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Digital twins are a new paradigm for our time, offering the possibility of interconnected virtual representations of the real world. The concept is very versatile and has been adopted by multiple communities of practice, policymakers, researchers, and innovators. A significant part of the digital twin paradigm is about interconnecting digital objects, many of which have previously not been combined. As a result, members of the newly forming digital twin community are often talking at cross-purposes, based on different starting points, assumptions, and cultural practices. These differences are due to the philosophical world-view adopted within specific communities. In this paper, we explore the philosophical context which underpins the digital twin concept. We offer the building blocks for a philosophical framework for digital twins, consisting of 21 principles that are intended to help facilitate their further development. Specifically, we argue that the philosophy of digital twins is fundamentally holistic and emergentist. We further argue that in order to enable emergent behaviors, digital twins should be designed to reconstruct the behavior of a physical twin by “dynamically assembling” multiple digital “components”. We also argue that digital twins naturally include aspects relating to the philosophy of artificial intelligence, including learning and exploitation of knowledge. We discuss the following four questions (i) What is the distinction between a model and a digital twin? (ii) What previously unseen results can we expect from a digital twin? (iii) How can emergent behaviours be predicted? (iv) How can we assess the existence and uniqueness of digital twin outputs?
5wPatients with end stage kidney disease (ESKD) who receive in-center hemodialysis are disproportionately vulnerable to extreme weather events, including hurricanes and heat waves, that may disrupt access to healthcare providers, and life-sustaining treatments. This current era of climate-driven compounding disasters is progressively elevating the level of threat to the health and well-being of patients with ESKD. This analysis brings together multi-disciplinary expertise to explore the contours of this increasingly complex risk landscape. Despite the challenges, important advances have been made for safeguarding this medically high-risk patient population. Hemodialysis services providers have devised innovative systems for preparing their patients and sustaining, or rapidly reestablishing, hemodialysis services in the aftermath of a disaster, and maintaining open lines of communication with their caseloads of ESKD patients throughout all phases of the event. A description of lessons learned along the path towards improved patient support in disasters, is provided. The article concludes with a detailed case example, describing dialysis providers’ effective response throughout Hurricane Ian’s passage across the State of Florida in 2022. Based on lessons learned, this analysis outlines strategies for protecting patients with ESKD that may be adapted for future climate-potentiated disaster scenarios.
Major depressive disorder (MDD) is a tremendous global disease burden and the leading cause of disability worldwide. Unfortunately, individuals diagnosed with MDD typically experience a delayed response to traditional antidepressants and many do not adequately respond to pharmacotherapy, even after multiple trials. The critical need for novel antidepressant treatments has led to a recent resurgence in the clinical application of psychedelics, and intravenous ketamine, which has been investigated as a rapid-acting treatment for treatment resistant depression (TRD) as well acute suicidal ideation and behavior. However, variations in the type and quality of experimental design as well as a range of treatment outcomes in clinical trials of ketamine make interpretation of this large body of literature challenging.
Objectives
This umbrella review aims to advance our understanding of the effectiveness of intravenous ketamine as a pharmacotherapy for TRD by providing a systematic, quantitative, large-scale synthesis of the empirical literature.
Methods
We performed a comprehensive PubMed search for peer-reviewed meta-analyses of primary studies of intravenous ketamine used in the treatment of TRD. Meta-analysis and primary studies were then screened by two independent coding teams according to pre-established inclusion criteria as well as PRISMA and METRICS guidelines. We then employed metaumbrella, a statistical package developed in R, to perform effect size calculations and conversions as well as statistical tests.
Results
In a large-scale analysis of 1,182 participants across 51 primary studies, repeated-dose administration of intravenous ketamine demonstrated statistically significant effects (p<0.05) compared to placebo-controlled as well as other experimental conditions in patients with TRD, as measured by standardized clinician-administered and self-report depression symptom severity scales.
