The effect of age on alpha rhythms in the human brain derived from source localized resting-state electroencephalography.

With increasing age, peak alpha frequency (PAF) is slowed, and alpha power is reduced during resting-states with eyes closed. These age-related changes are evident across the whole scalp but remained unclear at the source level. The purpose of this study was to determine whether age impacts the power and frequency of the dominant alpha rhythm equally across source generators or whether the impact of age varies across sources. A total of 28 young adults and 26 elderly adults were recruited. High-density EEG was recorded for 10 mins with eyes closed. Single dipoles for each independent component were localized and clustered based on their anatomical label, resulting in 36 clusters. Meta-analyses were then conducted to assess effect sizes for PAF and power at PAF for all 36 clusters. Subgroup analyses were then implemented for frontal, sensorimotor, parietal, temporal, and occipital regions. The results of the meta-analyses showed that the elderly group exhibited slower PAF and less power at PAF compared to the young group. Subgroup analyses revealed age effects on PAF in parietal (g = 0.38), temporal (g = 0.65), and occipital regions (g = 1.04), with the largest effects observed in occipital regions. For power at PAF, age effects were observed in sensorimotor (g = 0.84) and parietal regions (g = 0.80), with the sensorimotor region showing the largest effect. Our findings show that age-related slowing and attenuation of the alpha rhythm manifests differentially across cortical regions, with sensorimotor and occipital regions most susceptible to age effects.

Matching Patients to Accelerate Clinical Trials (MPACT): Enabling Technology for Oncology Clinical Trial Workflow.

Clinical trial enrollment is impeded by the significant time burden placed on research coordinators screening eligible patients. With 50,000 new cancer cases every year, the Veterans Health Administration (VHA) has made increased access for Veterans to high-quality clinical trials a priority. To aid in this effort, we worked with research coordinators to build the MPACT (Matching Patients to Accelerate Clinical Trials) platform with a goal of improving efficiency in the screening process. MPACT supports both a trial prescreening workflow and a screening workflow, employing Natural Language Processing and Data Science methods to produce reliable phenotypes of trial eligibility criteria. MPACT also has a functionality to track a patient's eligibility status over time. Qualitative feedback has been promising with users reporting a reduction in time spent on identifying eligible patients.

CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.

γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background1-5. γδ T cells can sense conserved cell stress signals prevalent in transformed cells2,3, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 T cells-the most abundant subset of human γδ T cells4-recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs. 6-8), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ T cell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ T cells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vγ9Vδ2 T cell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ T cell stress surveillance and suggests new avenues available to enhance γδ T cell anticancer activity.

The effect of chronic low back pain on postural control during quiet standing: A meta-analysis.

Low back pain (LBP) has been associated with altered body sway during quiet standing, but the pattern of results is inconsistent. The purpose of this meta-analysis is to examine the effects of vision (eyes open, eyes closed) and changing the support surface (foam surface, firm surface) on postural sway during quiet standing in individuals with chronic LBP (cLBP). Five electronic databases were searched on March 27th, 2022. Of 2,856, 16 studies (n = 663) were included. Across all conditions, we found a positive and medium effect size (g = 0.77 [0.50, 1.04]) that represented greater body sway in individuals with cLBP. Subgroup analyses revealed medium effects during eyes open conditions (firm surface: g = 0.60 [0.33, 0.87]; foam surface: g = 0.68 [0.38, 0.97]), and large effects during eyes closed conditions (firm surface: g = 0.97 [0.60, 1.35]; foam surface: g = 0.89 [0.28, 1.51]). We quantified effects of self-reported pain and found a moderate effect during eyes closed plus firm surface conditions (Q = 3.28; p = 0.070). We conclude that cLBP is associated with increased postural sway, with largest effect sizes evident when vision is removed and when self-reported pain intensity is higher.

Risk factors associated with venous thromboembolism in breast cancer: a narrative review.

