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Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PC) through whole-cell patch-clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV->PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV->PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore the crucial role of astrocytes in regulating inhibitory circuit development and discover a new role for EphB2 receptors in PV-specific inhibitory synapse development.Significance Statement The findings presented in this study describe a novel mechanism by which astrocytes regulate the establishment of connections between parvalbumin interneurons and pyramidal neurons. We also present new evidence showing the role of presynaptic EphB2 in the formation of inhibitory synapses, specifically between PV-expressing interneurons and pyramidal neurons. Impaired inhibition is suggested to underlie the development of neuronal hyperactivity in several neurodevelopmental disorders (NDDs), and EphB2 receptor itself is also implicated in the pathogenesis of autism. Therefore, this study not only addresses critical gaps in our understanding, but also offers clinical relevance as EphB2 signaling in PV interneurons may be a promising therapeutic target to correct inhibitory circuit dysfunction in NDDs.

The design and optimization of laser-Compton x-ray systems based on compact distributed charge accelerator structures can enable micron-scale imaging of disease and the concomitant production of beams of Very High Energy Electrons (VHEEs) capable of producing FLASH-relevant dose rates. The physics of laser-Compton x-ray scattering ensures that the scattered x-rays follow exactly the trajectory of the incident electrons, thus providing a route to image-guided, VHEE FLASH radiotherapy. The keys to a compact architecture capable of producing both laser-Compton x-rays and VHEEs are the use of X-band RF accelerator structures which have been demonstrated to operate with over 100 MeV/m acceleration gradients. The operation of these structures in a distributed charge mode in which each radiofrequency (RF) cycle of the drive RF pulse is filled with a low-charge, high-brightness electron bunch is enabled by the illumination of a high-brightness photogun with a train of UV laser pulses synchronized to the frequency of the underlying accelerator system. The UV pulse trains are created by a patented pulse synthesis approach which utilizes the RF clock of the accelerator to phase and amplitude modulate a narrow band continuous wave (CW) seed laser. In this way it is possible to produce up to 10 μA of average beam current from the accelerator. Such high current from a compact accelerator enables production of sufficient x-rays via laser-Compton scattering for clinical imaging and does so from a machine of "clinical" footprint. At the same time, the production of 1000 or greater individual micro-bunches per RF pulse enables > 10 nC of charge to be produced in a macrobunch of < 100 ns. The design, construction, and test of the 100-MeV class prototype system in Irvine, CA is also presented.

BACKGROUND: In the United States, there are over seven million stroke survivors, with many facing gait impairments due to foot drop. This restricts their community ambulation and hinders functional independence, leading to several long-term health complications. Despite the best available physical therapy, gait function is incompletely recovered, and this occurs mainly during the acute phase post-stroke. Therapeutic options are limited currently. Novel therapies based on neurobiological principles have the potential to lead to long-term functional improvements. The Brain-Computer Interface (BCI) controlled Functional Electrical Stimulation (FES) system is one such strategy. It is based on Hebbian principles and has shown promise in early feasibility studies. The current study describes the BCI-FES clinical trial, which examines the safety and efficacy of this system, compared to conventional physical therapy (PT), to improve gait velocity for those with chronic gait impairment post-stroke. The trial also aims to find other secondary factors that may impact or accompany these improvements and establish the potential of Hebbian-based rehabilitation therapies. METHODS: This Phase II clinical trial is a two-arm, randomized, controlled, longitudinal study with 66 stroke participants in the chronic (> 6 months) stage of gait impairment. The participants undergo either BCI-FES paired with PT or dose-matched PT sessions (three times weekly for four weeks). The primary outcome is gait velocity (10-meter walk test), and secondary outcomes include gait endurance, range of motion, strength, sensation, quality of life, and neurophysiological biomarkers. These measures are acquired longitudinally. DISCUSSION: BCI-FES holds promise for gait velocity improvements in stroke patients. This clinical trial will evaluate the safety and efficacy of BCI-FES therapy when compared to dose-matched conventional therapy. The success of this trial will inform the potential utility of a Phase III efficacy trial. TRIAL REGISTRATION: The trial was registered as BCI-FES Therapy for Stroke Rehabilitation on February 19, 2020, at clinicaltrials.gov with the identifier NCT04279067.

