0.6% of disability-adjusted life years globally. There is a paucity of research focused on cannabis-based medicinal products (CBMPs) for osteoarthritic chronic pain management. This study aims to assess changes in validated patient-reported outcome measures (PROMs) and CBMP clinical safety in patients with osteoarthritis. A prospective case series from the UK Medical Cannabis Registry was analyzed. Primary outcomes were changes in the Brief Pain Inventory (BPI), McGill Pain Questionnaire (MPQ2), EQ-5D-5L, Generalized Anxiety Disorder-7 (GAD-7) questionnaire, and Single-Item Sleep Quality Scale (SQS) at 1-, 3-, 6-, and 12-month follow-ups from baseline. Common Terminology Criteria for Adverse Events v.4.0 was used for adverse event (AE) analysis. Statistical significance was defined as p < 0.050. Seventy-seven patients met inclusion criteria. CBMP initiation correlated with BPI pain severity (p = 0.004), pain interference (p = 0.005), and MPQ2 (p = 0.017) improvements at all follow-ups compared to baseline. There were improvements in the EQ-5D-5L index (p = 0.026), SQS (p < 0.001), and GAD-7 (p = 0.038) up to 6 and 3 months, respectively. Seventeen participants (22.08%) recorded 76 mild AEs (34.86%), 104 moderate AEs (47.71%), and 38 severe AEs (17.43%). Though causality cannot be assumed in this observational study, results support development of randomized control trials for osteoarthritis pain management with CBMPs.

Social ageing can protect against infectious disease in a group-living primate.

The benefits of social living are well established, but sociality also comes with costs, including infectious disease risk. This cost-benefit ratio of sociality is expected to change across individuals' lifespans, which may drive changes in social behaviour with age. To explore this idea, we combine data from a group-living primate for which social ageing has been described with epidemiological models to show that having lower social connectedness when older can protect against the costs of a hypothetical, directly transmitted endemic pathogen. Assuming no age differences in epidemiological characteristics (susceptibility to, severity, and duration of infection), older individuals suffered lower infection costs, which was explained largely because they were less connected in their social networks than younger individuals. This benefit of 'social ageing' depended on epidemiological characteristics and was greatest when infection severity increased with age. When infection duration increased with age, social ageing was beneficial only when pathogen transmissibility was low. Older individuals benefited most from having a lower frequency of interactions (strength) and network embeddedness (closeness) and benefited less from having fewer social partners (degree). Our study provides a first examination of the epidemiology of social ageing, demonstrating the potential for pathogens to influence evolutionary dynamics of social ageing in natural populations.

Mechanical and morphometric approaches to body mass estimation in rhesus macaques: A test of skeletal variables.

OBJECTIVES: Estimation of body mass from skeletal metrics can reveal important insights into the paleobiology of archeological or fossil remains. The standard approach constructs predictive equations from postcrania, but studies have questioned the reliability of traditional measures. Here, we examine several skeletal features to assess their accuracy in predicting body mass. MATERIALS AND METHODS: Antemortem mass measurements were compared with common skeletal dimensions from the same animals postmortem, using 115 rhesus macaques (male: n = 43; female: n = 72). Individuals were divided into training (n = 58) and test samples (n = 57) to build and assess Ordinary Least Squares or multivariate regressions by residual sum of squares (RSS) and AIC weights. A leave-one-out approach was implemented to formulate the best fit multivariate models, which were compared against a univariate and a previously published catarrhine body-mass estimation model. RESULTS: Femur circumference represented the best univariate model. The best model overall was composed of four variables (femur, tibia and fibula circumference and humerus length). By RSS and AICw, models built from rhesus macaque data (RSS = 26.91, AIC = -20.66) better predicted body mass than did the catarrhine model (RSS = 65.47, AIC = 20.24). CONCLUSION: Body mass in rhesus macaques is best predicted by a 4-variable equation composed of humerus length and hind limb midshaft circumferences. Comparison of models built from the macaque versus the catarrhine data highlight the importance of taxonomic specificity in predicting body mass. This paper provides a valuable dataset of combined somatic and skeletal data in a primate, which can be used to build body mass equations for fragmentary fossil evidence.

