Plasma cells require autophagy for sustainable immunoglobulin production.

The role of autophagy in plasma cells is unknown. Here we found notable autophagic activity in both differentiating and long-lived plasma cells and investigated its function through the use of mice with conditional deficiency in the essential autophagic molecule Atg5 in B cells. Atg5(-/-) differentiating plasma cells had a larger endoplasmic reticulum (ER) and more ER stress signaling than did their wild-type counterparts, which led to higher expression of the transcriptional repressor Blimp-1 and immunoglobulins and more antibody secretion. The enhanced immunoglobulin synthesis was associated with less intracellular ATP and more death of mutant plasma cells, which identified an unsuspected autophagy-dependent cytoprotective trade-off between immunoglobulin synthesis and viability. In vivo, mice with conditional deficiency in Atg5 in B cells had defective antibody responses, complete selection in the bone marrow for plasma cells that escaped Atg5 deletion and fewer antigen-specific long-lived bone marrow plasma cells than did wild-type mice, despite having normal germinal center responses. Thus, autophagy is specifically required for plasma cell homeostasis and long-lived humoral immunity.

Developing a random forest algorithm to identify patent foramen ovale and atrial septal defects in Ontario administrative databases.

PURPOSE: Routinely collected administrative data is widely used for population-based research. However, although clinically very different, atrial septal defects (ASD) and patent foramen ovale (PFO) share a single diagnostic code (ICD-9: 745.5, ICD-10: Q21.1). Using machine-learning based approaches, we developed and validated an algorithm to differentiate between PFO and ASD patient populations within healthcare administrative data. METHODS: Using data housed at ICES, we identified patients who underwent transcatheter closure in Ontario between October 2002 and December 2017 using a Canadian Classification of Interventions code (1HN80GPFL, N = 4680). A novel random forest model was developed using demographic and clinical information to differentiate those who underwent transcatheter closure for PFO or ASD. Those patients who had undergone transcatheter closure and had records in the CorHealth Ontario cardiac procedure registry (N = 1482) were used as the reference standard. Several algorithms were tested and evaluated for accuracy, sensitivity, and specificity. Variable importance was examined via mean decrease in Gini index. RESULTS: We tested 7 models in total. The final model included 24 variables, including demographic, comorbidity, and procedural information. After hyperparameter tuning, the final model achieved 0.76 accuracy, 0.76 sensitivity, and 0.75 specificity. Patient age group had the greatest influence on node impurity, and thus ranked highest in variable importance. CONCLUSIONS: Our random forest classification method achieved reasonable accuracy in identifying PFO and ASD closure in administrative data. The algorithm can now be applied to evaluate long term PFO and ASD closure outcomes in Ontario, pending future external validation studies to further test the algorithm.

The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity.

Systemic light chain (AL) amyloidosis is caused by the clonal production of an unstable immunoglobulin light chain (LC), which affects organ function systemically. Although pathogenic LCs have been characterized biochemically, little is known about the biology of amyloidogenic plasma cells (PCs). Intrigued by the unique response rates of AL amyloidosis patients to the first-in-class proteasome inhibitor (PI) bortezomib, we purified and investigated patient-derived AL PCs, in comparison with primary multiple myeloma (MM) PCs, the prototypical PI-responsive cells. Functional, biochemical, and morphological characterization revealed an unprecedented intrinsic sensitivity of AL PCs to PIs, even higher than that of MM PCs, associated with distinctive organellar features and expression patterns indicative of cellular stress. These consisted of expanded endoplasmic reticulum (ER), perinuclear mitochondria, and a higher abundance of stress-related transcripts, and were consistent with reduced autophagic control of organelle homeostasis. To test whether PI sensitivity stems from AL LC production, we engineered PC lines that can be induced to express amyloidogenic and nonamyloidogenic LCs, and found that AL LC expression alters cell growth and proteostasis and confers PI sensitivity. Our study discloses amyloidogenic LC production as an intrinsic PC stressor, and identifies stress-responsive pathways as novel potential therapeutic targets. Moreover, we contribute a cellular disease model to dissect the biology of AL PCs.

Impact of Operators' Height on Individual Radiation Exposure Measurements During Catheter-Based Cardiovascular Interventions.