PURPOSE: To date, there is no universally acceptable risk assessment tool in clinical practice that accurately estimates the risk of venous thromboembolism (VTE) in patients with breast cancer, despite the large number of published studies. Thus, the aim of this narrative review was to summarize the most relevant risk factors for VTE in these patients. METHODS: We searched Ovid Embase and Ovid MEDLINE, from inception to March 26, 2021, to identify all articles that focused on breast cancer and multiple thromboembolic diseases. We also searched the references section of relevant articles to identify studies. We did not include case reports or case series with small sample size, N < 20. RESULTS: VTE in patients with breast cancer was strongly associated with patient-, tumor-, and non-tumor-related risk factors, such as age, disease stage, central catheter placement, and chemotherapy and tamoxifen use, especially within 2 years of breast cancer diagnosis. CDK inhibitors are emerging factors that may also increase the risk of VTE. CONCLUSIONS: The risk of VTE in patients with breast cancer depends on various patient-, tumor-, and non-tumor-related risk factors. Identifying these risk factors during breast cancer diagnosis and treatment is essential in developing a practical dynamic predictive tool that can help individualize strategies to prevent VTE.

Obesity alters pathology and treatment response in inflammatory disease.

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.

CRISPR activation and interference screens decode stimulation responses in primary human T cells.

Regulation of cytokine production in stimulated T cells can be disrupted in autoimmunity, immunodeficiencies, and cancer. Systematic discovery of stimulation-dependent cytokine regulators requires both loss-of-function and gain-of-function studies, which have been challenging in primary human cells. We now report genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screens in primary human T cells to identify gene networks controlling interleukin-2 (IL-2) and interferon-γ (IFN-γ) production. Arrayed CRISPRa confirmed key hits and enabled multiplexed secretome characterization, revealing reshaped cytokine responses. Coupling CRISPRa screening with single-cell RNA sequencing enabled deep molecular characterization of screen hits, revealing how perturbations tuned T cell activation and promoted cell states characterized by distinct cytokine expression profiles. These screens reveal genes that reprogram critical immune cell functions, which could inform the design of immunotherapies.

The SIRPα-CD47 immune checkpoint in NK cells.

Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRPα+ primary NK cells, but not against SIRPα- NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.

Thermal tuning of arsenic selenide glass thin films and devices.

We present a method of post-deposition tuning of the optical properties of thin film dielectric filters and mirrors containing chalcogenide glass (ChG) layers by thermally adjusting their refractive index. A common challenge associated with the use of ChG films in practical applications is that they suffer from slight run-to-run variations in optical properties resulting from hard-to-control changes in source material and deposition conditions. These variations lead to inconsistencies in optical constants, making the fabrication of devices with prescribed optical properties challenging. In this paper, we present new work that takes advantage of the large variation of a ChG films' refractive index as a function of annealing. We have carried out extensive characterization of the thermal index tuning and thickness change of arsenic selenide (As2Se3) ChG thin films and observed refractive index changes larger than 0.1 in some cases. We show results for refractive index as a function of annealing time and temperature and propose a model to describe this behavior based on bond rearrangement. We apply thermal refractive index tuning to permanently shift the resonance of a Fabry-Perot filter and the cutoff wavelength of a Bragg reflector. The Bragg reflector, consisting of alternating As2Se3 and CaF2 layers, exhibits high reflectance across a ∼550 nm band with only five layers. Modeling results are compared with spectroscopic measurements, demonstrating good agreement.

Functional CRISPR dissection of gene networks controlling human regulatory T cell identity.

Human regulatory T (Treg) cells are essential for immune homeostasis. The transcription factor FOXP3 maintains Treg cell identity, yet the complete set of key transcription factors that control Treg cell gene expression remains unknown. Here, we used pooled and arrayed Cas9 ribonucleoprotein screens to identify transcription factors that regulate critical proteins in primary human Treg cells under basal and proinflammatory conditions. We then generated 54,424 single-cell transcriptomes from Treg cells subjected to genetic perturbations and cytokine stimulation, which revealed distinct gene networks individually regulated by FOXP3 and PRDM1, in addition to a network coregulated by FOXO1 and IRF4. We also discovered that HIVEP2, to our knowledge not previously implicated in Treg cell function, coregulates another gene network with SATB1 and is important for Treg cell-mediated immunosuppression. By integrating CRISPR screens and single-cell RNA-sequencing profiling, we have uncovered transcriptional regulators and downstream gene networks in human Treg cells that could be targeted for immunotherapies.

Inclusion of actuator dynamics in simulations of assisted human movement.

