Gill morphology adapted to oxygen-limited caves in Astyanax mexicanus.

Sensing and acquiring dissolved oxygen is crucial for nearly all aquatic life. This may become even more vital as dissolved oxygen concentrations continue to decline in many aquatic environments. While certain phenotypes that enable fish to live in low oxygen have been characterized, adaptations that arise following sudden, drastic reductions in dissolved oxygen are relatively unknown. Here, we assessed the blind Mexican cavefish, Astyanax mexicanus, for alterations to gill morphology that may be adaptive for life in hypoxic caves. The Astyanax system provides the unique opportunity to compare gill morphology between stereotypical "surface" adapted morphotypes and obligate cave-dwelling conspecifics. While the surface environment is well-oxygenated, cavefish must cope with significantly reduced oxygen. We began by quantifying traditional morphological gill traits including filament number and length as well as lamellar density and height in surface fish and two distinct cave populations, Pachón and Tinaja. This enabled us to estimate total lamellar height, a proxy for gill surface area. We then used immunohistochemical staining to label 5-HT-positive neuroepithelial cells (NECs), which serve as key oxygen sensors in fish. We discovered an increase in gill surface area for both cavefish populations compared to surface, which may enable a higher capacity of oxygen acquisition. Additionally, we found more NECs in Pachón cavefish compared to both surface fish and Tinaja cavefish, suggesting certain selective pressures may be cave-specific. Collectively, this work provides evidence that cavefish have adapted to low oxygen conditions via alterations to gill morphology and oxygen sensing, and informs evolutionary mechanisms of rapid adaptation to dramatic, chronic hypoxia.

Neuropsychiatric Systemic Lupus Erythematosus: A Systematic Review.

Neuropsychiatric systemic lupus erythematosus (NPSLE) refers to the neurological and psychiatric manifestations of systemic lupus erythematosus (SLE), which remain poorly understood yet often have a profound effect on the lives of afflicted patients. The aim of this study is to synthesize the available information on the pathogenesis, diagnostics, management, and prognosis of this disease. Our hope is to increase awareness and call for further investigations that may optimize NPSLE patient outcomes and quality of life. We performed a literature review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, resulting in 11 studies of inclusion. Within each study, we extracted data on epidemiologic factors, diagnostics, therapeutic modalities, and prognosis for each neuropsychiatric condition. The most widely discussed neuropsychiatric manifestations of SLE based on the American College of Rheumatology (ACR) classifications included status epilepticus (SE) and seizures, transverse myelitis (TM), and cognitive dysfunction. SE and TM had a prevalence of 1-2%, while cognitive dysfunction was nearly 38%. Diagnostics varied depending on symptom presentation but often included brain magnetic resonance imaging (MRI) and antibody testing. Treatment for NPSLE is still widely understudied, but concurrent treatment with immunosuppressants and anti-inflammatories for symptom control and more targeted immunotherapies based on the specific condition is often effective. Prognosis is highly symptom dependent, ranging from a 12.5% one-year mortality in SE and seizure patients to near resolution of symptoms in certain presentations including idiopathic intracranial hypertension and cerebellar ataxia. Further studies are needed to better understand the pathophysiology, diagnostics, and effective therapeutic measures for NPSLE. The severity of these manifestations and generally poor prognosis highlight the need for more research to accurately diagnose and treat this disease. While there is still little data available, this literature review serves to provide updated context on this condition.

Phase stabilization with motion compensated diffusion weighted imaging.

