ABSTRACT
Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants.
Subject(s)
Intellectual Disability , Phosphatidylinositols , Animals , Syndrome , Actins , Zebrafish/genetics , Intellectual Disability/genetics , Phosphoric Monoester Hydrolases/genetics , Phosphatidylinositol PhosphatesABSTRACT
To evaluate the effect of the phosphodiesterase 4 inhibitor apremilast in biologic-naïve patients with early peripheral PsA in terms of disease activity, clinical manifestations, patient-perceived outcomes, as well as apremilast's safety profile in routine care settings of Greece. Non-interventional, multicenter, 52-week prospective cohort study, enrolling biologic-naïve patients with early active peripheral PsA who started apremilast after intolerance or inadequate response (within the first 12 months of treatment) to an initial conventional synthetic (cs)DMARD treatment. Non-responder imputation was applied for missing data.In total, 167 consecutive patients (mean age: 52.5 years; median PsA duration: 0.9 years) were analyzed. At baseline, the median (interquartile range) clinical Disease Activity in Psoriatic Arthritis (cDAPSA) score was 22.0 (16.0-29.0), with 86.8% of patients having at least moderate (29.3% high) disease activity; 87.4% had skin psoriasis, 37.7% nail psoriasis, 30.7% enthesitis, and 12.4% dactylitis. At 16, 24, and 52 weeks, 28.7, 42.5, and 48.5% of patients, achieved ≥ 50% improvement in their baseline cDAPSA score, respectively. At week 52, 55.6, 50, and 26.8% of evaluable patients achieved complete resolution of enthesitis, dactylitis and nail psoriasis, respectively. Improvements were also observed in patient's health state assessed by the Psoriatic Arthritis Impact of Disease 12-item questionnaire, and health-related quality of life. The 52-week drug survival rate was 75%, while 13.8% of patients experienced at least one adverse drug reaction.Biologic-naïve patients with early PsA, treated with apremilast experienced significant improvements in disease activity, extra-articular manifestations and patient-centered outcomes, accompanied by a favorable tolerability profile.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Arthritis, Psoriatic , Biological Products , Psoriasis , Humans , Middle Aged , Arthritis, Psoriatic/drug therapy , Biological Products/therapeutic use , Enthesopathy , Prospective Studies , Psoriasis/drug therapy , Quality of LifeABSTRACT
Mitochondrial complex V plays an important role in oxidative phosphorylation by catalyzing the generation of ATP. Most complex V subunits are nuclear encoded and not yet associated with recognized Mendelian disorders. Using exome sequencing, we identified a rare homozygous splice variant (c.87+3A>G) in ATP5PO, the complex V subunit which encodes the oligomycin sensitivity conferring protein, in three individuals from two unrelated families, with clinical suspicion of a mitochondrial disorder. These individuals had a similar, severe infantile and often lethal multi-systemic disorder that included hypotonia, developmental delay, hypertrophic cardiomyopathy, progressive epileptic encephalopathy, progressive cerebral atrophy, and white matter abnormalities on brain MRI consistent with Leigh syndrome. cDNA studies showed a predominant shortened transcript with skipping of exon 2 and low levels of the normal full-length transcript. Fibroblasts from the affected individuals demonstrated decreased ATP5PO protein, defective assembly of complex V with markedly reduced amounts of peripheral stalk proteins, and complex V hydrolytic activity. Further, expression of human ATP5PO cDNA without exon 2 (hATP5PO-∆ex2) in yeast cells deleted for yATP5 (ATP5PO homolog) was unable to rescue growth on media which requires oxidative phosphorylation when compared to the wild type construct (hATP5PO-WT), indicating that exon 2 deletion leads to a non-functional protein. Collectively, our findings support the pathogenicity of the ATP5PO c.87+3A>G variant, which significantly reduces but does not eliminate complex V activity. These data along with the recent report of an affected individual with ATP5PO variants, add to the evidence that rare biallelic variants in ATP5PO result in defective complex V assembly, function and are associated with Leigh syndrome.