AIM: This study is aimed to evaluate the impact of an operators' height on personal radiation exposure measurements during cardiovascular interventional procedures. Based upon both clinical data and phantom simulation, a new approach for monitoring an individual's exposure is proposed. METHODS: The clinical component of this study was composed of the operators and staff in a single center full service cardiovascular laboratory being divided into 2 groups based upon their height: group A included all individuals whose height was <165 cm; group B included the individuals >165 cm. All operators wore a standard TLD dosimeter at all times with doses recorded for 12 months. To support these clinical findings, a second investigation was performed utilizing a phantom. Measurements were obtained at 100 and 135 cm from the radiation source during simulation of different cardiovascular interventional procedures. RESULTS: The radiation dose measured from the personal dosimeters identified that Group A, operators <165 cm, had significantly higher doses than those recorded in Group B, operators >165 cm, when compared among individuals performing similar tasks (physicians, technicians, and nurses): 4.55 ± 4.0 (Group A) versus 1.95 ± 1.0 (Group B) mSv (P < 0.01). During procedure simulation with the phantom, the doses measured were similarly significantly higher if measured at 100 cm than at 135 cm from the radiation source. CONCLUSION: This study suggests that the height from radiation source does impact the measured dose from an operator worn personal TLD. This was operator specific, consistent thought-out multiple procedures, and confined with phantom measurements.

A Virtual Environment to Improve the Detection of Oral-Facial Malfunction in Children with Cerebral Palsy.

The importance of an early rehabilitation process in children with cerebral palsy (CP) is widely recognized. On the one hand, new and useful treatment tools such as rehabilitation systems based on interactive technologies have appeared for rehabilitation of gross motor movements. On the other hand, from the therapeutic point of view, performing rehabilitation exercises with the facial muscles can improve the swallowing process, the facial expression through the management of muscles in the face, and even the speech of children with cerebral palsy. However, it is difficult to find interactive games to improve the detection and evaluation of oral-facial musculature dysfunctions in children with CP. This paper describes a framework based on strategies developed for interactive serious games that is created both for typically developed children and children with disabilities. Four interactive games are the core of a Virtual Environment called SONRIE. This paper demonstrates the benefits of SONRIE to monitor children's oral-facial difficulties. The next steps will focus on the validation of SONRIE to carry out the rehabilitation process of oral-facial musculature in children with cerebral palsy.

Pathophysiology of paradoxical embolism: evaluation of the role of interatrial septum anatomy based on the intracardiac echocardiography assessment of patients with right-to-left shunting.

BACKGROUND: Detailed anatomic variants of the interatrial septum in patients with right-to-left shunt and contribution of specific anatomies to the risk of ischaemic recurrences has not yet been comprehensively classified. OBJECTIVE: To report a classification of the anatomic variants of the interatrial septum as observed by intracardiac echocardiography and its correlation with clinical and functional characteristics. METHODS: We retrospectively reviewed the medical and instrumental data of 520 consecutive patients (mean age 44±15. 5 years, 355 women) who had over a 10-year period undergone intracardiac echocardiography and right-to-left shunt catheter-based closure. The four main features used to analyse were: (a) diameter of the oval fossa, (b) presence and length of the channel, (c) presence and degree of atrial septal aneurysm, and (d) rim thickness. The presence of Eustachian valve was also tabulated. RESULTS: The combinations of interatrial septum anatomical features were classified into six main anatomical subgroups. Recurrent embolism, multiple ischaemic foci on brain magnetic resonance imaging, high grade shunt, and permanent shunt before transcatheter closure procedure were associated with type 2, type 4, and type 6. Type 4 anatomical subtype (OR 4.1, 1.5-8 [95% CI], p<0.001) and type 2+presence of Eustachian valve (OR 4.3, 1.6-9 [95% CI], p<0.001) were the strongest predictors of recurrent ischaemic events before transcatheter closure. CONCLUSION: Our study showed that interatrial septum anatomy greatly differs among patients with right-to-left shunt, as well as the risk of ischaemic recurrences in different anatomies.

Decentralised, collaborative, and privacy-preserving machine learning for multi-hospital data.