Quantifying the relationship between bone and soft tissue measures within the rhesus macaques of Cayo Santiago.

OBJECTIVES: Interpretations of the primate and human fossil record often rely on the estimation of somatic dimensions from bony measures. Both somatic and skeletal variation have been used to assess how primates respond to environmental change. However, it is unclear how well skeletal variation matches and predicts soft tissue. Here, we empirically test the relationship between tissues by comparing somatic and skeletal measures using paired measures of pre- and post-mortem rhesus macaques from Cayo Santiago, Puerto Rico. MATERIALS AND METHODS: Somatic measurements were matched with skeletal dimensions from 105 rhesus macaque individuals to investigate paired signals of variation (i.e., coefficients of variation, sexual dimorphism) and bivariate codependence (reduced major axis regression) in measures of: (1) limb length; (2) joint breadth; and (3) limb circumference. Predictive models for the estimation of soft tissue dimensions from skeletons were built from Ordinary Least Squares regressions. RESULTS: Somatic and skeletal measurements showed statistically equivalent coefficients of variation and sexual dimorphism as well as high epiphyses-present ordinary least square (OLS) correlations in limb lengths (R2 >0.78, 0.82), joint breadths (R2 >0.74, 0.83) and, to a lesser extent, limb circumference (R2 >0.53, 0.68). CONCLUSION: Skeletal measurements are good substitutions for somatic values based on population signals of variation. OLS regressions indicate that skeletal correlates are highly predictive of somatic dimensions. The protocols and regression equations established here provide a basis for reliable reconstruction of somatic dimension from catarrhine fossils and validate our ability to compare or combine results of studies based on population data of either hard or soft tissue proxies.

Neural signatures of natural behaviour in socializing macaques.

Our understanding of the neurobiology of primate behaviour largely derives from artificial tasks in highly controlled laboratory settings, overlooking most natural behaviours that primate brains evolved to produce1-3. How primates navigate the multidimensional social relationships that structure daily life4 and shape survival and reproductive success5 remains largely unclear at the single-neuron level. Here we combine ethological analysis, computer vision and wireless recording technologies to identify neural signatures of natural behaviour in unrestrained, socially interacting pairs of rhesus macaques. Single-neuron and population activity in the prefrontal and temporal cortex robustly encoded 24 species-typical behaviours, as well as social context. Male-female partners demonstrated near-perfect reciprocity in grooming, a key behavioural mechanism supporting friendships and alliances6, and neural activity maintained a running account of these social investments. Confronted with an aggressive intruder, behavioural and neural population responses reflected empathy and were buffered by the presence of a partner. Our findings reveal a highly distributed neurophysiological ledger of social dynamics, a potential computational foundation supporting communal life in primate societies, including our own.

The Brain Economy: Advancing Brain Science to Better Understand the Modern Economy.

The coming years are likely to be turbulent due to a myriad of factors or polycrisis, including an escalation in climate extremes, emerging public health threats, weak productivity, increases in global economic instability and further weakening in the integrity of global democracy. These formidable challenges are not exogenous to the economy but are in some cases generated by the system itself. They can be overcome, but only with far-reaching changes to global economics. Our current socio-economic paradigm is insufficient for addressing these complex challenges, let alone sustaining human development, well-being and happiness. To support the flourishing of the global population in the age of polycrisis, we need a novel, person-centred and collective paradigm. The brain economy leverages insights from neuroscience to provide a novel way of centralising the human contribution to the economy, how the economy in turn shapes our lives and positive feedbacks between the two. The brain economy is primarily based on Brain Capital, an economic asset integrating brain health and brain skills, the social, emotional, and the diversity of cognitive brain resources of individuals and communities. People with healthy brains are essential to navigate increasingly complex systems. Policies and investments that improve brain health and hence citizens' cognitive functions and boost brain performance can increase productivity, stimulate greater creativity and economic dynamism, utilise often underdeveloped intellectual resources, afford social cohesion, and create a more resilient, adaptable and sustainability-engaged population.