Subject(s)
Brain Diseases , Leigh Disease , Mitochondrial Proton-Translocating ATPases , Brain Diseases/metabolism , DNA, Complementary/metabolism , Humans , Leigh Disease/genetics , Leigh Disease/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Proton-Translocating ATPases/genetics , Mutation , Proteins/metabolismABSTRACT
Stochastic spatio-temporal processes are prevalent across domains ranging from the modeling of plasma, turbulence in fluids to the wave function of quantum systems. This letter studies a measure-theoretic description of such systems by describing them as evolutionary processes on Hilbert spaces, and in doing so, derives a framework for spatio-temporal manipulation from fundamental thermodynamic principles. This approach yields a variational optimization framework for controlling stochastic fields. The resulting scheme is applicable to a wide class of spatio-temporal processes and can be used for optimizing parameterized control policies. Our simulated experiments explore the application of two forms of this approach on four stochastic spatio-temporal processes, with results that suggest new perspectives and directions for studying stochastic control problems for spatio-temporal systems.
ABSTRACT
Inflammatory bowel disease (IBD) is a complex disorder that is associated with significant morbidity. While many recent advances have been made with new diagnostic and therapeutic tools, a deeper understanding of its basic pathophysiology is needed to continue this trend toward improving treatments. By utilizing an unbiased, high-throughput transcriptomic analysis of two well-established mouse models of colitis, we set out to uncover novel coding and noncoding RNAs that are differentially expressed in the setting of colonic inflammation. RNA-seq analysis was performed using colonic tissue from two mouse models of colitis, a dextran sodium sulfate-induced model and a genetic-induced model in mice lacking IL-10. We identified 81 coding RNAs that were commonly altered in both experimental models. Of these coding RNAs, 12 of the human orthologs were differentially expressed in a transcriptomic analysis of IBD patients. Interestingly, 5 of the 12 of human differentially expressed genes have not been previously identified as IBD-associated genes, including ubiquitin D. Our analysis also identified 15 noncoding RNAs that were differentially expressed in either mouse model. Surprisingly, only three noncoding RNAs were commonly dysregulated in both of these models. The discovery of these new coding and noncoding RNAs expands our transcriptional knowledge of mouse models of IBD and offers additional targets to deepen our understanding of the pathophysiology of IBD. NEW & NOTEWORTHY Much of the genome is transcribed as non-protein-coding RNAs; however, their role in inflammatory bowel disease is largely unknown. This study represents the first of its kind to analyze the expression of long noncoding RNAs in two mouse models of inflammatory bowel disease and correlate them to human clinical samples. Using high-throughput RNA-seq analysis, we identified new coding and noncoding RNAs that were differentially expressed such as ubiquitin D and 5730437C11Rik.
Subject(s)
Colitis/genetics , Inflammatory Bowel Diseases/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Animals , Caco-2 Cells , Cells, Cultured , Colitis/metabolism , Colon/metabolism , Colon/pathology , Humans , Inflammatory Bowel Diseases/metabolism , Male , Mice , Mice, Inbred C57BL , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , TranscriptomeABSTRACT
BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with an increased atherosclerotic risk compared to healthy population, partially explained by traditional cardiovascular (CV) risk factors. Recent data suggest B-cell activating factor (BAFF) as an important contributor in the pathogenesis of both SLE and atherosclerosis. The aim of the current study is to explore whether serum BAFF levels along with variants of the BAFF gene increase lupus related atherosclerotic risk. PATIENTS-METHODS: 250 SLE patients underwent assessment of plaque formation and/or intimal media thickness (IMT) measurements in carotid and femoral arteries by ultrasound. Disease related features and CV traditional risk factors were also assessed. Serum BAFF levels were determined by commercially available ELISA and five single nucleotide polymorphisms (SNPs) of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and the rs9514827) were evaluated by PCR-based assays in all patients and 200 healthy controls (HC) of similar age and sex distribution. SLE patients were further divided in high and low BAFF groups on the basis of the upper quartile level of the distribution (1358â¯pg/ml). Genotype and haplotype frequencies in SLE patients and HC were determined by SNPStats and SHEsis software. RESULTS: High-BAFF SLE group displayed increased rates of both plaque formation and arterial wall thickening (defined as IMT>0.90â¯mm) compared to patients with low BAFF levels (58.1% vs 43.6%, p:0.048 and 38.6% vs 23.2%, p-value: 0.024, respectively). The association remained significant after disease related features were taken into account (ORs [95%CI]: 2.2 [1.0-5.1] and 2.5 [1.1-5.5] for plaque formation and arterial wall thickening, respectively). Moreover, the presence of the AA genotype of the rs12583006 BAFF gene variant increased susceptibility for both lupus and lupus related plaque formation (ORs [95%CI]: 2.8 [1.1-7.1], and 4.4 [1.3-15.4] in the codominant model, respectively). Finally, the haplotype TTTAT was found to be protective for plaque formation among SLE patients (OR 0.3 [0.1-0.9]. No associations between BAFF gene variants with arterial wall thickening were detected. CONCLUSIONS: High BAFF serum levels in the upper 4th quartile as well as BAFF genetic variants seem to increase susceptibility for both lupus and lupus related subclinical atherosclerosis implying B-cell hyperactivity as a potential contributor in the pronounced lupus related atherosclerotic risk.
