Gesture encoding in human left precentral gyrus neuronal ensembles.

Understanding the cortical activity patterns driving dexterous upper limb motion has the potential to benefit a broad clinical population living with limited mobility through the development of novel brain-computer interface (BCI) technology. The present study examines the activity of ensembles of motor cortical neurons recorded using microelectrode arrays in the dominant hemisphere of two BrainGate clinical trial participants with cervical spinal cord injury as they attempted to perform a set of 48 different hand gestures. Although each participant displayed a unique organization of their respective neural latent spaces, it was possible to achieve classification accuracies of ~70% for all 48 gestures (and ~90% for sets of 10). Our results show that single unit ensemble activity recorded in a single hemisphere of human precentral gyrus has the potential to generate a wide range of gesture-related signals across both hands, providing an intuitive and diverse set of potential command signals for intracortical BCI use.

Electronically configurable microscopic metasheet robots.

Shape morphing is vital to locomotion in microscopic organisms but has been challenging to achieve in sub-millimetre robots. By overcoming obstacles associated with miniaturization, we demonstrate microscopic electronically configurable morphing metasheet robots. These metabots expand locally using a kirigami structure spanning five decades in length, from 10 nm electrochemically actuated hinges to 100 µm splaying panels making up the ~1 mm robot. The panels are organized into unit cells that can expand and contract by 40% within 100 ms. These units are tiled to create metasheets with over 200 hinges and independent electronically actuating regions that enable the robot to switch between multiple target geometries with distinct curvature distributions. By electronically actuating independent regions with prescribed phase delays, we generate locomotory gaits. These results advance a metamaterial paradigm for microscopic, continuum, compliant, programmable robots and pave the way to a broad spectrum of applications, including reconfigurable micromachines, tunable optical metasurfaces and miniaturized biomedical devices.

A Miniature Batteryless Bioelectronic Implant Using One Magnetoelectric Transducer for Wireless Powering and PWM Backscatter Communication.

Wireless minimally invasive bioelectronic implants enable a wide range of applications in healthcare, medicine, and scientific research. Magnetoelectric (ME) wireless power transfer (WPT) has emerged as a promising approach for powering miniature bio-implants because of its remarkable efficiency, safety limit, and misalignment tolerance. However, achieving low-power and high-quality uplink communication using ME remains a challenge. This paper presents a pulse-width modulated (PWM) ME backscatter uplink communication enabled by a switched-capacitor energy extraction (SCEE) technique. The SCEE rapidly extracts and dissipates the kinetic energy within the ME transducer during its ringdown period, enabling time-domain PWM in ME backscatter. Various circuit techniques are presented to realize SCEE with low power consumption. This paper also describes the high-order modeling of ME transducers to facilitate the design and analysis, which shows good matching with measurement. Our prototyping system includes a millimeter-scale ME implant with a fully integrated system-on-chip (SoC) and a portable transceiver for power transfer and bidirectional communication. SCEE is proven to induce >50% amplitude reduction within 2 ME cycles, leading to a PWM ME backscatter uplink with 17.73 kbps data rate and 0.9 pJ/bit efficiency. It also achieves 8.5 × 10-5 bit-error-rate (BER) at a 5 cm distance, using a lightweight multi-layer-perception (MLP) decoding algorithm. Finally, the system demonstrates continuous wireless neural local-field potential (LFP) recording in an in vitro setup.

Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington's Disease: Data from the TRACK and ENROLL HD Cohorts.

Background: There is evidence for dysregulated cholesterol homeostasis in Huntington's disease (HD). The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-OHC) is decreased in manifest HD. 24(S)-OHC is an endogenous positive allosteric modulator (PAM) of the N-methyl-D-aspartate (NMDA) receptor, suggesting lower 24(S)-OHC may contribute to NMDA receptor hypofunction in HD. We hypothesized changes in 24(S)-OHC would be associated with cognitive impairment in early HD. Objective: To determine the interactions between oxysterols (24(S)-OHC, 25-OHC, and 27-OHC) at the NMDA receptor, the plasma levels of these oxysterols, and how these levels relate to cognitive performance. Methods: An in vitro competition assay was used to evaluate interactions at the NMDA receptor, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was used to measure plasma 24(S)-OHC, 25-OHC, and 27-OHC levels, and correlation analyses investigated their relationship to performance on cognitive endpoints in TRACK and ENROLL-HD (NCT01574053). Results: In vitro, 25-OHC and 27-OHC attenuated the PAM activity of 24(S)-OHC on the NMDA receptor. Lower plasma 24(S)-OHC levels and 24(S)/25-OHC ratios were detected in participants with early HD. Moderate and consistent associations were detected between plasma 24(S)/25-OHC ratio and performance on Stroop color naming, symbol digit modality, Trails A/B, and emotion recognition. Little association was observed between the ratio and psychiatric or motor endpoints, suggesting specificity for the relationship to cognitive performance. Conclusions: Our findings support growing evidence for dysregulated CNS cholesterol homeostasis in HD, demonstrate a relationship between changes in oxysterols and cognitive performance in HD, and propose that NMDA receptor hypofunction may contribute to cognitive impairment in HD.