BACKGROUND: Machine Learning (ML) has demonstrated its great potential on medical data analysis. Large datasets collected from diverse sources and settings are essential for ML models in healthcare to achieve better accuracy and generalizability. Sharing data across different healthcare institutions or jurisdictions is challenging because of complex and varying privacy and regulatory requirements. Hence, it is hard but crucial to allow multiple parties to collaboratively train an ML model leveraging the private datasets available at each party without the need for direct sharing of those datasets or compromising the privacy of the datasets through collaboration. METHODS: In this paper, we address this challenge by proposing Decentralized, Collaborative, and Privacy-preserving ML for Multi-Hospital Data (DeCaPH). This framework offers the following key benefits: (1) it allows different parties to collaboratively train an ML model without transferring their private datasets (i.e., no data centralization); (2) it safeguards patients' privacy by limiting the potential privacy leakage arising from any contents shared across the parties during the training process; and (3) it facilitates the ML model training without relying on a centralized party/server. FINDINGS: We demonstrate the generalizability and power of DeCaPH on three distinct tasks using real-world distributed medical datasets: patient mortality prediction using electronic health records, cell-type classification using single-cell human genomes, and pathology identification using chest radiology images. The ML models trained with DeCaPH framework have less than 3.2% drop in model performance comparing to those trained by the non-privacy-preserving collaborative framework. Meanwhile, the average vulnerability to privacy attacks of the models trained with DeCaPH decreased by up to 16%. In addition, models trained with our DeCaPH framework achieve better performance than those models trained solely with the private datasets from individual parties without collaboration and those trained with the previous privacy-preserving collaborative training framework under the same privacy guarantee by up to 70% and 18.2% respectively. INTERPRETATION: We demonstrate that the ML models trained with DeCaPH framework have an improved utility-privacy trade-off, showing DeCaPH enables the models to have good performance while preserving the privacy of the training data points. In addition, the ML models trained with DeCaPH framework in general outperform those trained solely with the private datasets from individual parties, showing that DeCaPH enhances the model generalizability. FUNDING: This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2020-06189 and DGECR-2020-00294), Canadian Institute for Advanced Research (CIFAR) AI Catalyst Grants, CIFAR AI Chair programs, Temerty Professor of AI Research and Education in Medicine, University of Toronto, Amazon, Apple, DARPA through the GARD project, Intel, Meta, the Ontario Early Researcher Award, and the Sloan Foundation. Resources used in preparing this research were provided, in part, by the Province of Ontario, the Government of Canada through CIFAR, and companies sponsoring the Vector Institute.

Deep learning for automatic organ and tumor segmentation in nanomedicine pharmacokinetics.

Rationale: Multimodal imaging provides important pharmacokinetic and dosimetry information during nanomedicine development and optimization. However, accurate quantitation is time-consuming, resource intensive, and requires anatomical expertise. Methods: We present NanoMASK: a 3D U-Net adapted deep learning tool capable of rapid, automatic organ segmentation of multimodal imaging data that can output key clinical dosimetry metrics without manual intervention. This model was trained on 355 manually-contoured PET/CT data volumes of mice injected with a variety of nanomaterials and imaged over 48 hours. Results: NanoMASK produced 3-dimensional contours of the heart, lungs, liver, spleen, kidneys, and tumor with high volumetric accuracy (pan-organ average %DSC of 92.5). Pharmacokinetic metrics including %ID/cc, %ID, and SUVmax achieved correlation coefficients exceeding R = 0.987 and relative mean errors below 0.2%. NanoMASK was applied to novel datasets of lipid nanoparticles and antibody-drug conjugates with a minimal drop in accuracy, illustrating its generalizability to different classes of nanomedicines. Furthermore, 20 additional auto-segmentation models were developed using training data subsets based on image modality, experimental imaging timepoint, and tumor status. These were used to explore the fundamental biases and dependencies of auto-segmentation models built on a 3D U-Net architecture, revealing significant differential impacts on organ segmentation accuracy. Conclusions: NanoMASK is an easy-to-use, adaptable tool for improving accuracy and throughput in imaging-based pharmacokinetic studies of nanomedicine. It has been made publicly available to all readers for automatic segmentation and pharmacokinetic analysis across a diverse array of nanoparticles, expediting agent development.

Incidence of new-onset atrial fibrillation after transcatheter patent foramen ovale closure using 15 years of Ontario administrative health data.