Subject(s)
Atherosclerosis/genetics , B-Cell Activating Factor/genetics , B-Lymphocytes/immunology , Genotype , Lupus Erythematosus, Systemic/genetics , Adult , Aged , Atherosclerosis/epidemiology , B-Cell Activating Factor/blood , Carotid Intima-Media Thickness , Female , Gene Frequency , Genetic Predisposition to Disease , Greece/epidemiology , Humans , Lupus Erythematosus, Systemic/epidemiology , Lymphocyte Activation , Male , Middle Aged , Polymorphism, Single Nucleotide , RiskABSTRACT
PURPOSE OF REVIEW: The medical management of inflammatory bowel disease (IBD) remains problematic with a pressing need for innovation in drug development as well as delivery of personalized therapies. Both the disease's inherent pathophysiologic complexity and heterogeneity in its etiology conspire in making it difficult to accurately model for either the purposes of basic research or drug development. Multiple attempts at creating meaningful experimental models have fallen short of adequately recapitulating the disease and most do not capture any aspect of the cause or the effects of patient heterogeneity that underlays most of the difficulties faced by physicians and their patients. In vivo animal models, tissue culture systems, and more recent synthetic biology approaches are all too simplistically reductionist for the task. However, ex vivo culture platforms utilizing patient biopsies offer a system that more closely mimics end-stage disease processes that can be studied in detail and subjected to experimental manipulations. RECENT FINDINGS: Recent studies describe further optimization of mucosal explant cultures in order to increase tissue viability and maintain a polarized epithelial layer. Current applications of the platform include studies of the interplay between the epithelial, immune and stromal compartment of the intestinal tissue, investigation of host-microbial interactions, preclinical evaluation of candidate drugs and uncovering mechanisms of action of established or emerging treatments for IBD. SUMMARY: Patient explant-based assays offer an advanced biological system in IBD that recapitulates disease complexity and reflects the heterogeneity of the patient population. In its current stage of development, the system can be utilized for drug testing prior to the costlier and time-consuming evaluation by clinical trials. Further refinement of the technology and establishment of assay readouts that correlate with therapeutic outcomes will yield a powerful tool for personalized medicine approaches in which individual patient responses to available treatments are assessed a priori, thus reducing the need for trial and error within the clinical setting.
Subject(s)
Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/pathology , Models, Biological , Biopsy , Drug Evaluation, Preclinical/methods , Humans , Inflammatory Bowel Diseases/physiopathology , Precision Medicine/methods , Tissue Culture TechniquesABSTRACT
Empirically derived continuum models of collective behavior among large populations of dynamic agents are a subject of intense study in several fields, including biology, engineering, and finance. We formulate and study a mean-field game model whose behavior mimics an empirically derived nonlocal homogeneous flocking model for agents with gradient self-propulsion dynamics. The mean-field game framework provides a non-cooperative optimal control description of the behavior of a population of agents in a distributed setting. In this description, each agent's state is driven by optimally controlled dynamics that result in a Nash equilibrium between itself and the population. The optimal control is computed by minimizing a cost that depends only on its own state and a mean-field term. The agent distribution in phase space evolves under the optimal feedback control policy. We exploit the low-rank perturbative nature of the nonlocal term in the forward-backward system of equations governing the state and control distributions and provide a closed-loop linear stability analysis demonstrating that our model exhibits bifurcations similar to those found in the empirical model. The present work is a step towards developing a set of tools for systematic analysis, and eventually design, of collective behavior of non-cooperative dynamic agents via an inverse modeling approach.
ABSTRACT
OBJECTIVES: Aim of this study was to assess and compare health, quality of life, well-being, job satisfaction and job insecurity between nurses, in a tertiary hospital in Greece, working either under permanent or temporary contract. MATERIAL AND METHODS: In this cross-sectional study, consecutively recruited nurses answered a structured questionnaire, the WHO-5 Well-being Index (WHO-5), the Job Insecurity Index (JII), the Work Ability Index (WAI), and the Well-Being at Work Scale (WBWS). RESULTS: Included were 323 nurses (87.6% women, age M±SD 43.68±8.10 years). Tem- porary contract employees had worse quality of life (p = 0.009) and higher job insecurity: both in cognitive dimension (p = 0.013) and emotional dimension (p < 0.001). They also scored worse in the positive affect (p < 0.001), negative affect (p = 0.002) and fulfillment of expectations in work environment (p < 0.001) domains of the WBWS. Additionally, they reported less frequently occupational accidents and injuries (p = 0.001), muscu - loskeletal disorders of the spine or neck (p = 0.007), cardiovascular (p = 0.017), and gastrointestinal (p = 0.010) disorders, while they reported more frequently mental disorders (p < 0.001). Multivariate linear regression analysis showed that temporary work predicted high cognitive (p = 0.010) and emotional (p < 0.001) insecurity, low positive emotions and mood index (p = 0.007), low achievement-fulfillment index (p = 0.047) and high index of negative emotions (p = 0.006), regardless of gender and age. CONCLUSIONS: Temporary employment among nurses is associated with a lower sense of job security and well-being, and a higher prevalence of mental disorders, independently of age or gender without a significantly negative effect on their ability to work. Managers, as well as occupational physicians, should recognize the extent of nurses' job insecurity and assess their ability to work, to provide them with the necessary support and to stimulate the sense of occupational security and work capacity, so that they can thrive in their workplace and therefore be more productive and provide high quality healthcare. Int J Occup Med Environ Health. 2024;37(1):98-109.
Subject(s)
Job Security , Quality of Life , Humans , Female , Male , Cross-Sectional Studies , Work Capacity Evaluation , Employment/psychology , Job Satisfaction , Workplace/psychology , Surveys and QuestionnairesABSTRACT
We investigate adaptation under a reaching task with an acceleration-based force field perturbation designed to alter the nominal straight hand trajectory in a potentially benign manner: pushing the hand off course in one direction before subsequently restoring towards the target. In this particular task, an explicit strategy to reduce motor effort requires a distinct deviation from the nominal rectilinear hand trajectory. Rather, our results display a clear directional preference during learning, as subjects adapted perturbed curved trajectories towards their initial baselines. We model this behavior using the framework of stochastic optimal control theory and an objective function that trades off the discordant requirements of 1) target accuracy, 2) motor effort, and 3) kinematic invariance. Our work addresses the underlying objective of a reaching movement, and we suggest that robustness, particularly against internal model uncertainly, is as essential to the reaching task as terminal accuracy and energy efficiency.
