Search

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s−1) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s−1) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine. [ABSTRACT FROM AUTHOR]

Purpose: To translate and cross-culturally adapt the King's Parkinson's Disease Pain Scale (KPPS) into Spanish., Methods: The English KPPS was forward translated into Spanish, back translated, and revised by the original developers. Cross-cultural adaptation of relevant target groups was conducted following COSMIN standards. Cognitive pretesting in Spanish people with Parkinson's Disease (PD) and pain was performed via three semi-structured focus group meetings. Changes were implemented based on qualitative and quantitative analyses. A Delphi study (two rounds) of individual assessments by Spanish experts was conducted. Changes were implemented based on the Content Validity Index (CVI) at item and scale levels (I-CVI/S-CVI)., Results: Five Spanish professionals performed the initial translation. Thirty-eight inter-translation inconsistencies were identified, and consensus was reached for a unified version. After back translation and confirmation with scale developers, the pre-final Spanish KPPS was obtained. Cognitive pretesting in 30 people with PD-related pain identified 5 items where terminology changes were made to assure comprehensibility. The Delphi study in 14 Spanish experts underlined the necessity to further modify two items. After the second round, all experts agreed on the modifications and I-CVI and S-CVI were satisfactory., Conclusions: The KPPS was successfully translated and cross-culturally adapted into Spanish.

Objective: To assess the psychometric properties of the Spanish King's Parkinson's Disease Pain Scale (KPPS). Design: A descriptive transversal study at a Spanish hospital. Methods: Fifty-three Parkinson's disease (PD) patients suffering from otherwise explained pain (34 females, age = 63.42 ± 10.52 years, time with disease = 7.25 ± 4.65 years) were evaluated by the KPPS, Brief Pain Inventory (BPI), two Pain Pressure Thresholds (PPTs), Widespread Mechanical Hyperalgesia (WMH), and Conditioned Pain Modulation (CPM). A retest of the KPPS was performed 7-15 days later. Internal consistency, test-retest reliability (intraclass correlation coefficient (ICC)), measurement error, factor structure, and criterion/convergent validity were assessed. Results: Internal consistency of the Spanish KPPS was acceptable (Cronbach's alpha = 0.77). The mean test and retest total KPPS scores were similar (test = 34.83 ± 23.50 points, retest = 35.87 ± 26.23 points), and test-retest reliability was good (ICC = 0.85, 95% CI = 0.75-0.91). Standard error of measurement (SEM) was 9.1 points and smallest detectable change (SDC) was 25.22 points. The sampling adequacy was not sufficient to perform factor analysis. The total KPPS score was not correlated to the BPI intensity subscale ( r  = 0.18, p =0.19), but it was moderately and positively correlated to the interference subscale ( r  = 0.43, p =0.001). The total KPPS was moderately and negatively correlated to both the remote PPT ( r  = -0.4, p =0.003) and WMH ( r  = -0.38, p =0.005). No statistical correlations were found with local PPT or CPM. Conclusion: The present study provides evidence that the Spanish KPPS effectively measures pain in individuals with PD, with its total score demonstrating good reliability, minimal measurement error, and adequate criterion and convergent validity., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Yeray González-Zamorano et al.)

Objective: To synthetize the evidence on the effects of hand rehabilitation (RHB) interventions on cognition post-stroke and compare their efficacy., Data Sources: PubMed, Embase, Cochrane, Scopus, Web of Science, and CINAHL were searched from inception to November 2022., Data Selection: Randomized controlled trials conducted in adults with stroke where the effects of hand motor interventions on any cognitive domains were assessed., Data Extraction: Data were extracted by 2 independent reviewers. A Bayesian Network Meta-analysis (NMA) was applied for measures with enough studies and comparisons. Risk of bias was assessed with the Cochrane Risk of Bias tool., Data Synthesis: Fifteen studies were included in qualitative synthesis, and 11 in NMA. Virtual reality (VR) (n=7), robot-assisted (n=5), or handgrip strength (n=3) training were the experimental interventions and conventional RHB (n=14) control intervention. Two separate NMA were performed with MoCA (n=480 participants) and MMSE (n=350 participants) as outcome measures. Both coincided that the most probable best interventions were robot-assisted and strength training, according to SUCRA and rankogram, followed by conventional RHB and VR training. No significant differences between any of the treatments were found in the MoCA network, but in the MMSE, robot-assisted and strength training were significantly better than conventional RHB and VR. No significant differences between robot-assisted and strength training were found nor between conventional RHB and VR., Conclusions: Motor interventions can improve MoCA/MMSE scores post-stroke. Most probable best interventions were robot-assisted and strength training. Limited literature assessing domain-specific cognitive effects was found., (Copyright © 2024 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) and EEG-guided neurofeedback techniques can reduce motor symptoms in Parkinson's disease (PD). However, the effects of their combination are unknown. Our objective was to determine the immediate and short-term effects on motor and non-motor symptoms, and neurophysiological measures, of rTMS and EEG-guided neurofeedback, alone or combined, compared to no intervention, in people with PD., Methods: A randomized, single-blinded controlled trial with 4 arms was conducted. Group A received eight bilateral, high-frequency (10 Hz) rTMS sessions over the Primary Motor Cortices; Group B received eight 30-minute EEG-guided neurofeedback sessions focused on reducing average bilateral alpha and beta bands; Group C received a combination of A and B; Group D did not receive any therapy. The primary outcome measure was the UPDRS-III at post-intervention and two weeks later. Secondary outcomes were functional mobility, limits of stability, depression, health-related quality-of-life and cortical silent periods. Treatment effects were obtained by longitudinal analysis of covariance mixed-effects models., Results: Forty people with PD participated (27 males, age = 63 ± 8.26 years, baseline UPDRS-III = 15.63 ± 6.99 points, H&Y = 1-3). Group C showed the largest effect on motor symptoms, health-related quality-of-life and cortical silent periods, followed by Group A and Group B. Negligible differences between Groups A-C and Group D for functional mobility or limits of stability were found., Conclusions: The combination of rTMS and EEG-guided neurofeedback diminished overall motor symptoms and increased quality-of-life, but this was not reflected by changes in functional mobility, postural stability or depression levels., Trial Registration: NCT04017481., (© 2024. The Author(s).)

