Sharing and Reusing Computable Phenotype Definitions.

Background: A scalable approach for the sharing and reuse of human-readable and computer-executable phenotype definitions can facilitate the reuse of electronic health records for cohort identification and research studies. Description: We developed a tool called Sharephe for the Informatics for Integrating Biology and the Bedside (i2b2) platform. Sharephe consists of a plugin for i2b2 and a cloud-based searchable repository of computable phenotypes, has the functionality to import to and export from the repository, and has the ability to link to supporting metadata. Discussion: The i2b2 platform enables researchers to create, evaluate, and implement phenotypes without knowing complex query languages. In an initial evaluation, two sites on the Evolve to Next-Gen ACT (ENACT) network used Sharephe to successfully create, share, and reuse phenotypes. Conclusion: The combination of a cloud-based computable repository and an i2b2 plugin for accessing the repository enables investigators to store and retrieve phenotypes from anywhere and at any time and to collaborate across sites in a research network.

The Impact of Cognitive Impairment on Robot-Based Upper-Limb Motor Assessment in Chronic Stroke.

BACKGROUND: Chronic upper extremity motor deficits are present in up to 65% of stroke survivors, and cognitive impairment is prevalent in 46-61% of stroke survivors even 10 years after their stroke. Robot-assisted therapy programs tend to focus on motor recovery and do not include stroke patients with cognitive impairment. OBJECTIVE: This study aims to investigate performance on the individual cognitive domains evaluated in the MoCA and their relation to upper-limb motor performance on a robotic system. METHODS: Participants were recruited from the stroke population with a wide range of cognitive and motor levels to complete a trajectory tracking task using the Haptic TheraDrive rehabilitation robot system. Motor performance was evaluated against standard clinical cognitive and motor assessments. Our hypothesis is that the cognitive domains involved in the visuomotor tracking task are significant predictors of performance on the robot-based task and that impairment in these domains results in worse motor performance on the task compared to subjects with no cognitive impairment. RESULTS: Our results support the hypothesis that visuospatial and executive function have a significant impact on motor performance, with differences emerging between different functional groups on the various robot-based metrics. We also show that the kinematic metrics from this task differentiate cognitive-motor functional groups differently. CONCLUSION: This study demonstrates that performance on a motor-based robotic assessment task also involves a significant visuospatial and executive function component and highlights the need to account for cognitive impairment in the assessment of motor performance.

Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell-specific manner.

Hematopoietic protein-1 (Hem-1) is a member of the actin-regulatory WASp family verprolin homolog (WAVE) complex. Loss-of-function variants in the NCKAP1L gene encoding Hem-1 were recently discovered to result in primary immunodeficiency disease (PID) in children, characterized by poor specific Ab responses, increased autoantibodies, and high mortality. However, the mechanisms of how Hem-1 deficiency results in PID are unclear. In this study, we utilized constitutive and B cell-specific Nckap1l-KO mice to dissect the importance of Hem-1 in B cell development and functions. B cell-specific disruption of Hem-1 resulted in reduced numbers of recirculating follicular (FO), marginal zone (MZ), and B1 B cells. B cell migration in response to CXCL12 and -13 were reduced. T-independent Ab responses were nearly abolished, resulting in failed protective immunity to Streptococcus pneumoniae challenge. In contrast, T-dependent IgM and IgG2c, memory B cell, and plasma cell responses were more robust relative to WT control mice. B cell-specific Hem-1-deficient mice had increased autoantibodies against multiple autoantigens, and this correlated with hyperresponsive BCR signaling and increased representation of CD11c+T-bet+ age-associated B cell (ABC cells) - alterations associated with autoimmune diseases. These results suggest that dysfunctional B cells may be part of a mechanism explaining why loss-of-function Hem-1 variants result in recurring infections and autoimmunity.

Robot-Based Assessment of HIV-Related Motor and Cognitive Impairment for Neurorehabilitation.

