Shoulder function and outcome evaluation after surgery using 3D inertial sensors

The importance of outcome evaluation of a medical treatment in orthopedics is currently recognized. In shoulder disease, a large variety of evaluation tools is employed to assess the results of the surgery. However, even if the majority of these evaluations are largely widespread, none was accepted as a universal standard. Since 1990, few researchers have been evaluating the assumption that the movement analysis (with camera-based or electromagnetic systems) is likely to provide objective results. In clinical practice, these techniques are not always applicable for outcome evaluation of a treatment. The surgeons lack a convenient and simple method of evaluating in an objective way a patient's activity and quality of life after a surgery of the shoulder. This project provides a new tool for the objective functional evaluation of shoulder pathologies, a tool that can be easily used by a doctor at a hospital and by the patient at home. It allows the measurement of the biodynamic changes as well as 3D kinematics of the treated shoulder by noting the effects of these changes on clinical results and on the patient's daily activity. The project was split in four complementary studies. In the first study, a new ambulatory device allowing long-term monitoring of the shoulder movement using several inertial sensors (3D gyroscopes, 3D accelerometers) attached on the trunk, the humerus and the scapula's spine was designed. By combining acceleration and angular velocity features of the both humerus during 9 tests, three kinematic scores for the functional assessment of the shoulder were presented to evaluate the shoulder function in patient before and after surgery. The kinematic scores objectively showed the shoulder improvement after surgery. In the second study, a new method was proposed to detect and quantify the dominant upper-limb segment during daily activity. The method was tested on healthy subjects (N=31) and a patient group (N=10, at baseline, 3, 6 and 12 months after surgery) while carrying the system during 8 hours of their daily life. The results showed the dominance of the arm during standing, sitting and walking periods for healthy subjects and the quantification of the shoulder improvement after surgery, by taking into account the presence of the disease in the dominant or the non dominant arm. In the third study, 3D gyroscopes attached on the humerus were used to identify the movements of flexion-extension, abduction-adduction and internal/external rotation of the humerus and to identify the rates of adjunct (deliberate rotation) and conjunct rotations (inherent or automatic rotation) within each movement. The frequencies of each movement (number/hour) for the different ranges of the arm speed, as well as the rate of adjunct and conjunct rotations for each movement were estimated during daily activity in healthy and patient groups. The results provided the values of frequency of each movement and adjunct/conjunct rate based on the data obtained from the healthy group. In the pathological case, we found that the painful dominant shoulder of the patients lost its predominance in favor of the healthy shoulder, the non dominant shoulder. Patients had less pure internal/external rotations and performed less fast movements while after surgery these parameters presented no significant differences with the healthy group. In the fourth study, a new method of detecting the working level of the shoulder was presented. By measuring the arm elevation during motionless periods, we proposed a new score to evaluate the ability of working at a specific level for a definite duration. We showed that this score had an average of 100% (±31%) for healthy subjects while the working level of the painful shoulder was lower than the healthy shoulder and improved significantly after surgery (up to 87% at 6 months). This study provides preliminary evidence of the effectiveness of the proposed system in clinical practice and objectively assesses upper-limb activity during daily activity

Detection of the movement of the humerus during daily activity

A new ambulatory technique for qualitative and quantitative movement analysis of the humerus is presented. 3D gyroscopes attached on the humerus were used to recognize the movement of the arm and to classify it as flexion, abduction and internal/external rotations. The method was first validated in a laboratory setting and then tested on 31 healthy volunteer subjects while carrying the ambulatory system during 8h of their daily life. For each recording, the periods of sitting, standing and walking during daily activity were detected using an inertial sensor attached on the chest. During each period of daily activity the type of arm movement (flexion, abduction, internal/external rotation) its velocity and frequency (number of movement/hour) were estimated. The results showed that during the whole daily activity and for each activity (i.e. walking, sitting and walking) the frequency of internal/external rotation was significantly higher while the frequency of abduction was the lowest (P<0.009). In spite of higher number of flexion, abduction and internal/external rotation in the dominant arm, we have not observed in our population a significant difference with the non-dominant arm, implying that in healthy subjects the arm dominance does not lie considerably on the number of movements. As expected, the frequency of the movement increased from sitting to standing and from standing to walking, while we provide a quantitative value of this change during daily activity. This study provides preliminary evidence that this system is a useful tool for objectively assessing upper-limb activity during daily activity. The results obtained with the healthy population could be used as control data to evaluate arm movement of patients with shoulder diseases during daily activit