Academic productivity and career trajectory of international medical graduates in US neurosurgery residency programs.

OBJECTIVE: The objective of this study was to review and compare the research experiences and career outcomes of international medical graduates (IMGs) with those of US medical graduates (USMGs). METHODS: Neurosurgery graduates from 2018 to 2020 were evaluated on the basis of medical school, degree, residency program, publications before and during residency, postresidency fellowships, and career progression. Publications were further categorized by author order and type (laboratory, comprehensive clinical, or short communication). RESULTS: Of 550 neurosurgery graduates, 39 (7%) were IMGs, with the largest percentages from India (8/39, 21%) and in a residency position in Pennsylvania (5/39, 13%). Prior to residency, IMGs had a higher median number of all publications (4 vs 1, p < 0.001), first-author articles (2 vs 0, p < 0.001), comprehensive clinical articles (1 vs 0, p = 0.002), and short communication articles (1 vs 0, p < 0.001) than USMGs. Similarly, the median number of papers published by IMGs during residency was also higher compared with that of USMGs for all publications (20 vs 9, p = 0.004), laboratory articles (1 vs 0, p < 0.001), and short communication articles (4 vs 3, p = 0.04). The percentage of early academic appointments was higher for IMGs (25/39, 64%) than for USMGs (232/511, 45%) (p = 0.03). No significant difference was observed between the percentages of postresidency clinical fellowships completed by IMGs (28/39, 72%) and USMGs (302/511, 59%) (p = 0.15). No statistical significance was found between the ranking of neurosurgery residency programs attended by IMGs and USMGs (p = 0.65). CONCLUSIONS: The results indicate that IMGs often exhibit higher academic productivity than USMGs. Although there was no discernible difference in residency program rankings or postresidency fellowships completed, early academic appointments were more prevalent among IMGs.

IRE1α regulates ROS and immune responses after UVB irradiation.

Objective: UV irradiation of the skin induces photo damage and generates cytotoxic intracellular reactive oxygen species (ROS), activating the unfolded protein response (UPR) to adapt or reduce these UVB-mediated damages. This study was designed to understand the role of the UPR mediator IRE1α in the antioxidant response following UVB irradiation of mouse skin and keratinocytes. Methods: We used mice with an epidermal deletion of IRE1α and primary mouse keratinocytes to examine effects of UV on different parameters of the antioxidant response in the presence and absence of functional IRE1α. Results: In the absence of IRE1α, PERK activity and protein levels are significantly compromised following UVB irradiation. Additionally, the loss of IRE1α suppressed phosphorylation of the PERK target, nuclear factor erythroid-2-related factor 2 (NRF2), and NRF2-dependent antioxidant gene expression after UVB irradiation. Interestingly, IRE1α-deficient keratinocytes exhibit elevated basal ROS levels, while a robust ROS induction upon UVB exposure is abolished. Because UVB-induced ROS plays an essential role in regulating skin inflammation, we analyzed recruited immune cell populations and the expression of pro-inflammatory cytokines, Il-6 and Tnfα in mice with epidermally-targeted deletion of Ire1α. Following UVB irradiation, there was significantly less recruitment of neutrophils and leukocytes and reduced expression of pro-inflammatory cytokine genes in the skin of mice lacking IRE1α. Furthermore, keratinocyte proliferation was also significantly reduced after chronic UVB exposure in the skin of these mice. Conclusions: Collectively, our findings indicate that IRE1α is essential for basal and UVB-induced oxidative stress response, UV-induced skin immune responses, and keratinocyte proliferation. Significance: These findings shed new light on the protective function of IRE1α in the response to UV. IRE1α plays an important role in the regulation of ROS, PERK stability, and antioxidant gene expression in response to UVB in mouse keratinocytes and epidermis.

CD40 stimulation activates CD8+ T cells and controls HBV in CD4-depleted mice.