Astrocytes have been implicated in oligodendrocyte development and myelination, however, the mechanisms by which astrocytes regulate oligodendrocytes remain unclear. Our findings suggest a new mechanism that regulates astrocyte-mediated oligodendrocyte development through ephrin-B1 signaling in astrocytes. Using a mouse model, we examined the role of astrocytic ephrin-B1 signaling in oligodendrocyte development by deleting ephrin-B1 specifically in astrocytes during the postnatal days (P)14-P28 period and used mRNA analysis, immunohistochemistry, and mouse behaviors to study its effects on oligodendrocytes and myelination. We found that deletion of astrocytic ephrin-B1 downregulated many genes associated with oligodendrocyte development, myelination, and lipid metabolism in the hippocampus and the corpus callosum. Additionally, we observed a reduced number of oligodendrocytes and impaired myelination in the corpus callosum of astrocyte-specific ephrin-B1 KO mice. Finally, our data show reduced motor strength in these mice exhibiting clasping phenotype and impaired performance in the rotarod test most likely due to impaired myelination. Our studies provide new evidence that astrocytic ephrin-B1 positively regulates oligodendrocyte development and myelination, potentially through astrocyte-oligodendrocyte interactions.

OBJECTIVE: We aimed to identify key aspects of the learning dynamics of proprioception training including: 1) specificity to the training type, 2) acquisition of proprioceptive skills, 3) retention of learning effects, and 4) transfer to different proprioceptive skills. METHODS: We performed a systematic literature search using the database (MEDLINE, EMBASE, Cochrane Library, and PEDro). The inclusion criteria required adult participants who underwent any training program that could enhance proprioceptive function, and at least 1 quantitative assessment of proprioception before and after the intervention. We analyzed within-group changes to quantify the effectiveness of an intervention. RESULTS: In total, 106 studies with 343 participant-outcome groups were included. Proprioception-specific training resulted in large effect sizes with a mean improvement of 23.4 to 42.6%, nonspecific training resulted in medium effect sizes with 12.3 to 22% improvement, and no training resulted in small effect sizes with 5.0 to 8.9% improvement. Single-session training exhibited significant proprioceptive improvement immediately (10 studies). For training interventions with a midway evaluation (4 studies), trained groups improved by approximately 70% of their final value at the midway point. Proprioceptive improvements were largely maintained at a delayed follow-up of at least 1 week (12 studies). Finally, improvements in 1 assessment were significantly correlated with improvements in another assessment (10 studies). CONCLUSIONS: Proprioceptive learning appears to exhibit several features similar to motor learning, including specificity to the training type, 2 time constant learning curves, good retention, and improvements that are correlated between different assessments, suggesting a possible, common mechanism for the transfer of training.

BACKGROUND: For patients who may permanently or temporarily lose their ability to communicate preferences, advance care planning is a critical mechanism to guide medical decision-making but is currently underused among surgical patients. METHODS: A resident-led quality improvement project, including education and performance measurement, was conducted on an emergency general surgery service to increase the completion of inpatient advance care planning notes using a specialized template in the electronic health record. Advance care planning documentation was defined as either preadmission advance care planning documentation (eg, advance directive) or inpatient advance care planning (use of the electronic health record template). Data from patients admitted to the emergency general surgery service for 12+ hours were analyzed, and baseline data (July 2020 to June 2021) were compared with data from the intervention period (July 2021 to June 2022). The chart review evaluated the content of the inpatient advance care planning documentation from the intervention period. RESULTS: The frequency of inpatient advance care planning documentation increased (9.3%, n = 56 to 16.6%, n = 92, P < .001) with a greater contribution of inpatient advance care planning notes by the surgery team (16.7% to 55.4%) in the intervention period. Content analysis indicated that 79.0% of inpatient advance care planning notes listed preferences for life-sustaining therapy, 78.3% listed surrogacy, 57.3% listed overall health goals, and 50.3% listed treatment goals specific to the surgical encounter. CONCLUSION: Although a resident-led quality improvement project contributed to greater adoption of standardized inpatient advance care planning documentation on an emergency general surgery service, progress was slow, and integration into standard work was not achieved. Future efforts are needed to better understand the integration of essential advance care planning elements into workflows and to establish inclusive educational programming to prepare all team members for conducting and documenting advance care planning conversations.