Subject(s)
Adaptation, Physiological/physiology , Arm/physiology , Movement/physiology , Adult , Biomechanical Phenomena , Female , Humans , Male , Models, Biological , Young AdultABSTRACT
AtoSC two-component system (TCS) upregulates the high-molecular weight poly-(R)-3-hydroxybutyrate (PHB) biosynthesis in recombinant phaCAB (+) Escherichia coli strains, with the Cupriavidus necator phaCAB operon. We report here that AtoSC upregulates also the copolymer P(3HB-co-3HV) biosynthesis in phaCAB (+) E. coli. Acetoacetate-induced AtoSC maximized P(3HB-co-3HV) to 1.27 g/l with a 3HV fraction of 25.5 % wt. and biopolymer content of 75 % w/w in a time-dependent process. The atoSC locus deletion in the ∆atoSC strains resulted in 4.5-fold P(3HB-co-3HV) reduction, while the 3HV fraction of the copolymer was restricted to only 6.4 % wt. The ∆atoSC phenotype was restored by extrachromosomal introduction of AtoSC. Deletion of the atoDAEB operon triggered a significant decrease in P(3HB-co-3HV) synthesis and 3HV content in ∆atoDAEB strains. However, the acetoacetate-induced AtoSC in those strains increased P(3HB-co-3HV) to 0.8 g/l with 21 % 3HV, while AtoC or AtoS expression increased P(3HB-co-3HV) synthesis 3.6- or 2.4-fold, respectively, upon acetoacetate. Complementation of the ∆atoDAEB phenotype was achieved by the extrachromosomal introduction of the atoSCDAEB regulon. Individual inhibition of ß-oxidation and mainly fatty acid biosynthesis pathways by acrylic acid or cerulenin, respectively, reduced P(3HB-co-3HV) biosynthesis. Under those conditions, introduction of atoSC or atoSCDAEB regulon was capable of upregulating biopolymer accumulation. Concurrent inhibition of both the fatty acid metabolic pathways eliminated P(3HB-co-3HV) production. P(3HB-co-3HV) upregulation in phaCAB (+) E. coli by AtoSC signaling through atoDAEB operon and its participation in the fatty acids metabolism interplay provide additional perceptions of AtoSC critical involvement in E. coli regulatory processes towards biotechnologically improved polyhydroxyalkanoates biosynthesis.
Subject(s)
Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression Regulation, Bacterial , Polyesters/metabolism , Regulon , Acetoacetates/metabolism , Cupriavidus necator/genetics , Gene Deletion , Genetic Complementation Test , Metabolic Engineering , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Transcriptional Activation , Up-RegulationABSTRACT
Hardware prominence remains a clinical challenge in focus for implant design in subcutaneous plate applications. Existing evaluation of hardware prominence relies on plate-to-bone distance at a single point or on average. A reproducible measure for plate prominence remains undefined. This study mathematically defines the plate prominence linked to the cross-sectional area change due to the plate presence on the bone. Two anatomical plate designs were fitted to 100 clavicles, and afterwards plate prominence parameters were evaluated and compared. This methodology enables the quantification of hardware prominence for different plate designs to inform the development of implants targeting low prominence.
Subject(s)
Fractures, Bone , Humans , Fractures, Bone/surgery , Clavicle/surgery , Fracture Fixation, Internal/methods , Bone Plates , Retrospective StudiesABSTRACT
One of the main challenges in autonomous robotic exploration and navigation in unknown and unstructured environments is determining where the robot can or cannot safely move. A significant source of difficulty in this determination arises from stochasticity and uncertainty, coming from localization error, sensor sparsity and noise, difficult-to-model robot-ground interactions, and disturbances to the motion of the vehicle. Classical approaches to this problem rely on geometric analysis of the surrounding terrain, which can be prone to modeling errors and can be computationally expensive. Moreover, modeling the distribution of uncertain traversability costs is a difficult task, compounded by the various error sources mentioned above. In this work, we take a principled learning approach to this problem. We introduce a neural network architecture for robustly learning the distribution of traversability costs. Because we are motivated by preserving the life of the robot, we tackle this learning problem from the perspective of learning tail-risks, i.e. the conditional value-at-risk (CVaR). We show that this approach reliably learns the expected tail risk given a desired probability risk threshold between 0 and 1, producing a traversability costmap which is more robust to outliers, more accurately captures tail risks, and is more computationally efficient, when compared against baselines. We validate our method on data collected by a legged robot navigating challenging, unstructured environments including an abandoned subway, limestone caves, and lava tube caves.