Conclusions
This study provides large-scale, quantitative support for the effectiveness of intravenous, repeated-dose ketamine as a therapy for TRD and a report of the relative effectiveness of several treatment parameters across a large and rapidly growing literature. Future investigations should use similar analytic tools to examine evidence-stratified conditions and the comparative effectiveness of other routes of administration and treatment schedules as well as the moderating influence of other clinical and demographic variables on the effectiveness of ketamine on TRD and suicidal ideation and behavior.
Panic disorder (PD) and agoraphobia (AG) are highly comorbid anxiety disorders with an increasing prevalence that have a significant clinical and public health impact but are not adequately recognized and treated. Although the current functional neuroimaging literature has documented a range of neural abnormalities in these disorders, primary studies are often not sufficiently powered and their findings have been inconsistent.
Objectives
This meta-analysis aims to advance our understanding of the neural underpinnings of PD and AG by identifying the most robust patterns of differential neural activation that differentiate individuals diagnosed with one of or both these disorders from age-matched healthy controls.
Methods
We conducted a comprehensive literature search in the PubMed database for all peer-reviewed, whole-brain, task-based functional magnetic resonance imaging (fMRI) activation studies that compared adults diagnosed with PD and/or AG with age-matched healthy controls. Each of these articles was screened by two independent coding teams using formal inclusion criteria and according to current PRISMA guidelines. We then performed a voxelwise, whole-brain, meta-analytic comparison of PD/AG participants with age-matched healthy controls using multilevel kernel density analysis (MKDA) with ensemble thresholding (p<0.05-0.0001) to minimize cluster size detection bias and 10,000 Monte Carlo simulations to correct for multiple comparisons.
Results
With data from 34 primary studies and a substantial sample size (N=2138), PD/AG participants, relative to age-matched healthy controls, exhibited a reliable pattern of statistically significant, (p<.05-0.0001; FWE-corrected) abnormal neural activation in multiple brain regions of the cerebral cortex and basal ganglia across a variety of experimental tasks.
Conclusions
In this meta-analysis we found robust patterns of differential neural activation in participants diagnosed with PD/AG relative to age-matched healthy controls. These findings advance our understanding of the neural underpinnings of PD and AG and inform the development of brain-based clinical interventions such as non-invasive brain stimulation (NIBS) and treatment prediction and matching algorithms. Future studies should also investigate the neural similarities and differences between PD and AG to increase our understanding of possible differences in their etiology, diagnosis, and treatment.
There has been rapidly growing interest in understanding the pharmaceutical and clinical properties of psychedelic and dissociative drugs, with a particular focus on ketamine. This compound, long known for its anesthetic and dissociative properties, has garnered attention due to its potential to rapidly alleviate symptoms of depression, especially in individuals with treatment-resistant depression (TRD) or acute suicidal ideation or behavior. However, while ketamine’s psychopharmacological effects are increasingly well-documented, the specific patterns of its neural impact remain a subject of exploration and basic questions remain about its effects on functional activation in both clinical and healthy populations.
Objectives
This meta-analysis seeks to contribute to the evolving landscape of neuroscience research on dissociative drugs such as ketamine by comprehensively examining the effects of acute ketamine administration on neural activation, as measured by functional magnetic resonance imaging (fMRI), in healthy participants.
Methods
We conducted a meta-analysis of existing fMRI activation studies of ketamine using multilevel kernel density analysis (MKDA). Following a comprehensive PubMed search, we quantitatively synthesized all published primary fMRI whole-brain activation studies of the effects of ketamine in healthy subjects with no overlapping samples (N=18). This approach also incorporated ensemble thresholding (α=0.05-0.0001) to minimize cluster-size detection bias and Monte Carlo simulations to correct for multiple comparisons.
Results
Our meta-analysis revealed statistically significant (p<0.05-0.0001; FWE-corrected) alterations in neural activation in multiple cortical and subcortical regions following the administration of ketamine to healthy participants (N=306).
