MRI-Based Classification of Neuropsychiatric Systemic Lupus Erythematosus Patients With Self-Supervised Contrastive Learning.

INTRODUCTION/PURPOSE: Systemic lupus erythematosus (SLE) is a chronic auto-immune disease with a broad spectrum of clinical presentations, including heterogeneous neuropsychiatric (NP) syndromes. Structural brain abnormalities are commonly found in SLE and NPSLE, but their role in diagnosis is limited, and their usefulness in distinguishing between NPSLE patients and patients in which the NP symptoms are not primarily attributed to SLE (non-NPSLE) is non-existent. Self-supervised contrastive learning algorithms proved to be useful in classification tasks in rare diseases with limited number of datasets. Our aim was to apply self-supervised contrastive learning on T1-weighted images acquired from a well-defined cohort of SLE patients, aiming to distinguish between NPSLE and non-NPSLE patients. SUBJECTS AND METHODS: We used 3T MRI T1-weighted images of 163 patients. The training set comprised 68 non-NPSLE and 34 NPSLE patients. We applied random geometric transformations between iterations to augment our data sets. The ML pipeline consisted of convolutional base encoder and linear projector. To test the classification task, the projector was removed and one linear layer was measured. Validation of the method consisted of 6 repeated random sub-samplings, each using a random selection of a small group of patients of both subtypes. RESULTS: In the 6 trials, between 79% and 83% of the patients were correctly classified as NPSLE or non-NPSLE. For a qualitative evaluation of spatial distribution of the common features found in both groups, Gradient-weighted Class Activation Maps (Grad-CAM) were examined. Thresholded Grad-CAM maps show areas of common features identified for the NPSLE cohort, while no such communality was found for the non-NPSLE group. DISCUSSION/CONCLUSION: The self-supervised contrastive learning model was effective in capturing common brain MRI features from a limited but well-defined cohort of SLE patients with NP symptoms. The interpretation of the Grad-CAM results is not straightforward, but indicates involvement of the lateral and third ventricles, periventricular white matter and basal cisterns. We believe that the common features found in the NPSLE population in this study indicate a combination of tissue loss, local atrophy and to some extent that of periventricular white matter lesions, which are commonly found in NPSLE patients and appear hypointense on T1-weighted images.

Pharmacologic Activation of STING in the Bladder Induces Potent Antitumor Immunity in Non-Muscle Invasive Murine Bladder Cancer.

Stimulator of interferon genes (STING) is an innate immune receptor activated by natural or synthetic agonists to elicit antitumoral immune response via type I IFNs and other inflammatory cytokines. Bacillus Calmette-Guerin (BCG) is the standard of care as intravesical therapy for patients with high-risk non-muscle invasive bladder cancer (NMIBC). There are limited options available for patients with NMIBC who developed BCG unresponsiveness. In this study, we characterized in vitro and in vivo antitumor effects of E7766, a macrocyle-bridged STING agonist, via intravesical instillation in two syngeneic orthotopic murine NMIBC tumor models resistant to therapeutic doses of BCG and anti-PD-1 agents. E7766 bound to recombinant STING protein with a Kd value of 40 nmol/L and induced IFNß expression in primary human peripheral blood mononuclear cells harboring any of seven major STING genotypes with EC50 values of 0.15 to 0.79 µmol/L. Intravesical E7766 was efficacious in both NMIBC models with induction of effective immunologic memory in the treated animals. Pharmacologic activation of the STING pathway in the bladder resulted in IFN pathway activation, infiltration of T cells and natural killer (NK) cells, dendritic cell activation, and antigen presentation in bladder epithelium, leading to the antitumor activity and immunity. In addition, measurements of the pharmacodynamic markers, Ifnß1 and CXCL10, in bladder, urine, and plasma, and of STING pathway intactness in cancer cells, supported this mode of action. Taken together, our studies reveal an antitumor immune effect of pharmacologic activation of the STING pathway in bladder epithelium and thus provide a rationale for subsequent clinical studies in patients with NMIBC.

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity.

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.

Prediction of Transporter-Mediated Drug-Drug Interactions and Phenotyping of Hepatobiliary Transporters Involved in the Clearance of E7766, a Novel Macrocycle-Bridged Dinucleotide.