BACKGROUND: Individuals with patent foramen ovale (PFO) routinely undergo transcatheter closure (TC) for secondary prevention of recurrent stroke. However, some evidence suggests that TC may increase the risk of new-onset atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the risk of new-onset AF following PFO closure and to explore predictors of AF development. METHODS: We created a retrospective cohort of all Ontarians over 18 years of age who received TC between October 2002 and December 2017 using administrative health data and the CorHealth cardiac registry. Poisson regression determined event rates of AF and secondary outcomes such as stroke and mortality per 1000 person-years. A multivariable Cox proportional hazards model identified predictors of new-onset AF following TC. RESULTS: Of 1533 patients, 96 (6.26%) developed new-onset AF following PFO closure, over average follow-up time of 8.2 years. Age >60 years (hazard ratio [HR] 2.82; 95% confidence interval [CI] 1.76-4.51; P <.001) and diabetes (HR 2.49; 95% CI 1.48-4.18; P <.001) were statistically significant, independent predictors of AF according to the Cox model. CONCLUSIONS: The incidence of new-onset AF after PFO closure was relatively low. Having diabetes and age >60 years were the most important factors associated with new-onset AF in this population.

Atrial fibrillation following transcatheter atrial septal defect closure: a systematic review and meta-analysis.

OBJECTIVE: The ostium secundum atrial septal defect (ASD) is among the most common congenital cardiac anomalies diagnosed in adulthood. A known complication of transcatheter ASD closure is the development of new-onset atrial fibrillation and flutter (AFi/AFl). These arrhythmias confer an increased risk of postoperative stroke, thrombus formation and systemic emboli. This systematic review examines the burden of de novo AFi/AFl in adults following transcatheter closure and seeks to identify risk factors for AFi/AFl development. METHODS: Studies were identified by a search of MEDLINE, EMBASE and Cochrane databases from inception until 29 April 2020. A meta-analysis of AFi/AFl incidence was performed using a random-effects model. RESULTS: A total of 31 studies met inclusion criteria, comprising 4788 adult patients without a history of AFi/AFl. Twenty-three studies were included in quantitative synthesis and demonstrated an overall incidence rate of 1.82 patients per 100 person-years of follow-up (I2=83%). In studies that enrolled only patients ≥60 years old, the incidence was 5.21 patients per 100 person-years (I2=0%). Studies with follow-up duration ≤2 years reported an incidence of 4.05 per 100 person-years (I2=55%) compared with a rate of 1.19 per 100 person-years (I2=85%) for studies with follow-up duration >2 years. CONCLUSIONS: The incidence of new-onset AFi/AFl is relatively low following transcatheter closure of secundum ASDs. The rate of de novo AFi/AFl, however, was significantly higher in elderly patients. Shorter follow-up time was associated with a higher reported incidence of AFi/AFl.

Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma.

Multiple myeloma grows by establishing multiple interactions with bone marrow cells. These include expansion of myeloid-derived suppressor cells, which drive immunoevasion via mechanisms that include arginase-1-driven depletion of L-arginine, thus indirectly promoting myeloma cell survival and tumor progression. The peculiar biology of malignant plasma cells postulates that arginine depletion may benefit their fitness also directly, e.g., by engaging the integrated stress response, or by stimulating autophagy through mTORC1 inhibition. We thus investigated the direct impact of arginine deprivation on myeloma cells and challenged its pathophysiological relevance in vitro and in vivo. First, we found that partial arginine depletion spared proliferation of human multiple myeloma cells at concentrations that arrest human T cells. Next, we asked if arginine shortage activates putative adaptive pathways in myeloma cells. Low arginine failed to activate the integrated stress response, as indicated by unmodified phosphorylation of the eukaryotic initiation factor 2α, but sizably inhibited mTORC1, as revealed by reduced phosphorylation of ribosomal protein S6. Notably, depressed mTORC1 activity was not sufficient to increase autophagy, as assessed by the lysosomal digestion rate of the autophagosome-associated protein, LC3-II. Rather, it stimulated mTORC2, resulting in increased phosphatidylinositol-3 kinase-dependent AKT phosphorylation and activity, leading to heightened inhibitory phosphorylation of the pro-apoptotic BAD protein. We then tested whether arginine depletion-activated AKT may protect malignant plasma cells from cell death. Indeed, culturing myeloma cells in low arginine medium significantly reduced the apoptotic effect of the first-in-class proteasome inhibitor, bortezomib, an outcome prevented by pharmacological inhibition of AKT phosphorylation. Finally, we challenged the relevance of the identified circuit in vivo. To gauge the pathophysiologic relevance of low arginine to myeloma growth independently of immunoevasion, we xenotransplanted human myeloma cells subcutaneously into T cell-deficient Rag2-/-γc-/- recipient mice and treated palpable tumor-bearing mice with the clinical-grade arginase inhibitor CB1158. Arginase inhibition significantly raised serum arginine concentration, reduced tumor growth by caliper assessment, and decreased intra-tumor AKT phosphorylation in vivo. Altogether, our results reveal a novel direct pro-survival effect of arginine deprivation on myeloma cells, with potential therapeutic implications.