There is a pressing need for strategies to slow or treat the progression of functional decline in people living with HIV. This paper explores a novel rehabilitation robotics approach to measuring cognitive and motor impairment in adults living with HIV, including a subset with stroke. We conducted a cross-sectional study with 21 subjects exhibiting varying levels of cognitive and motor impairment. We tested three robot-based tasks - trajectory tracking, N-back, and spatial span - to assess if metrics derived from these tasks were sensitive to differences in subjects with varying levels of executive function and upper limb motor impairments. We also examined how well these metrics could estimate clinical cognitive and motor scores. The results showed that the average sequence length on the robot-based spatial span task was the most sensitive to differences between various cognitive and motor impairment levels. We observed strong correlations between robot-based measures and clinical cognitive and motor assessments relevant to the HIV population, such as the Color Trails 1 (rho = 0.83), Color Trails 2 (rho = 0.71), Digit Symbol - Coding (rho = 0.81), Montreal Cognitive Assessment - Executive Function subscore (rho = 0.70), and Box and Block Test (rho = 0.74). Importantly, our results highlight that gross motor impairment may be overlooked in the assessment of HIV-related disability. This study shows that rehabilitation robotics can be expanded to new populations beyond stroke, namely to people living with HIV and those with cognitive impairments.

Robot-based assessment of HIV-related motor and cognitive impairment for neurorehabilitation.

There is a pressing need for strategies to slow or treat the progression of functional decline in people living with HIV. This paper explores a novel rehabilitation robotics approach to measuring cognitive and motor impairment in adults living with HIV, including a subset with stroke. We conducted a cross-sectional study with 21 subjects exhibiting varying levels of cognitive and motor impairment. We developed three robot-based tasks trajectory tracking, N-back, and spatial span - to assess if metrics derived from these tasks were sensitive to differences in subjects with varying levels of executive function and upper limb motor impairments. We also examined if these metrics could estimate clinical cognitive and motor scores. The results showed that the average sequence length on the robot-based spatial span task was the most sensitive to differences between subjects' cognitive and motor impairment levels. We observed strong correlations between robot-based measures and clinical cognitive and motor assessments relevant to the HIV population, such as the Color Trails 1 (rho = 0.83), Color Trails 2 (rho = 0.71), Digit Symbol - Coding (rho = 0.81), Montreal Cognitive Assessment - Executive Function subscore (rho = 0.70), and Box and Block Test (rho = 0.74). Importantly, our results highlight that gross motor impairment may be overlooked in the assessment of HIV-related disability. This study shows that rehabilitation robotics can be expanded to new populations beyond stroke, namely to people living with HIV and those with cognitive impairments.

During infant maltreatment, stress targets hippocampus, but stress with mother present targets amygdala and social behavior.

Infant maltreatment increases vulnerability to physical and mental disorders, yet specific mechanisms embedded within this complex infant experience that induce this vulnerability remain elusive. To define critical features of maltreatment-induced vulnerability, rat pups were reared from postnatal day 8 (PN8) with a maltreating mother, which produced amygdala and hippocampal deficits and decreased social behavior at PN13. Next, we deconstructed the maltreatment experience to reveal sufficient and necessary conditions to induce this phenotype. Social behavior and amygdala deficits (volume, neurogenesis, c-Fos, local field potential) required combined chronic high corticosterone and maternal presence (not maternal behavior). Hippocampal deficits were induced by chronic high corticosterone regardless of social context. Causation was shown by blocking corticosterone during maltreatment and suppressing amygdala activity during social behavior testing. These results highlight (1) that early life maltreatment initiates multiple pathways to pathology, each with distinct causal mechanisms and outcomes, and (2) the importance of social presence on brain development.

Robot-Based Measures of Upper Limb Cognitive-Motor Interference Across the HIV-Stroke Spectrum.

Robot-based neurorehabilitation strategies often ignore cognitive performance during treatment, but this is a need in populations dealing with a wide variety of cognitive and motor impairments, such as the stroke and HIV populations, for which an association between the two have been established. In this study, we concurrently measure cognitive and motor performance on a robotic cognitive-motor task and quantify cognitive-motor interference. We apply this method to a pilot group of healthy, stroke, and HIV-stroke subjects, and we demonstrate the potential of smoothness and correct response rate as metrics to capture motor and cognitive-related dual-task effects.

Functional status-based risk-benefit analyses of high-KDPI kidney transplant versus dialysis.