This case report presents a comprehensive assessment and therapeutic intervention using non-invasive motor cortex neuromodulation for a 70-year-old female patient diagnosed with corticobasal degeneration (CBD). The study followed the CARE guidelines. The patient meets the criteria for probable CBD, with neuroimaging evidence of exclusively cortical impairment. The patient underwent a non-invasive neuromodulation protocol involving transcranial direct current stimulation (tDCS) and action observation plus motor imagery (AO+MI). The neuromodulation protocol comprised 20 sessions involving tDCS over the primary motor cortex and combined AO+MI. Anodal tDCS was delivered a 2 mA excitatory current for 20 minutes. AO+MI focused on lower limb movements, progressing over four weeks with video observation and gradual execution, both weekly and monthly. The neuromodulation techniques were delivered online (i.e. applied simultaneously in each session). Outcome measures were obtained at baseline, post-intervention and follow-up (1 month later), and included motor (lower limb), cognitive/neuropsychological and functional assessments. Walking speed improvements were not observed, but balance (Berg Balance Scale) and functional strength (Five Times Sit-to-Stand Test) improved post-treatment. Long-term enhancements in attentional set-shifting, inhibitory control, verbal attentional span, and working memory were found. There was neurophysiological evidence of diminished intracortical inhibition. Functional changes included worsening in Cortico Basal Ganglia Functional Scale score. Emotional well-being and general health (SF-36) increased immediately after treatment but were not sustained, while Falls Efficacy Scale International showed only long-term improvement. The findings suggest potential benefits of the presented neuromodulation protocol for CBD patients, highlighting multifaceted outcomes in motor, cognitive, and functional domains., Competing Interests: The authors declare that they have no conflict of interest, because the beforementioned institution did not have any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript., (Copyright © 2024 Romero et al.)

Objective: To evaluate the effects of transcranial direct current stimulation (tDCS) on Parkinson's disease (PD)-related pain., Methods: This triple-blind randomized controlled trial included twenty-two patients (age range 38-85, 10 male) with PD-related pain. Eleven subjects received ten sessions of 20 minutes tDCS over the primary motor cortex contralateral to pain at 2 mA intensity. Eleven subjects received sham stimulation. Outcome measures included changes in the Kinǵs Parkinsońs Pain Scale (KPPS), Brief Pain Inventory (BPI), widespread mechanical hyperalgesia (WMH), temporal summation of pain (TS), and conditioned pain modulation (CPM)., Results: Significant differences were found in KPPS between groups favoring the active-tDCS group compared to the sham-tDCS group at 15-days follow-up (p = 0.014) but not at 2 days post-intervention (p = 0.059). The active-group showed significant improvements over the sham-group after 15 days (p = 0.017). Significant changes were found in CPM between groups in favor of active-tDCS group at 2 days post-intervention (p = 0.002) and at 15 days (p = 0.017). No meaningful differences were observed in BPI or TS., Conclusions: tDCS of the primary motor cortex alleviates perceived PD-related pain, reduces pain sensitization, and enhances descending pain inhibition., Significance: This is the first study to test and demonstrate the use of tDCS for improving PD-related pain., Competing Interests: Declaration of competing interests The authors report no competing interests., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To examine the clinical effects of combining motor imagery-based neurofeedback training with bilateral repetitive transcranial magnetic stimulation for upper limb motor function in subacute and chronic stroke., Design: Clinical trial following an AB/BA crossover design with counterbalanced assignment., Subjects: Twenty individuals with subacute (n = 4) or chronic stroke (n = 16)., Methods: Ten consecutive sessions of bilateral repetitive transcranial magnetic stimulation alone (therapy A) were compared vs a combination of10 consecutive sessions of bilateral repetitive transcranial magnetic stimulation with 12 non-consecutive sessions of motor imagery-based neurofeedback training (therapy B). Patients received both therapies (1-month washout period), in sequence AB or BA. Participants were assessed before and after each therapy and at 15-days follow-up, using the Fugl-Meyer Assessment-upper limb, hand-grip strength, and the Nottingham Sensory Assessment as primary outcome measures., Results: Both therapies resulted in improved functionality and sensory function. Therapy B consistently exhibited superior effects compared with therapy A, according to Fugl-Meyer Assessment and tactile and kinaesthetic sensory function across multiple time-points, irrespective of treatment sequence. No statistically significant differences between therapies were found for hand-grip strength., Conclusion: Following subacute and chronic stroke, integrating bilateral repetitive transcranial magnetic stimulation and motor imagery-based neurofeedback training has the potential to enhance functional performance compared with using bilateral repetitive transcranial magnetic stimulation alone in upper limb recovery.

Stroke survivors usually exhibit concurrent motor and cognitive impairment. Historically, rehabilitation strategies post-stroke occur separately in terms of motor and cognitive functions. However, recent studies show that hand motor interventions can have a positive impact on cognitive recovery. In this work, we introduce AMBER (portAble and Modular device for comprehensive Brain Evaluation and Rehabilitation), a new device developed for the evaluation and rehabilitation of both hand motor function and cognition simultaneously. AMBER is a simple, portable, ergonomic and cheap device based on Force Sensitive Resistors, in which every finger interaction is recorded to provide information about finger strength, processing speed, and memory status. This paper presents the requirements of the device and the design of the system. In addition, a pilot study was conducted with 36 healthy individuals using the evaluation module of the device to assess its psychometric properties, as test-retest reliability and measurement error. Its validity was also evaluated comparing its measurements with three different gold standards for strength, processing speed and memory. The device showed good test-retest reliability for strength (ICC =0.741-0.852), reaction time (ICC =0.715 - 0.900) and memory (ICC =0.556-0.885). These measures were correlated with their corresponding gold standards (r =0.780-890). AMBER shows great potential to impact hand rehabilitation, offering therapists a valid, reliable and versatile tool to comprehensively assess patients. With ongoing advancements and refinements, it has the opportunity to significantly impact rehabilitation practices and improve patient outcomes.

Hemiparetic gait is the most common motor-disorder after stroke and, in spite of rehabilitation efforts, it is persistent in 50% of community dwelling stroke-survivors. Robotic exoskeletons have been proposed as assistive devices to support impaired joints. An example of these devices is the REFLEX knee exoskeleton, which assists the gait of hemiparetic subjects and whose action seems to be properly embodied by stroke survivors, who were able to adapt the motion of their non-assisted limbs and, therefore, reduce their compensation mechanisms. This paper presents an experimental validation carried out to deepen into the effects of REFLEX's assistance in hemiparetic subjects. Special attention was paid to the effect produced in the muscular activity as a metric to evaluate the embodiment of this technology. Significant differences were obtained at the subject level due to the assistance; however, the high dispersion of the measured outcomes avoided extracting global effects at the group level. These results highlight the need of individually tailoring the action of the robot to the individual needs of each patient to maximize the beneficial outcomes. Extra research effort should be done to elucidate the neural mechanisms involved in the embodiment of external devices by stroke survivors., (© 2023. The Author(s).)