Detection of Argonaute (Ago) protein associated MiRNA by combining anti-ago antibody recognition with real-time PCR

MicroRNAs (miRNAs) are small molecules of noncoding RNA that range between ~19-22 nucleotides in length. In recent years, scientists have observed that these small RNA molecules exist in the extracellular environment within eukaryotic organisms. Furthermore, these microRNA molecules are known to associate with a family of proteins named Argonaute proteins. These microRNA/Argonaute protein complexes are the core of a larger assembly of proteins that compose the RNA Induced Silencing Complex (RISC). The RISC has exhibited the ability to inhibit the translation of, or cleave, its target messenger RNA (mRNA), the latter of which being exclusive only to Argonaute 2 protein (Ago2). It has also been observed in the literature that these Argonaute/miRNA complexes often target genomic regions associated with various cancers in humans and, currently, more than 2000 miRNAs have been discovered and published in the literature. Current methods for analyzing miRNA expression involve total RNA extraction using methods such as ethanol precipitation. However, total RNA extraction does not take into consideration that the major functional component of post-transcriptional inhibition is indeed that Argonaute protein/miRNA complex and not the miRNA alone. In this study, we investigate a novel method to capture and detect the active Ago2/miRNA (miRNP) complex and quantitate associated miRNAs by utilizing an antibody against Ago2 and subsequent application of real-time PCR to successfully capture the active miRNP complex and quantitate the associated miRNAs

Analyzing Learned Molecular Representations for Property Prediction

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors, and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule. However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has rarely examined these new models in industry research settings in comparison to existing employed models. In this paper, we benchmark models extensively on 19 public and 16 proprietary industrial datasets spanning a wide variety of chemical endpoints. In addition, we introduce a graph convolutional model that consistently matches or outperforms models using fixed molecular descriptors as well as previous graph neural architectures on both public and proprietary datasets. Our empirical findings indicate that while approaches based on these representations have yet to reach the level of experimental reproducibility, our proposed model nevertheless offers significant improvements over models currently used in industrial workflows

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy

<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1) A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2) an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3) the use of viral doses to accommodate current limitations imposed by vector production methods; 4) and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation.</p> <p>Methods</p> <p>The capacity of AAV1, AAV6 or AAV8 to cross the vascular endothelial barrier carrying a micro-dystrophin cDNA was compared under identical conditions with delivery through a catheter placed in the femoral artery of the mdx mouse. Transduction efficiency was assessed by immuno-staining using an antibody (Manex1a) that recognizes the N-terminus of micro-dystrophin. The degree of physiologic correction was assessed by measuring tetanic force and protection from eccentric contraction in the extensor digitorum longus muscle (EDL). The vascular delivery paradigm found successful in the mouse was carried to the non-human primate to test its potential translation to boys with DMD.</p> <p>Results</p> <p>Regional vascular delivery resulted in transduction by rAAV8.micro-dystrophin reaching 94.5 ± 0.9 (1 month), 91.3 ± 3.1 (2 months), and 89.6 ± 1.6% (3 months). rAAV6.micro-dystrophin treated animals demonstrated 87.7 ± 6.8 (1 month), 78.9 ± 7.4 (2 months), and 81.2 ± 6.2% (3 months) transduction. In striking contrast, rAAV1 demonstrated very low transduction efficiency [0.9 ± 0.3 (1 month), 2.1 ± 0.8 (2 months), and 2.1 ± 0.7% (3 months)] by vascular delivery. Micro-dystrophin delivered by rAAV8 and rAAV6 through the femoral artery significantly improved tetanic force and protected against eccentric contraction. Mouse studies translated to the hindlimb of cynamologous macaques using a similar vascular delivery paradigm. rAAV8 carrying eGFP in doses proportional to the mouse (5 × 10¹²vg/kg in mouse vs 2 × 10¹²vg/kg in monkey) demonstrated widespread gene expression [medial gastrocnemius – 63.8 ± 4.9%, lateral gastrocnemius – 66.0 ± 4.5%, EDL – 80.2 ± 3.1%, soleus – 86.4 ± 1.9%, TA – 72.2 ± 4.0%.</p> <p>Conclusion</p> <p>These studies demonstrate regional vascular gene delivery with AAV serotype(s) in mouse and non-human primate at doses, pressures and volumes applicable for clinical trials in children with DMD.</p

