Endovascular stimulation of the pudendal nerve using a stent-mounted electrode array.

OBJECTIVE: Previous preclinical and clinical studies have demonstrated that pudendal nerve is a promising target for restoring bladder control. The spatial proximity between the pudendal nerve and its accompanying blood vessels in the pudendal canal provides an opportunity for endovascular neurostimulation, which is a less invasive approach compared to conventional chronically implanted electrodes. In this study, we investigated the feasibility of excitative stimulation and kilohertz-frequency block of the compound pudendal nerve in sheep using a stent-mounted electrode array. Approach: In a set of acute animal experiments, a commercially available hexapolar electrode catheter was introduced in the unilateral internal pudendal artery to deliver bipolar electrical stimulation of the adjacent compound pudendal nerve. The catheter electrode was replaced with a custom-made stent-mounted electrode array and the stimulation sessions were repeated. Global electromyogram (EMG) activity of the external urethral sphincter was recorded concurrently. Main results: We demonstrated the feasibility of endovascular stimulation of the pudendal nerve efferents with both electrode types. The threshold current of endovascular stimulation was influenced by electrode-nerve distance and electrode orientation. Increasing the axial inter-electrode distance significantly decreased threshold current. Endovascular kilohertz-frequency nerve block was possible with the electrode catheter. Significance: The present study demonstrated that endovascular stimulation of the pudendal nerve with the stent-mounted electrode array may be a promising less invasive alternative to conventional implantable electrodes, which has important clinical implications in the treatment of urinary incontinence. Endovascular blocking of pudendal nerve efferents may provide an alternative solution to the bladder-sphincter dyssynergia problem in bladder management for people with spinal cord injury. .

Talent development in female soccer: Developmental activities of professional players in England.

The activities soccer players engage in during their formative years are thought to significantly contribute to the acquisition of expert performance. Whilst this area has seen great interest in male players, there has been little research in females. The study examined developmental activities engaged in by professional female soccer players in England. 56 female soccer players that had either progressed to professional status in adulthood (professional), or did not (ex-academy), completed the Participant History Questionnaire. Professional players started engaging in soccer at an earlier age than their ex-academy counterparts, resulting in greater engagement in practice and play during childhood. During adolescence, professional players engaged in higher amounts of practice than ex-academy players. Engagement in competition and practice was rated as high in physical and cognitive effort by all, yet ex-academy players reported higher levels of physical effort during early adolescence, and cognitive effort during late adolescence. Findings provide an illustration of the talent pathways of professional female soccer players in England and may inform future talent development systems. Large interindividual variation in soccer-specific and other-sport activity data highlight the importance of further understanding the environments of individual soccer nations and their potential impact on the talent identification and development processes.

Maramycin, a Cytotoxic Isoquinolinequinone Terpenoid Produced through Heterologous Expression of a Bifunctional Indole Prenyltransferase/Tryptophan Indole-Lyase in S. albidoflavus.

Isoquinolinequinones represent an important family of natural alkaloids with profound biological activities. Heterologous expression of a rare bifunctional indole prenyltransferase/tryptophan indole-lyase enzyme from Streptomyces mirabilis P8-A2 in S. albidoflavus J1074 led to the activation of a putative isoquinolinequinone biosynthetic gene cluster and production of a novel isoquinolinequinone alkaloid, named maramycin (1). The structure of maramycin was determined by analysis of spectroscopic (1D/2D NMR) and MS spectrometric data. The prevalence of this bifunctional biosynthetic enzyme was explored and found to be a recent evolutionary event with only a few representatives in nature. Maramycin exhibited moderate cytotoxicity against human prostate cancer cell lines, LNCaP and C4-2B. The discovery of maramycin (1) enriched the chemical diversity of natural isoquinolinequinones and also provided new insights into crosstalk between the host biosynthetic genes and the heterologous biosynthetic genes in generating new chemical scaffolds.