Oxidative stress protection and growth promotion activity of Pseudomonas mercuritolerans sp. nov., in forage plants under mercury abiotic stress conditions.

SAICEUPSMT strain was isolated from soils in the mining district of Almadén (Ciudad Real, Spain), subjected to a high concentration of mercury. Using the plant model of lupinus, the strain was inoculated into the rhizosphere of the plant in a soil characterized by a high concentration of mercury (1,710 ppm) from an abandoned dump in the mining district of Almadén (Ciudad Real, Spain). As a control, a soil with a minimum natural concentration of mercury, from a surrounding area, was used. Under greenhouse conditions, the effect that the inoculum of the SAICEUPSMT strain had on the antioxidant capacity of the plant was studied, through the quantification of the enzymatic activity catalase (CAT), ascorbate peroxidase (APX), superoxide dismutase (SOD), and glutathione reductase (GR). Likewise, the capacity of the plant to bioaccumulate mercury in the presence of the inoculum was studied, as well as the effect on the biometric parameters total weight (g), shoot weight (g), root weight (g), shoot length (cm), root length (cm), total number of leaves (N), and total number of secondary roots (No). Finally, in view of the results, the SAICEUPSMT strain was identified from the phenotypic and genotypic point of view (housekeeping genes and complete genome sequencing). The inoculum with the SAICEUPSMT strain in the presence of mercury produced a significant reduction in the enzymatic response to oxidative stress (CAT, APX, and SOD). It can be considered that the strain exerts a phytoprotective effect on the plant. This led to a significant increase in the biometric parameters total plant weight, root weight and the number of leaves under mercury stress, compared to the control without abiotic stress. When analyzing the mercury content of the plant with and without bacterial inoculum, it was found that the incorporation of the SAICEUPSMT strain significantly reduced the uptake of mercury by the plant, while favoring its development in terms of biomass. Given the positive impact of the SAICEUPSMT strain on the integral development of the plant, it was identified, proving to be a Gram negative bacillus, in vitro producer of siderophores, auxins and molecules that inhibit stress precursors. The most represented fatty acids were C16:0 (33.29%), characteristic aggregate 3 (22.80%) comprising C16:1 ω7c and C16: 1ω6c, characteristic aggregate 8 (13.66%) comprising C18:1 ω7c, and C18: 1 cycle ω6c and C 17:0 (11.42%). From the genotypic point of view, the initial identification of the strain based on the 16S rRNA gene sequence classified it as Pseudomonas iranensis. However, genome-wide analysis showed that average nucleotide identity (ANI, 95.47%), DNA-DNA in silico hybridization (dDDH, 61.9%), average amino acid identity (AAI, 97.13%), TETRA (0.99%) and intergenic distance (0.04) values were below the established thresholds for differentiation. The results of the genomic analysis together with the differences in the phenotypic characteristics and the phylogenetic and chemotaxonomic analysis support the proposal of the SAICEUPSMT strain as the type strain of a new species for which the name Pseudomonas mercuritolerans sp. is proposed. No virulence genes or transmissible resistance mechanisms have been identified, which reveals its safety for agronomic uses, under mercury stress conditions.

Plant growth promotion of the forage plant Lupinus albus Var. Orden Dorado using Pseudomonas agronomica sp. nov. and Bacillus pretiosus sp. nov. added over a valorized agricultural biowaste.