BACKGROUND: Unanticipated changes in health status and worsening of chronic conditions often prompt the need to consider emergency general surgery (EGS). Although discussions about goals of care may promote goal-concordant care and reduce patient and caregiver depression and anxiety, these conversations, as well as standardized documentation, remain infrequent for EGS patients. METHODS: We conducted a retrospective cohort study using electronic health record data from patients admitted to an EGS service at a tertiary academic center to determine the prevalence of clinically meaningful advance care planning (ACP) documentation (conversations and legal ACP forms) during the EGS hospitalization. Multivariable regression was performed to identify patient, clinician, and procedural factors associated with the lack of ACP. RESULTS: Among 681 patients admitted to the EGS service in 2019, only 20.1% had ACP documentation in the electronic health record at any time point during their hospitalization (of those, 75.5% completed before and 24.5% completed during admission). Two thirds (65.8%) of the total cohort had surgery during their admission, but none of them had a documented ACP conversation with the surgical team preoperatively. Patients with ACP documentation tended to have Medicare insurance (adjusted odds ratio, 5.06; 95% confidence interval, 2.09-12.23; p < 0.001) and had greater burden of comorbid conditions (adjusted odds ratio, 4.19; 95% confidence interval, 2.55-6.88; p < 0.001). CONCLUSION: Adults experiencing a significant, often abrupt change in health status leading to an EGS admission are infrequently engaged in ACP conducted by the surgical team. This is a critical missed opportunity to promote patient-centered care and to communicate patients care preferences to the surgical and other inpatient medical teams. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

INTRODUCTION: It would be valuable if home-based rehabilitation training technologies could automatically assess arm impairment after stroke. Here, we tested whether a simple measure-the repetition rate (or rep rate) when performing specific exercises as measured with simple sensors-can be used to estimate Upper Extremity Fugl-Meyer (UEFM) score. METHODS: 41 individuals with arm impairment after stroke performed 12 sensor-guided exercises under therapist supervision using a commercial sensor system comprised of two pucks that use force and motion sensing to measure the start and end of each exercise repetition. 14 of these participants then used the system at home for three weeks. RESULTS: Using linear regression, UEFM score was well estimated using the rep rate of one forward-reaching exercise from the set of 12 exercises (r2 = 0.75); this exercise required participants to alternately tap pucks spaced about 20 cm apart (one proximal, one distal) on a table in front of them. UEFM score was even better predicted using an exponential model and forward-reaching rep rate (Leave One Out Cross Validation (LOOCV) r2 = 0.83). We also tested the ability of a nonlinear, multivariate model (a regression tree) to predict UEFM, but such a model did not improve prediction (LOOCV r2 = 0.72). However, the optimal decision tree also used the forward-reaching task along with a pinch grip task to subdivide more and less impaired patients in a way consistent with clinical intuition. At home, rep rate for the forward-reaching exercise well predicted UEFM score using an exponential model (LOOCV r2 = 0.69), but only after we re-estimated coefficients using the home data. DISCUSSION: These results show how a simple measure-exercise rep rate measured with simple sensors-can be used to infer an arm impairment score and suggest that prediction models should be tuned separately for the clinic and home environments.