Magnitude shifts spatial attention from left to right in rhesus monkeys as in the human mental number line.

Humans typically represent numbers and quantities along a left-to-right continuum. Early perspectives attributed number-space association to culture; however, recent evidence in newborns and animals challenges this hypothesis. We investigate whether the length of an array of dots influences spatial bias in rhesus macaques. We designed a touch-screen task that required monkeys to remember the location of a target. At test, monkeys maintained high performance with arrays of 2, 4, 6, or 10 dots, regardless of changes in the array's location, spacing, and length. Monkeys remembered better left targets with 2-dot arrays and right targets with 6- or 10-dot arrays. Replacing the 10-dot array with a long bar, yielded more accurate performance with rightward locations, consistent with an underlying left-to-right oriented magnitude code. Our study supports the hypothesis of a spatially oriented mental magnitude line common to humans and animals, countering the idea that this code arises from uniquely human cultural learning.

Attention deficits linked with proclivity to explore while foraging.

All mobile organisms forage for resources, choosing how and when to search for new opportunities by comparing current returns with the average for the environment. In humans, nomadic lifestyles favouring exploration have been associated with genetic mutations implicated in attention deficit hyperactivity disorder (ADHD), inviting the hypothesis that this condition may impact foraging decisions in the general population. Here we tested this pre-registered hypothesis by examining how human participants collected resources in an online foraging task. On every trial, participants chose either to continue to collect rewards from a depleting patch of resources or to replenish the patch. Participants also completed a well-validated ADHD self-report screening assessment at the end of sessions. Participants departed resource patches sooner when travel times between patches were shorter than when they were longer, as predicted by optimal foraging theory. Participants whose scores on the ADHD scale crossed the threshold for a positive screen departed patches significantly sooner than participants who did not meet this criterion. Participants meeting this threshold for ADHD also achieved higher reward rates than individuals who did not. Our findings suggest that ADHD attributes may confer foraging advantages in some environments and invite the possibility that this condition may reflect an adaptation favouring exploration over exploitation.

Taking identity-by-descent analysis into the wild: Estimating realized relatedness in free-ranging macaques.

Biological relatedness is a key consideration in studies of behavior, population structure, and trait evolution. Except for parent-offspring dyads, pedigrees capture relatedness imperfectly. The number and length of DNA segments that are identical-by-descent (IBD) yield the most precise estimates of relatedness. Here, we leverage novel methods for estimating locus-specific IBD from low coverage whole genome resequencing data to demonstrate the feasibility and value of resolving fine-scaled gradients of relatedness in free-living animals. Using primarily 4-6× coverage data from a rhesus macaque (Macaca mulatta) population with available long-term pedigree data, we show that we can call the number and length of IBD segments across the genome with high accuracy even at 0.5× coverage. The resulting estimates demonstrate substantial variation in genetic relatedness within kin classes, leading to overlapping distributions between kin classes. They identify cryptic genetic relatives that are not represented in the pedigree and reveal elevated recombination rates in females relative to males, which allows us to discriminate maternal and paternal kin using genotype data alone. Our findings represent a breakthrough in the ability to understand the predictors and consequences of genetic relatedness in natural populations, contributing to our understanding of a fundamental component of population structure in the wild.

Immune cell composition varies by age, sex and exposure to social adversity in free-ranging Rhesus Macaques.