Background: The "Triana Test" is a novel story recall test based on emotional material with demonstrated accuracy in diagnosing mild cognitive impairment patients., Objective: This study aims to obtain normative data for the "Triana Test"., Methods: A normative study was conducted at a university hospital in Spain. Partners of patients were systematically recruited if eligible (age ≥50, no memory complaints, and a total TMA-93 score at or above the 10th percentile). The "Triana Test" was administered and scored. For developing the normative data, a regression-based method was followed., Results: The final sample included 362 participants (median age = 66, range = 50-88; 64.9% females). A model including age and educational level better predicted the total scores. Combinations of these variables resulted in different 10th percentile scores., Conclusions: Norms for using the "Triana Test" are now available. The provided cutoffs for the 10th percentile will aid in the diagnosis of prodromal Alzheimer's disease., Competing Interests: Silvia Rodrigo-Herrero and Emilio Franco-Macías are the authors of the “Triana Test”., (© 2023 – The authors. Published by IOS Press.)

Objectives: It is uncertain, if omitting post-dilatation and stent oversizing (stent optimization) is safe and may decrease the risk for distal thrombus embolization (DTE) in STEMI patients with large thrombus burden (LTB)., Background: In patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) with stenting, (DTE) and flow deterioration are common and increase infarct size leading to worse outcomes., Methods: From a prospective registry, 74 consecutive STEMI patients with LTB undergoing pPCI with stenting and intentionally deferred stent optimization were analyzed. Imaging data and outcomes up to 2 years follow-up were analyzed., Results: Overall, 74 patients (18% females) underwent deferred stent optimization. Direct stenting was performed in 13 (18%) patients. No major complications occurred during pPCI. Staged stent optimization was performed after a median of 4 (interquartile range (IQR) 3; 7) days. On optical coherence tomography, under-expansion and residual thrombus were present in 59 (80%) and 27 (36%) cases, respectively. During deferred stent optimization, we encountered no case of flow deterioration (slow or no-reflow) or side branch occlusion. Minimal lumen area (mm 2 ) and stent expansion (%) were corrected from 4.87±1.86mm to 6.82±2.36mm (p<0.05) and from 69±18% to 91±12% (p<0.001), respectively. During follow-up, 1 patient (1.4%) required target lesion revascularization and 1 (1.4%) patient succumbed from cardiovascular death., Conclusions: Among STEMI patients with LTB, deferring stent optimization in the setting of pPCI appears safe and potentially mitigates the risk of DTE. The impact of this approach on infarct size and clinical outcomes warrants further investigation in a dedicated trial., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Objectives: The cerebello-thalamo-cortical circuit plays a critical role in essential tremor (ET). However, abnormalities have been reported in multiple brain regions outside this circuit, leading to inconsistent characterization of ET pathophysiology. Here, we test whether these mixed findings in ET localize to a common functional network and whether this network has therapeutic relevance., Methods: We conducted a systematic literature search to identify studies reporting structural or metabolic brain abnormalities in ET. We then used 'coordinate network mapping,' which leverages a normative connectome (n = 1,000) of resting-state fMRI data to identify regions commonly connected to findings across all studies. To assess whether these regions may be relevant for the treatment of ET, we compared our network with a therapeutic network derived from lesions that relieved ET. Finally, we investigated whether the functional connectivity of this ET symptom network is abnormal in an independent cohort of patients with ET as compared with healthy controls., Results: Structural and metabolic brain abnormalities in ET were located in heterogeneous regions throughout the brain. However, these coordinates were connected to a common functional brain network, including the cerebellum, thalamus, motor cortex, precuneus, inferior parietal lobe, and insula. The cerebellum was identified as the hub of this network because it was the only brain region that was both functionally connected to the findings of over 90% of studies and significantly different in connectivity compared with a control data set of other movement disorders. This network was strikingly similar to the therapeutic network derived from lesions improving ET, with key regions aligning in the thalamus and cerebellum. Furthermore, positive functional connectivity between the cerebellar network hub and the sensorimotor cortices was significantly reduced in patients with ET compared with healthy controls, and connectivity within this network was correlated with tremor severity and cognitive functioning., Discussion: These findings suggest that the cerebellum is the central hub of a network commonly connected to structural and metabolic abnormalities in ET. This network may have therapeutic utility in refining and informing new targets for neuromodulation of ET., (© 2023 American Academy of Neurology.)

Context: Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown., Objective: Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipose tissue insulin resistance index [adipo-IR]) and liver (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) IR in people with T2D and NAFLD., Design: Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (a marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/adipo-IR., Setting: University ambulatory care practice., Participants: A total of 483 participants with T2D., Intervention: Screening for steatosis and fibrosis with elastography., Main Outcome Measures: Liver steatosis (controlled attenuation parameter), fibrosis (liver stiffness measurement), and measurements of IR (adipo-IR, HOMA-IR) and fibrosis (cytokeratin-18)., Results: Clinically significant liver fibrosis (stage F ≥ 2 = liver stiffness measurement ≥8.0 kPa) was found in 11%, having more features of the metabolic syndrome, lower adiponectin, and higher aspartate aminotransferase (AST), alanine aminotransferase, liver fat, and cytokeratin-18 (P < 0.05-0.01). In multivariable analysis including just clinical variables (model 1), obesity (body mass index [BMI]) had the strongest association with fibrosis (odds ratio, 2.56; CI, 1.87-3.50; P < 0.01). When metabolic measurements and cytokeratin-18 were included (model 2), only BMI, AST, and liver fat remained significant. When fibrosis stage was adjusted for BMI, AST, and steatosis (model 3), only Adipo-IR remained strongly associated with fibrosis (OR, 1.51; CI, 1.05-2.16; P = 0.03), but not BMI, hepatic IR, or steatosis., Conclusions: These findings pinpoint to the central role of dysfunctional, insulin-resistant adipose tissue to advanced fibrosis in T2D, beyond simply BMI or steatosis. The clinical implication is that targeting adipose tissue should be the priority of treatment in NAFLD., Competing Interests: Conflict of Interest K.C. has received research support as principal investigator from the University of Florida from the National Institutes of Health, Cirius, Echosens, Inventiva, Novartis, Novo Nordisk, Poxel, and Zydus. K.C. is also a consultant for Allergan, Altimmune, Arrowhead, AstraZeneca, BMS, Boehringer Ingelheim, Coherus, Eli Lilly, Fractyl, Hanmi, Genentech, Gilead, Intercept, Janssen, Pfizer, Prosciento, Madrigal, and Novo Nordisk. All other authors have no potential conflicts of interest relevant to this article., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize an enriched population of human HSPCs obtained from young and elderly healthy individuals., Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain aging-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks (GRNs) and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRNs regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2, and RUNX1 suggesting a role of these transcription factors (TFs) in the pathogenesis of the disease., In summary, we demonstrate that the combination of single-cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients., Competing Interests: MA, TE, NB, AA, AV, PS, DA, JL, MS, TJ, FL, SM, FS, AM, JM, GS, AD, ML, DG, MD, DV, MH, FP No competing interests declared, JR Employed by 10x Genomics since February 2021; this employment had no bearing on this work, (© 2023, Ainciburu, Ezponda et al.)

