Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease.

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1ß cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasome-dependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

Elevated Anti-Cyclic Citrullinated Peptide Levels Associated with Filamentary Keratitis.

PURPOSE: To assess two cases of filamentary keratitis with elevated serum levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies without known rheumatoid arthritis (RA). METHODS: A retrospective chart review was conducted on cases with filamentary keratitis and elevated anti-CCP antibodies between January 2021 and January 2023. Patient demographics, clinical characteristics, and serological test results were reviewed. RESULTS: The first patient, a 77-year-old man, presented with foreign body sensation and eye redness. He reported mild dry mouth but no joint pain or known autoimmune disease, though he had a family history of RA. Schirmer test scores were 7 and 12 mm in the right and left eyes, with an ocular staining score (OSS) of 12 in each eye. His serum anti-CCP antibody level was >2,777 U. Over 3 years of follow-up, he showed no signs of RA development. The second patient, an 84-year-old man, presented with severe burning and light sensitivity but no dry mouth or joint pain. Schirmer test scores were 2 and 3 mm in the right and left eyes, with OSS of 9 and 5, respectively. His serum anti-CCP level was 1330 U. He developed inflammatory arthritis and was diagnosed with RA 16 months after initial presentation. CONCLUSION: This report suggests that filamentary keratitis with elevated serum anti-CCP antibody levels may indicate early RA. These findings underscore the importance of anti-CCP testing in filamentary keratitis patients, even without typical RA symptoms. Further research is needed to explore the link between anti-CCP antibodies and ocular surface diseases in RA.

Mucosal sugars delineate pyrazine vs pyrazinone autoinducer signaling in Klebsiella oxytoca.

Virulent Klebsiella oxytoca strains are associated with gut and lung pathologies, yet our understanding of the molecular signals governing pathogenesis remains limited. Here, we characterized a family of K. oxytoca pyrazine and pyrazinone autoinducers and explored their roles in microbial and host signaling. We identified the human mucin capping sugar Neu5Ac as a selective elicitor of leupeptin, a protease inhibitor prevalent in clinical lung isolates of K. oxytoca, and leupeptin-derived pyrazinone biosynthesis. Additionally, we uncovered a separate pyrazine pathway, regulated by general carbohydrate metabolism, derived from a broadly conserved PLP-dependent enzyme. While both pyrazine and pyrazinone signaling induce iron acquisition responses, including enterobactin biosynthesis, pyrazinone signaling enhances yersiniabactin virulence factor production and selectively activates the proinflammatory human histamine receptor H4 (HRH4). Our findings suggest that the availability of specific carbohydrates delineates distinct autoinducer pathways in K. oxytoca that may have differential effects on bacterial virulence and host immune responses.

CCL2-mediated endothelial injury drives cardiac dysfunction in long COVID.

Evidence linking the endothelium to cardiac injury in long coronavirus disease (COVID) is well documented, but the underlying mechanisms remain unknown. Here we show that cytokines released by endothelial cells (ECs) contribute to long-COVID-associated cardiac dysfunction. Using thrombotic vascular tissues from patients with long COVID and induced pluripotent stem cell-derived ECs (iPSC-ECs), we modeled endotheliitis and observed similar dysfunction and cytokine upregulation, notably CCL2. Cardiac organoids comprising iPSC-ECs and iPSC-derived cardiomyocytes showed cardiac dysfunction after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, driven by CCL2. Profiling of chromatin accessibility and gene expression at a single-cell resolution linked CCL2 to 'phenotype switching' and cardiac dysfunction, validated by high-throughput proteomics. Disease modeling of cardiac organoids and exposure of human ACE2 transgenic mice to SARS-CoV-2 spike proteins revealed that CCL2-induced oxidative stress promoted post-translational modification of cardiac proteins, leading to cardiac dysfunction. These findings suggest that EC-released cytokines contribute to cardiac dysfunction in long COVID, highlighting the importance of early vascular health monitoring in patients with long COVID.

DNA damage drives antigen diversification through mosaic Variant Surface Glycoprotein (VSG) formation in Trypanosoma brucei.