Yearly, over half of deceased-donor kidneys with kidney donor profile index (KDPI) > 85 were discarded, yet they could improve survival outcomes for dialysis patients. The potential risk of high-KDPI kidney transplant (KT) depends on the patient's overall health summarized by functional status, which should be examined. The analyzed cohort consisted of adult deceased-donor KT candidates on dialysis listed in 2005-2014. A multivariate Cox proportional hazards model was fitted with functional status, measured using Karnofsky Performance Score (KPS), and transplant status as time-varying covariates. Derived from the Cox model, survival curves were analyzed to compare the survival outcomes between dialysis and transplant with different kidney qualities across three different KPS strata: 10-40, 50-70, and 80-100. With KDPI 0-99 KT, KPS 10-40 patients will survive ≥4.38 years median compared with 3.21 years median if they remained on dialysis. For KPS 50+ patients, the median survival years increase from 5.82 to 6.60 years on dialysis to ≥7.83 years after KDPI < 100 KT. The risk-adjusted analyses suggested that patients are expected to benefit more from KDPI 81-99 KT than from remaining on dialysis.

Mouse Extraocular Muscles and the Musculotopic Organization of Their Innervation.

The organization of extraocular muscles (EOMs) and their motor nuclei was investigated in the mouse due to the increased importance of this model for oculomotor research. Mice showed a standard EOM organization pattern, although their eyes are set at the side of the head. They do have more prominent oblique muscles, whose insertion points differ from those of frontal-eyed species. Retrograde tracers revealed that the motoneuron layout aligns with the general vertebrate plan with respect to nuclei and laterality. The mouse departed in some significant respects from previously studied species. First, more overlap between the distributions of muscle-specific motoneuronal pools was present in the oculomotor nucleus (III). Furthermore, motoneuron dendrites for each pool filled the entire III and extended beyond the edge of the abducens nucleus (VI). This suggests mouse extraocular motoneuron afferents must target specific pools based on features other than dendritic distribution and nuclear borders. Second, abducens internuclear neurons are located outside the VI. We concluded this because no unlabeled abducens internuclear neurons were observed following lateral rectus muscle injections and because retrograde tracer injections into the III labeled cells immediately ventral and ventrolateral to the VI, not within it. This may provide an anatomical substrate for differential input to motoneurons and internuclear neurons that allows rodents to move their eyes more independently. Finally, while soma size measurements suggested motoneuron subpopulations supplying multiply and singly innervated muscle fibers are present, markers for neurofilaments and perineuronal nets indicated overlap in the size distributions of the two populations. Anat Rec, 302:1865-1885, 2019. © 2019 American Association for Anatomy.

Evaluation of Accepting Kidneys of Varying Quality for Transplantation or Expedited Placement With Decision Trees.

BACKGROUND: Underutilization of marginal-quality kidneys for transplantation produced ideas of expediting kidney placement for populations with decreased opportunities of receiving transplants. Such policies can be less efficacious for specific individuals and should be scrutinized until the decision-making for accepting marginal-quality organs, which has relied on experiential judgment, is better understood at the individual level. There exist rigorous tools promoting personalized decisions with useful and objective information. METHODS: This article introduces a decision-tree methodology that analyzes a patient's dilemma: to accept a kidney offer now or reject it. The methodology calculates the survival benefit of accepting a kidney given a certain quality now and the survival benefit of rejecting it. Survival benefit calculation accounts for patients' and donors' characteristics and transplant centers' and organ procurement organizations' performances and incorporates patients' perceived transplant and dialysis utilities. Valuations of rejecting an offer are contingent on future opportunities and subject to uncertainty in the timing of successive kidney offers and their quality and donor characteristics. RESULTS: The decision tree was applied to a realistic patient profile as a demonstration. The tool was tested on 1000 deceased-donor kidney offers in 2016. Evaluating up to 1 year of future offers, the tool attains 61% accuracy, with transplant utility of 1.0 and dialysis utility of 0.5. The accuracy reveals potential bias in kidney offer acceptance/rejection at transplant centers. CONCLUSIONS: The decision-tree tool presented could aid personalized transplant decision-making in the future by providing patients with calculated, individualized survival benefits between accepting and rejecting a kidney offer.