Conclusions
These results offer valuable insights into the functional neuroanatomical effects caused by acute ketamine administration. These findings may also inform development of therapeutic applications of ketamine for various psychiatric and neurological conditions. Future studies should investigate the neural effects of ketamine administration, including both short-term and long-term effects, in clinical populations and their relation to clinical and functional improvements.
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric condition that frequently originates in early development and is associated with a variety of functional impairments. Despite a large functional neuroimaging literature on ADHD, our understanding of the neural basis of this disorder remains limited, and existing primary studies on the topic include somewhat divergent results.
Objectives
The present meta-analysis aims to advance our understanding of the neural basis of ADHD by identifying the most statistically robust patterns of abnormal neural activation throughout the whole-brain in individuals diagnosed with ADHD compared to age-matched healthy controls.
Methods
We conducted a meta-analysis of task-based functional magnetic resonance imaging (fMRI) activation studies of ADHD. This included, according to PRISMA guidelines, a comprehensive PubMed search and predetermined inclusion criteria as well as two independent coding teams who evaluated studies and included all task-based, whole-brain, fMRI activation studies that compared participants diagnosed with ADHD to age-matched healthy controls. We then performed multilevel kernel density analysis (MKDA) a well-established, whole-brain, voxelwise approach that quantitatively combines existing primary fMRI studies, with ensemble thresholding (p<0.05-0.0001) and multiple comparisons correction.
Results
Participants diagnosed with ADHD (N=1,550), relative to age-matched healthy controls (N=1,340), exhibited statistically significant (p<0.05-0.0001; FWE-corrected) patterns of abnormal activation in multiple brains of the cerebral cortex and basal ganglia across a variety of cognitive control tasks.
Conclusions
This study advances our understanding of the neural basis of ADHD and may aid in the development of new brain-based clinical interventions as well as diagnostic tools and treatment matching protocols for patients with ADHD. Future studies should also investigate the similarities and differences in neural signatures between ADHD and other highly comorbid psychiatric disorders.
OBJECTIVES/GOALS: Serious video games are designed for skill-building and are increasingly being used for healthcare interventions with adolescents and young adults (AYAs). The study goal was to identify AYAs’ preferred game features, by demographic groups, to inform the development of a game to improve AYA’s engagement in their congenital heart disease (CHD) care. METHODS/STUDY POPULATION: Pediatric patients, 12-18 years old, completed surveys at a routine CHD care visit. Participants rated their likelihood of using games to learn CHD management skills (5-point Likert) and preferences for ten game features commonly used, such as: personalization (make your own avatar) and levels (unlock new, advanced stages as you do better). Participants selected one of three response options: 1=would make me less interested in the game, 2=doesn’t matter, 3=would make me more interested in the game. Descriptives and frequencies assessed interest in different game features. Chi-square tests were used to identify potential differences in game feature preferences by gender identity, age group (early/mid-adolescence vs. late adolescence), and race and ethnicity. RESULTS/ANTICIPATED RESULTS: Of 83 participants who completed surveys, the mean age was 15 years old (12-18; SD=1.73), 55% were male, 79% were Non-Hispanic White, and 70% were interested in video games for gaining CHD management skills. The top-rated game features were: levels (78%; unlock advanced stages), conflict (74%; face challenges), personalization (70%; create avatar), and story (70%; journey-based). The three lowest-ranked features were: time (29%; restricted time to complete challenge), competition (47%; score/play against others), strategy (53%; plan to reach goal). No significant differences in game feature preferences were found by demographic characteristics. DISCUSSION/SIGNIFICANCE: Most AYAs with CHD were interested in games, offering a promising avenue for future healthcare interventions. Given no significantly different preferences by demographics, the game may not require tailoring game features for certain groups. However, additional research with diverse participants is needed to fully inform game development.