E7766 represents a novel class of macrocycle-bridged dinucleotides and is under clinical development for immuno-oncology. In this report, we identified mechanism of systemic clearance E7766 and investigated the hepatobiliary transporters involved in the disposition of E7766 and potential drug interactions of E7766 as a victim of organic anion-transporting polypeptide (OATP) inhibitors. In bile-duct cannulated rats and dogs, E7766 was mainly excreted unchanged in bile (>80%) and to a lesser extent in urine (<20%). Sandwich-cultured human hepatocytes (SCHHs), transfected cells, and vesicles were used to phenotype the hepatobiliary transporters involved in the clearance of E7766. SCHH data showed temperature-dependent uptake of E7766 followed by active biliary secretion. In vitro transport assays using transfected cells and membrane vesicles confirmed that E7766 was a substrate of OATP1B1, OATP1B3, and multidrug resistance-associated protein 2. Phenotyping studies suggested predominant contribution of OATP1B3 over OATP1B1 in the hepatic uptake of E7766. Studies in OATP1B1/1B3 humanized mice showed that plasma exposure of E7766 increased 4.5-fold when coadministered with Rifampicin. Physiologically based pharmacokinetic models built upon two independent bottom-up approaches predicted elevation of E7766 plasma exposure when administered with Rifampicin, a clinical OATP inhibitor. In conclusion, we demonstrate that OATP-mediated hepatic uptake is the major contributor to the clearance of E7766, and inhibition of OATP1B may increase its systemic exposure. Predominant contribution of OATP1B3 in the hepatic uptake of E7766 was observed, suggesting polymorphisms in OATP1B1 would be unlikely to cause variability in the exposure of E7766. SIGNIFICANCE STATEMENT: Understanding the clearance mechanisms of new chemical entities is critical to predicting human pharmacokinetics and drug interactions. A physiologically based pharmacokinetic model that incorporated parameters from mechanistic in vitro and in vivo experiments was used to predict pharmacokinetics and drug interactions of E7766, a novel dinucleotide drug. The findings highlighted here may shed a light on the pharmacokinetic profile and transporter-mediated drug interaction propensity of other dinucleotide drugs.

Prediction of motor recovery using indirect connectivity in a lesion network after ischemic stroke.

BACKGROUND: Recovery prediction can assist in the planning for impairment-focused rehabilitation after a stroke. This study investigated a new prediction model based on a lesion network analysis. To predict the potential for recovery, we focused on the next link-step connectivity of the direct neighbors of a lesion. METHODS: We hypothesized that this connectivity would contribute to recovery after stroke onset. Each lesion in a patient who had suffered a stroke was transferred to a healthy subject. First link-step connectivity was identified by observing voxels functionally connected to each lesion. Next (second) link-step connectivity of the first link-step connectivity was extracted by calculating statistical dependencies between time courses of regions not directly connected to a lesion and regions identified as first link-step connectivity. Lesion impact on second link-step connectivity was quantified by comparing the lesion network and reference network. RESULTS: The lower the impact of a lesion was on second link-step connectivity in the brain network, the better the improvement in motor function during recovery. A prediction model containing a proposed predictor, initial motor function, age, and lesion volume was established. A multivariate analysis revealed that this model accurately predicted recovery at 3 months poststroke (R 2 = 0.788; cross-validation, R 2 = 0.746, RMSE = 13.15). CONCLUSION: This model can potentially be used in clinical practice to develop individually tailored rehabilitation programs for patients suffering from motor impairments after stroke.

Biomechanics of Long Cane Use.

INTRODUCTION: The modern long cane has been used by people who are blind for traveling for decades. This article describes parameters surrounding the collection of over 10,000 trials of people walking with the long cane to detect drop-offs or obstacles. METHODS: The data include 10,069 trials representing 101 different participants in 366 conditions over 11 studies spanning the 9 years from 2007 to 2016. Each of the studies investigated different participant or cane characteristics or both in terms of their effect on either drop-off or obstacle detection. Results of detection performance in these studies appear in other articles. This article describes biomechanical measures derived from 3-D motion analysis equipment used during the studies. RESULTS: Initial treatment of the large data set indicated that participants tended to not center their cane arc laterally on their body, deviating up to about 20 centimeters from midline. Arc widths averaged almost a meter, and arcs were generally centered. Participants were generally poor at being in step or having consistent rhythm. Coverage rates averaged about 85%. DISCUSSION: Although participants might have demonstrated artificially high skill performance due to being in a research study, data do offer insights into mechanical performance of skills. This survey of the data set indicates that not centering the hand holding the cane does not decrease body coverage less than about 85%. However, further analyses will be conducted to delve more deeply into all aspects of the data. IMPLICATIONS FOR PRACTITIONERS: Basic cane skills can be taught with short sessions and massed practice. Novices can acquire basic cane skills on par with cane users who are blind, but individual differences exist and the interplay of biomechanical variables needs to more fully understood.