PURPOSE: Diffusion encoding gradient waveforms can impart intra-voxel and inter-voxel dephasing owing to bulk motion, limiting achievable signal-to-noise and complicating multishot acquisitions. In this study, we characterize improvements in phase consistency via gradient moment nulling of diffusion encoding waveforms. METHODS: Healthy volunteers received neuro ( N = 10 $$ N=10 $$ ) and cardiac ( N = 10 $$ N=10 $$ ) MRI. Three gradient moment nulling levels were evaluated: compensation for position ( M 0 $$ {M}_0 $$ ), position + velocity ( M 1 $$ {M}_1 $$ ), and position + velocity + acceleration ( M 1 + M 2 $$ {M}_1+{M}_2 $$ ). Three experiments were completed: (Exp-1) Fixed Trigger Delay Neuro DWI; (Exp-2) Mixed Trigger Delay Neuro DWI; and (Exp-3) Fixed Trigger Delay Cardiac DWI. Significant differences ( p < 0 . 05 $$ p<0.05 $$ ) of the temporal phase SD between repeated acquisitions and the spatial phase gradient across a given image were assessed. RESULTS: M 0 $$ {M}_0 $$ moment nulling was a reference for all measures. In Exp-1, temporal phase SD for G z $$ {G}_z $$ diffusion encoding was significantly reduced with M 1 $$ {M}_1 $$ (35% of t-tests) and M 1 + M 2 $$ {M}_1+{M}_2 $$ (68% of t-tests). The spatial phase gradient was reduced in 23% of t-tests for M 1 $$ {M}_1 $$ and 2% of cases for M 1 + M 2 $$ {M}_1+{M}_2 $$ . In Exp-2, temporal phase SD significantly decreased with M 1 + M 2 $$ {M}_1+{M}_2 $$ gradient moment nulling only for G z $$ {G}_z $$ (83% of t-tests), but spatial phase gradient significantly decreased with only M 1 $$ {M}_1 $$ (50% of t-tests). In Exp-3, M 1 + M 2 $$ {M}_1+{M}_2 $$ gradient moment nulling significantly reduced temporal phase SD and spatial phase gradients (100% of t-tests), resulting in less signal attenuation and more accurate ADCs. CONCLUSION: We characterized gradient moment nulling phase consistency for DWI. Using M1 for neuroimaging and M1 + M2 for cardiac imaging minimized temporal phase SDs and spatial phase gradients.

Real-world effectiveness of sotrovimab in preventing hospitalization and mortality in high-risk patients with COVID-19 in the United States: A cohort study from the Mayo Clinic electronic health records.

BACKGROUND: To describe outcomes of high-risk patients with coronavirus disease 2019 (COVID-19) treated with sotrovimab, other monoclonal antibodies (mAbs), or antivirals, and patients who did not receive early COVID-19 treatment. We also evaluate the comparative effectiveness of sotrovimab versus no treatment in preventing severe clinical outcomes. METHODS: This observational retrospective cohort study analyzed Mayo Clinic electronic health records. Non-hospitalized adult patients diagnosed with COVID-19 from May 26, 2021 and April 23, 2022 and at high risk of COVID-19 progression were eligible. The primary outcome was 29-day all-cause hospitalization and/or death. Outcomes were described for patients treated with sotrovimab, other mAbs, or antivirals, and eligible but untreated patients, and compared between sotrovimab-treated and propensity score (PS)-matched untreated cohorts. RESULTS: We included 35,485 patients (sotrovimab, 1369; other mAbs, 6488; antivirals, 133; high-risk untreated, 27,495). A low proportion of patients treated with sotrovimab (n = 33/1369, 2.4%), other mAbs (n = 147/6488, 2.3%), or antivirals (n = 2/133, 1.5%) experienced all-cause hospitalization or death. Among high-risk untreated patients, the percentage of all-cause hospitalization or death was 3.3% (n = 910/27,495). In the PS-matched analysis, 2.5% (n = 21/854) of sotrovimab-treated patients experienced all-cause hospitalization and/or death versus 2.8% (n = 48/1708) of untreated patients (difference, -0.4%; p = 0.66). Significantly fewer sotrovimab-treated patients required intensive care unit admission (0.5% vs 1.8%; difference, -1.3%; p = 0.002) or respiratory support (3.5% vs 8.7%; difference, -5.2%; p < 0.001). CONCLUSIONS: There was no significant difference in the proportion of sotrovimab-treated and PS-matched untreated patients experiencing 29-day all-cause hospitalization or mortality, although significantly fewer sotrovimab-treated patients required intensive care unit admission or respiratory support.

An electrocardiogram-based AI algorithm for early detection of pulmonary hypertension.