ABSTRACT
Rheumatoid Arthritis (RA) is a common chronic inflammatory disorder affecting 0,5-1% of the population, characterised by intense cellular activation and inflammation in the affected joints ultimately leading to bone and cartilage destruction. Cardiovascular disease is the leading cause of death among patients suffering from RA, with chronic inflammation and genetic background emerging as major predisposing factors. Although the pathogenetic events leading to an increased rate of atherosclerosis in the affected group are not precisely described, several genetic variations have been suggested as possible mediators of this process. The aim of the current research proposal is to investigate the role of B-cell activating factor (BAFF) variants in the pathogenesis of RA-related atherosclerosis. Stored DNA samples from the Biobank in the Department of Physiology of the Medical School of the University of Athens from RA individuals and healthy controls will be analysed for polymorphisms of B-cell activating factor (BAFF) by polymeric chain reaction (PCR) based assays. Detection of plaque formation and calculation of the mean intima media thickness (mIMT) of the vessel wall will be performed in RA patients by using carotid and femoral artery ultrasonography. Complete personal and family history, biochemical and serological markers will be obtained from the RA group and associated with the genetic and IMT data. The results will be compared across the different subgroups in order to determine whether any particular genetic variants can act as prognostic markers for RA-related cardiovascular disease giving eventually new insights to atherosclerotic processes in the context of chronic inflammatory diseases. Such a result would invariably lead to a possible new treatment approach and/or prevention method to benefit this group of patients.
ABSTRACT
Healthy bone homeostasis hinges upon a delicate balance and regulation of multiple processes that contribute to bone development and metabolism. While examining hematopoietic regulation by Tle4, we have uncovered a previously unappreciated role of Tle4 on bone calcification using a novel Tle4 null mouse model. Given the significance of osteoblasts in both hematopoiesis and bone development, this study investigated how loss of Tle4 affects osteoblast function. We used dynamic bone formation parameters and microCT to characterize the adverse effects of Tle4 loss on bone development. We further demonstrated loss of Tle4 impacts expression of several key osteoblastogenic genes, including Runx2, Oc, and Ap, pointing toward a potential novel mechanism for Tle4-dependent regulation of mammalian bone development in collaboration with the RUNX family members.
ABSTRACT
Determining how the nervous system controls tendon-driven bodies remains an open question. Stochastic optimal control (SOC) has been proposed as a plausible analogy in the neuroscience community. SOC relies on solving the Hamilton-Jacobi-Bellman equation, which seeks to minimize a desired cost function for a given task with noisy controls. We evaluate and compare three SOC methodologies to produce tapping by a simulated planar 3-joint human index finger: iterative Linear Quadratic Gaussian (iLQG), Model-Predictive Path Integral Control (MPPI), and Deep Forward-Backward Stochastic Differential Equations (FBSDE). We show that averaged over 128 repeats these methodologies can place the fingertip at the desired final joint angles but-because of kinematic redundancy and the presence of noise-they each have joint trajectories and final postures with different means and variances. iLQG in particular, had the largest kinematic variance and departure from the final desired joint angles. We demonstrate that MPPI and FBSDE have superior performance for such nonlinear, tendon-driven systems with noisy controls.Clinical relevance- The mathematical framework provided by MPPI and FBSDE may be best suited for tendon-driven anthropomorphic robots, exoskeletons, and prostheses for amputees.
Subject(s)
Algorithms , Tendons , Biomechanical Phenomena , Fingers , Humans , Normal DistributionABSTRACT
OBJECTIVES: We evaluated the feasibility of optimising coronary perfusion pressure (CPP) during cardiopulmonary resuscitation (CPR) with a closed-loop, machine-controlled CPR system (MC-CPR) that sends real-time haemodynamic feedback to a set of machine learning and control algorithms which determine compression/decompression characteristics over time. BACKGROUND: American Heart Association CPR guidelines (AHA-CPR) and standard mechanical devices employ a "one-size-fits-all" approach to CPR that fails to adjust compressions over time or individualise therapy, thus leading to deterioration of CPR effectiveness as duration exceeds 15-20 âmin. METHODS: CPR was administered for 30 âmin in a validated porcine model of cardiac arrest. Intubated anaesthetised pigs were randomly assigned to receive MC-CPR (6), mechanical CPR conducted according to AHA-CPR (6), or human-controlled CPR (HC-CPR) (10). MC-CPR directly controlled the CPR piston's amplitude of compression and decompression to maximise CPP over time. In HC-CPR a physician controlled the piston amplitudes to maximise CPP without any algorithmic feedback, while AHA-CPR had one compression depth without adaptation. RESULTS: MC-CPR significantly improved CPP throughout the 30-min resuscitation period compared to both AHA-CPR and HC-CPR. CPP and carotid blood flow (CBF) remained stable or improved with MC-CPR but deteriorated with AHA-CPR. HC-CPR showed initial but transient improvement that dissipated over time. CONCLUSION: Machine learning implemented in a closed-loop system successfully controlled CPR for 30 âmin in our preclinical model. MC-CPR significantly improved CPP and CBF compared to AHA-CPR and ameliorated the temporal haemodynamic deterioration that occurs with standard approaches.