An Intersection Database Facilitates Access to Complex Signalized Intersections for Pedestrians with Vision Disabilities.

A growing number of intersections and crosswalks pose barriers to pedestrians with vision disabilities. This project investigated the effects of providing verbal descriptions of intersections and crosswalks on the performance of street-crossing subtasks by individuals who are totally blind. The authors designed an intersection database containing information relevant to crossing subtasks such as finding and aligning with the crosswalk, deciding when to cross, remaining in the crosswalk, and recognizing the end of a crossing. The authors conducted an experiment with 22 blind adults at two intersections in Portland, Oregon. The intersections included crosswalks that varied widely in geometric and operational characteristics, including the presence or absence of accessibility features. In the no database condition, participants used their typical street-crossing procedures. In the database condition, participants additionally listened to database-generated descriptions of the intersections and crosswalks before crossing. The database descriptions had significant positive effects on some subtasks (primarily "crossing" subtasks such as deciding when to cross) and not others (primarily "wayfinding" subtasks such as remaining in the crosswalk). Participants' reports of the usefulness of specific features of the database were supported by the empirical findings. Implications of the findings for database development, transportation engineers, blind pedestrians, and orientation and mobility specialists are discussed.

Synthesis of a Polycyclic Halichondrin C1-C14 Fragment via Intermolecular Oxy-Michael/ Trans-Ketalization.

Syntheses of a crystalline polycyclic halichondrin C1-C14 building block starting from a d-gulono-1,4-lactone-derived intermediate in the current Halaven manufacturing process are described. Key features of the syntheses include an acid-catalyzed tandem intermolecular oxy-Michael/intramolecular trans-ketalization reaction and stereoselective Kishi reductions.

Synthesis of the Halichondrin C1-C15 Fragment from a Halaven C27-C35 Byproduct: Stereospecific Intramolecular Kishi Reduction.

A byproduct from a Halaven C27-C35 manufacturing process was transformed into a crystalline halichondrin C1-C15 building block by employing a stereospecific intramolecular Kishi reduction as the key step.

Modulating Brain Connectivity by Simultaneous Dual-Mode Stimulation over Bilateral Primary Motor Cortices in Subacute Stroke Patients.

Repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used for the modulation of stroke patients' motor function. Recently, more challenging approaches have been studied. In this study, simultaneous stimulation using both rTMS and tDCS (dual-mode stimulation) over bilateral primary motor cortices (M1s) was investigated to compare its modulatory effects with single rTMS stimulation over the ipsilesional M1 in subacute stroke patients. Twenty-four patients participated; 12 participants were assigned to the dual-mode stimulation group while the other 12 participants were assigned to the rTMS-only group. We assessed each patient's motor function using the Fugl-Meyer assessment score and acquired their resting-state fMRI data at two times: prior to stimulation and 2 months after stimulation. Twelve healthy subjects were also recruited as the control group. The interhemispheric connectivity of the contralesional M1, interhemispheric connectivity between bilateral hemispheres, and global efficiency of the motor network noticeably increased in the dual-mode stimulation group compared to the rTMS-only group. Contrary to the dual-mode stimulation group, there was no significant change in the rTMS-only group. These data suggested that simultaneous dual-mode stimulation contributed to the recovery of interhemispheric interaction than rTMS only in subacute stroke patients. This trial is registered with NCT03279640.

Alteration and Role of Interhemispheric and Intrahemispheric Connectivity in Motor Network After Stroke.

This study investigated local and global changes in the motor network using longitudinal resting-state functional magnetic resonance imaging (rs-fMRI). Motor impairment was measured in 81 stroke patients using Fugl-Meyer assessment on the same day as rs-fMRI acquisition at both 2 weeks and 3 months post-stroke. The relationships between network measures and motor function scores were assessed. With regard to local connectivity, interhemispheric connectivity was noticeably altered at each time point. Interhemispheric connectivity was also related to residual motor function and improvement in motor function. The anterior intraparietal sulcus and other well-known primary and secondary motor-related regions played important roles in motor function. Changes in global connectivity according to stroke type and initial severity were investigated. In global connectivity, interhemispheric connectivity was disrupted at 2 weeks post-stroke regardless of stroke type and initial severity. During the recovery period, interhemispheric connectivity recovered well in patients with hemorrhagic stroke or low severity. In contrast, there were no significant between-group and within-group alterations in intrahemispheric connectivity. Intrahemispheric connectivity of the inferior frontal cortex (IFC) exhibited opposite alterations compared to other connections. There were no differences between groups in IFC connectivity alterations; however, decreasing ipsilesional IFC connectivity and contralesional IFC during recovery were noticeable in patients with mild to moderate impairments and patients with severe impairments, respectively. These results may be helpful in understanding the network changes that occur after stroke and could have important implications for treatment strategy development in future studies.

Obstacle Detection with the Long Cane: Effect of Cane Tip Design and Technique Modification on Performance.

INTRODUCTION: The purpose of this study was to investigate the effect of cane tip design and cane technique modification on obstacle detection performance as they interact with the size, height, and position of obstacles. METHODS: A repeated-measures design with block randomization was used for the study. In experiment one, participants attempted to detect obstacles with either a marshmallow tip or a bundu basher tip. In experiment two, participants were asked to detect obstacles using either the constant-contact technique or a modified constant-contact technique. RESULTS: As predicted, the obstacle detection rate with the bundu basher tip (M = 66.1%, SD = 7.4%) was significantly higher than that with the marshmallow tip (M = 54.6%, SD =6.8%), F(1, 11) = 24.19, p < .001, r = .83. However, contrary to our hypothesis, the obstacle detection rate with the modified constant-contact technique (M =56.0%, SD = 7.4%) was significantly lower than that with the constant-contact technique (M = 61.3%, SD = 5.2%), F(1, 13) = 6.49, p = .024, r = .58. In addition, participants detected the obstacles that were positioned at the center of their walking path (M = 61.9%, SD = 6.6%) at a significantly higher rate than those positioned slightly off to the side (M = 55.4%, SD = 7.3%), F(1, 13) =10.73, p = .006, r = .67. DISCUSSION: A bundu basher tip was more advantageous than the marshmallow tip for detecting obstacles. IMPLICATIONS FOR PRACTITIONERS: Given the findings of the study, cane users and orientation and mobility (O&M) specialists should consider using or recommending a bundu basher tip (or a similar tip that has an increased contact area with the walking surface), particularly when the traveling environment often presents unexpected obstacles that may trip the cane user.

A new primary mobility tool for the visually impaired: A white cane-adaptive mobility device hybrid.

This article describes pilot testing of an adaptive mobility device-hybrid (AMD-H) combining properties of two primary mobility tools for people who are blind: the long cane and adaptive mobility devices (AMDs). The long cane is the primary mobility tool used by people who are blind and visually impaired for independent and safe mobility and AMDs are adaptive devices that are often lightweight frames approximately body width in lateral dimension that are simply pushed forward to clear the space in front of a person. The prototype cane built for this study had a wing apparatus that could be folded around the shaft of a cane but when unfolded, deployed two wheeled wings 25 cm (9.8 in) to each side of the canetip. This project explored drop-off and obstacle detection for 6 adults with visual impairment using the deployed AMD-H and a standard long cane. The AMD-H improved obstacle detection overall, and was most effective for the smallest obstacles (2 and 6 inch diameter). The AMD-H cut the average drop off threshold from 1.79 inches (4.55 cm) to .96 inches (2.44 cm). All participants showed a decrease in drop off detection threshold and an increase in detection rate (13.9% overall). For drop offs of 1 in (2.54 cm) and 3 in (7.62 cm), all participants showed large improvements with the AMD-H, ranging from 8.4 to 50%. The larger drop offs of 5 in (12.7 cm) and 7 in (17.8 cm) were well detected by both types of canes.

Effect of cane length and swing arc width on drop-off and obstacle detection with the long cane.

A repeated-measures design with block randomization was used for the study, in which 15 adults with visual impairments attempted to detect the drop-offs and obstacles with the canes of different lengths, swinging the cane in different widths (narrow vs wide). Participants detected the drop-offs significantly more reliably with the standard-length cane (79.5% ± 6.5% of the time) than with the extended-length cane (67.6% ± 9.1%), p <.001. The drop-off detection threshold of the standard-length cane (4.1 ± 1.1 cm) was also significantly smaller than that of the extended-length cane (6.5±1.8cm), p <.001. In addition, participants detected drop-offs at a significantly higher percentage when they swung the cane approximately 3 cm beyond the widest part of the body (78.6% ± 7.6%) than when they swung it substantially wider (30 cm; 68.5% ± 8.3%), p <.001. In contrast, neither cane length (p =.074) nor cane swing arc width (p =.185) had a significant effect on obstacle detection performance. The findings of the study may help orientation and mobility specialists recommend appropriate cane length and cane swing arc width to visually impaired cane users.

Prins Reaction of Homoallenyl Alcohols: Access to Substituted Pyrans in the Halichondrin Series.