Naive human pluripotent stem cells (hPSCs) are defined as the in vitro counterpart of the human preimplantation embryo's epiblast and are used as a model system to study developmental processes. In this study, we report the discovery and characterization of distinct cell populations coexisting with epiblast-like cells in 5iLAF naive human induced PSC (hiPSC) cultures. It is noteworthy that these populations closely resemble different cell types of the human embryo at early developmental stages. While epiblast-like cells represent the main cell population, interestingly we detect a cell population with gene and transposable element expression profile closely resembling the totipotent eight-cell (8C)-stage human embryo, and three cell populations analogous to trophectoderm cells at different stages of their maturation process: transition, early, and mature stages. Moreover, we reveal the presence of cells resembling primitive endoderm. Thus, 5iLAF naive hiPSC cultures provide an excellent opportunity to model the earliest events of human embryogenesis, from the 8C stage to the peri-implantation period., Competing Interests: Conflict of interests J.P.R. is an employee and shareholder of 10x Genomics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Coronary Artery Fistulae (CAFs) are cardiac congenital anomalies consisting of an abnormal communication of a coronary artery with either a cardiac chamber or another cardiac vessel. In humans, these congenital anomalies can lead to complications such as myocardial hypertrophy, endocarditis, heart dilatation, and failure. Unfortunately, despite their clinical relevance, the aetiology of CAFs remains unknown. In this work, we have used two different species (mouse and avian embryos) to experimentally model CAFs morphogenesis. Both conditional Itga4 (alpha 4 integrin) epicardial deletion in mice and cryocauterisation of chick embryonic hearts disrupted epicardial development and ventricular wall growth, two essential events in coronary embryogenesis. Our results suggest that myocardial discontinuities in the embryonic ventricular wall promote the early contact of the endocardium with epicardial-derived coronary progenitors at the cardiac surface, leading to ventricular endocardial extrusion, precocious differentiation of coronary smooth muscle cells, and the formation of pouch-like aberrant coronary-like structures in direct connection with the ventricular lumen. The structure of these CAF-like anomalies was compared with histopathological data from a human CAF. Our results provide relevant information for the early diagnosis of these congenital anomalies and the molecular mechanisms that regulate their embryogenesis., (© 2023. The Author(s).)

This article analyzes the experiences of seven forensic anthropologists working on exhumations in cases related to political violence and armed conflict in Colombia and Peru. From a critical social psychology perspective, we investigate the ways in which these professionals manage their emotions in the face of situations of violence, including murder, massacres, and enforced disappearances. We analyze both the emotional impact of confronting mass violence and the coping mechanisms developed by these professionals in order to continue doing their work. The experiences recounted by the forensic anthropologists interviewed for this study oscillate between a marked professional commitment and the need for distance to safeguard their own emotional well-being.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34 + cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients., (© 2022. The Author(s).)

Background: Hemiparetic gait is characterized by strong asymmetries that can severely affect the quality of life of stroke survivors. This type of asymmetry is due to motor deficits in the paretic leg and the resulting compensations in the nonparetic limb. In this study, we aimed to evaluate the effect of actively promoting gait symmetry in hemiparetic patients by assessing the behavior of both paretic and nonparetic lower limbs. This paper introduces the design and validation of the REFLEX prototype, a unilateral active knee-ankle-foot orthosis designed and developed to naturally assist the paretic limbs of hemiparetic patients during gait., Methods: REFLEX uses an adaptive frequency oscillator to estimate the continuous gait phase of the nonparetic limb. Based on this estimation, the device synchronically assists the paretic leg following two different control strategies: (1) replicating the movement of the nonparetic leg or (2) inducing a healthy gait pattern for the paretic leg. Technical validation of the system was implemented on three healthy subjects, while the effect of the generated assistance was assessed in three stroke patients. The effects of this assistance were evaluated in terms of interlimb symmetry with respect to spatiotemporal gait parameters such as step length or time, as well as the similarity between the joint's motion in both legs., Results: Preliminary results proved the feasibility of the REFLEX prototype to assist gait by reinforcing symmetry. They also pointed out that the assistance of the paretic leg resulted in a decrease in the compensatory strategies developed by the nonparetic limb to achieve a functional gait. Notably, better results were attained when the assistance was provided according to a standard healthy pattern, which initially might suppose a lower symmetry but enabled a healthier evolution of the motion of the nonparetic limb., Conclusions: This work presents the preliminary validation of the REFLEX prototype, a unilateral knee exoskeleton for gait assistance in hemiparetic patients. The experimental results indicate that assisting the paretic leg of a hemiparetic patient based on the movement of their nonparetic leg is a valuable strategy for reducing the compensatory mechanisms developed by the nonparetic limb., (© 2022. The Author(s).)