Compared to older men, Alzheimer’s Disease (AD) is more common in older women, who present with higher levels of pathological tau and accelerated memory decline, although it is unclear why. Furthermore, sleep complaints increase with age, with older women reporting worse sleep quality than older men, and past studies have linked sleep disturbances to tau. Because of the life-long “verbal memory advantage” in women over men, nonverbal memory may more accurately reflect tau burden in women since sex differences are not as apparent. Here, in a sample of older women in the Women Inflammation Tau Study (WITS), we examined the associations between subjective sleep quality, tau in temporal regions, and memory, and whether tau would be more strongly related to nonverbal memory than verbal memory.
Participants and Methods:
In WITS, women have elevated AD polygenic hazard scores and have mild cognitive impairment as indicated by the telephone Montreal Cognitive Assessment (range:13-20). This preliminary sample of 20 women (aged 72.0±3.7) completed the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality in 7 domains of sleep health over the past month. A global score (range:0-21) is calculated, with a score >5 indicative of being a poor sleeper. Participants also underwent positron emission tomography (PET) with the 18F-MK6240 tracer and T1-weighted magnetic resonance imagining (MRI) to determine tau deposition. Standardized uptake value ratio (SUVR) was calculated using the inferior cerebellum grey matter as the reference region, which was created from Automated Anatomic Labeling atlas in native T1 space. The region of interest (ROI) was a composite meta-temporal region. The Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) Story A and B were administered to assess verbal memory. The Brief Visuospatial Memory Test-Revised (BVMT-R) was administered to assess nonverbal memory. Analysis focused on the delayed recall scores from the memory tests. Partial correlation was used to analyze the associations between PSQI global score, tau-PET SUVR in meta-temporal ROI, and memory delayed recall scores, while adjusting for age and education years.
Results:
8 women were poor sleepers indicated by the PSQI global score (mean:4.9±2). Worse subjective sleep quality was associated with greater tau in meta-temporal ROI (r=0.63, p=0.005) and lower BVMT-R delayed recall (r=-0.46, p=0.05). Sleep quality was not significantly related to either RAVLT or LM delayed recall (all p’s>0.40). Tau in meta-temporal ROI was not significantly associated with nonverbal (p=0.23) or verbal memory (all p’s>0.40) delayed recall.
Conclusions:
In this preliminary analysis, subjective sleep quality was linked to temporal tau deposition and nonverbal memory delayed recall, which may suggest that poor sleep exacerbates pathogenesis of tau that leads to memory difficulties in older women at increased risk for AD. Although tau was not significantly related to any memory measures, we will explore whether tau will mediate or moderate the relationship between sleep quality and nonverbal memory once we are powered to do so. Continual evaluation and treatment of sleep may be imperative in mitigating AD risk, especially for older women, however, future longitudinal studies will be necessary to investigate this.
Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph–based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly “Question-of-the-Month (QotM) Challenge” series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system.
Work stress, anxiety and depression have an enormous impact on the well-being of employees, their employers, and society. Due to the loss of productivity, common mental disorders have a substantial economic impact. Major depression alone has been attributed to 50% of long-term absences from work, and depressive symptoms are related to lowered productivity while at work. Anxiety also contributes to loss of productivity and sickness absence. Treatment of common mental disorders in a work setting may improve symptoms, however, that does not automatically lead to improved work productivity. Addressing mental well-being at the workplace might improve work functioning, and digital interventions have been introduced with that objective. However, their evaluation in research has been limited.
The European Intervention to Promote Wellbeing and Health in the Workplace (EMPOWER) digital intervention is designed to provide and evaluate an integrative user programme that meets the needs of employees and employers in addressing work stress.
This work was supported by the European Union Horizon 2020 Research and Innovation Programme Health (grant number APP1195937, 848180). The EMPOWER project started 1.1.2020 and is currently ongoing.
Objectives
We aim to
1) describe the design and development of the digital intervention.
2) culturally validate the intervention in three countries
3) test the prototype and beta version for its usability in the RCT to evaluate its effect in four countries that is currently ongoing.