Demographic and facility volume related outcomes in radiofrequency ablation for early-stage hepatocellular carcinoma.

BACKGROUND: To evaluate outcomes related to disparities in facility volume and patient demographics in patients with early-stage hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA). METHODS: This is a retrospective study of patients with stage I/II HCC treated with RFA in the National Cancer Database. Independent contributors to overall survival were determined with Cox regression analysis. The Kaplan-Meier method and log-rank analyses were used to estimate overall survival and compare survival curves. A propensity score matched cohort analysis was performed. P-values < 0.05 were considered statistically significant. RESULTS: In total, 2911 patients were included. Stage II disease (p-value = 0.006), increasing alpha fetoprotein (p-value = 0.007), and increasing bilirubin (p-value < 0.001) were associated with worse survival. Improved survival was seen in patients treated at high-volume centers (p-value = 0.004), which persisted following propensity score adjustment (p-value = 0.003). Asian race was associated with significantly improved survival (p-value < 0.001), while governmental insurance was associated with a significant decrease in survival (p-value < 0.001). CONCLUSION: Treatment at a high-volume center and Asian race were significantly associated with improved survival following RFA for early-stage HCC. Governmental insurance, increasing alpha fetoprotein, increasing bilirubin, and higher disease stage were significantly associated with worse survival.

Patient Functional Status at Transplant and Its Impact on Posttransplant Survival of Adult Deceased-donor Kidney Recipients.

BACKGROUND: Recorded at the time of transplant and reported to the Organ Procurement and Transplantation Network, patient's functional status is measured using the Karnofsky performance score (KPS), ranging 0 to 100. Functional status analysis may provide insights on candidate listing and posttransplant survival outcomes for deceased-donor kidney transplants. METHODS: The cohort consisted of adult deceased-donor kidney transplant recipients transplanted beginning January 2007. One-year and 3-year Cox models for posttransplant survival were fitted with current Scientific Registry of Transplant Recipients (SRTR) variables and KPS. Comparative analyses were performed between the SRTR model without KPS and augmented model with it. Using the augmented model, we examined the impact of Kidney Donor Profile Index on posttransplant survivals for 5 different KPS strata: 10 to 30, 40 to 50, 60 to 70, 80 to 90, and 100. RESULTS: Comparative analyses showed that KPS was a statistically significant predictor for posttransplant survival: it improved model calibration, discrimination, and predictive accuracy. From the augmented model, the survival curves illustrated that recipients with KPS 40 to 50 and kidneys with Kidney Donor Profile Index as high as 99 have expected survival probabilities of above 90% in 1 year and above 80% in 3 years. The expected survival probabilities improve as KPS increases. Recipients with KPS 10 to 30 have the worst survival probability, even if they received high-quality kidneys. CONCLUSIONS: Insights from the survival analyses recommend possible inclusion of functional status into SRTR's risk-adjusted models. Moreover, they invite further examination of its use to improve current listing and transplantation strategies at transplant centers and potentially reduce deceased-donor kidney discard rate.

Towards Robot-Based Cognitive and Motor Assessment Across the HIV-Stroke Spectrum.

There is an increasing population of people living with both HIV and stroke around the world with no effective neurorehabilitation strategies to deal with the combination of physical, cognitive, and social impairment that result from both diseases. This gap is caused by a lack of tools that are able to assess the various impairments across the HIV-stroke spectrum. Rehabilitation robotics provide a potential approach to address this problem. In this study, we implement a motor and cognitive task on the Haptic TheraDrive, a single degree-of-freedom upper limb rehabilitation robot. We collect data on healthy and HIV-stroke subjects from both upper limbs. Our preliminary data show that mean performance error on a trajectory tracking task and total score and reaction time on the n-back task are metrics that show differences between HIV-stroke patients and a healthy population.

Patient and Facility Demographics Related Outcomes in Early-Stage Non-Small Cell Lung Cancer Treated with Radiofrequency Ablation: A National Cancer Database Analysis.