Eradicating leukemia requires a deep understanding of the interaction between leukemic cells and their protective microenvironment. The CXCL12/CXCR4 axis has been postulated as a critical pathway dictating leukemia stem cell (LSC) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of CXCL12 in the acute myeloid leukemia (AML) microenvironment and the mechanism by which CXCL12 exerts its protective role in vivo remain unresolved. Here, we show that CXCL12 produced by Prx1+ mesenchymal cells but not by mature osteolineage cells provide the necessary cues for the maintenance of LSCs in the marrow of an MLL::AF9-induced AML model. Prx1+ cells promote survival of LSCs by modulating energy metabolism and the REDOX balance in LSCs. Deletion of Cxcl12 leads to the accumulation of reactive oxygen species and DNA damage in LSCs, impairing their ability to perpetuate leukemia in transplantation experiments, a defect that can be attenuated by antioxidant therapy. Importantly, our data suggest that this phenomenon appears to be conserved in human patients. Hence, we have identified Prx1+ mesenchymal cells as an integral part of the complex niche-AML metabolic intertwining, pointing towards CXCL12/CXCR4 as a target to eradicate parenchymal LSCs in AML., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism., Competing Interests: Declaration of interests A patent has been submitted to use human organoids to study SARS-CoV-2 infections and possibly develop new therapies. J.M.P. is a shareholder of Apeiron Biologics, which is developing ACE2 decoys for COVID-19 therapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Understanding the regulation of normal and malignant human hematopoiesis requires comprehensive cell atlas of the hematopoietic stem cell (HSC) regulatory microenvironment. Here, we develop a tailored bioinformatic pipeline to integrate public and proprietary single-cell RNA sequencing (scRNA-seq) datasets. As a result, we robustly identify for the first time 14 intermediate cell states and 11 stages of differentiation in the endothelial and mesenchymal BM compartments, respectively. Our data provide the most comprehensive description to date of the murine HSC-regulatory microenvironment and suggest a higher level of specialization of the cellular circuits than previously anticipated. Furthermore, this deep characterization allows inferring conserved features in human, suggesting that the layers of microenvironmental regulation of hematopoiesis may also be shared between species. Our resource and methodology is a stepping-stone toward a comprehensive cell atlas of the BM microenvironment., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Adoptive cell transfer therapy using CD8 + T lymphocytes showed promising results eradicating metastatic malignancies. However, several regulatory mechanisms limit its efficacy. We studied the role of the expression of the transcription factor FOXP3 on CD8 + T cell function and anti-tumor immunity. Here we show that suboptimal T cell receptor stimulation of CD8 + T cells upregulates FOXP3 in vitro. Similarly, CD8 T cells transferred into tumor-bearing mice upregulate FOXP3 in vivo. Cell-intrinsic loss of FOXP3 by CD8 + T cells resulted in improved functionality after TCR stimulation and better antitumor responses in vivo. Inhibition of the FOXP3/NFAT interaction likewise improved CD8 + T cell functionality. Transcriptomic analysis of cells after TCR stimulation revealed an enrichment of genes implicated in the response to IFN-γ, IFN-α, inflammatory response, IL-6/JAK/STAT, G2M checkpoint and IL-2/STAT signaling in FOXP3-deficient CD8 + T cells with respect to FOXP3-wt CD8 + T cells. Our results suggest that transient expression of FOXP3 by CD8 + T cells in the tumor microenvironment restrains their anti-tumor activity, with clear implications for improving T cell responses during immunotherapy., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Smartphone use in biomedical research is becoming more prevalent in different clinical settings. We performed a pilot study to obtain information on smartphone use by patients with essential tremor (ET) and healthy controls, with a view to determining whether performance of touchscreen tasks is different between these groups and describing touchscreen interaction factors., Method: A total of 31 patients with ET and 40 sex- and age-matched healthy controls completed a descriptive questionnaire about the use of smartphones. Participants subsequently interacted with an under-development Android application, and performed 4 tests evaluating typical touchscreen interaction gestures; each test was performed 5 times., Result: The type of smartphone use and touchscreen interaction were not significantly different between patients and controls. Age and frequency of smartphone use are key factors in touchscreen interaction., Conclusion: Our results support the use of smartphone touchscreens for research into ET, although further studies are required., (Copyright © 2018 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Background and Objectives: The motor sequelae after a stroke are frequently persistent and cause a high degree of disability. Cortical ischemic or hemorrhagic strokes affecting the cortico-spinal pathways are known to cause a reduction of cortical excitability in the lesioned area not only for the local connectivity impairment but also due to a contralateral hemisphere inhibitory action. Non-invasive brain stimulation using high frequency repetitive magnetic transcranial stimulation (rTMS) over the lesioned hemisphere and contralateral cortical inhibition using low-frequency rTMS have been shown to increase the excitability of the lesioned hemisphere. Mental representation techniques, neurofeedback, and virtual reality have also been shown to increase cortical excitability and complement conventional rehabilitation. Materials and Methods: We aim to carry out a single-blind, randomized, controlled trial aiming to study the efficacy of immersive multimodal Brain-Computer Interfacing-Virtual Reality (BCI-VR) training after bilateral neuromodulation with rTMS on upper limb motor recovery after subacute stroke (>3 months) compared to neuromodulation combined with conventional motor imagery tasks. This study will include 42 subjects in a randomized controlled trial design. The main expected outcomes are changes in the Motricity Index of the Arm (MI), dynamometry of the upper limb, score according to Fugl-Meyer for upper limb (FMA-UE), and changes in the Stroke Impact Scale (SIS). The evaluation will be carried out before the intervention, after each intervention and 15 days after the last session. Conclusions: This trial will show the additive value of VR immersive motor imagery as an adjuvant therapy combined with a known effective neuromodulation approach opening new perspectives for clinical rehabilitation protocols.

Aim: To report on the impact of COVID-19 on a brain damage unit., Methods: We reviewed the records of all patients admitted to our brain damage unit. The study included all the significant clinical events from the first positive qualitative real-time reverse-transcriptase-polymerase-chain-reaction assay (April 8th, 2020) for SARS-CoV-2 to the day all patients tested negative (June 8th, 2020)., Results: Of the 20 patients (14 men) (age 57.7 ± 14.9; 2-71 months after brain damage; all with a modified Rankin scale score > 4), 16 tested positive for SARS-CoV-2 and remained positive for a mean of 32.3 days (ranging from 26 to 61). One patient died from COVID-19, while 12 patients were asymptomatic and three suffered mild pneumonia without acute respiratory distress syndrome. All patients received prophylactic subcutaneous heparin. Intravenous methylprednisolone was prescribed for three patients with bilateral pneumonia with excellent results., Conclusions: Most positive cases (93.7%) were not severe. The good outcome was most likely due to the use of prophylactic anticoagulation therapy, the early use of methylprednisolone for pneumonia and the previously reported immunosuppression amid patients with brain damage. This study hopes to encourage further study into brain damage immunity., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Severe traumatic brain injury residual cognitive impairments significantly impact the quality of life. EEG-based neurofeedback is a technique successfully used in traumatic brain injury and stroke to rehabilitate cognitive and motor sequelae. There are not individualized comparisons of the effects of EEG-based neurofeedback versus conventional neuropsychological rehabilitation. We present a case study of a traumatic brain injury subject in whom eight sessions of a neuropsychological rehabilitation protocol targeting attention, executive functions, and working memory as compared with a personalized EEG-based neurofeedback protocol focused on the electrodes and bands that differed from healthy subjects (F3, F1, Fz, FC3, FC1, and FCz), targeting the inhibition of theta frequency band (3 Hz-7 Hz) in the same number of sessions. Quantitative EEG and neuropsychological testing were performed. Clear benefits of EEG-based neurofeedback were found in divided and sustained attention and several aspects related to visuospatial skills and the processing speed of motor-dependent tasks. Correlative quantitative EEG changes justify the results. EEG-based neurofeedback is probably an excellent complementary technique to be considered to enhance conventional neuropsychological rehabilitation., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