Introduction: The overexploitation of natural ecosystems and the evolution of climate change currently force us to design new strategies for more sustainable agronomic uses. The recovery of plant residues, as an alternative to agrochemicals, can help alleviate these problems, for example, through its use for the synthesis of biofertilizers. In this work, the effect of the organic fertilizer matrix ORGAON® from the valorization of horticultural waste is tested, to which two strains of bacteria (and their consortium) are added (SAICEU11T identified as Bacillus pretiosus and SAICEU22T identified as Pseudomonas agronomica), selected for their demonstrated ability to promote plant growth (PGPB), on the lupine forage plant (Lupinus albus). Methods: For the synthesis of the biofertilizer, both strains were added to the ORGAON® organic matrix separately, until reaching a final optical density (OD) of 0.5 McFarland in each case in the irrigation matrix. As a control, sterile ORGAON® (ORGAON®st) was used, also supplemented with the PGPB strains and a chemical fertilizer widely used in agronomy (Chem-F). With these treatments, a 6-week experiment was started under controlled laboratory conditions and on agricultural substrate, to recreate field conditions as accurately as possible. All the tests were carried out with 9 repetitions and 3 replicates of each treatment. After harvest, the improvements on the following biometric variables were studied for each treatment: total weight (Weight_T, g), shoot weight (Weight_S, g), root weight (Weight_R, g), number of leaves (Leaves, No.), shoot length (Length_S), root length (Length_R) and number of secondary roots (Roots, No.). Likewise, the identification of the tested strains and their description as new species was carried out. For this, they were studied from the phenotypic point of view (Transmission electron microscopy (TEM), metabolic profile, PGP activities, fatty acid profile and Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)) and genotypic (sequencing of the main housekeeping genes and sequencing of the whole genome, genomic characteristics (dDDH and ANI) and phylogenetic analysis). Results and discussion: After the statistical analysis of the results, it is shown that the individual addition of both strains on the ORGAON® and ORGAON®st organic matrix improve certain biometric variables. In the case of the SAICEU11T (Bacillus pretiosus) strain, the variables root weight (Weight_R, g), total weight (Weight_T, g) and length of the plant, and number of secondary roots (Roots, No.) significantly improve, while in the case of the strain SAICEU22T (Pseudmonas agronomica), a significant improvement of root length (Length_R) and number of secondary roots (Roots, No.) is demonstrated. On the other hand, the genotaxonomic analysis showed that both species have not been described to date. The identification based on the main housekeeping genes, show that for the Bacillus strain (SAICEU11T) the sequence similarity of the 16S rRNA was 100%, gyrB 92.69%, rpoB 97.70% and rpoD 94.67%. For the Pseudomonas strain (SAICEU22T) the results were 100% for 16S rRNA, 98.43% for rpoD and 96.94% for gyrB. However, in both cases, the dDDH and ANI values, as well as the phylogenetic analysis, show that both species are below the species threshold, which would support the hypothesis that both are new species, in line with the chemotaxonomic results obtained by MALDI-TOF spectrometry and fatty acid profile. To verify the biosafety in their handling and release into the natural environment, we have ruled out the presence of genes that encode virulence factors or resistance to antibiotics, concluding that they are suitable for use in the field to improve the yield of crop plants. Type strains are SAICEU11T (= DSM 114702T = CECT30674T) for Bacillus pretiosus and SAICEU22T (= DSM 114959T = CECT30673T) for Pseudomonas agronomicae.

Reflex Locomotion Therapy for Balance, Gait, and Fatigue Rehabilitation in Subjects with Multiple Sclerosis.

This study evaluates the effects of a rehabilitation program based on reflex locomotion therapy (RLT) on balance, gait, and fatigue in patients with multiple sclerosis (MS). Twenty-three patients diagnosed with MS participated in this study. Reversal design was carried out. The assessment tools included the Berg Balance Scale (BBS), the Performance Oriented Mobility Assessment (POMA), the Fatigue Severity Scale (FSS) and the instrumental analysis of the gait recorded by Vicon Motion System®. We analyzed spatio-temporal parameters and kinematic variables of the hip, knee, and ankle joints. Additionally, the Client Satisfaction Questionnaire (CSQ-8) was administrated. We did find a significant improvement in balance and gait tools after the RLT period. Regarding instrumental analysis, the statistical analysis of spatio-temporal parameters showed a significant improvement in stride length, double support, and velocity after the RLT period. Concerning kinematic parameters, the analysis showed improvements in hip and knee range of motion (ROM) after RLT period. RLT could improve gait and balance in patients with MS. The patients reported a high level of satisfaction with the therapy received.

The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition.