Feasibility of endovascular stimulation of the femoral nerve using a stent-mounted electrode array.

Objective.Electrical stimulation of peripheral nerves has long been a treatment option to restore impaired neural functions that cannot be restored by conventional pharmacological therapies. Endovascular neurostimulation with stent-mounted electrode arrays is a promising and less invasive alternative to traditional implanted electrodes, which typically require invasive implantation surgery. In this study, we investigated the feasibility of endovascular stimulation of the femoral nerve using a stent-mounted electrode array and compared its performance to that of a commercially available pacing catheter.Approach.In acute animal experiments, a pacing catheter was implanted unilaterally in the femoral artery to stimulate the femoral nerve in a bipolar configuration. Electromyogram of the quadriceps and electroneurogram of a distal branch of the femoral nerve were recorded. After retrieval of the pacing catheter, a bipolar stent-mounted electrode array was implanted in the same artery and the recording sessions were repeated.Main Results.Stimulation of the femoral nerve was feasible with the stent-electrode array. Although the threshold stimulus intensities required with the stent-mounted electrode array (at 100-500µs increasing pulse width, 2.17 ± 0.87 mA-1.00 ± 0.11 mA) were more than two times higher than the pacing catheter electrodes (1.05 ± 0.48 mA-0.57 ± 0.28 mA), we demonstrated that, by reducing the stimulus pulse width to 100µs, the threshold charge per phase and charge density can be reduced to 0.22 ± 0.09µC and 24.62 ± 9.81µC cm-2, which were below the tissue-damaging limit, as defined by the Shannon criteria.Significance.The present study is the first to reportin vivofeasibility and efficiency of peripheral nerve stimulation using an endovascular stent-mounted electrode array.

Combination immunotherapy with vaccine and oncolytic HSV virotherapy is time dependent.

PURPOSE: Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSVs) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell mediated immunity may lead to more durable tumor regression. EXPERIMENTAL DESIGN: To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine co-delivering peptide antigens and Toll-like receptor-7 and -8 agonists (TLR-7/8a) (referred to as SNAPvax™), that induces robust tumor specific T cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T cell responses, viral replication, and preclinical efficacy. RESULTS: The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax™ vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumour volume and increases in virus replication and tumor antigen specific CD8+ T cells. CONCLUSIONS: These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors.

Exposure to outdoor ambient air toxics and risk of breast cancer: The multiethnic cohort.

BACKGROUND: A growing literature has reported associations between traffic-related air pollution and breast cancer, however there are fewer investigations into specific ambient agents and any putative risk of breast cancer development, particularly studies occurring in populations residing in higher pollution areas such as Los Angeles. OBJECTIVES: To estimate breast cancer risks related to ambient air toxics exposure at residential addresses. METHODS: We examined the relationships between ambient air toxics and breast cancer risk in the Multiethnic Cohort among 48,665 California female participants followed for cancer from 2003 through 2013. We obtained exposure data on chemicals acting as endocrine disruptors or mammary gland carcinogens from the National-Scale Air Toxics Assessment. Cox proportional hazards models were used to estimate breast cancer risk per one interquartile range (IQR) increase in air toxics exposure lagged by 5-years. Stratified analyses were conducted by race, ethnicity, and hormone receptor types. RESULTS: Among all women, increased risks of invasive breast cancer were observed with toxicants related to industries [1,1,2,2-tetrachloroethane (hazard ratio [HR] = 4.22, 95% confidence interval [95% CI] 3.18-5.60), ethylene dichloride (HR = 2.81, 95% CI 2.20-3.59), and vinyl chloride (HR = 2.27, 95% CI 1.81, 2.85); these 3 agents were correlated (r2 = 0.45-0.77)]. Agents related to gasoline production or combustion were related to increased breast cancer risk [benzene (HR = 1.32, 95% CI 1.24, 1.41), ethylbenzene (HR = 1.20, 95% CI 1.13-1.28), toluene (HR = 1.29, 95% CI 1.20-1.38), naphthalene (HR = 1.11, 95% CI 1.02-2.22), acrolein (HR = 2.26, 95% CI 1.92, 2.65)]. Higher hazard ratios were observed in African Americans and Whites compared to other racial and ethnic groups (p-heterogeneity <0.05 for traffic-related air toxics, acrolein, and vinyl acetate). CONCLUSIONS: Our findings suggest that specific toxic air pollutants may be associated with increase breast cancer risk.