Monitoring of motor symptom fluctuations in Parkinson's disease (PD) patients is currently performed through the subjective self-assessment of patients. Clinicians require reliable information about a fluctuation's occurrence to enable a precise treatment rescheduling and dosing adjustment. In this review, we analyzed the utilization of sensors for identifying motor fluctuations in PD patients and the application of machine learning techniques to detect fluctuations. The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Ten studies were included between January 2010 and March 2021, and their main characteristics and results were assessed and documented. Five studies utilized daily activities to collect the data, four used concrete scenarios executing specific activities to gather the data, and only one utilized a combination of both situations. The accuracy for classification was 83.56-96.77%. In the studies evaluated, it was not possible to find a standard cleaning protocol for the signal captured, and there is significant heterogeneity in the models utilized and in the different features introduced in the models (using spatiotemporal characteristics, frequential characteristics, or both). The two most influential factors in the good performance of the classification problem are the type of features utilized and the type of model.

Background : Parkinson's disease (PD) is the second most common neurodegenerative disorder. This disease is characterized by motor symptoms, such as bradykinesia, tremor, and rigidity. Although balance impairment is characteristic of advanced stages, it can be present with less intensity since the beginning of the disease. Approximately 60% of PD patients fall once a year and 40% recurrently. On the other hand, cognitive symptoms affect up to 20% of patients with PD in early stages and can even precede the onset of motor symptoms. There are cognitive requirements for balance and can be challenged when attention is diverted or reduced, linking a worse balance and a higher probability of falls with a slower cognitive processing speed and attentional problems. Cognitive rehabilitation of attention and processing speed can lead to an improvement in postural stability in patients with Parkinson's. Methods : We present a parallel and controlled randomized clinical trial (RCT) to assess the impact on balance of a protocol based on cognitive rehabilitation focused on sustained attention through the NeuronUP platform (Neuronup SI, La Rioja, Spain) in patients with PD. For 4 weeks, patients in the experimental group will receive cognitive therapy three days a week while the control group will not receive any therapy. The protocol has been registered at trials.gov NCT04730466. Conclusions : Cognitive therapy efficacy on balance improvement may open the possibility of new rehabilitation strategies for prevention of falls in PD, reducing morbidity, and saving costs to the health care system.

Introduction: Bradyphrenia is a key cognitive feature in Parkinson's disease (PD). There is no consensus on whether information processing speed is impaired or not beyond motor performance., Objective: This study aims to explore which perceptual, motor, or cognitive components of information processing are involved in the slowdown affecting cognitive performance., Methods: The study included 48 patients with PD (age: 63, 3 ± 8, 18; HY I-III; UPDRS 15,46 ± 7,76) and 53 healthy controls (age: 60,09 ± 12,83). Five reaction time (RT) tasks were administered to all participants. The average RT in each of the tasks and the percentage of correct answers were measured. Patients with PD were in "ON state" at the time of the evaluation. Perceptual, motor, and cognitive components were isolated by means of a series of ANCOVAs., Results: As expected, the motor component was slowed down in patients with PD. Moreover, while patients with PD showed slower RT than controls in all tasks, differences between groups did not exponentially increase with the increasing task complexity. ANCOVA analyses also revealed that the perceptual and sustained alert component resulted to be slowed down, with no differences being found in any of the remaining isolated cognitive components (i.e., response strategy-inhibition, decisional, visual search, or interference control)., Conclusions: The results revealed that slowness of information processing in PD was mainly associated with an impaired processing speed of the motor and perceptual-alertness components analyzed. The results may help designing new neurorehabilitation strategies, focusing on the improvement of perceptual and alertness mechanisms., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Transcranial direct current stimulation (tDCS) of the motor cortex (M1) produces short-term inhibition of pain. Unihemispheric concurrent dual-site tDCS (UHCDS-tDCS) over the M1 and dorsolateral prefrontal cortex (DLPFC) has greater effects on cortical excitability than when applied alone, although its effect on pain is unknown. The aim of this study was to test if anodal UHCDS-tDCS over the M1 and DLPFC in healthy participants could potentiate conditioned pain modulation (CPM) and diminish pain temporal summation (TS)., Methods: Thirty participants were randomized to receive a sequence of UHCDS-tDCS, M1-tDCS and sham-tDCS. A 20 min 0.1 mA/cm 2 anodal or sham-tDCS intervention was applied to each participant during three test sessions, according to a triple-blind cross-over trial design. For the assessment of pain processing before and after tDCS intervention, the following tests were performed: tourniquet conditioned pain modulation (CPM), pressure pain temporal summation (TS), pressure pain thresholds (PPTs), pressure pain tolerance, mechanosensitivity and cold hyperalgesia. Motor function before and after tDCS intervention was assessed with a dynamometer to measure maximal isometric grip strength., Results: No statistically significant differences were found between groups for CPM, pressure pain TS, PPT, pressure pain tolerance, neural mechanosensitivity, cold hyperalgesia or grip strength ( p > 0.05)., Conclusions: Neither UHCDS-tDCS nor M1-tDCS facilitated CPM or inhibited TS in healthy subjects following one intervention session.

Kidney disease is poorly understood because of the organ's cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model., Competing Interests: Declaration of Interests The Susztak lab is supported by Boehringer Ingelheim, Lilly, Regeneron, GSK, Merck, Bayer, and Gilead for work that is not related to the current manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pain is an under-reported but prevalent symptom in Parkinson's Disease (PD), impacting patients' quality of life. Both pain and PD conditions cause cortical excitability reduction and non-invasive brain stimulation. Mental representation techniques are thought to be able to counteract it, also resulting effectively in chronic pain conditions. We aim to conduct two independent studies in order to evaluate the efficacy of transcranial direct current stimulation (tDCS) and mental representation protocol in the management of pain in PD patients during the ON state: (1) tDCS over the Primary Motor Cortex (M1); and (2) Action Observation (AO) and Motor Imagery (MI) training through a Brain-Computer Interface (BCI) using Virtual Reality (AO + MI-BCI). Both studies will include 32 subjects in a longitudinal prospective parallel randomized controlled trial design under different blinding conditions. The main outcomes will be score changes in King's Parkinson's Disease Pain Scale, Brief Pain Inventory, Temporal Summation, Conditioned Pain Modulation, and Pain Pressure Threshold. Assessment will be performed pre-intervention, post-intervention, and 15 days post-intervention, in both ON and OFF states.