BackgroundUpper extremity (UE) stroke rehabilitation requires patients to perform exercises at home, yet patients show limited benefit from paper-based home exercise programs.ObjectiveTo compare the effectiveness of 2 home exercise programs for reducing UE impairment: a paper-based approach and a sensorized exercise system that incorporates recommended design features for home rehabilitation technology.MethodsIn this single-blind, randomized controlled trial, 27 participants in the subacute phase of stroke were assigned to the sensorized exercise (n = 14) or conventional therapy group (n = 13), though 2 participants in the conventional therapy group were lost to follow-up. Participants were instructed to perform self-guided movement training at home for at least 3 hours/week for 3 consecutive weeks. The sensorized exercise group used FitMi, a computer game with 2 puck-like sensors that encourages movement intensity and auto-progresses users through 40 exercises. The conventional group used a paper book of exercises. The primary outcome measure was the change in Upper Extremity Fugl-Meyer (UEFM) score from baseline to follow-up. Secondary measures included the Modified Ashworth Scale for spasticity (MAS) and the Visual Analog Pain (VAP) scale.ResultsParticipants who used FitMi improved by an average of 8.0 ± 4.6 points on the UEFM scale compared to 3.0 ± 6.1 points for the conventional participants, a significant difference (t-test, P = .029). FitMi participants exhibited no significant changes in UE MAS or VAP scores.ConclusionsA sensor-based exercise system incorporating a suite of recommended design features significantly and safely reduced UE impairment compared to a paper-based, home exercise program.Trial registrationClinicalTrials.gov Identifier: NCT03503617.

We measured the austenitic FeCr18Ni12.5 stainless steel Hugoniot as a function of crystallographic direction to approximately 60 GPa. We shock-compressed FeCr18Ni12.5 samples oriented along ⟨ 100 ⟩ , ⟨ 110 ⟩ , and ⟨ 111 ⟩ to mean stresses ranging 30.5–58.1 GPa via Ta plate impact in a large-bore powder gun and measured the free-surface velocities with laser interferometry. We unambiguously observed the largest post-shock free-surface velocity along ⟨ 100 ⟩ in each experiment, which consequently produced the lowest shock velocity along that orientation. However, the propagation of experimental uncertainties through the impedance matching scheme used to compute the shock velocity produced sufficient uncertainty overlap to preclude definitive conclusion of Hugoniot anisotropy. [ABSTRACT FROM AUTHOR]

Spontaneous pneumoperitoneum in a patient with a tracheostomy tube following cardiopulmonary resuscitation is exceedingly rare, with little experimental nor observational data to guide evidence-based management. We present the case of a 75-year-old woman with a tracheostomy tube who developed pneumoperitoneum following CPR. The patient experienced pulseless electrical activity arrest requiring nine rounds of chest compressions to return to spontaneous circulation. Computerized tomography demonstrated pneumothoraces, subcutaneous emphysema and extensive intraperitoneal, extraperitoneal and retroperitoneal free air without evidence of visceral perforation. The patient's abdomen was distended without tenderness, guarding or rebound. She had a white blood cell count mildly elevated from her baseline levels. The management plan of serial abdominal exams without operative intervention was chosen given the absence of clinical and laboratory signs of peritonitis. This case highlights the importance of developing a standardized management algorithm for patients with pneumoperitoneum in the setting of tracheostomy tubes without evidence of perforation.

Li-ion batteries will lose both capacity and power over time due to calendar aging caused by slow parasitic processes that consume Li+ ions. Studying and mitigating these processes is traditionally an equally slow venture, which is especially taxing for the validation of new active materials and electrolyte additives. Here, we evaluate whether potentiostatic holds can be used to accelerate the diagnosis of Li+ loss during calendar aging. The technique is based on the idea that, under the right conditions, the current measured as the cell voltage is held constant can be correlated with the instantaneous rate of side reactions. Thus, in principle, these measurements could capture the rate of capacity fade in real time. In practice, we show that this method is incapable of quantitatively forecasting calendar aging trends. Instead, our study demonstrates that potentiostatic holds can be applied for initial qualitative screening of systems that exhibit promising long-term stability, which can be useful to shrink the parameter space for calendar aging studies. By facilitating the identification of improved formulations, this approach can help accelerate innovation in the battery industry.