PURPOSE: To determine facility and patient demographics associated with survival in early-stage non-small cell lung cancer (NSCLC) treated with radiofrequency (RF) ablation. MATERIALS AND METHODS: The National Cancer Database was queried for cases of stage 1a NSCLC treated with RF ablation without chemotherapy or radiotherapy from 2004 to 2014. High-volume centers (HVCs) were defined as the top 95th percentile of facilities by number of procedures performed. Overall survival (OS) was estimated with the Kaplan-Meier method, and comparisons between survival curves were performed with the log-rank test. Propensity score-matched cohort analysis was performed. P values less than .05 were considered statistically significant. RESULTS: In the final cohort, 967 cases were included. Estimated median survival and follow-up were 33.1 and 62.5 months, respectively. Of 305 facilities, 15 were determined to be HVCs, treating 13 or more patients from 2004 to 2014. A total of 335 cases (34.6%) were treated at HVCs. On multivariate Cox regression analysis, treatment at an HVC was independently associated with improved OS (hazard ratio [HR] = 0.766; P = .006). After propensity score adjustment, 1-, 3-, and 5-year OS was 89.8%, 51.2%, and 27.7%, respectively, for patients treated at HVCs, compared to 85.2%, 41.5%, and 19.6%, respectively, for patients treated at non-HVCs (P = .015). Increasing age (HR = 1.012; P = .013) and higher T-classification (HR = 1.392; P < .001) were independently associated with worse OS. CONCLUSION: Patients with early-stage NSCLC treated with RF ablation at HVCs experienced a significant increase in OS, suggesting regionalization of lung cancer management as a means of improving outcomes.

Designing robot-assisted neurorehabilitation strategies for people with both HIV and stroke.

There is increasing evidence that HIV is an independent risk factor for stroke, resulting in an emerging population of people living with both HIV and stroke all over the world. However, neurorehabilitation strategies for the HIV-stroke population are distinctly lacking, which poses an enormous global health challenge. In order to address this gap, a better understanding of the HIV-stroke population is needed, as well as potential approaches to design effective neurorehabilitation strategies for this population. This review goes into the mechanisms, manifestations, and treatment options of neurologic injury in stroke and HIV, the additional challenges posed by the HIV-stroke population, and rehabilitation engineering approaches for both high and low resource areas. The aim of this review is to connect the underlying neurologic properties in both HIV and stroke to rehabilitation engineering. It reviews what is currently known about the association between HIV and stroke and gaps in current treatment strategies for the HIV-stroke population. We highlight relevant current areas of research that can help advance neurorehabilitation strategies specifically for the HIV-stroke population. We then explore how robot-assisted rehabilitation combined with community-based rehabilitation could be used as a potential approach to meet the challenges posed by the HIV-stroke population. We include some of our own work exploring a community-based robotic rehabilitation exercise system. The most relevant strategies will be ones that not only take into account the individual status of the patient but also the cultural and economic considerations of their respective environment.

A National Cancer Database Analysis of Radiofrequency Ablation versus Stereotactic Body Radiotherapy in Early-Stage Non-Small Cell Lung Cancer.

PURPOSE: To compare overall survival (OS) after radiofrequency (RF) ablation and stereotactic body radiotherapy (SBRT) at high-volume centers in patients with early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Cases in the National Cancer Database of stage 1a and 1b NSCLC treated with primary RF ablation or SBRT from 2004 to 2014 were included. Patients treated at low-volume centers, defined as facilities below the 95th percentile in volume of cases performed, were excluded. Outcomes measured include OS and rate of 30-day readmission. The Kaplan-Meier method was used to estimate OS. The log-rank test was used to compare survival curves. Propensity score matched cohort analysis was performed. P < .05 was considered statistically significant. RESULTS: The final cohort comprised 4,454 cases of SBRT and 335 cases of RF ablation. Estimated median survival and follow-up were 38.8 months and 42.0 months, respectively. Patients treated with RF ablation had significantly more comorbidities (P < .001) and higher risk for an unplanned readmission within 30 days (hazard ratio = 11.536; P < .001). No difference in OS for the unmatched groups was found on multivariate Cox regression analysis (P = .285). No difference was found in the matched groups with 1-, 3-, and 5-year OS of 85.5%, 54.3%, and 31.9% in the SBRT group vs 89.3%, 52.7%, and 27.1% in the RF ablation group (P = .835). CONCLUSIONS: No significant difference in OS was seen between patients with early-stage NSCLC treated with RF ablation and SBRT.

Radiogenomics and IR.

Radiogenomics involves the integration of mineable data from imaging phenotypes with genomic and clinical data to establish predictive models using machine learning. As a noninvasive surrogate for a tumor's in vivo genetic profile, radiogenomics may potentially provide data for patient treatment stratification. Radiogenomics may also supersede the shortcomings associated with genomic research, such as the limited availability of high-quality tissue and restricted sampling of tumoral subpopulations. Interventional radiologists are well suited to circumvent these obstacles through advancements in image-guided tissue biopsies and intraprocedural imaging. Comprehensive understanding of the radiogenomic process is crucial for interventional radiologists to contribute to this evolving field.

A Concentric Neighborhood Solution to Disparity in Liver Access That Contains Current UNOS Districts.

BACKGROUND: Policymakers are deliberating reforms to reduce geographic disparity in liver allocation. Public comments and the United Network for Organ Sharing Liver and Intestinal Committee have expressed interest in refining the neighborhoods approach. Share 35 and Share 15 policies affect geographic disparity. METHODS: We construct concentric neighborhoods superimposing the current 11 regions. Using concepts from concentric circles, we construct neighborhoods for each donor service area (DSA) that consider all DSAs within 400, 500, or 600 miles as neighbors. We consider limiting each neighborhood to 10 DSAs and use no metrics for liver supplies and demands. We change Model for End-Stage Liver Disease (MELD) thresholds for the Share 15 policy to 18 or 20 and apply 3- and 5-point MELD proximity boosts to enhance local priority, control travel distances, and reduce disparity. We conduct simulations comparing current allocation with the neighborhoods and sharing policies. RESULTS: Concentric neighborhoods structures provide an array of solutions where simulation results indicate that they reduce geographic disparity, annual mortalities, and the airplane travel distances by varying degrees. Tuning of the parameters and policy combinations can lead to beneficial improvements with acceptable transplant volume loss and reductions in geographic disparity and travel distance. Particularly, the 10-DSA, 500-mile neighborhood solution with Share 35, Share 15, and 0-point MELD boost achieves such while limiting transplant volume losses to below 10%. CONCLUSIONS: The current 11 districts can be adapted systematically by adding neighboring DSAs to improve geographic disparity, mortality, and airplane travel distance. Modifications to Share 35 and Share 15 policies result in further improvements. The solutions may be refined further for implementation.

End-to-end workflow for finite element analysis of tumor treating fields in glioblastomas.

Tumor Treating Fields (TTFields) therapy is an approved modality of treatment for glioblastoma. Patient anatomy-based finite element analysis (FEA) has the potential to reveal not only how these fields affect tumor control but also how to improve efficacy. While the automated tools for segmentation speed up the generation of FEA models, multi-step manual corrections are required, including removal of disconnected voxels, incorporation of unsegmented structures and the addition of 36 electrodes plus gel layers matching the TTFields transducers. Existing approaches are also not scalable for the high throughput analysis of large patient volumes. A semi-automated workflow was developed to prepare FEA models for TTFields mapping in the human brain. Magnetic resonance imaging (MRI) pre-processing, segmentation, electrode and gel placement, and post-processing were all automated. The material properties of each tissue were applied to their corresponding mask in silico using COMSOL Multiphysics (COMSOL, Burlington, MA, USA). The fidelity of the segmentations with and without post-processing was compared against the full semi-automated segmentation workflow approach using Dice coefficient analysis. The average relative differences for the electric fields generated by COMSOL were calculated in addition to observed differences in electric field-volume histograms. Furthermore, the mesh file formats in MPHTXT and NASTRAN were also compared using the differences in the electric field-volume histogram. The Dice coefficient was less for auto-segmentation without versus auto-segmentation with post-processing, indicating convergence on a manually corrected model. An existent but marginal relative difference of electric field maps from models with manual correction versus those without was identified, and a clear advantage of using the NASTRAN mesh file format was found. The software and workflow outlined in this article may be used to accelerate the investigation of TTFields in glioblastoma patients by facilitating the creation of FEA models derived from patient MRI datasets.