Antigenic variation, using large genomic repertoires of antigen-encoding genes, allows pathogens to evade host antibody. Many pathogens, including the African trypanosome Trypanosoma brucei, extend their antigenic repertoire through genomic diversification. While evidence suggests that T. brucei depends on the generation of new variant surface glycoprotein (VSG) genes to maintain a chronic infection, a lack of experimentally tractable tools for studying this process has obscured its underlying mechanisms. Here, we present a highly sensitive targeted sequencing approach for measuring VSG diversification. Using this method, we demonstrate that a Cas9-induced DNA double-strand break within the VSG coding sequence can induce VSG recombination with patterns identical to those observed during infection. These newly generated VSGs are antigenically distinct from parental clones and thus capable of facilitating immune evasion. Together, these results provide insight into the mechanisms of VSG diversification and an experimental framework for studying the evolution of antigen repertoires in pathogenic microbes.

Symbolic Visual Reinforcement Learning: A Scalable Framework with Object-Level Abstraction and Differentiable Expression Search.

Learning efficient and interpretable policies has been a challenging task in reinforcement learning (RL), particularly in the visual RL setting with complex scenes. While neural networks have achieved competitive performance, the resulting policies are often over-parameterized black boxes that are difficult to interpret and deploy efficiently. More recent SRL frameworks have shown that high-level domain-specific programming logic can be designed to handle both policy learning and symbolic planning. However, these approaches rely on coded primitives with little feature learning, and when applied to high-dimensional visual scenes, they can suffer from scalability issues and perform poorly when images have complex object interactions. To address these challenges, we propose Differentiable Symbolic Expression Search (DiffSES), a novel symbolic learning approach that discovers discrete symbolic policies using partially differentiable optimization. By using object-level abstractions instead of raw pixel-level inputs, DiffSES is able to leverage the simplicity and scalability advantages of symbolic expressions, while also incorporating the strengths of neural networks for feature learning and optimization. Our experiments demonstrate that DiffSES is able to generate symbolic policies that are simpler and more and scalable than state-of-the-art SRL methods, with a reduced amount of symbolic prior knowledge. Our codes are available at: https://github.com/VITA-Group/DiffSES.

Parsimonious immune-response endotypes and global outcome in patients with traumatic brain injury.

BACKGROUND: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. METHODS: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. FINDINGS: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. INTERPRETATION: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. FUNDING: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Transcranial direct stimulation over left inferior frontal gyrus improves language production and comprehension in post-stroke aphasia: A double-blind randomized controlled study.

Transcranial direct current stimulation (tDCS) targeting Broca's area has shown promise for augmenting language production in post-stroke aphasia (PSA). However, previous research has been limited by small sample sizes and inconsistent outcomes. This study employed a double-blind, parallel, randomized, controlled design to evaluate the efficacy of anodal Broca's tDCS, paired with 20-minute speech and language therapy (SLT) focused primarily on expressive language, across 5 daily sessions in 45 chronic PSA patients. Utilizing the Western Aphasia Battery-Revised, which assesses a spectrum of linguistic abilities, we measured changes in both expressive and receptive language skills before and after intervention. The tDCS group demonstrated significant improvements over sham in aphasia quotient, auditory verbal comprehension, and spontaneous speech. Notably, tDCS improved both expressive and receptive domains, whereas sham only benefited expression. These results underscore the broader linguistic benefits of Broca's area stimulation and support the integration of tDCS with SLT to advance aphasia rehabilitation.

Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells.

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

Preemptive Impella 5.5 insertion to reduce operative risk in high-risk cardiac surgery: A case report.