Methods
A user-centred design process was followed from January 2020 until November 2021 to create a beta version for usability testing. A tailored algorithm was developed to provide support at the individual employee level and the company level. Each element of the digital intervention was translated and culturally validated in four languages in Spain, the United Kingdom, Poland, and Finland. Usability testing was conducted in each country (n=31) to explore validity, usability, and user experience.
Results
The digital intervention consists of a website and a mobile application (app). The website has a public section and an employer portal that provides recommendations to reduce psychosocial risks in their company based upon clustered input from employees. The app provides algorithm-based personalised content after assessing a user’s physical and psychological symptoms, work functioning, and psychosocial risk factors for work stress. The usability testing improved the flow through the app and high ease of use and completion of tasks by participants.
Conclusions
The EMPOWER digital intervention is a tailored multimodal intervention addressing wellbeing, work stress, mental and physical health problems, and work productivity. Usability testing provided validation of the app as version to be evaluated in the EMPOWER RCT.
Generalized anxiety disorder (GAD) is a highly prevalent mental illness that is associated with clinically significant distress, functional impairment, and poor emotional regulation. Primary functional magnetic resonance imaging (fMRI) studies of GAD report neural abnormalities in comparison to healthy controls. However, many of these findings in the primary literature are inconsistent, and it is unclear whether they are specific to GAD or shared transdiagnostically across related disorders.
Objectives
This meta-analysis seeks to establish the most reliable neural abnormalities observed in individuals with GAD, as reported in the primary fMRI activation literature.
Methods
We conducted an exhaustive literature search in PubMed to identify primary studies that met our pre-specified inclusion criteria and then extracted relevant data from primary, whole-brain fMRI activation studies of GAD that reported coordinates in Talairach or MNI space. We then used multilevel kernel density analysis (MKDA) with ensemble thresholding to examine the differences between adults with GAD and healthy controls in order to identify brain regions that reached statistical significance across primary studies.
Results
Patients with GAD showed statistically significant (α=0.05–0.0001; family-wise-error-rate corrected) neural activation in various regions of the cerebral cortex and basal ganglia across a variety of experimental tasks.
Conclusions
These results inform our understanding of the neural basis of GAD and are interpreted using a frontolimbic model of anxiety as well as specific clinical symptoms of this disorder and its relation to other mood and anxiety disorders. These results also suggest possible novel targets for emerging neurostimulation therapies (e.g., transcranial magnetic stimulation) and may be used to advance our understanding of the effects of current pharmaceutical treatments and ways to improve treatment selection and symptom-targeting for patients diagnosed with GAD.
Functional magnetic resonance imaging (fMRI) has been used to identify the neural activity of both youth and adults diagnosed with major depressive disorder (MDD) in comparison to healthy age-matched controls. Previously reported abnormalities in depressed youth appear to mostly align with those found in depressed adults; however, some of the reported aberrant brain activity in youth has not been consistent with what is observed in adults, and to our knowledge there has not yet been a formal, quantitative comparison of these two groups. In addition, it is not known whether these observed differences between youth and adults with depression are attributable to developmental age or length-of-illness.
Objectives
The aim of this study is to elucidate the similarities and differences in patterns of abnormal neural activity between adults and youth diagnosed with MDD and to then determine whether these observed differences are due to either developmental age or length-of-illness.
Methods
We used multilevel kernel density analysis (MKDA) with ensemble thresholding and triple subtraction to separately determine neural abnormalities throughout the whole brain in primary studies of depressed youth and depressed adults and then directly compare the observed abnormalities between each of those age groups. We then conducted further comparisons between multiple subgroups to control for age and length-of-illness and thereby determine the source of the observed differences between youth and adults with depression.
Results
Adults and youth diagnosed with MDD demonstrated reliable, differential patterns of abnormal activation in various brain regions throughout the cerebral cortex that are statistically significant (p < .05; FWE-corrected). In addition, several of these brain regions that exhibited differential patterns of neural activation between the two age groups can be reliably attributed to either developmental age or length-of-illness.