Increasing age is associated with dysregulated immune function and increased inflammation-patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the immune system and how it might promote age-related diseases. Here, we investigated how immune cell diversity varied with age, sex and social adversity (operationalized as low social status) in free-ranging rhesus macaques. We found age-related signatures of immunosenescence, including lower proportions of CD20 + B cells, CD20 + /CD3 + ratio, and CD4 + /CD8 + T cell ratio - all signs of diminished antibody production. Age was associated with higher proportions of CD3 + /CD8 + Cytotoxic T cells, CD16 + /CD3- Natural Killer cells, CD3 + /CD4 + /CD25 + and CD3 + /CD8 + /CD25 + T cells, and CD14 + /CD16 + /HLA-DR + intermediate monocytes, and lower levels of CD14 + /CD16-/HLA-DR + classical monocytes, indicating greater amounts of inflammation and immune dysregulation. We also found a sex-dependent effect of exposure to social adversity (i.e., low social status). High-status males, relative to females, had higher CD20 + /CD3 + ratios and CD16 + /CD3 Natural Killer cell proportions, and lower proportions of CD8 + Cytotoxic T cells. Further, low-status females had higher proportions of cytotoxic T cells than high-status females, while the opposite was observed in males. High-status males had higher CD20 + /CD3 + ratios than low-status males. Together, our study identifies the strong age and sex-dependent effects of social adversity on immune cell proportions in a human-relevant primate model. Thus, these results provide novel insights into the combined effects of demography and social adversity on immunity and their potential contribution to age-related diseases in humans and other animals.

Interpersonal heart rate synchrony predicts effective information processing in a naturalistic group decision-making task.

Groups often outperform individuals in problem-solving. Nevertheless, failure to critically evaluate ideas risks sub-optimal outcomes through so-called groupthink. Prior studies have shown that people who hold shared goals, perspectives or understanding of the environment show similar patterns of brain activity, which itself can be enhanced by consensus building discussions. Whether shared arousal alone can predict collective decision-making outcomes, however, remains unknown. To address this gap, we computed interpersonal heart rate synchrony, a peripheral index of shared arousal associated with joint attention, empathic accuracy and group cohesion, in 44 groups (n=204) performing a collective decision-making task. The task required critical examination of all available information to override inferior, default options and make the right choice. Using multi-dimensional recurrence quantification analysis (MdRQA) and machine learning, we found that heart rate synchrony predicted the probability of groups reaching the correct consensus decision with greater than 70% cross-validation accuracy-significantly higher than that predicted by the duration of discussions, subjective assessment of team function or baseline heart rates alone. We propose that heart rate synchrony during group discussion provides a biomarker of interpersonal engagement that facilitates adaptive learning and effective information sharing during collective decision-making.

Evaluation of narrow-band imaging in the diagnosis of sinonasal inverted papilloma.

KEY POINTS: Narrow-band imaging (NBI) can be used to differentiate benign sinonasal lesions NBI can be used in the preoperative identification of sinonasal inverted papilloma Future studies can focus on NBI for recurrent inverted papilloma and surgical margin guidance.

An observational study of clinical outcome measures in patients treated with cannabis-based medicinal products on the UK Medical Cannabis Registry.

INTRODUCTION: While there is increasing evidence of the effects of cannabis-based medicinal products (CBMPs) on health-related quality of life (HRQoL), a major limitation of the current literature is the heterogeneity of studied CBMPs. This study aims to analyze changes in HRQoL in patients prescribed a homogenous selection of CBMPs. METHODS: Primary outcomes were changes in patient-reported outcomes (PROMs) at 1, 3, 6, and 12 months from baseline. The secondary outcome was an adverse events analysis. Statistical significance was defined as p < 0.050. RESULTS: 1378 patients prescribed Adven® CBMPs (Curaleaf International, Guernsey, UK) were included in the final analysis. 581 (42.16%) participants were current users of cannabis at baseline. 641 (46.51%), 235 (17.05%), and 502 (36.43%) patients were treated with oils, dried flowers, or a combination of the two, respectively. Improvements were found in all PROMs in each route of administration at 1, 3, 6, and 12 months from baseline (p < 0.010). Those prescribed dried flower only or both oils and dried flower experienced greater improvements in GAD-7, SQS, and EQ-5D-5L index values at 12 months (p < 0.050). There was no difference in outcomes between those prescribed dried flower only or dried flower with oils (p > 0.050). 3663 (265.82%) adverse events were reported by 297 (21.55%) patients. CONCLUSION: There was an associated improvement in self-reported anxiety, sleep quality, and HRQoL in patients treated with the CBMPs. Those prescribed treatment formulations including dried flower were most likely to show a clinical improvement. However, these results must be interpreted with caution given the limitations of study design.