Background & Aims: HBV treatment is challenging due to the persistence of the covalently closed circular DNA replication pool, which remains unaffected by antiviral intervention. In this study, we determined whether targeting antigen-presenting cells via CD40 stimulation represents an appropriate therapeutic approach for achieving sustained HBV control in a mouse model of HBV replication. Methods: Mice were transduced with an adeno-associated virus encoding the HBV genome (AAV-HBV) to initiate HBV replication and were administered agonistic CD40 antibody. CD4-depleting antibody was administered in addition to the CD40 antibody. Viral antigens in the blood were measured over time to determine HBV control. HBV-specific CD8+ T cells were quantified in the spleen and liver at the experimental endpoint. Results: CD40 stimulation in CD4-depleted AAV-HBV mice resulted in the clearance of HBsAg and HBeAg, along with a reduction in liver HBV mRNA, contrasting with CD4-competent counterparts. CD8+ T cells were indispensable for CD40-mediated HBV control, determined by HBV persistence following their depletion. In CD4-replete mice, CD40 stimulation initially facilitated the expansion of HBV-specific CD8+ T cells, which subsequently could not control HBV. Finally, α-CD4/CD40 treatment reduced antigenemia and liver HBV mRNA levels in chronic AAV-HBV mice, with further enhancement through synergy with immunization by VSV-MHBs (vesicular stomatitis virus expressing middle HBsAg). Conclusions: Our findings underscore the potential of CD40 stimulation as a targeted therapeutic strategy for achieving sustained HBV control and reveal a CD4+ T cell-dependent limitation on CD40-mediated antiviral efficacy. Impact and implications: Immunotherapy has the potential to overcome immune dysfunction in chronic HBV infection. Using a mouse model of HBV replication, this study shows that CD40 stimulation can induce sustained HBV control, which is dependent on CD8+ T cells and further enhanced by co-immunization. Unexpectedly, CD40-mediated HBV reduction was improved by the depletion of CD4+ cells. These findings suggest potential strategies for reversing HBV persistence in infected individuals.

Implementation of collaborative care for depression in VA HIV clinics: Translating Initiatives for Depression into Effective Solutions (HITIDES): protocol for a cluster-randomized type 3 hybrid effectiveness-implementation trial.

BACKGROUND: Depression is the most diagnosed mental health condition among people living with HIV. Collaborative care is an effective intervention for depression, typically delivered in primary care settings. The HIV Translating Initiatives for Depression into Effective Solutions (HITIDES) clinical intervention involves a depression care team housed off-site that supports depression care delivery by HIV care providers. In a randomized controlled trial, HITIDES significantly improved depression symptoms for veterans living with HIV and delivered cost savings. However, no HIV clinics in the Veterans Health Administration (VHA) have implemented HITIDES; as such, it is unclear what implementation strategies are necessary to launch and sustain this intervention. METHODS: This hybrid type-3 effectiveness-implementation trial examines the implementation and effectiveness of HITIDES in 8 VHA HIV clinics randomly assigned to one of two implementation arms. Each arm uses a different implementation strategy package. Arm 1 includes an intervention operations guide; an on-site clinical champion who, with the help of a peer community of practice, will work with local clinicians and leadership to implement HITIDES at their site; and patient engagement in implementation tools. Arm 2 includes all strategies from Arm 1 with assistance from an external facilitator. The primary implementation outcomes is reach; secondary outcomes include adoption, implementation dose, depressive symptoms, and suicidal ideation. We will conduct a budget impact analysis of the implementation strategy packages. We hypothesize that Arm 2 will be associated with greater reach and adoption and that Arm 1 will be less costly. DISCUSSION: Preliminary work identified implementation strategies acceptable to veterans living with HIV and HIV care providers; however, the effectiveness and cost of these strategies are unknown. While the depression care team can deliver services consistently with high quality, the ability of the depression care team to engage with HIV care providers at sites is unknown. Findings from this study will be used to inform selection of implementation strategies for a broad rollout to enhance depression and suicide care for people living with HIV. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05901272, Registered 10 May 2023, https://clinicaltrials.gov/study/NCT05901272.

Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.

Autoimmune destruction of pancreatic ß cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, ß cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.

Outpatient Patient Controlled Analgesia (PCA) for the Palliative Care Patient.

This study explores the under-researched domain of patient-controlled analgesia (PCA) for cancer pain management in adult outpatients, focusing on the transition from patient-controlled analgesia pumps (PCA pump) to oral medications. While existing literature primarily addresses the use of PCA in inpatient settings, this descriptive study investigates the initiation of outpatient PCA in palliative care patients. The retrospective chart review includes data from all admissions between July 1, 2014, and December 31, 2020. Among the 49 identified patients, 41 were admitted for cancer-related pain, with an indication for PCA such as insufficient pain relief, highly fluctuating pain, or inadequate response to other routes. Of these patients, 13 were successfully transitioned from outpatient PCA to oral opioids. The study underscores the effective use of PCA as a transitional tool following a pain crisis that necessitates inpatient admission. Future research avenues could explore healthcare utilization, length of stay, and required outpatient resources, such as home visits or telehealth, for optimal PCA use in outpatient settings.