Haemodynamics of stent-mounted neural interfaces in tapered and deformed blood vessels.

The endovascular neural interface provides an appealing minimally invasive alternative to invasive brain electrodes for recording and stimulation. However, stents placed in blood vessels have long been known to affect blood flow (haemodynamics) and lead to neointimal growth within the blood vessel. Both the stent elements (struts and electrodes) and blood vessel wall geometries can affect the mechanical environment on the blood vessel wall, which could lead to unfavourable vascular remodelling after stent placement. With increasing applications of stents and stent-like neural interfaces in venous blood vessels in the brain, it is necessary to understand how stents affect blood flow and tissue growth in veins. We explored the haemodynamics of a stent-mounted neural interface in a blood vessel model. Results indicated that blood vessel deformation and tapering caused a substantial change to the lumen geometry and the haemodynamics. The neointimal proliferation was evaluated in sheep implanted with an endovascular neural interface. Analysis showed a negative correlation with the mean Wall Shear Stress pattern. The results presented here indicate that the optimal stent oversizing ratio must be considered to minimise the haemodynamic impact of stenting.

Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates.

Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.

Audiovisualization of real-time neuroimaging data.

Advancements in brain imaging techniques have significantly expanded the size and complexity of real-time neuroimaging and behavioral data. However, identifying patterns, trends and synchronies within these datasets presents a significant computational challenge. Here, we demonstrate an approach that can translate time-varying neuroimaging data into unique audiovisualizations consisting of audible representations of dynamic data merged with simplified, color-coded movies of spatial components and behavioral recordings. Multiple variables can be encoded as different musical instruments, letting the observer differentiate and track multiple dynamic parameters in parallel. This representation enables intuitive assimilation of these datasets for behavioral correlates and spatiotemporal features such as patterns, rhythms and motifs that could be difficult to detect through conventional data interrogation methods. These audiovisual representations provide a novel perception of the organization and patterns of real-time activity in the brain, and offer an intuitive and compelling method for complex data visualization for a wider range of applications.

Chronic Stress Exposure Alters the Gut Barrier: Sex-Specific Effects on Microbiota and Jejunum Tight Junctions.

Background: Major depressive disorder (MDD) is the leading cause of disability worldwide. Of individuals with MDD, 30% to 50% are unresponsive to common antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis has been implicated in MDD pathogenesis. Exposure to chronic stress disrupts blood-brain barrier integrity; still, little is known about intestinal barrier function in these conditions, particularly for the small intestine, where absorption of most foods and drugs takes place. Methods: We investigated how chronic social or variable stress, two mouse models of depression, impact the jejunum intestinal barrier in males and females. Mice were subjected to stress paradigms followed by analysis of gene expression profiles of intestinal barrier-related targets, fecal microbial composition, and blood-based markers. Results: Altered microbial populations and changes in gene expression of jejunum tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We used machine learning to characterize in detail morphological tight junction properties, identifying a cluster of ruffled junctions in stressed animals. Junctional ruffling is associated with inflammation, so we evaluated whether lipopolysaccharide injection recapitulates stress-induced changes in the jejunum and observed profound sex differences. Finally, lipopolysaccharide-binding protein, a marker of gut barrier leakiness, was associated with stress vulnerability in mice, and translational value was confirmed on blood samples from women with MDD. Conclusions: Our results provide evidence that chronic stress disrupts intestinal barrier homeostasis in conjunction with the manifestation of depressive-like behaviors in a sex-specific manner in mice and, possibly, in human depression.

Most of the photons that reionized the Universe came from dwarf galaxies.

The identification of sources driving cosmic reionization, a major phase transition from neutral hydrogen to ionized plasma around 600-800 Myr after the Big Bang1-3, has been a matter of debate4. Some models suggest that high ionizing emissivity and escape fractions (fesc) from quasars support their role in driving cosmic reionization5,6. Others propose that the high fesc values from bright galaxies generate sufficient ionizing radiation to drive this process7. Finally, a few studies suggest that the number density of faint galaxies, when combined with a stellar-mass-dependent model of ionizing efficiency and fesc, can effectively dominate cosmic reionization8,9. However, so far, comprehensive spectroscopic studies of low-mass galaxies have not been done because of their extreme faintness. Here we report an analysis of eight ultra-faint galaxies (in a very small field) during the epoch of reionization with absolute magnitudes between MUV ≈ -17 mag and -15 mag (down to 0.005L⋆ (refs. 10,11)). We find that faint galaxies during the first thousand million years of the Universe produce ionizing photons with log[ξion (Hz erg-1)] = 25.80 ± 0.14, a factor of 4 higher than commonly assumed values12. If this field is representative of the large-scale distribution of faint galaxies, the rate of ionizing photons exceeds that needed for reionization, even for escape fractions of the order of 5%.

A high black-hole-to-host mass ratio in a lensed AGN in the early Universe.

Early JWST observations have uncovered a population of red sources that might represent a previously overlooked phase of supermassive black hole growth1-3. One of the most intriguing examples is an extremely red, point-like object that was found to be triply imaged by the strong lensing cluster Abell 2744 (ref. 4). Here we present deep JWST/NIRSpec observations of this object, Abell2744-QSO1. The spectroscopy confirms that the three images are of the same object, and that it is a highly reddened (AV ≃ 3) broad emission line active galactic nucleus at a redshift of zspec = 7.0451 ± 0.0005. From the width of Hß (full width at half-maximum = 2,800 ± 250 km s-1), we derive a black hole mass of M BH = 4 - 1 + 2 × 1 0 7 M ⊙ . We infer a very high ratio of black-hole-to-galaxy mass of at least 3%, an order of magnitude more than that seen in local galaxies5 and possibly as high as 100%. The lack of strong metal lines in the spectrum together with the high bolometric luminosity (Lbol = (1.1 ± 0.3) × 1045 erg s-1) indicate that we are seeing the black hole in a phase of rapid growth, accreting at 30% of the Eddington limit. The rapid growth and high black-hole-to-galaxy mass ratio of Abell2744-QSO1 suggest that it may represent the missing link between black hole seeds6 and one of the first luminous quasars7.

A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

Wearable Transmitter Coil Design for Inductive Wireless Power Transfer to Implantable Devices.

Wireless endovascular sensors and stimulators are emerging biomedical technologies for applications such as endovascular pressure monitoring, hyperthermia, and neural stimulations. Recently, coil-shaped stents have been proposed for inductive power transfer to endovascular devices using the stent as a receiver. However, less work has been done on the external transmitter components, so the maximum power transferable remains unknown. In this work, we design and evaluate a wearable transmitter coil that allows 50 mW power transfer in simulation.Clinical Relevance-This allows more accurate measurements and precise control of endovascular devices.

Predictive Shared Control of Robotic Arms Using Simulated Brain-Computer Interface Inputs.