Simulation of musculoskeletal systems using dynamic optimization is a powerful approach for studying the biomechanics of human movements and can be applied to human-robot interactions. The simulation results of human movements augmented by robotic devices may be used to evaluate and optimize the device design and controller. However, simulations are limited by the accuracy of the models which are usually simplified for computation efficiency. Typically, the powered robotic devices are often modeled as massless, ideal torque actuators that is without mass and internal dynamics, which may have significant impacts on the simulation results. This article investigates the effects of including the mass and internal dynamics of the device in simulations of assisted human movement. The device actuator was modeled in various ways with different detail levels. Dynamic optimization was used to find the muscle activations and actuator commands in motion tracking and predictive simulations. The results showed that while the effects of device mass and inertia can be small, the electrical dynamics of the motor can significantly impact the results. This outcome suggests the importance of using an accurate actuator model in simulations of human movement augmented by assistive devices. NOVELTY: Demonstrating the effects of including mass and internal dynamics of the actuator in simulations of assisted human movement A new OpenSim electric motor actuator class to capture the electromechanical dynamics for use in simulation of human movement assisted by powered robotic devices.

Predictive Simulation of Human Walking Augmented by a Powered Ankle Exoskeleton.

The human ankle provides significant positive power during the stance phase of walking, which has resulted in studies focusing on methods to reduce the energetic walking cost by augmenting the ankle with exoskeletons. Recently, a few devices have successfully reduced the metabolic cost of walking by replacing part of the biological ankle plantar flexor torque. Despite these achievements, development of assistive ankle devices remains challenging, partly because the current practice of design and control of powered exoskeletons is highly time and effort consuming, which prevents quickly exploring different design and control parameters. Predictive simulations using musculoskeletal models coupled with robotic devices may facilitate the process of design and control of assistive devices. In this study, we simulate human walking augmented by a powered ankle exoskeleton. The walking problem was formulated as a predictive dynamic optimization in which both the optimal assistive device torque and the gait were solved simultaneously. Cases with exoskeletons assisting one ankle and both ankles were considered. The results showed that the energetic cost of walking could be reduced by 45% with one ankle augmented, and by 52% with both ankles augmented. This study contributes towards the goal of providing optimal assistive torque through external devices and theoretical peak reductions that could be expected from such devices.

Bilevel Optimization for Cost Function Determination in Dynamic Simulation of Human Gait.

Predictive simulation based on dynamic optimization using musculoskeletal models is a powerful approach for studying human gait. Predictive musculoskeletal simulation may be used for a variety of applications from designing assistive devices to testing theories of motor control. However, the underlying cost function for the predictive optimization is unknown and is generally assumed a priori. Alternatively, the underlying cost function can be determined from among a family of possible cost functions, representing an inverse optimal control problem that may be solved using a bilevel optimization approach. In this study, a nested evolutionary approach is proposed to solve the bilevel optimization problem. The lower level optimization is solved by a direct collocation method, and the upper level is solved by a genetic algorithm. We demonstrate our approach to solve different bilevel optimization problems, including finding the weights among three common performance criteria in the cost function for normal human walking. The proposed approach was found to be effective at solving the bilevel optimization problems. This approach should provide practical utility in designing assistive devices to aid mobility, and could yield insights about the control of human walking.

Myocarditis with checkpoint inhibitor immunotherapy: case report of late gadolinium enhancement on cardiac magnetic resonance with pathology correlate.

BACKGROUND: Nivolumab is a human IgG4 anti-programmed cell death protein-1 (PD-1) monoclonal antibody that works by augmenting the immune response against tumour cells. It has the potential of causing multiple autoimmune-related events, including cardiac. However, the real incidence and diagnosis of cardiac complications remains unclear. CASE SUMMARY: A 47-year-old woman with a history of carotid artery dissection and metastatic melanoma presented with acute heart failure. One year prior to presentation, she had received one cycle only of checkpoint inhibitor therapy with both ipilimumab and nivolumab, and nivolumab only was restarted 4 months prior to presentation. On admission, she was hypotensive, tachycardic due to atrial tachycardia and with pulmonary oedema. An echocardiogram revealed a left ventricular ejection fraction of 26%. Cardiovascular magnetic resonance (CMR) demonstrated a non-ischaemic pattern of late gadolinium enhancement (LGE), most consistent with myocarditis. The diagnosis of immunotherapy-mediated cardiac toxicity was highly considered and immunosuppressive therapy was initiated. However, she went into refractory cardiogenic shock and did not survive. An autopsy performed with samples from areas of myocardium with and without LGE on the CMR, found correlation. DISCUSSION: According to the literature, cardiac complications develop in less than 1% of patients treated with checkpoint inhibitors, with a 0.06% incidence reported in nivolumab specifically. However, it may be higher, given the lack of cardiac monitoring during treatment. We present the first case demonstrating direct histological correlation of T-lymphocytic infiltration with areas of LGE on CMR. Future investigation using CMR for early detection of inflammation and left ventricular dysfunction may help to diagnosis disease earlier.

Author Correction: Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived ß cells.

In the version of this article originally published, the Gene Expression Omnibus (GEO) accession number listed in the data availability section was incorrectly given as GSE10979 instead of GSE109795. The sentence should read "RNA-seq data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE109795," and the code should link to https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE109795. The error has been corrected in the HTML and PDF versions of the paper.

Left atrial fibrosis correlates with extent of left ventricular myocardial delayed enhancement and left ventricular strain in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with increased left ventricular (LV) mass, decreased myocardial strain, and the presence of LV fibrosis and scar. The relationship between LV scar and fibrosis with left atrial (LA) fibrosis in the setting of HCM has not been examined. The purpose of this study is to demonstrate a correlation between the degree of LA fibrosis and LV parameters in subjects with HCM. Twenty-eight subjects with HCM were imaged on a 1.5T MRI scanner with cine, LV and LA late gadolinium enhancement (LGE) sequences. LA LGE and LA measurements were correlated with LV measurements of volumes, mass, strain, and LGE. Other clinical conditions and medication usage were also examined and evaluated for correlation with LA and LV parameters. LV LGE was identified in 24 (86%) of the cases and LA LGE was identified in all of the cases. Extent of LA fibrosis significantly correlated with percent LV LGE (r = 0.64, p = 0.001), but not with indexed LV mass or maximum wall thickness. Extent of LA fibrosis also moderately correlated with decreased LV global strain (radial, r = - 0.50, p = 0.013; circumferential, r = 0.47, p = 0.02; longitudinal, r = 0.52, p = 0.013). Increased LA systolic volume correlated moderately with LV end diastolic volume (r = 0.50, p = 0.006). Patients on therapy with Renin-Angiotensin-Aldosterone System (RAAS) Inhibition had significantly less LA LGE compared to those without (18.6% vs 10.8%, p = 0.023). LA fibrosis, as measured by LGE, is prevalent in HCM and is correlated with LV LGE. The correlation between LA and LV LGE might suggest either that LA fibrosis is a consequence of LV remodeling, or that LA and LV fibrosis are both manifestations of the same cardiomyopathic process. Further study is warranted to determine the causality of LA scar in this population.

Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived ß cells.

Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional ß cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and ß cell maturation. In particular, we have focused on recapitulating endocrine cell clustering by isolating and reaggregating immature ß-like cells to form islet-sized enriched ß-clusters (eBCs). eBCs display physiological properties analogous to primary human ß cells, including robust dynamic insulin secretion, increased calcium signalling in response to secretagogues, and improved mitochondrial energization. Notably, endocrine cell clustering induces metabolic maturation by driving mitochondrial oxidative respiration, a process central to stimulus-secretion coupling in mature ß cells. eBCs display glucose-stimulated insulin secretion as early as three days after transplantation in mice. In summary, replicating aspects of endocrine cell clustering permits the generation of stem-cell-derived ß cells that resemble their endogenous counterparts.

Optical Properties of a Sulfur-Rich Organically Modified Chalcogenide Polymer Synthesized via Inverse Vulcanization and Containing an Organometallic Comonomer.

Inverse vulcanization is the method by which molten sulfur can be combined with comonomers to form stable polymers termed "organically modified chalcogenide" or "ORMOCHALC" polymers. One advantage to ORMOCHALC polymers is that they can possess important optical properties, such as high refractive index and strong infrared (IR) transmission, while being easier to fabricate than glass materials with similar optical properties. In the present work, a new ORMOCHALC is fabricated by using tetravinyltin as a comomoner with sulfur. This is the first example of an organometallic molecule being used as a comonomer to develop ORMOCHALCs. The result is an ORMOCHALC polymer that has the highest refractive index reported for a "sulfur and comonomer" polymer and that demonstrates unprecedented transmission in the IR region.