Prins reaction of homoallenyl alcohols with aldehyde dimethylacetals in the presence of methoxyacetic acid directly affords tetrasubstituted pyrans relevant to halichondrins with complete control of the C27 stereogenic center. Regioselective Tsuji reduction of the resultant allylic acetates stereoselectively establishes the C25 stereogenic center and C26 exocyclic olefin. Building upon these findings, we achieved concise access to the halichondrin C14-C38 and eribulin C14-C35 fragments.

Reconstruction of Arm Movement Directions from Human Motor Cortex Using fMRI.

Recent advances in functional magnetic resonance imaging (fMRI) have been used to reconstruct cognitive states based on brain activity evoked by sensory or cognitive stimuli. To date, such decoding paradigms were mostly used for visual modalities. On the other hand, reconstructing functional brain activity in motor areas was primarily achieved through more invasive electrophysiological techniques. Here, we investigated whether non-invasive fMRI responses from human motor cortex can also be used to predict individual arm movements. To this end, we conducted fMRI studies in which participants moved their arm from a center position to one of eight target directions. Our results suggest that arm movement directions can be distinguished from the multivoxel patterns of fMRI responses in motor cortex. Furthermore, compared to multivoxel pattern analysis, encoding models were able to also reconstruct unknown movement directions from the predicted brain activity. We conclude for our study that non-invasive fMRI signal can be utilized to predict directional motor movements in human motor cortex.

Hierarchical ordering with partial pairwise hierarchical relationships on the macaque brain data sets.

Hierarchical organizations of information processing in the brain networks have been known to exist and widely studied. To find proper hierarchical structures in the macaque brain, the traditional methods need the entire pairwise hierarchical relationships between cortical areas. In this paper, we present a new method that discovers hierarchical structures of macaque brain networks by using partial information of pairwise hierarchical relationships. Our method uses a graph-based manifold learning to exploit inherent relationship, and computes pseudo distances of hierarchical levels for every pair of cortical areas. Then, we compute hierarchy levels of all cortical areas by minimizing the sum of squared hierarchical distance errors with the hierarchical information of few cortical areas. We evaluate our method on the macaque brain data sets whose true hierarchical levels are known as the FV91 model. The experimental results show that hierarchy levels computed by our method are similar to the FV91 model, and its errors are much smaller than the errors of hierarchical clustering approaches.

Beaconing Signalization Substantially Reduces Blind Pedestrians' Veer on Snow-Covered Pavement.

Veering outside of crosswalks is a common problem experienced by individuals who are blind. One technology found to be effective for reducing this veer when other guidance cues are absent is audible beaconing. However, veering in general and veering from crosswalks in particular have been studied primarily on smooth, flat walking surfaces such as clear pavement. This experiment compared veering on clear pavement with veering on snow-covered pavement, with and without audible beaconing. Eleven blind participants traveling with long canes attempted to walk a straight path for 72 ft (21.9 m), a typical length of a six-lane crosswalk. Beaconing substantially reduced veering at 36 ft (11.0 m) and 72 ft from the starting point and enabled participants to remain within a simulated crosswalk. Walking on snow was not found to affect veering but did increase the number of steps taken. The findings suggest that in snowy and clear conditions alike, audible beaconing is an effective wayfinding tool for intersections equipped with accessible pedestrian signals.

A pumpless multi-organ-on-a-chip (MOC) combined with a pharmacokinetic-pharmacodynamic (PK-PD) model.

A multi-organ-on-a-chip (MOC), also known as a human-on-a-chip, aims to simulate whole body response to drugs by connecting microscale cell cultures of multiple tissue types via fluidic channels and reproducing the interaction between them. While several studies have demonstrated the usefulness of MOC at a proof-of-concept level, improvements are needed to enable wider acceptance of such systems; ease of use for general biological researchers, and a mathematical framework to design and interpret the MOC systems. Here, we introduce a pumpless, user-friendly MOC which can be easily assembled and operated, and demonstrate the use of a PK-PD model for interpreting drug's action inside the MOC. The metabolism-dependent anticancer activity of a flavonoid, luteolin, was evaluated in a two-compartment MOC containing the liver (HepG2) and the tumor (HeLa) cells, and the observed anticancer activity was significantly weaker than that anticipated from a well plate study. Simulation of a PK-PD model revealed that simultaneous metabolism and tumor-killing actions likely resulted in a decreased anti-cancer effect. Our work demonstrates that the combined platform of mathematical PK-PD model and an experimental MOC can be a useful tool for gaining an insight into the mechanism of action of drugs with interactions between multiple organs. Biotechnol. Bioeng. 2017;114: 432-443. © 2016 Wiley Periodicals, Inc.