Background: Cardiac fibroblasts (CFs) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Because of the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is lacking. The purpose of this study was to define CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate CF function., Methods: Collagen1α1-GFP (green fluorescent protein)-positive CFs were characterized after myocardial infarction (MI) by single-cell and bulk RNA sequencing, assay for transposase-accessible chromatin sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing., Results: We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear profibrotic signature, express high levels of Cthrc1 (collagen triple helix repeat containing 1), and localize into the scar. Noncanonical transforming growth factor-β signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Absence of CTHRC1 results in pronounced lethality attributable to ventricular rupture. A population of CFs with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy., Conclusions: We report CF heterogeneity and their dynamics during the course of MI and redefine the CFs that respond to cardiac injury and participate in myocardial remodeling. Our study identifies CTHRC1 as a novel regulator of the healing scar process and a target for future translational studies.

We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections., Competing Interests: Declaration of Interests J.M.P. declares a conflict of interest as a founder, supervisory board member, and shareholder of Apeiron Biologics. G.W. is an employee of Apeiron Biologics. Apeiron holds a patent on the use of ACE2 for the treatment of lung, heart, or kidney injury and applied for a patent to treat COVID-19 with hrsACE2 and use organoids to test new drugs for SARS-CoV-2 infections. R.C. and M.S. are employees of STEMCELL Technologies Inc. A.S.S. has been a consultant to Apeiron Biologics. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Parkinson's disease (PD) patients are known to suffer from subtle cognitive and balance deficits from the early stages although they usually manifest in advanced stages. Postural instability (PI) has been correlated with slower information processing speed. Simple reaction time (SRT) tasks can be used to measure the speed of information processing. The main objective of this study was to examine the usefulness of SRT as a valid predictor of balance in PD, thus providing a simple and complementary assessment method., Methods: This cross-sectional study included 52 PD patients without dementia who were evaluated for balance using the pull test (PT) maneuver and Biodex® limits of stability (LOS). In addition, a reaction time task was used to measure processing speed. Correlation and linear regression analyses were performed., Results: The performance of SRT tasks was correlated with the evaluation of LOS% and PT, suggesting that the SRT may be a predictor of balance performance. Longer reaction time and poorer postural stability were also associated with disease duration but not with age., Conclusions: Poor performance in a simple reaction task can predict altered PI and can complement staging and evaluation in PD patients., (© 2021 S. Karger AG, Basel.)

Objective: Orthostatic tremor (OT) is an extremely rare, misdiagnosed, and underdiagnosed disorder affecting adults in midlife. There is debate as to whether it is a different condition or a variant of essential tremor (ET), or even, if both conditions coexist. Our objective was to use data mining classification methods, using magnetic resonance imaging (MRI)-derived brain volume and cortical thickness data, to identify morphometric measures that help to discriminate OT patients from those with ET., Methods: MRI-derived brain volume and cortical thickness were obtained from 14 OT patients and 15 age-, sex-, and education-matched ET patients. Feature selection and machine learning methods were subsequently applied., Results: Four MRI features alone distinguished the two, OT from ET, with 100% diagnostic accuracy. More specifically, left thalamus proper volume (normalized by the total intracranial volume), right superior parietal volume, right superior parietal thickness, and right inferior parietal roughness (i.e., the standard deviation of cortical thickness) were shown to play a key role in OT and ET characterization. Finally, the left caudal anterior cingulate thickness and the left caudal middle frontal roughness allowed us to separate with 100% diagnostic accuracy subgroups of OT patients (primary and those with mild parkinsonian signs)., Conclusions: A data mining approach applied to MRI-derived brain volume and cortical thickness data may differentiate between these two types of tremor with an accuracy of 100%. Our results suggest that OT and ET are distinct conditions., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Essential tremor (ET) is a neurological disease with both motor and nonmotor manifestations; however, little is known about its underlying brain basis. Furthermore, the overall organization of the brain network in ET remains largely unexplored. We investigated the topological properties of brain functional network, derived from resting-state functional magnetic resonance imaging (MRI) data, in 23 ET patients versus 23 healthy controls. Graph theory analysis was used to assess the functional network organization. At the global level, the functional network of ET patients was characterized by lower small-worldness values than healthy controls-less clustered functionality of the brain. At the regional level, compared with the healthy controls, ET patients showed significantly higher values of global efficiency, cost and degree, and a shorter average path length in the left inferior frontal gyrus (pars opercularis), right inferior temporal gyrus (posterior division and temporo-occipital part), right inferior lateral occipital cortex, left paracingulate, bilateral precuneus bilaterally, left lingual gyrus, right hippocampus, left amygdala, nucleus accumbens bilaterally, and left middle temporal gyrus (posterior part). In addition, ET patients showed significant higher local efficiency and clustering coefficient values in frontal medial cortex bilaterally, subcallosal cortex, posterior cingulate cortex, parahippocampal gyri bilaterally (posterior division), right lingual gyrus, right cerebellar flocculus, right postcentral gyrus, right inferior semilunar lobule of cerebellum and culmen of vermis. Finally, the right intracalcarine cortex and the left orbitofrontal cortex showed a shorter average path length in ET patients, while the left frontal operculum and the right planum polare showed a higher betweenness centrality in ET patients. In conclusion, the efficiency of the overall brain functional network in ET is disrupted. Further, our results support the concept that ET is a disorder that disrupts widespread brain regions, including those outside of the brain regions responsible for tremor., (© 2019 Wiley Periodicals, Inc.)