Low decoding accuracy makes brain-computer interface (BCI) control of a robotic arm difficult. Shared control (SC) can overcome limitations of a BCI by leveraging external sensor data and generating commands to assist the user. Our study explored whether reaching targets with a robot end-effector was easier using SC rather than direct control (DC). We simulated a motor imagery BCI using a joystick with noise introduced to explicitly control interface accuracy to be 65% or 79%. Compared to DC, our prediction-based implementation of SC led to a significant reduction in the trajectory length of successful reaches for 4 (3) out of 5 targets using the 65% (79%) accurate interface, with failure rates being equivalent to DC for 2 (1) out of 5 targets. Therefore, this implementation of SC is likely to improve reaching efficiency but at the cost of more failures. Additionally, the NASA Task Load Index results suggest SC reduced user workload.Clinical relevance-Shared control can minimise the impact of BCI decoder errors on robot motion, making robotic arm control using noninvasive BCIs more viable.

Computational Fluid Dynamics of Stent-Mounted Neural Interfaces in an Idealized Cerebral Venous Sinus.

Hemodynamic changes in stented blood vessels play a critical role in stent-associated complications. The majority of work on the hemodynamics of stented blood vessels has focused on coronary arteries but not cerebral venous sinuses. With the emergence of endovascular electrophysiology, there is a growing interest in stenting cerebral blood vessels. We investigated the hemodynamic impact of a stent-mounted neural interface inside the cerebral venous sinus. The stent was virtually implanted into an idealized superior sagittal sinus (SSS) model. Local venous blood flow was simulated. Results showed that blood flow was altered by the stent, generating recirculation and low wall shear stress (WSS) around the device. However, the effect of the electrodes on blood flow was not prominent due to their small size. This is an early exploration of the hemodynamics of a stent-mounted neural interface. Future work will shed light on the key factors that influence blood flow and stenting outcomes.Clinical Relevance-The study investigates blood flow through a stent-based electrode array inside the cerebral venous sinus. The hemodynamic impact of the stent can provide insight into neointimal growth and thrombus formation.

Comparison of Sub-Scalp EEG and Endovascular Stent-Electrode Array for Visual Evoked Potential Brain-Computer Interface.

Brain-computer interfaces (BCI) have the potential to improve the quality of life for persons with paralysis. Sub-scalp EEG provides an alternative BCI signal acquisition method that compromises between the limitations of traditional EEG systems and the risks associated with intracranial electrodes, and has shown promise in long-term seizure monitoring. However, sub-scalp EEG has not yet been assessed for suitability in BCI applications. This study presents a preliminary comparison of visual evoked potentials (VEPs) recorded using sub-scalp and endovascular stent electrodes in a sheep. Sub-scalp electrodes recorded comparable VEP amplitude, signal-to-noise ratio and bandwidth to the stent electrodes.Clinical relevance-This is the first study to report a comparision between sub-scalp and stent electrode array signals. The use of sub-scalp EEG electrodes may aid in the long-term use of brain-computer interfaces.

Feasibility of Using Source-Level Brain Computer Interface for People with Multiple Sclerosis.

This work evaluates the feasibility of using a source level Brain-Computer Interface (BCI) for people with Multiple Sclerosis (MS). Data used was previously collected EEG of eight participants (one participant with MS and seven neurotypical participants) who performed imagined movement of the right and left hand. Equivalent current dipole cluster fitting was used to assess related brain activity at the source level and assessed using dipole location and power spectrum analysis. Dipole clusters were resolved within the motor cortices with some notable spatial difference between the MS and control participants. Neural sources that generate motor imagery originated from similar motor areas in the participant with MS compared to the neurotypical participants. Power spectral analysis indicated a reduced level of alpha power in the participant with MS during imagery tasks compared to neurotypical participants. Power in the beta band may be used to distinguish between left and right imagined movement for users with MS in BCI applications.Clinical Relevance- This paper demonstrates the cortical areas activated during imagined BCI-type tasks in a participant with Multiple Sclerosis (MS), and is a proof of concept for translating BCI research to potential users with MS.

Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (-11.1%, -12.6%), apoB (-15.6%, -18.0%), triglycerides (-15.4%, -20.4%), 16-week hepatic fat (-34.9%, -38.6%), (P < 0.0001) and liver stiffness (-1.02, -1.70) and 52-week hepatic fat (-28.8, -33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479 ).