ABSTRACT
Juvenile idiopathic arthritis is a heterogeneous group of conditions encompassing all forms of unknown origin arthritis before the age of 16 years that persist for more than 6 weeks. It is the most common rheumatic disease in young patients and causes severe disabilities, thus an early initiation of the appropriate treatment modalities is necessary. First therapeutic options are nonsteroidal anti-inflammatory drugs, corticosteroids, and conventional non-biologic disease-modifying anti-rheumatic drugs, such as methotrexate. Insufficiency of these drugs led to the introduction of new biological medications that selectively target specific cytokines with an objective to suppress the disease. Despite the success in treatment and physical therapy, some of the patients develop advanced arthritis that can result in severe pain and disability. In such cases, surgical intervention is required to improve quality of life. The surgical methods include soft tissue release, osteotomies, synovectomies, and arthrodesis. Total joint replacement is the last option for endstage degenerative conditions (patients with deformity, poor motion, and severe pain). Deep infections, bone perforation, acetabular protrusion, postoperative dislocations, and the need for re-operation are some of the complications of total joint arthroplasty. This review summarizes published studies of the treatment of juvenile idiopathic arthritis focusing mainly on surgical treatment. Our purpose is to evaluate the general trends in treatment of juvenile idiopathic arthritis, focusing on methods, therapeutic advances, and outcomes of the intervention applied.
Subject(s)
Arthritis, Juvenile , Postoperative Complications , Quality of Life , Surgical Procedures, Operative , Adolescent , Arthritis, Juvenile/physiopathology , Arthritis, Juvenile/psychology , Arthritis, Juvenile/surgery , Conservative Treatment/methods , Humans , Postoperative Complications/etiology , Postoperative Complications/surgery , Reoperation , Surgical Procedures, Operative/adverse effects , Surgical Procedures, Operative/methods , Treatment OutcomeABSTRACT
We present a trajectory optimization approach to reinforcement learning in continuous state and action spaces, called probabilistic differential dynamic programming (PDDP). Our method represents systems dynamics using Gaussian processes (GPs), and performs local dynamic programming iteratively around a nominal trajectory in Gaussian belief spaces. Different from model-based policy search methods, PDDP does not require a policy parameterization and learns a time-varying control policy via successive forward-backward sweeps. A convergence analysis of the iterative scheme is given, showing that our algorithm converges to a stationary point globally under certain conditions. We show that prior model knowledge can be incorporated into the proposed framework to speed up learning, and a generalized optimization criterion based on the predicted cost distribution can be employed to enable risk-sensitive learning. We demonstrate the effectiveness and efficiency of the proposed algorithm using nontrivial tasks. Compared with a state-of-the-art GP-based policy search method, PDDP offers a superior combination of learning speed, data efficiency, and applicability.
ABSTRACT
This study presents a model predictive control approach for seizure reduction in a computational model of epilepsy. The differential dynamic programming (DDP) algorithm is implemented in a model predictive fashion to optimize a controller for suppressing seizures in a chaotic oscillator model. The chaotic oscillator model uses proportional-integral (PI) controller to represent the internal control mechanism that maintains stable neural activity in a healthy brain. In the pathological case, the gains of this PI controller are reduced, preventing sufficient feedback to suppress correlation increase between normal and pathological brain dynamics. This increase in correlation leads to synchronization of oscillator dynamics leading to the destabilization of neural activity and epileptic behavior. The pathological case of the chaotic oscillator model is formulated as an optimal control problem, which we solve using the dynamic programming principle. We propose using model predictive control with differential dynamic programming optimization as a possible method for controlling epileptic seizures in known models of epilepsy.