Novel sequential ChIP and simplified basic ChIP protocols for promoter co-occupancy and target gene identification in human embryonic stem cells

<p>Abstract</p> <p>Background</p> <p>The investigation of molecular mechanisms underlying transcriptional regulation, particularly in embryonic stem cells, has received increasing attention and involves the systematic identification of target genes and the analysis of promoter co-occupancy. High-throughput approaches based on chromatin immunoprecipitation (ChIP) have been widely used for this purpose. However, these approaches remain time-consuming, expensive, labor-intensive, involve multiple steps, and require complex statistical analysis. Advances in this field will greatly benefit from the development and use of simple, fast, sensitive and straightforward ChIP assay and analysis methodologies.</p> <p>Results</p> <p>We initially developed a simplified, basic ChIP protocol that combines simplicity, speed and sensitivity. ChIP analysis by real-time PCR was compared to analysis by densitometry with the ImageJ software. This protocol allowed the rapid identification of known target genes for SOX2, NANOG, OCT3/4, SOX17, KLF4, RUNX2, OLIG2, SMAD2/3, BMI-1, and c-MYC in a human embryonic stem cell line. We then developed a novel Sequential ChIP protocol to investigate <it>in vivo </it>promoter co-occupancy, which is basically characterized by the absence of antibody-antigen disruption during the assay. It combines centrifugation of agarose beads and magnetic separation. Using this Sequential ChIP protocol we found that c-MYC associates with the SOX2/NANOG/OCT3/4 complex and identified a novel RUNX2/BMI-1/SMAD2/3 complex in BG01V cells. These two TF complexes associate with two distinct sets of target genes. The RUNX2/BMI-1/SMAD2/3 complex is associated predominantly with genes not expressed in undifferentiated BG01V cells, consistent with the reported role of those TFs as transcriptional repressors.</p> <p>Conclusion</p> <p>These simplified basic ChIP and novel Sequential ChIP protocols were successfully tested with a variety of antibodies with human embryonic stem cells, generated a number of novel observations for future studies and might be useful for high-throughput ChIP-based assays.</p

Complex modeling with detailed temporal predictors does not improve health records-based suicide risk prediction

Suicide risk prediction models can identify individuals for targeted intervention. Discussions of transparency, explainability, and transportability in machine learning presume complex prediction models with many variables outperform simpler models. We compared random forest, artificial neural network, and ensemble models with 1500 temporally defined predictors to logistic regression models. Data from 25,800,888 mental health visits made by 3,081,420 individuals in 7 health systems were used to train and evaluate suicidal behavior prediction models. Model performance was compared across several measures. All models performed well (area under the receiver operating curve [AUC]: 0.794-0.858). Ensemble models performed best, but improvements over a regression model with 100 predictors were minimal (AUC improvements: 0.006-0.020). Results are consistent across performance metrics and subgroups defined by race, ethnicity, and sex. Our results suggest simpler parametric models, which are easier to implement as part of routine clinical practice, perform comparably to more complex machine learning methods

Multi-Ancestry Genome-Wide Association Analyses Improve Resolution of Genes and Pathways Influencing Lung Function and Chronic Obstructive Pulmonary Disease Risk

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

Worldwide Argus II implantation: recommendations to optimize patient outcomes

Abstract Background A position paper based on the collective experiences of Argus II Retinal Prosthesis System investigators to review strategies to optimize outcomes in patients with retinitis pigmentosa undergoing retinal prosthesis implantation. Methods Retinal surgeons, device programmers, and rehabilitation specialists from Europe, Canada, Middle East, and the United States were convened to the first international Argus II Investigator Meeting held in Ann Arbor, MI in March 2015. The recommendations from the collective experiences were collected. Factors associated with successful outcomes were determined. Results Factors leading to successful outcomes begin with appropriate patient selection, expectation counseling, and preoperative retinal assessment. Challenges to surgical implantation include presence of staphyloma and inadequate Tenon’s capsule or conjunctiva. Modified surgical technique may reduce risks of complications such as hypotony and conjunctival erosion. Rehabilitation efforts and correlation with validated outcome measures following implantation are critical. Conclusions Bringing together Argus II investigators allowed the identification of strategies to optimize patient outcomes. Establishing an on-line collaborative network will foster coordinated research efforts to advance outcome assessment and rehabilitation strategies.http://deepblue.lib.umich.edu/bitstream/2027.42/134581/1/12886_2016_Article_225.pd

Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders

Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood–brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations