Gemogenovatucel-T (Vigil): bi-shRNA plasmid-based targeted immunotherapy.

We describe in this review the historical evidence leading up to the concept and design of Vigil and subsequent clinical applications including safety and efficacy in a randomized, controlled Phase IIB trial. Vigil (gemogenovatucel-T) is a unique triple function targeted immunotherapy that demonstrates preclinical and clinical systemic anticancer activity. Construction of Vigil involves harvest of autologous malignant tissue for neoantigen targeting (ideally containing clonal neoantigens) followed by a two-day process involving transfection with a plasmid to provide a permissive 'training environment' for the patient's immune system. Transfected plasmid components contain an expressive human GMCSF DNA segment to enhance anticancer immune functional response and a second component expressing bi-shRNAfurin which reduces TGFß isomers (TGFß1 and TGFß2) thereby reducing cancer inhibition of the targeted immune response. Results generated to date justify advancement to confirmatory clinical trials supporting product regulatory approval.

Vigil is an anticancer treatment that employs three methods of enhancing the body's immune system to identify and kill cancer cells. The construction of Vigil involves cancer cells from the same person being treated (personalized therapy) in combination with added anticancer genetic signals to enhance the number and function anti-anticancer immune cells and to guide the immune cells to the cancer and not to normal organs of the body. In this manner, an army of immune cells are created that can move to attacking the cancer using blood vessels to get to the cancer anywhere it tries to grow in the body. One study (Phase I) performed with this product to determine safety and dose range demonstrated an optimal dose and schedule. Another study (Phase IIA) showed initial clinical benefit. A third more complex study (Phase IIB) in patients treated with Vigil compared with standard of care without Vigil demonstrated the ability to prolong the patients life and time without their cancer getting worse without any significant side effects associated with the treatment in a unique subset of ovarian cancer patients, those with the ability to repair their DNA. Based on the composite of these results, Vigil is an attractive targeted immunotherapy justified for late-stage clinical testing.

Premalignant Progression in the Lung: Knowledge Gaps and Novel Opportunities for Interception of Non-Small Cell Lung Cancer. An Official American Thoracic Society Research Statement.

RATIONALE: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing for timely and effective intervention before cancer development. OBJECTIVES: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. METHODS: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. RESULTS: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. CONCLUSIONS: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, along with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.

Intrapartum and postpartum antibiotic use in seven low- and middle-income countries: Findings from the A-PLUS trial.

OBJECTIVE: To describe the intrapartum and postpartum use of non-study antibiotics in low- and middle-income countries (LMICs) during the double-blinded NICHD Global Network Azithromycin in Labor (A-PLUS) trial. DESIGN: The antibiotic use sub-study was a planned prospective, observational sub-study of the A-PLUS trial. SETTINGS: The study was carried out in hospitals or health centres affiliated with eight sites of the Global Network for Women's and Children's Health Research (Global Network) in seven countries: Bangladesh, Pakistan, India (two sites), Kenya, Zambia, The Democratic Republic of the Congo (DRC) and Guatemala. POPULATION: Totally, 29 278 pregnant women enrolled in the A-PLUS trial. METHODS: We collected data on 29 278 pregnant women admitted to a facility for delivery related to non-study antibiotic use overall and during three time periods: (1) in the facility prior to delivery, (2) after delivery until facility discharge and (3) after discharge to 42 days post-partum. MAIN OUTCOME MEASURES: Non-study antibiotic use overall and for treatment or prophylaxis by the site during the three time periods. RESULTS: Of the 29 278 women in the study, 5020 (17.1%; 95% CI 16.7%-17.6%) received non-study antibiotics in the facility prior to delivery, 11 956 (40.8%; 95% CI 40.3%-41.4%) received non-study antibiotics in the facility after delivery, and 13 390 (47.6%; 95% CI 47.0%-48.2%) women received non-study antibiotics after delivery and after facility discharge. Antibiotics were prescribed more often among women in the Asian and Guatemalan sites than in the African sites. In the three time-periods, among those receiving antibiotics, prophylaxis was the indication in 82.3%, 97.7% and 90.7% of the cases, respectively. The type of antibiotics used varied substantially by time-period and site, but generally, penicillin-type drugs, cephalosporin-type drugs and metronidazole were used more frequently than other types. CONCLUSIONS: Across the eight sites of the Global Network, in the facility before delivery, and in the post-partum periods before and after facility discharge, antibiotics were used frequently, but use was highly variable by site and time-period.

Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms.

Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms.

Screening and early intervention for substance use during pregnancy: A retrospective case note review of antenatal care records.

INTRODUCTION: Screening for substance use during pregnancy is critical for enhancing maternal health and perinatal outcomes. However, disparities persist in screening and intervention rates within maternity services. This retrospective case note review explored contemporaneous practices around screening and interventions for substance use among pregnant women during routine antenatal care. METHODS: A random sample of 100 sets of maternity records were reviewed. Eligible cases included any woman attending initial pregnancy assessments at one of two South Australian metropolitan Hospital-based antenatal clinics, from July 2019-September 2020. Screening rates for past and current alcohol, tobacco and other substance use were identified and compared with data from a subset of a nationally representative survey. Intervention details and referral pathways were also assessed. RESULTS: The final sample of eligible cases (n = 93) demonstrated prioritisation of screening for current use, over past use, across all substances (p < 0.001). Screening was most likely for tobacco and least likely for e-cigarettes (p < 0.001). Significant underreporting of past use compared with the benchmark was identified for all substances (except tobacco, p = 0.224). Interventions typically involved written resources, which were usually declined by clients. DISCUSSION AND CONCLUSIONS: Despite longstanding recommendations, screening and intervention practices for substance use appear inconsistent. With the recent emergence of vaping, no evidence of updated approaches to identifying e-cigarette consumption in pregnant women was found. Several opportunities for enhancing routine screening and intervention practices within antenatal clinics were identified, and will inform the development of policy directives, targeted training modules, and other resources for health professionals working in these services.

Saliva-derived DNA is suitable for the detection of clonal haematopoiesis of indeterminate potential.

Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with many adverse health outcomes. However, further research is required to understand the critical genes and pathways relevant to CHIP subtypes, evaluate how CHIP clones evolve with time, and further advance functional characterisation and therapeutic studies. Large epidemiological studies are well placed to address these questions but often collect saliva rather than blood from participants. Paired saliva- and blood-derived DNA samples from 94 study participants were sequenced using a targeted CHIP-gene panel. The ten genes most frequently identified to carry CHIP-associated variants were analysed. Fourteen unique variants associated with CHIP, ten in DNMT3A, two in TP53 and two in TET2, were identified with a variant allele fraction (VAF) between 0.02 and 0.2 and variant depth ≥ 5 reads. Eleven of these CHIP-associated variants were detected in both the blood- and saliva-derived DNA sample. Three variants were detected in blood with a VAF > 0.02 but fell below this threshold in the paired saliva sample (VAF 0.008-0.013). Saliva-derived DNA is suitable for detecting CHIP-associated variants. Saliva can offer a cost-effective biospecimen that could both advance CHIP research and facilitate clinical translation into settings such as risk prediction, precision prevention, and treatment monitoring.

Comparison of EV characterization by commercial high-sensitivity flow cytometers and a custom single-molecule flow cytometer.

High-sensitivity flow cytometers have been developed for multi-parameter characterization of single extracellular vesicles (EVs), but performance varies among instruments and calibration methods. Here we compare the characterization of identical (split) EV samples derived from human colorectal cancer (DiFi) cells by three high-sensitivity flow cytometers, two commercial instruments, CytoFLEX/CellStream, and a custom single-molecule flow cytometer (SMFC). DiFi EVs were stained with the membrane dye di-8-ANEPPS and with PE-conjugated anti-EGFR or anti-tetraspanin (CD9/CD63/CD81) antibodies for estimation of EV size and surface protein copy numbers. The limits of detection (LODs) for immunofluorescence and vesicle size based on calibration using cross-calibrated, hard-dyed beads were ∼10 PE/∼80 nm EV diameter for CytoFLEX and ∼10 PEs/∼67 nm for CellStream. For the SMFC, the LOD for immunofluorescence was 1 PE and ≤ 35 nm for size. The population of EVs detected by each system (di-8-ANEPPS+/PE+ particles) differed widely depending on the LOD of the system; for example, CellStream/CytoFLEX detected only 5.7% and 1.5% of the tetraspanin-labelled EVs detected by SMFC, respectively, and median EV diameter and antibody copy numbers were much larger for CellStream/CytoFLEX than for SMFC as measured and validated using super-resolution/single-molecule TIRF microscopy. To obtain a dataset representing a common EV population analysed by all three platforms, we filtered out SMFC and CellStream measurements for EVs below the CytoFLEX LODs as determined by bead calibration (10 PE/80 nm). The inter-platform agreement using this filtered dataset was significantly better than for the unfiltered dataset, but even better concordance between results was obtained by applying higher cutoffs (21 PE/120 nm) determined by threshold analysis using the SMFC data. The results demonstrate the impact of specifying LODs to define the EV population analysed on inter-instrument reproducibility in EV flow cytometry studies, and the utility of threshold analysis of SMFC data for providing semi-quantitative LOD values for other flow cytometers.

Vagus nerve stimulation during training fails to improve learning in healthy rats.

Learning new skills requires neuroplasticity. Vagus nerve stimulation (VNS) during sensory and motor events can increase neuroplasticity in networks related to these events and might therefore serve to facilitate learning on sensory and motor tasks. We tested if VNS could broadly improve learning on a wide variety of tasks across different skill domains in healthy, female adult rats. VNS was paired with presentation of stimuli or on successful trials during training, strategies known to facilitate plasticity and improve recovery in models of neurological disorders. VNS failed to improve either rate of learning or performance for any of the tested tasks, which included skilled forelimb motor control, speech sound discrimination, and paired-associates learning. These results contrast recent findings from multiple labs which found VNS pairing during training produced learning enhancements across motor, auditory, and cognitive domains. We speculate that these contrasting results may be explained by key differences in task designs, training timelines and animal handling approaches, and that while VNS may be able to facilitate rapid and early learning processes in healthy subjects, it does not broadly enhance learning for difficult tasks.

Robot-Aided Training of Propulsion: Effects of Torque Pulses Applied to the Hip and Knee Joint Under User-Driven Treadmill Control.

OBJECTIVE: to establish whether torque pulses ap-plied by an exoskeleton to the hip and knee joint modulate propulsion mechanics and whether changes in propulsion me-chanics are sustained after exposure to torque pulses under user-driven treadmill control. METHODS: we applied twelve for-mulations of torque pulses consecutively over 300 strides to 22 healthy participants, and quantified the evolution of four outcome measures - gait speed (GS), hip extension (HE), trailing limb angle (TLA), normalized propulsive impulse (NPI) - before, during, and immediately after training. RESULTS: Metrics of propulsion mechanics significantly changed both during and after training. Increases in HE during and after training were observed primarily in conjunction with hip/knee flexion pulses during early stance, or hip/knee extension during late stance. Increases in NPI during training were associated with hip/knee extension during early stance, or knee flexion during late stance. Knee flexion dur-ing early stance resulted in positive after-effects in NPI. Increases in GS were associated with the application of hip flexion pulses. Conditions exhibiting the largest positive changes in HE, and not NPI, during training resulted in increased GS after training. Analysis of the relationship between the effects measured during and after training suggests that after-effects primarily arise from retention of training effects, and that such retention is amplified compared to fixed-speed training. CONCLUSION AND SIGNIFICANCE: Combination of exoskeleton training and user-driven treadmill control modulates propulsion mechanics both during and after training and can be considered for the formulation of propulsion- oriented methods for individuals with impairments in propulsion mechanics.

Cardiac Magnetic Resonance Studies in a Large Animal Model That Simulates the Cardiac Abnormalities of Human Septic Shock.

BACKGROUND: Septic shock is associated with increases in end-diastolic volume (EDV) and decreases in ejection fraction that reverse within 10 days. Nonsurvivors do not develop EDV increases. The mechanism is unknown. METHODS AND RESULTS: Purpose-bred beagles (n=33) were randomized to receive intrabronchial Staphylococcus aureus or saline. Over 96 hours, cardiac magnetic resonance imaging and echocardiograms were performed. Tissue was obtained at 66 hours. From 0 to 96 hours after bacterial challenge, septic animals versus controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%). On histology, the major finding was nonocclusive microvascular injury with edema in myocytes, the interstitium, and endothelial cells. Edema was associated with significant worsening of biventricular ejection fractions, ventricular-arterial coupling, and circumferential strain. Early during sepsis, (0-24 hours), the EDV decreased; significantly more in nonsurvivors (ie, greater diastolic dysfunction). From 24 to 48 hours, septic animals' biventricular chamber sizes increased; in survivors significantly greater than baseline and nonsurvivors, whose EDVs were not different from baseline. Preload, afterload, or heart rate differences did not explain these differential changes. CONCLUSIONS: The cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death.

Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity-IVY Network, 26 Hospitals, October 18, 2023-March 9, 2024.

BACKGROUND: Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial divergence from co-circulating XBB lineages. METHODS: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. RESULTS: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. CONCLUSIONS: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB.

Clinician-Reported Management Recommendations in Response to Universal Germline Genetic Testing in Patients With Prostate Cancer.

PURPOSE: Identification of pathogenic germline variants in patients with prostate cancer can help inform treatment selection, screening for secondary malignancies, and cascade testing. Limited real-world data are available on clinician recommendations following germline genetic testing in patients with prostate cancer. MATERIALS AND METHODS: Patient data and clinician recommendations were collected from unselected patients with prostate cancer who underwent germline testing through the PROCLAIM trial. Differences among groups of patients were determined by 2-tailed Fisher's exact test with significance set at P < .05. Logistic regression was performed to assess the influence of test results in clinical decision-making while controlling for time of diagnosis (newly vs previously diagnosed). RESULTS: Among 982 patients, 100 (10%) were positive (>1 pathogenic germline variant), 482 (49%) had uncertain results (>1 variant of uncertain significance), and 400 (41%) were negative. Patients with positive results were significantly more likely than those with negative or uncertain results to receive recommendations for treatment changes (18% vs 1.4%, P < .001), follow-up changes (64% vs 11%, P < .001), and cascade testing (71% vs 5.4%, P < .001). Logistic regression demonstrated that positive and uncertain results were significantly associated with both changes to treatment and follow-up (P < .001) when controlling for new or previous diagnosis. CONCLUSIONS: Germline genetic testing results informed clinical recommendations for patients with prostate cancer, especially in patients with positive results. Higher than anticipated rates of clinical management changes in patients with uncertain results highlight the need for increased genetic education of clinicians treating patients with prostate cancer.

Serpentoviruses in Free-Ranging Shingleback Skinks (Tiliqua rugosa) in Western Australia and South Australia, Australia.

Serpentoviruses are strongly associated with upper respiratory tract disease in captive and free-ranging bluetongued skinks (Tiliqua spp.). In Australia, bluetongue serpentoviruses were first reported in shingleback skinks (Tiliqua rugosa) with upper respiratory tract disease that presented to wildlife rehabilitation facilities in Perth, Western Australia. Since then, serpentoviruses have been detected commonly in captive bluetongued skinks from most areas of Australia, yet knowledge about the prevalence and distribution of these viruses in free-ranging bluetongued skinks, and other skink species, remains limited. Oral swabs were collected from 162 shingleback skinks from four areas in Western Australia and neighboring South Australia to screen for bluetongue serpentoviruses by PCR. The proportions of PCR positives were 0% (0/4) for Rottnest Island (a small island west of Perth, Western Australia), 3% (1/32) for the Shire of Kent (∼5,600 km2 in the southwest of Western Australia), 1% (1/91) from an approximately 250,000 km2 area across southern Southern Australia and Western Australia, and 0% (0/35) from Mount Mary (∼150 km2 in the Mid North of South Australia). Neither of the two PCR-positive shingleback skinks had overt signs of upper respiratory tract disease. These results are consistent with serpentoviruses occurring at a relatively low crude prevalence of 1.4% (95% confidence interval, 0.2-4.9%) across these areas, although the potential bias from sampling active and apparently healthy individuals may mean that this estimate is lower than the true prevalence. This contrasts with the high proportion of PCR positives reported in captive individuals. In the absence of experimental or observational data on viral clearance and recovery, Tiliqua spp. skinks that are intended for release into the wild should be housed with strict biosecurity to prevent interactions with captive individuals and screened to ensure that they are not PCR positive before release.

Quadrant darkfield (QDF) for label-free imaging of intracellular puncta.

Measuring changes in cellular structure and organelles is crucial for understanding disease progression and cellular responses to treatments. A label-free imaging method can aid in advancing biomedical research and therapeutic strategies. This study introduces a computational darkfield imaging approach named quadrant darkfield (QDF) to separate smaller cellular features from large structures, enabling label-free imaging of cell organelles and structures in living cells. Using a programmable LED array as illumination source, we vary the direction of illumination to encode additional information about the feature size within cells. This is possible due to the varying level of directional scattering produced by features based on their sizes relative to the wavelength of light used. QDF successfully resolved small cellular features without interference from larger structures. QDF signal is more consistent during cell shape changes than traditional darkfield. QDF signals correlate with flow cytometry side scatter measurements, effectively differentiating cells by organelle content. QDF imaging enhances the study of subcellular structures in living cells, offering improved quantification of organelle content compared to darkfield without labels. This method can be simultaneously performed with other techniques such as quantitative phase imaging to generate a multidimensional picture of living cells in real-time.

Ultrastructure of the extraordinary pedal gland in Asplanchna aff. herricki (Rotifera: Monogononta).

Rotifers possess complex morphologies despite their microscopic size and simple appearance. Part of this complexity is hidden in the structure of their organs, which may be cellular or syncytial. Surprisingly, organs that are cellular in one taxon can be syncytial in another. Pedal glands are widespread across Rotifera and function in substrate attachment and/or egg brooding. These glands are normally absent in Asplanchna, which lack feet and toes that function as outlets for pedal glandular secretions in other rotifers. Here, we describe the ultrastructure of a pedal gland that is singular and syncytial in Asplanchna aff. herricki, but is normally paired and cellular in all other rotifers. Asplanchna aff. herricki has a single large pedal gland that is active and secretory; it has a bipartite, binucleate, syncytial body and a cytosol filled with rough endoplasmic reticulum, Golgi, and several types of secretory vesicles. The most abundant vesicle type is large and contains a spherical electron-dense secretion that appears to be produced through homotypic fusion of condensing vesicles produced by the Golgi. The vesicles appear to undergo a phase transition from condensed to decondensed along their pathway toward the gland lumen. Decondensation changes the contents to a mucin-like matrix that is eventually exocytosed in a "kiss-and-run" fashion with the plasma membrane of the gland lumen. Exocytosed mucus enters the gland lumen and exits through an epithelial duct that is an extension of the syncytial integument. This results in mucus that extends from the rotifer as a long string as the animal swims through the water. The function of this mucus is unknown, but we speculate it may function in temporary attachment, prey capture, or floatation.

Lateralization of acquisition and consolidation in direction but not amplitude of a motor skill task.

Previous research suggests that the neural processes underlying specification of movement direction and amplitude are independently represented in the nervous system. However, our understanding of acquisition and consolidation processes in the direction and distance learning remains limited. We designed a virtual air hockey task, in which the puck direction is determined by the hand direction at impact, while the puck distance is determined by the amplitude of the velocity. In two versions of this task, participants were required to either specify the direction or the distance of the puck, while the alternate variable did not contribute to task success. Separate groups of right-handed participants were recruited for each task. Each participant was randomly assigned to one of two groups with a counter-balanced arm practice sequence (right to left, or left to right). We examined acquisition and, after 24 h, we examined two aspects of consolidation: 1) same hand performance to test the durability and 2) the opposite hand to test the effector-independent consolidation (interlimb transfer) of learning. The distance task showed symmetry between hands in the extent of acquisition as well as in both aspects of consolidation. In contrast, the direction task showed asymmetry in both acquisition and consolidation: the dominant right arm showed faster and greater acquisition and greater transfer from the opposite arm training. The asymmetric acquisition and consolidation processes shown in the direction task might be explained by lateralized control and mapping of direction, an interpretation consistent with previous findings on motor adaptation paradigms.

Role of proprioception in corrective visually-guided movements: larger movement errors in both arms of a deafferented individual compared to control participants.

Proprioception plays an important role in both feedforward and feedback processes underlying movement control. This has been shown with individuals who suffered a profound proprioceptive loss and use vision to partially compensate for the sensory loss. The purpose of this study was to specifically examine the role of proprioception in feedback motor responses to visual perturbations by examining voluntary arm movements in an individual with a rare case of selective peripheral deafferentation (GL). We compared her left and right hand movements with those of age-matched female control participants (70.0 years ± 0.2 SEM) during a reaching task. Participants were asked to move their unseen hand, represented by a cursor on the screen, quickly and accurately to reach a visual target. A visual perturbation could be pseudorandomly applied, at movement onset, to either the target position (target jump) or the cursor position (cursor jump). Results showed that despite the continuous visual feedback that was provided, GL produced larger errors in final position accuracy compared to control participants, with her left nondominant hand being more erroneous after a cursor jump. We also found that the proprioceptively-deafferented individual produced less spatially efficient movements than the control group. Overall, these results provide evidence of a heavier reliance on proprioceptive feedback for movements of the nondominant hand relative to the dominant hand, supporting the view of a lateralization of the feedback processes underlying motor control.

RF shimming in the cervical spinal cord at 7 T.

PURPOSE: Advancing the development of 7 T MRI for spinal cord imaging is crucial for the enhanced diagnosis and monitoring of various neurodegenerative diseases and traumas. However, a significant challenge at this field strength is the transmit field inhomogeneity. Such inhomogeneity is particularly problematic for imaging the small, deep anatomical structures of the cervical spinal cord, as it can cause uneven signal intensity and elevate the local specific absorption ratio, compromising image quality. This multisite study explores several RF shimming techniques in the cervical spinal cord. METHODS: Data were collected from 5 participants between two 7 T sites with a custom 8Tx/20Rx parallel transmission coil. We explored two radiofrequency (RF) shimming approaches from an MRI vendor and four from an open-source toolbox, showcasing their ability to enhance transmit field and signal homogeneity along the cervical spinal cord. RESULTS: The circularly polarized (CP), coefficient of variation (CoV), and specific absorption rate (SAR) efficiency shim modes showed the highest B1 + efficiency, and the vendor-based "patient" and "volume" modes showed the lowest B1 + efficiency. The coefficient of variation method produced the highest CSF/spinal cord contrast on T2*-weighted scans (ratio of 1.27 ± 0.03), and the lowest variation of that contrast along the superior-inferior axis. CONCLUSION: The study's findings highlight the potential of RF shimming to advance 7 T MRI's clinical utility for central nervous system imaging by enabling more homogenous and efficient spinal cord imaging. Additionally, the research incorporates a reproducible Jupyter Notebook, enhancing the study's transparency and facilitating peer verification.