Conclusions
These findings indicate that there are common and disparate patterns of brain activity between youth and adults with MDD, several of which can be reliably attributed to developmental age or length-of-illness. These results expand our understanding of the neural basis of depression across development and course of illness and may be used to inform the development of new, age-specific clinical treatments as well as prevention strategies for this disorder.
Mental health problems in the workplace are common and have a considerable impact on employee wellbeing and productivity. Mental ill-health costs employers between £33 billion and £42 billion a year. According to a 2020 HSE report, roughly 2,440 per 100,000 workers in the UK were affected by work-related stress, depression, or anxiety, resulting in an estimated 17.9 million working days lost.
This study is part of the EMPOWER study. The European Intervention to Promote Wellbeing and Health in the Workplace (EMPOWER) consortium’s aim is to create an individualised digital tool that promotes employee wellbeing, mental health, and work productivity. It has received funding from the European Union’s Horizon 2020 research https://ec.europa.eu/programmes/horizon2020/en/home) and innovation program under grant agreement No 848180.
Objectives
We performed a systematic review of randomised controlled trials (RCTs) to assess the effect of tailored digital health interventions provided in the workplace aiming to improve mental health, presenteeism and absenteeism of employees.
Methods
We searched several databases for RCTs published from 2000 onwards. Data were extracted into a standardised data extraction form. The quality of the included studies was assessed using the Cochrane Risk of Bias tool. Due to the heterogeneity of outcome measures, narrative synthesis was used to summarise the findings.
Results
Seven RCTs (eight publications) were included that evaluated tailored digital interventions versus waiting list control or usual care to improve physical and mental health outcomes and work productivity.
The results are promising to the advantage of tailored digital interventions regarding presenteeism, sleep, stress levels, and physical symptoms related to somatisation.
There is less evidence for addressing depression, anxiety, and absenteeism in the general working population, but they significantly reduced depression and anxiety in employees with higher levels of psychological distress.
Conclusions
Tailored digital interventions seem more effective in employees with higher levels of distress, presenteeism or absenteeism than in the general working population. However, so far, there are not many studies in this domain. Given the promising results, tailoring of digital interventions based upon employee input should be a focus in future research.
Major depressive disorder (MDD) is a highly prevalent mental illness that frequently originates in early development and is pervasive during adolescence. Despite its high prevalence and early age of onset, our understanding of the potentially unique neural basis of MDD in this age group is still not well understood, and the existing primary literature on the topic includes many new and divergent results. This limited understanding of MDD in youth presents a critical need to further investigate its neural basis in youth and presents an opportunity to also improve clinical treatments that target its neural abnormalities.
Objectives
The present study aims to advance our understanding of the neural basis of MDD in youth by identifying abnormal functional activation in various brain regions compared with healthy controls.
Methods
We conducted a meta-analysis of functional magnetic resonance imaging (fMRI) studies of MDD by using a well-established method, multilevel kernel density analysis (MKDA) with ensemble thresholding, to quantitatively combine all existing whole-brain fMRI studies of MDD in youth compared with healthy controls. This method involves a voxel-wise, whole-brain approach, that compares neural activation of patients with MDD to age-matched healthy controls across variations of task-based conditions, which we subcategorize into affective processing, executive functioning, positive valence, negative valence, and symptom provocation tasks.
Results
Youth with MDD exhibited statistically significant (p<0.05; FWE-corrected) hyperactivation and hypoactivation in multiple brain regions compared with age-matched healthy controls. These results include significant effects that are stable across various tasks as well as some that appear to depend on task conditions.
Conclusions
This study strengthens our understanding of the neural basis of MDD in youth and may also be used to help identify possible similarities and differences between youth and adults with depression. It may also help inform the development of new treatment interventions and tools for predicting unique treatment responses in youth with depression.
Curiosity toward the effects of psychedelic drugs on neural activation has increased due to their potential therapeutic benefits, particularly serotonergic psychedelics that act as 5-HT2A receptor agonists such as LSD, psilocybin, and MDMA. However, the pattern of their effects on neural activity in various brain regions in both clinical and healthy populations is still not well understood, and primary studies addressing this issue have sometimes generated inconsistent results.
Objectives
The present meta-analysis aims to advance our understanding of the most widely used serotonergic psychedelics – LSD, psilocybin, and MDMA – by examining their effects on the functional activation throughout the whole brain among both clinical and healthy participants.
Methods
We conducted this meta-analysis by applying multilevel kernel density analysis (MKDA) with ensemble thresholding to quantitatively combine existing functional magnetic resonance imaging (fMRI) studies that examined whole-brain functional activation of clinical or healthy participants who were administered a serotonergic psychedelic.
Results
Serotonergic psychedelics, including LSD, psilocybin, and MDMA, exhibited significant effects (α=0.05) on neural activation in several regions throughout the cerebral cortex and basal ganglia, including effects that may be common across and unique within each drug.
Conclusions
These observed effects of serotonergic psychedelics on neural activity advance our understanding of the functional neuroanatomy associated with their administration and may inform future studies of both their adverse and therapeutic effects, including emerging clinical applications for the treatment of several psychiatric disorders.
Major depressive disorder (MDD) is a highly prevalent mental illness that often first occurs or persists into adulthood and is considered the leading cause of disability and disease burden worldwide. Unfortunately, individuals diagnosed with MDD who seek treatment often experience limited symptom relief and may not achieve long-term remission, which is due in part to our limited understanding of its underlying pathophysiology. Many studies that use task-based functional magnetic resonance imaging (fMRI) have found abnormal activation in brain regions in adults diagnosed with MDD, but those findings are often inconsistent; in addition, previous meta-analyses that quantitatively integrate this large body literature have found conflicting results.
Objectives
This meta-analysis aims to advance our understanding of the neural basis of MDD in adults, as measured by fMRI activation studies, and address inconsistencies and discrepancies in the empirical literature.
Methods
We employed multilevel kernel density analysis (MKDA) with ensemble thresholding, a well-established method for voxel-wise, whole-brain meta-analyses, to conduct a quantitative comparison of all relevant primary fMRI activation studies of adult patients with MDD compared to age-matched healthy controls.
Results
We found that adults with MDD exhibited a reliable pattern of statistically significant (p<0.05; FWE-corrected) hyperactivation and hypoactivation in several brain regions compared to age-matched healthy controls across a variety of experimental tasks.
Conclusions
This study supports previous findings that there is reliable neural basis of MDD that can be detected across heterogenous fMRI studies. These results can be used to inform development of promising treatments for MDD, including protocols for personalized interventions. They also provide the opportunity for additional studies to examine the specificity of these effects among various populations-of-interest, including youth vs. adults with depression as well as other related mood and anxiety disorders.
The Buffalo National River in northwest Arkansas preserves an extensive Quaternary record of fluvial bedrock incision and aggradation across lithologies of variable resistance. In this work, we apply optically stimulated luminescence (OSL) dating to strath and fill terraces along the Buffalo River to elucidate the role of lithology and climate on the development of the two youngest terrace units (Qtm and Qty). Our OSL ages suggest a minimum strath planation age of ca. 250 ka for the Qtm terraces followed by a ca. 200 ka record of aggradation. Qtm incision likely occurred near the last glacial maximum (LGM), prior to the onset of Qty fill terrace aggradation ca. 14 ka. Our terrace ages are broadly consistent with other regional terrace records, and comparison with available paleoclimatic archives suggests that terrace aggradation and incision occurred during drier and wetter hydrological conditions, respectively. Vertical bedrock incision rates were also calculated using OSL-derived estimates of Qtm strath planation and displayed statistically significant spatial variability with bedrock lithology, ranging from ~35 mm/ka in the higher resistance reaches and ~16 mm/ka in the lower resistance reaches. In combination with observations of valley width and terrace distribution, these results suggest that vertical processes outpace lateral ones in lithologic reaches with higher resistance.