Proteasome inhibitors (PIs) are effective against multiple myeloma (MM), but the mechanisms of action and bases of individual susceptibility remain unclear. Recent work linked PI sensitivity to protein synthesis and proteasome activity, raising the question whether different levels of proteasome expression and workload underlie PI sensitivity in MM cells (MMCs). Exploiting human MM lines characterized by differential PI sensitivity, we report that highly sensitive MMCs express lower proteasome levels and higher proteasomal workload than relatively PI-resistant MMCs, resulting in the accumulation of polyubiquitinated proteins at the expense of free ubiquitin (proteasome stress). Manipulating proteasome expression or workload alters apoptotic sensitivity to PI, demonstrating a cause-effect relationship between proteasome stress and apoptotic responses in MMCs. Intracellular immunostaining in primary, patient-derived MMCs reveals that polyubiquitinated proteins hallmark neoplastic plasma cells, in positive correlation with immunoglobulin (Ig) content, both intra- and interpatient. Moreover, overall proteasome activity of primary MMCs inversely correlates with apoptotic sensitivity to PI. Altogether, our data indicate that the balance between proteasome workload and degradative capacity represents a critical determinant of apoptotic sensitivity of MMCs to PI, potentially providing a framework for identifying indicators of responsiveness and designing novel combination therapies.

New-onset atrial fibrillation following percutaneous closure of patent foramen ovale: a systematic review and meta-analysis.

PURPOSE: A patent foramen ovale (PFO), present in up to 25% of adults, is an embryologic remnant which allows for right to left shunting and has been implicated in cryptogenic stroke (Neill and Lin, Methodist Debakey Cardiovasc J. 13(3):152-159, 2017; Bass 2015). The current standard of care for selected patients with PFO and cryptogenic stroke is transcatheter closure, but the risk of post-closure, new-onset atrial fibrillation (AF) is unknown (Vaidya et al., Cardiovasc Diagn Ther. 8(6):739-753, 2018; Kjeld et al., Acta Radiol Open. 7(9):2058460118793922, 2018; Staubach et al., Catheter Cardiovasc Interv. 74(6):889-95, 2009). This systematic review and meta-analysis synthesized evidence on AF development post transcatheter PFO closure and predictors of AF development, and assessed existing knowledge gaps. METHODS: Randomized controlled trials and observational studies were selected according to the inclusion criteria of adults that underwent a transcatheter PFO closure without a history of AF. Studies were retrieved from electronic databases from inception until February 2019. A Freeman-Tukey arcsine transformation was performed for meta-analysis of AF incidence rate. RESULTS: From 765 studies, 45 were included in quantitative data synthesis. Study sample sizes ranged between 20 and 1887 individuals, and average patient age between 37 to 67 years across studies. The overall incidence rate was 0.013 person-years, and 0.014 person-years for the within 6 months follow-up subgroup. There was no consistency in reported predictors of AF development. CONCLUSIONS: The incidence of AF post-PFO closure was low across studies, with a high level of between-study heterogeneity. Until a concerted effort is made to improve accurate AF diagnosis, it will be difficult to gauge the association between transcatheter PFO closure and incidence of AF.

The effect of swimming program on body composition levels in adolescents with Down syndrome.

BACKGROUND: Down syndrome has been associated with more than 80 clinical characteristics such as diabetes, cardiovascular problems or obesity. AIMS: The current study determined the effect of a 36 weeks swimming program on different indicators of body composition in adolescents with Down syndrome. METHODS AND PROCEDURES OUTCOMES: 45 adolescents with Down syndrome were recruited and randomized to two groups (control group vs. exercise group). Adolescents allocated in the control group carried out a recreational swimming program twice a week during 36 weeks meanwhile adolescents allocated in the exercise group did exercise three time a week during 36 weeks. BMI, Waist circumference, waist-to-height ratio, triceps, subscapular, suprailiac and thigh skinfold were measured. RESULTS: ANCOVA tests were used to evaluate differences between groups in post-test intervention. Repeated measures of ANOVA were performed in order to assess differences in pre-test intervention in each group. t test were carried out to compare the pre-post-intervention differences in physical characteristics and body composition within each group. The exercise group had significant improvements in all variables of body composition (p < 0.05) except in subscapular and thigh skinfold. CONCLUSIONS AND IMPLICATIONS: The results suggest that a 36 weeks swimming program consisting of 3 sessions of 50 minutes is able to decrease levels of body composition in a sample of adolescents with Down syndrome. The findings indicate that it would be important to generate high intensity sports programs in sports associations in order to obtain positive impact on body composition levels within this population.

Classification of general and personal semantic details in the Autobiographical Interview.

The Autobiographical Interview (AI) separates internal (episodic) and external (non-episodic) details from transcribed protocols using an exhaustive and reliable scoring system. While the details comprising the internal composite are centered on elements of episodic memory, external details are more heterogeneous as they are meant to capture a variety of non-episodic utterances: general semantics, different types of personal semantics details, metacognitive statements, repetitions, and details about off topic events. Elevated external details are consistently observed in aging and in neurodegenerative diseases. In the present study, we augmented the AI scoring system to differentiate subtypes of external details to test whether the elevation of these details in aging and in frontotemporal lobar degeneration (including mixed frontotemporal/semantic dementia [FTD/SD] and progressive non-fluent aphasia [PNFA]) would be specific to general and personal semantics or would concern all subtypes. Specifically, we separated general semantic details from personal semantic details (including autobiographical facts, self-knowledge, and repeated events). With aging, external detail elevation was observed for general and personal semantic details but not for other types of external details. In frontotemporal lobar degeneration, patients with FTD/SD (but not PNFA) generated an excess of personal semantic details but not general semantic details. The increase in personal but not general semantic details in FTD/SD is consistent with prevalent impairment of general semantic memory in SD, and with the personalization of concepts in this condition. Under standard AI instructions, external details were intended to capture off-topic utterances and were not intended as a direct measure of semantic abilities. Future investigations concerned with semantic processing in aging and in dementia could modify standard instructions of the AI to directly probe semantic content.

Education, and obtaining of informed consent, using multimedia before adults with congenitally malformed hearts are submitted to transcatheter interventions.

BACKGROUND: Multimedia programmes relating to education and consents may be useful for decreasing anxiety during catheter-based repair in patients with congenitally malformed hearts. OBJECTIVE: Our study was aimed at evaluating the impact of multimedia protocols for education of a population of consecutive patients with congenitally malformed hearts prior to transcatheter repair. METHODS: Between September, 2006, and May, 2008, we enrolled 100 consecutive patients, with a mean age of 45 +/- 19 years, of whom 69 were female, for catheter-based repair of their congenitally malformed hearts. In the first 50 patients, we used a written form for informed consent sent to the patients 15 days before the procedure, coupled with a personal interview of 30 minutes. In the subsequent 50 patients, we used multimedia protocol for education, comprising a booklet of 4 pages containing a simple and brief explanation of the intervention, and a digital film of 4 minutes showing the transcatheter procedure with a commentary provided by the referring physician, prior to obtaining the signature for informed consent. We then compared the scores for anxiety, the pre-operative heart rate, the frequency of vaso-vagal episodes, and the need for conscious sedation between the two groups. RESULTS: Patients who underwent preconditioning using the multimedia programme were significantly less anxious, and had significantly lower heart rates. Vaso-vagal episodes were also significantly less in this group, with no episodes compared to 14% in those providing standard informed consent. Conscious sedation was needed more frequently in those providing standard informed consent. CONCLUSION: Our brief study suggests that a comprehensive multimedia programme of preparation increases the tolerability, and decrease the emotional state, of adults about to undergo catheter-based interventions for congenital cardiac disease.

Analgesic effects of a capacitive-resistive monopolar radiofrequency in patients with myofascial chronic neck pain: a pilot randomized controlled trial.

BACKGROUND: To date, there is a lack of prior studies on the use of capacitive resistive monopolar radiofrequency (RF) to treat neck pain. The objective of this study was to investigate the immediate effect of capacitive resistive monopolar radiofrequency (RF=448 kHz), in comparison with a placebo, on (1) reducing neck pain intensity at myofascial trigger points (MTrP), (2) decreasing neck disability and (3) improving cervical range of motion (CROM). METHODS: A randomized, double-blind, placebo-controlled trial (NCT02353195) was carried out. Patients with myofascial chronic neck pain (N=24) with active MTrP in one upper trapezius muscle were randomly divided into two groups: a radio-frequency group, which received eight sessions of a monopolar capacitive resistive radio-frequency application over the upper trapezius muscle, and a placebo group (PG), which received eight sessions of placebo radio-frequency over the same muscle. Visual analog scale (VAS), CROM and Neck Disability Index (NDI) were evaluated after the first session and after the eight sessions. RESULTS: The Wilcoxon test for VAS showed statistically significant differences between baseline, immediately after the first session and after eight sessions (p<.001). No significant differences for PG were found. No differences were observed between groups. NDI improved in both groups after eight sessions, but no differences were found between groups (p<.05). ANOVA for time factor showed statistically significant changes in the right cervical rotation in both groups (F=4.112; p=.026) after eight sessions. CONCLUSIONS: Even though there were no differences between both groups, the monopolar capacitive, resistive RF could have a potential effect on pain intensity.