BACKGROUND: Early diagnosis of pulmonary hypertension (PH) is critical for effective treatment and management. We aimed to develop and externally validate an artificial intelligence algorithm that could serve as a PH screening tool, based on analysis of a standard 12-lead ECG. METHODS: The PH Early Detection Algorithm (PH-EDA) is a convolutional neural network developed using retrospective ECG voltage-time data, with patients classified as "PH-likely" or "PH-unlikely" (controls) based on right heart catheterisation or echocardiography. In total, 39 823 PH-likely patients and 219 404 control patients from Mayo Clinic were randomly split into training (48%), validation (12%) and test (40%) sets. ECGs taken within 1 month of PH diagnosis (diagnostic dataset) were used to train the PH-EDA at Mayo Clinic. Performance was tested on diagnostic ECGs within the test sets from Mayo Clinic (n=16 175/87 998 PH-likely/controls) and Vanderbilt University Medical Center (VUMC; n=6045/24 256 PH-likely/controls). In addition, performance was tested on ECGs taken 6-18 months (pre-emptive dataset), and up to 5 years prior to a PH diagnosis at both sites. RESULTS: Performance testing yielded an area under the receiver operating characteristic curve (AUC) of 0.92 and 0.88 in the diagnostic test sets at Mayo Clinic and VUMC, respectively, and 0.86 and 0.81, respectively, in the pre-emptive test sets. The AUC remained a minimum of 0.79 at Mayo Clinic and 0.73 at VUMC up to 5 years before diagnosis. CONCLUSION: The PH-EDA can detect PH at diagnosis and 6-18 months prior, demonstrating the potential to accelerate diagnosis and management of this debilitating disease.

Short Report: Clinical Features and Epilepsy Monitoring in an Adult With 22q11.2 Deletion Syndrome.

Background: 22q11.2 microdeletion is the most common microdeletion syndrome in humans with a prevalence of 13 per 100 000 live births, and it is a multisystem condition with variable phenotypic presentations. Methods: We present a case of an adult patient with Dandy-Walker syndrome who presented to our epilepsy clinic with 2 years of new-onset seizures and cognitive decline and 1 year of psychotic symptoms. Results: Patient had a non-revealing autoimmune and malignancy work-up. Continuous scalp vEEG study showed bursts of 1-2 Hz generalized fronto-centrally predominant spike or polyspike and slow wave discharges. Several myoclonic jerks were time-locked with the generalized discharges indicative of cortical myoclonus. MRI brain revealed periventricular nodular heterotopia in addition to findings suggestive of Dandy-Walker syndrome. Array-based comparative genomic hybridization demonstrated a 22q11.2 microdeletion seen in 22q11.2 deletion syndrome. Conclusion: Our case illustrates the challenges of diagnosing genetic disorders in adults especially when the initial diagnosis is dependent on a number of factors, including the patient's age, the severity of the phenotypic features, and the awareness of the physician.

Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance.

Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects.

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which bind to sugars on the inner endosomal membrane and then regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo . We show that rapidly biodegradable ionizable lipids can preferentially create endosomal holes that are smaller in size and reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Ionizable lipids producing such ESCRT-recruiting endosomal holes can produce high expression from cargo mRNA with minimal inflammation. Finally, we show that both routes to non-inflammatory LNPs, either galectin inhibition or ESCRT-recruiting ionizable lipids, are compatible with therapeutic mRNAs that ameliorate inflammation in disease models. LNPs without galectin inhibition or biodegradable ionizable lipids lead to severe exacerbation of inflammation in these models. In summary, endosomal escape induces endosomal membrane damage that can lead to inflammation. However, the inflammation can be controlled by inhibiting galectins (large hole detectors) or by using biodegradable lipids, which create smaller holes that are reparable by the ESCRT pathway. These strategies should lead to generally safer LNPs that can be used to treat inflammatory diseases.

Physiologically based modeling of LNP-mediated delivery of mRNA in the vascular system.

RNA therapeutics are an emerging, powerful class of drugs with potential applications in a wide range of disorders. A central challenge in their development is the lack of clear pharmacokinetic (PK)-pharmacodynamic relationship, in part due to the significant delay between the kinetics of RNA delivery and the onset of pharmacologic response. To bridge this gap, we have developed a physiologically based PK/pharmacodynamic model for systemically administered mRNA-containing lipid nanoparticles (LNPs) in mice. This model accounts for the physiologic determinants of mRNA delivery, active targeting in the vasculature, and differential transgene expression based on nanoparticle coating. The model was able to well-characterize the blood and tissue PKs of LNPs, as well as the kinetics of tissue luciferase expression measured by ex vivo activity in organ homogenates and bioluminescence imaging in intact organs. The predictive capabilities of the model were validated using a formulation targeted to intercellular adhesion molecule-1 and the model predicted nanoparticle delivery and luciferase expression within a 2-fold error for all organs. This modeling platform represents an initial strategy that can be expanded upon and utilized to predict the in vivo behavior of RNA-containing LNPs developed for an array of conditions and across species.

Medication recommendations for treatment of lumbosacral radiculopathy: A systematic review of clinical practice guidelines.

OBJECTIVE: The purpose of this systematic review was to ascertain guideline-recommended pharmaceutical approaches to lumbosacral radicular symptoms, assess the quality of the clinical practice guidelines (CPGs) with the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool, and qualitatively synthesize the guideline recommendations. LITERATURE SURVEY: Literature searches were performed in PubMed, Cochrane Database of Systematic Reviews, Index to Chiropractic Literature, Allied and Complementary Medicine Database (AMED), Cumulative Index for Nursing and Allied Health Literature (CINAHL), and Physiotherapy Evidence Database (PEDro). We included guidelines published between January 1, 2017, and January 9, 2022, written in the English language, related to radiculopathy, sciatica, and/or low back pain with leg pain, and that provided recommendations on oral medication. METHODOLOGY: The review was performed in accordance with Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) and the protocol was pre-registered with the International Prospective Register of Systematic Reviews (PROSPERO). Eligibility screening, full-text review, extraction of information pertaining to pharmacological management, and synthesis of results were performed independently by two authors and a third investigator was recruited to arbitrate any disagreements. The AGREE II tool was administered by four authors to appraise CPG quality. SYNTHESIS: After screening 413 citations and assessing 37 full-text articles, 11 CPGs met the inclusion criteria. They represented seven countries (Belgium, Canada, England, France, Japan, Korea, and United States) and three continents (Asia, Europe, and North America), as well as the Global Spine Care Initiative aimed at a worldwide presence. The mean overall AGREE II score was 87.1% (standard deviation [SD] 12.6%), generally reflecting high-quality CPGs. The highest domain mean score was for Clarity of Presentation (96.7%, SD 4.4%), and the lowest was Applicability (75.6%, SD 22.8%). Five classes of medications were recommended by at least one CPG: anticonvulsants, antidepressants, oral corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. CONCLUSIONS: The most common medication class recommended by the CPGs for lumbar radiculopathy was antidepressants. No CPGs recommended prescribing acetaminophen, benzodiazepines, muscle relaxants, or antibiotics. There was very little agreement between the CPGs, and all the medication classes had at least one CPG recommended against its use. Three guidelines reviewed did not recommend any medications due to lack of supporting literature, and instead recommended nonpharmacologic therapy.

Myelodysplastic Neoplasms (MDS) with Ring Sideroblasts or SF3B1 Mutations: The Improved Clinical Utility of World Health Organization and International Consensus Classification 2022 Definitions, a Single-Centre Retrospective Chart Review.

Myelodysplastic neoplasms (MDS) with ring sideroblasts (RS) are diagnosed via bone marrow aspiration in the presence of either (i) ≥15% RS or (ii) 5-14% RS and an SF3B1 mutation. In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment. A total of 6817 patients with suspected hematologic malignancies underwent molecular testing using a next-generation-sequencing-based genetic assay and 395 MDS patients, seen at our centre from 1 January 2018 to 31 May 2023, were reviewed. Of these, we identified 39 evaluable patients as having lower-risk MDS with SF3B1 mutations: there were 20 (51.3%) males and 19 (48.7%) females, with a median age of 77 years (range of 57 to 92). Nineteen (48.7%) patients had an isolated SF3B1 mutation with a mean variant allele frequency of 35.2% +/- 8.1%, ranging from 7.4% to 46.0%. There were 29 (74.4%) patients with ≥15% RS, 6 (15.4%) with 5 to 14% RS, one (2.6%) with 1% RS, and 3 (7.7%) with no RS. Our study suggests that a quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15% and supports the revised 2022 definitions of the World Health Organization (WHO) and International Consensus Classification (ICC), which shift toward molecularly defined subtypes of MDS and appropriate testing.

Identification and Characterization of Immune Checkpoint Inhibitor-Induced Toxicities From Electronic Health Records Using Natural Language Processing.

PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their use is associated with immune-related adverse events (irAEs). Estimating the prevalence and patient impact of these irAEs in the real-world data setting is critical for characterizing the benefit/risk profile of ICI therapies beyond the clinical trial population. Diagnosis codes, such as International Classification of Diseases codes, do not comprehensively illustrate a patient's care journey and offer no insight into drug-irAE causality. This study aims to capture the relationship between ICIs and irAEs more accurately by using augmented curation (AC), a natural language processing-based innovation, on unstructured data in electronic health records. METHODS: In a cohort of 9,290 patients treated with ICIs at Mayo Clinic from 2005 to 2021, we compared the prevalence of irAEs using diagnosis codes and AC models, which classify drug-irAE pairs in clinical notes with implied textual causality. Four illustrative irAEs with high patient impact-myocarditis, encephalitis, pneumonitis, and severe cutaneous adverse reactions, abbreviated as MEPS-were analyzed using corticosteroid administration and ICI discontinuation as proxies of severity. RESULTS: For MEPS, only 70% (n = 118) of patients found by AC were also identified by diagnosis codes. Using AC models, patients with MEPS received corticosteroids for their respective irAE 82% of the time and permanently discontinued the ICI because of the irAE 35.9% (n = 115) of the time. CONCLUSION: Overall, AC models enabled more accurate identification and assessment of patient impact of ICI-induced irAEs not found using diagnosis codes, demonstrating a novel and more efficient strategy to assess real-world clinical outcomes in patients treated with ICIs.

A deep learning approach for fast muscle water T2 mapping with subject specific fat T2 calibration from multi-spin-echo acquisitions.

This work presents a deep learning approach for rapid and accurate muscle water T2 with subject-specific fat T2 calibration using multi-spin-echo acquisitions. This method addresses the computational limitations of conventional bi-component Extended Phase Graph fitting methods (nonlinear-least-squares and dictionary-based) by leveraging fully connected neural networks for fast processing with minimal computational resources. We validated the approach through in vivo experiments using two different MRI vendors. The results showed strong agreement of our deep learning approach with reference methods, summarized by Lin's concordance correlation coefficients ranging from 0.89 to 0.97. Further, the deep learning method achieved a significant computational time improvement, processing data 116 and 33 times faster than the nonlinear least squares and dictionary methods, respectively. In conclusion, the proposed approach demonstrated significant time and resource efficiency improvements over conventional methods while maintaining similar accuracy. This methodology makes the processing of water T2 data faster and easier for the user and will facilitate the utilization of the use of a quantitative water T2 map of muscle in clinical and research studies.

Development and cross-validation of a circumference-based predictive equation to estimate body fat in an active population.

Objective: The U.S. Army uses sex-specific circumference-based prediction equations to estimate percent body fat (%BF) to evaluate adherence to body composition standards. The equations are periodically evaluated to ensure that they continue to accurately assess %BF in a diverse population. The objective of this study was to develop and validate alternative field expedient equations that may improve upon the current Army Regulation (AR) body fat (%BF) equations. Methods: Body size and composition were evaluated in a representatively sampled cohort of 1904 active-duty Soldiers (1261 Males, 643 Females), using dual-energy X-ray absorptiometry (%BFDXA), and circumferences obtained with 3D imaging and manual measurements. Sex stratified linear prediction equations for %BF were constructed using internal cross validation with %BFDXA as the criterion measure. Prediction equations were evaluated for accuracy and precision using root mean squared error, bias, and intraclass correlations. Equations were externally validated in a convenient sample of 1073 Soldiers. Results: Three new equations were developed using one to three circumference sites. The predictive values of waist, abdomen, hip circumference, weight and height were evaluated. Changing from a 3-site model to a 1-site model had minimal impact on measurements of model accuracy and performance. Male-specific equations demonstrated larger gains in accuracy, whereas female-specific equations resulted in minor improvements in accuracy compared to existing AR equations. Equations performed similarly in the second external validation cohort. Conclusions: The equations developed improved upon the current AR equation while demonstrating robust and consistent results within an external population. The 1-site waist circumference-based equation utilized the abdominal measurement, which aligns with associated obesity related health outcomes. This could be used to identify individuals at risk for negative health outcomes for earlier intervention.

Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke.

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers (NCs) with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, NCs targeted to vascular cellular adhesion molecule-1 (VCAM) achieved the highest level of brain delivery, nearly two orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (interleukin-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted NCs. Thus, VCAM-targeted lipid NCs represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS.

Reduced Subjective Cognitive Concerns With Neurobehavioral Therapy in Functional Seizures and Traumatic Brain Injury.

OBJECTIVE: Functional seizures are common among people with traumatic brain injury (TBI). Subjective cognitive concerns refer to a person's own perception of problems with cognitive functioning in everyday life. The authors investigated the presence and correlates of subjective cognitive concerns and the response to neurobehavioral therapy among adults with TBI and functional seizures (TBI+FS group). METHODS: In this observational study, participants in the TBI+FS group (N=47) completed a 12-session neurobehavioral therapy protocol for seizures, while participants in the comparison group (TBI without seizures) (N=50) received usual treatment. Subjective cognitive concerns, objective cognition, mental health, and quality of life were assessed before and after treatment. Data collection occurred from 2018 to 2022. RESULTS: Baseline subjective cognitive concerns were reported for 37 (79%) participants in the TBI+FS group and 20 (40%) participants in the comparison group. In a multivariable regression model in the TBI+FS group, baseline global mental health (ß=-0.97) and obsessive-compulsive symptoms (ß=-1.01) were associated with subjective cognitive concerns at baseline. The TBI+FS group had fewer subjective cognitive concerns after treatment (η2=0.09), whereas the TBI comparison group showed a nonsignificant increase in subjective cognitive concerns. CONCLUSIONS: Subjective cognitive concerns are common among people with TBI and functional seizures and may be related to general mental health and obsessive-compulsive symptoms. Evidence-based neurobehavioral therapy for functional seizures is a reasonable treatment option to address such concerns in this population, although additional studies in culturally diverse samples are needed. In addition, people with functional seizures would likely benefit from rehabilitation specifically targeted toward cognitive functioning.

IL7 increases targeted lipid nanoparticle-mediated mRNA expression in T cells in vitro and in vivo by enhancing T cell protein translation.

The use of lipid nanoparticles (LNP) to encapsulate and deliver mRNA has become an important therapeutic advance. In addition to vaccines, LNP-mRNA can be used in many other applications. For example, targeting the LNP with anti-CD5 antibodies (CD5/tLNP) can allow for efficient delivery of mRNA payloads to T cells to express protein. As the percentage of protein expressing T cells induced by an intravenous injection of CD5/tLNP is relatively low (4-20%), our goal was to find ways to increase mRNA-induced translation efficiency. We showed that T cell activation using an anti-CD3 antibody improved protein expression after CD5/tLNP transfection in vitro but not in vivo. T cell health and activation can be increased with cytokines, therefore, using mCherry mRNA as a reporter, we found that culturing either mouse or human T cells with the cytokine IL7 significantly improved protein expression of delivered mRNA in both CD4+ and CD8+ T cells in vitro. By pre-treating mice with systemic IL7 followed by tLNP administration, we observed significantly increased mCherry protein expression by T cells in vivo. Transcriptomic analysis of mouse T cells treated with IL7 in vitro revealed enhanced genomic pathways associated with protein translation. Improved translational ability was demonstrated by showing increased levels of protein expression after electroporation with mCherry mRNA in T cells cultured in the presence of IL7, but not with IL2 or IL15. These data show that IL7 selectively increases protein translation in T cells, and this property can be used to improve expression of tLNP-delivered mRNA in vivo.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with activated RAS from upstream mutations were equally sensitive. Conversely, cells from normal tissues or RAS WT cancer cells harboring downstream BRAF mutations were insensitive. Insensitivity to ADT-007 was attributed to low activated RAS levels and metabolic deactivation by UDP-glucuronosyltransferases expressed in normal cells but repressed in RAS mutant cancer cells. Cellular, biochemical, and biophysical experiments show ADT-007 binds nucleotide-free RAS to block GTP activation of RAS and MAPK/AKT signaling. Local administration of ADT-007 strongly inhibited tumor growth in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer while activating innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for treating RAS-driven cancers. SIGNIFICANCE: ADT-007 is a 1 st -in-class pan-RAS inhibitor with ultra-high potency and unique selectivity for cancer cells with mutant or activated RAS capable of circumventing resistance and activating antitumor immunity. Further development of ADT-007 analogs or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy is warranted.

Characterization of pentosan polysulfate patients for development of an alert and screening system for ophthalmic monitoring.

OBJECTIVE: Pentosan polysulfate (PPS; ELMIRON, Janssen Pharmaceuticals, Titusville, NJ) is a U.S. Food and Drug Administration-approved oral medication for interstitial cystitis. Numerous reports have been published detailing retinal toxicity with the use of PPS. Studies characterizing this condition are primarily retrospective, and consequently, alert and screening systems need to be developed to actively screen for this disease. The goal of this study was to characterize ophthalmic monitoring trends of a PPS-using patient sample to construct an alert and screening system for monitoring this condition. METHODS: A single-institution retrospective chart review was conducted between January 2005 and November 2020 to characterize PPS use. An electronic medical record (EMR) alert was constructed to trigger based on new PPS prescriptions and renewals offering ophthalmology referral. RESULTS: A total of 1407 PPS users over 15 years was available for characterization, with 1220 (86.7%) being female, the average duration of exposure being 71.2 ± 62.6 months, and the average medication cumulative exposure being 669.7 ± 569.2 g. A total of 151 patients (10.7%) had a recorded visit with an ophthalmologist, with 71 patients (5.0%) having optical coherence tomography imaging. The EMR alert fired for 88 patients over 1 year, with 34 patients (38.6%) either already being screened by an ophthalmologist or having been referred for screening. CONCLUSIONS: An EMR support tool can improve referral rates of PPS maculopathy screening with an ophthalmologist and may serve as an efficient method for longitudinal screening of this condition with the added benefit of informing pentosan polysulfate prescribers about this condition. Effective screening and detection may help determine which patients are at high risk for this condition.

Selective Electrocatalytic Degradation of Ether-Containing Polymers.

Leveraging electrochemistry to degrade robust polymeric materials has the potential to impact society's growing issue of plastic waste. Herein, we develop an electrocatalytic oxidative degradation of polyethers and poly(vinyl ethers) via electrochemically mediated hydrogen atom transfer (HAT) followed by oxidative polymer degradation promoted by molecular oxygen. We investigated the selectivity and efficiency of this method, finding our conditions to be highly selective for polymers with hydridic, electron-rich C-H bonds. We leveraged this reactivity to degrade polyethers and poly(vinyl ethers) in the presence of polymethacrylates and polyacrylates with complete selectivity. Furthermore, this method made polyacrylates degradable by incorporation of ether units into the polymer backbone. We quantified degradation products, identifying up to 36 mol % of defined oxidation products, including acetic acid, formic acid, and acetaldehyde, and we extended this method to degrade a polyether-based polyurethane in a green solvent. This work demonstrates a facile, electrochemically-driven route to degrade polymers containing ether functionalities.