Objective: The pathogenesis of orthostatic tremor (OT) is unknown. We investigated OT-related white matter changes and their correlations with scores from a neuropsychological testing battery., Methods: Diffusion tensor imaging measures were compared between 14 OT patients and 14 age- and education-matched healthy controls, using whole-brain tract-based spatial statistics analysis. Correlations between altered diffusion metrics and cognitive performance in OT group were assessed., Results: In all cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language), OT patients' cognitive performance was significantly worse than that of healthy controls. OT patients demonstrated altered diffusivity metrics not only in the posterior lobe of the cerebellum (left cerebellar lobule VI) and in its efferent cerebellar fibers (left superior cerebellar peduncle), but also in medial lemniscus bilaterally (pontine tegmentum), anterior limb of the internal capsule bilaterally, right posterior limb of the internal capsule, left anterior corona radiata, right insula, and the splenium of corpus callosum. No relationship was found between diffusion measures and disease duration in OT patients. Diffusion white matter changes, mainly those located in right anterior limb of the internal capsule, were correlated with poor performance on tests of executive function, visuospatial ability, verbal memory, and visual memory in OT patients., Interpretation: White matter changes were preferentially located in the cerebellum, its efferent pathways, as well as in the pontine tegmentum and key components of the frontal-thalamic-cerebellar circuit. Further work needs to be done to understand the evolution of these white matter changes and their functional consequences., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Alternative splicing (AS) has shown to play a pivotal role in the development of diseases, including cancer. Specifically, all the hallmarks of cancer (angiogenesis, cell immortality, avoiding immune system response, etc.) are found to have a counterpart in aberrant splicing of key genes. Identifying the context-specific regulators of splicing provides valuable information to find new biomarkers, as well as to define alternative therapeutic strategies. The computational models to identify these regulators are not trivial and require three conceptual steps: the detection of AS events, the identification of splicing factors that potentially regulate these events and the contextualization of these pieces of information for a specific experiment. In this work, we review the different algorithmic methodologies developed for each of these tasks. Main weaknesses and strengths of the different steps of the pipeline are discussed. Finally, a case study is detailed to help the reader be aware of the potential and limitations of this computational approach., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Wearable technology used in Parkinson's disease (PD) research has become an increasing focus of interest in this field. Our group assessed the feasibility, clinical correlation, reliability, and acceptance of smartwatches in order to quantify arm resting tremors in PD patients. An Android application on a smartwatch was used to obtain raw data from the smartwatch's gyroscopes. Twenty-two PD patients were consecutively recruited and followed for 1 year. Arm rest tremors were video filmed and scored by two independent raters using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS-III). The tremor intensity parameter was defined by the root mean square of the angular speed measured by the smartwatch at the wrist. Sixty-four smartwatch evaluations were completed. The Spearman coefficient among the mean of the resting tremor (UPDRS-III) scores and smartwatch measurements for tremor intensity was 0.81 (p < .001); smartwatch reliability to quantify tremors was checked by intraclass reliability coefficient with a resting tremor = 0.89, minimum detectable change = 59.03%. Good acceptance of the system was shown. Smartwatch use for PD tremor analysis is possible, reliable, well-correlated with clinical scores, and well-accepted by patients for clinical follow-up. The results from these experiments suggest that this commodity hardware has the potential to quantify PD patients' tremors objectively in a consulting-room., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Although the cerebello-thalamo-cortical network has often been suggested to be of importance in the pathogenesis of essential tremor (ET), the origins of tremorgenic activity in this disease are not fully understood. We used a combination of cortical thickness imaging and neurophysiological studies to analyze whether the severity of tremor was associated with anatomical changes in the brain in ET patients ., Methods: Magnetic resonance imaging (MRI) and a neurophysiological assessment were performed in 13 nondemented ET patients. High field structural brain MRI images acquired in a 3T scanner and analyses of cortical thickness and surface were carried out. Cortical reconstruction and volumetric segmentation was performed with the FreeSurfer image analysis software. We used high-density surface electromyography (hdEMG) and inertial measurement units (IMUs) to quantify the tremor severity in upper extrimities of patients. In particular, advanced computer tool was used to reliably identify discharge patterns of individual motor units from surface hdEMG and quantify motor unit synchronization., Results: We found significant association between increased motor unit synchronization (i.e., more severe tremor) and cortical changes (i.e., atrophy) in widespread cerebral cortical areas, including the left medial orbitofrontal cortex, left isthmus of the cingulate gyrus, right paracentral lobule, right lingual gyrus, as well as reduced left supramarginal gyrus (inferior parietal cortex), right isthmus of the cingulate gyrus, left thalamus, and left amygdala volumes., Interpretation: Given that most of these brain areas are involved in controlling movement sequencing, ET tremor could be the result of an involuntary activation of a program of motor behavior used in the genesis of voluntary repetitive movements.

Background: Traditional studies on the neural mechanisms of tremor use coherence analysis to investigate the relationship between cortical and muscle activity, measured by electroencephalograms (EEG) and electromyograms (EMG). This methodology is limited by the need of relatively long signal recordings, and it is sensitive to EEG artifacts. Here, we analytically derive and experimentally validate a new method for automatic extraction of the tremor-related EEG component in pathological tremor patients that aims to overcome these limitations. Methods: We exploit the coupling between the tremor-related cortical activity and motor unit population firings to build a linear minimum mean square error estimator of the tremor component in EEG. We estimated the motor unit population activity by decomposing surface EMG signals into constituent motor unit spike trains, which we summed up into a cumulative spike train (CST). We used this CST to initialize our tremor-related EEG component estimate, which we optimized using a novel approach proposed here. Results: Tests on simulated signals demonstrate that our new method is robust to both noise and motor unit firing variability, and that it performs well across a wide range of spectral characteristics of the tremor. Results on 9 essential (ET) and 9 Parkinson's disease (PD) patients show a ~2-fold increase in amplitude of the coherence between the estimated EEG component and the CST, compared to the classical EEG-EMG coherence analysis. Conclusions: We have developed a novel method that allows for more precise and robust estimation of the tremor-related EEG component. This method does not require artifact removal, provides reliable results in relatively short datasets, and tracks changes in the tremor-related cortical activity over time.

Objectives: Characterizing pharmacological response in Parkinson's Disease (PD) patients may be a challenge in early stages but gives valuable clues for diagnosis. Neurotropic drugs may modulate Electroencephalography (EEG) microstates (MS). We investigated EEG-MS default-mode network changes in response to dopaminergic stimulation in PD. Methods: Fourteen PD subjects in HY stage III or less were included, and twenty-one healthy controls. All patients were receiving dopaminergic stimulation with levodopa or dopaminergic agonists. Resting EEG activity was recorded before the first daily PD medication dose and 1 h after drug intake resting EEG activity was again recorded. Time and frequency variables for each MS were calculated. Results: Parkinson's disease subjects MS A duration decreases after levodopa intake, MS B appears more often than before levodopa intake. MS E was not present, but MS G was. There were no significant differences between control subjects and patients after medication intake. Conclusion: Clinical response to dopaminergic drugs in PD is characterized by clear changes in MS profile. Significance: This work demonstrates that there are clear EEG MS markers of PD dopaminergic stimulation state. The characterization of the disease and its response to dopaminergic medication may be of help for early therapeutic diagnosis.