Thirty years after the discovery of an Early Neolithic timber hall at Balbridie in Scotland was reported in Antiquity, new analysis of the site's archaeobotanical assemblage, featuring 20 000 cereal grains preserved when the building burnt down in the early fourth millennium BC, provides new insights into early farming practices. The results of stable isotope analyses of cereals from Balbridie, alongside archaeobotanical and stable isotope results from three other sites, indicate that while cereals were successfully cultivated in well-established plots without manuring at Balbridie, a variety of manuring strategies was implemented at the other sites. These differences reinforce the picture of variability in cultivation practices across Neolithic North-west Europe.
No established risk prediction tool exists in United Kingdom and Irish Paediatric Cardiology practice for patients undergoing cardiac catheterisation. The Catheterisation RISk score for Paediatrics is used primarily in North American practice to assess risk prior to cardiac catheterisation. Validating the utility and transferability of such a tool in practice provides the opportunity to employ an already established risk assessment tool in everyday practice.
Aims:
To ascertain whether the Catheterisation RISk score for Paediatrics assessment tool can accurately predict complications within United Kingdom and Irish congenital catheterisation practice.
Methods:
Clinical and procedural data including National Institute for Cardiovascular Outcomes Research derived outcome data from 1500 patients across five large congenital cardiology centres in the United Kingdom and Ireland were retrospectively collected. Catheterisation RISk score for Paediatrics were then calculated for each case and compared with the observed procedural outcomes. Chi-square analysis was used to determine the relationship between observed and predicted events.
Results:
Ninety-eight (6.6%) patients in this study experienced a significant complication as qualified by National Institute for Cardiovascular Outcomes Research classification. 4% experienced a moderate complication, 2.3% experienced a major complication and 0.3% experienced a catastrophic complication resulting in death. Calculated Catheterisation RISk score for Paediatrics scores correlated well with all observed adverse events for paediatric patients across all CRISP categories. The association was also transferable to adult congenital heart disease patients in lower Catheterisation RISk score for Paediatrics categories (CRISP 1–3).
Conclusion:
The Catheterisation RISk score for Paediatrics score accurately predicts significant complications in congenital catheterisation practice in the United Kingdom and Ireland. Our data validated the Catheterisation RISk score for Paediatrics assessment tool in five congenital centres using National Institute for Cardiovascular Outcomes Research-derived outcome data.
Individuals with lower limb amputation experience reduced ankle push-off work in the absence of functional muscles spanning the joint, leading to decreased walking performance. Conventional energy storage and return (ESR) prostheses partially compensate by storing mechanical energy during midstance and returning this energy during the terminal stance phase of gait. These prostheses can provide approximately 30% of the push-off work performed by a healthy ankle–foot during walking. Novel prostheses that return more normative levels of mechanical energy may improve walking performance. In this work, we designed a Decoupled ESR (DESR) prosthesis which stores energy usually dissipated at heel-strike and loading response, and returns this energy during terminal stance, thus increasing the mechanical push-off work done by the prosthesis. This decoupling is achieved by switching between two different cam profiles that produce distinct, nonlinear torque–angle mechanics. The cams automatically interchange at key points in the gait cycle via a custom magnetic switching system. Benchtop characterization demonstrated the successful decoupling of energy storage and return. The DESR mechanism was able to capture energy at heel-strike and loading response, and return it later in the gait cycle, but this recycling was not sufficient to overcome mechanical losses. In addition to its potential for recycling energy, the DESR mechanism also enables unique mechanical customizability, such as dorsiflexion during swing phase for toe clearance, or increasing the rate of energy release at push-off.