INTRODUCTION AND IMPORTANCE: Society of thoracic surgery (STS) risk score has been used as a tool to gauge operative risk of cardiac surgery patients. High-risk patients, with STS risk score > 8 %, are considered as having prohibitive risk and are not offered surgery. There is no established strategy to minimize postoperative hemodynamic instability using mechanical circulatory support (MCS), despite growing interest in utilizing MCS prior to hemodynamic instability. The Impella 5.5 can provide enough perfusion and unload the left ventricle. CASE PRESENTATION: We managed a 75-year-old male with multiple comorbidities and a presumed Society of Thoracic Surgeons (STS) score higher than 9.8 %, who had redo coronary artery bypass grafting and aortic and mitral valve replacement with concomitant implantation of the Impella 5.5. Patient had a good recovery despite developing post-operative atrial fibrillation. DISCUSSION: Impella is used as a mechanical circulatory support device in patients with cardiogenic shock. It provides forward flow and effectively unloads the left ventricle. The concomitant placement of the Impella 5.5 in high-risk cardiac candidates may be associated with reduced operative risk. CONCLUSION: Placement of the device as part of surgical plan can potentially mitigate the perioperative risk by providing adequate endogean perfusion, decrease pressor support, unloading LV.

Ambulatory Surgery Centers Reduce Patient Out-of-Pocket Expenditures for Isolated Arthroscopic Rotator Cuff Repair, but Patient Out-of-Pocket Expenditures Are Increasing at a Faster Rate Than Total Healthcare Utilization Reimbursement From Payers.

PURPOSE: To categorize and trend annual out-of-pocket expenditures for arthroscopic rotator cuff repair (RCR) patients relative to total healthcare utilization (THU) reimbursement and compare drivers of patient out-of-pocket expenditures (POPE) in a granular fashion via analyses by insurance type and surgical setting. METHODS: Patients who underwent outpatient arthroscopic RCR in the United States from 2013 to 2018 were identified from the IBM MarketScan Database. Primary outcome variables were total POPE and THU reimbursement, which were calculated for all claims in the 9-month perioperative period. Trends in outcome variables over time and differences across insurance types were analyzed. Multivariable analysis was performed to investigate drivers of POPE. RESULTS: A total of 52,330 arthroscopic RCR patients were identified. Between 2013 and 2018, median POPE increased by 47.5% ($917 to $1,353), and median THU increased by 9.3% ($11,964 to $13,076). Patients with high deductible insurance plans paid $1,910 toward their THU, 52.5% more than patients with preferred provider plans ($1,253, P = .001) and 280.5% more than patients with managed care plans ($502, P = .001). All components of POPE increased over the study period, with the largest observed increase being POPE for the immediate procedure (P = .001). On multivariable analysis, out-of-network facility, out-of-network surgeon, and high-deductible insurance most significantly increased POPE. CONCLUSIONS: POPE for arthroscopic RCR increased at a higher rate than THU over the study period, demonstrating that patients are paying an increasing proportion of RCR costs. A large percentage of this increase comes from increasing POPE for the immediate procedure. Out-of-network facility status increased POPE 3 times more than out-of-network surgeon status, and future cost-optimization strategies should focus on facility-specific reimbursements in particular. Last, ambulatory surgery centers (ASCs) significantly reduced POPE, so performing arthroscopic RCRs at ASCs is beneficial to cost-minimization efforts. CLINICAL RELEVANCE: This study highlights that although payers have increased reimbursement for RCR, patient out-of-pocket expenditures have increased at a much higher rate. Furthermore, this study elucidates trends in and drivers of patient out-of-pocket payments for RCR, providing evidence for development of cost-optimization strategies and counseling of patients undergoing RCR.

AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery.

Ionizable lipid nanoparticles (LNPs) are seeing widespread use in mRNA delivery, notably in SARS-CoV-2 mRNA vaccines. However, the expansion of mRNA therapies beyond COVID-19 is impeded by the absence of LNPs tailored for diverse cell types. In this study, we present the AI-Guided Ionizable Lipid Engineering (AGILE) platform, a synergistic combination of deep learning and combinatorial chemistry. AGILE streamlines ionizable lipid development with efficient library design, in silico lipid screening via deep neural networks, and adaptability to diverse cell lines. Using AGILE, we rapidly design, synthesize, and evaluate ionizable lipids for mRNA delivery, selecting from a vast library. Intriguingly, AGILE reveals cell-specific preferences for ionizable lipids, indicating tailoring for optimal delivery to varying cell types. These highlight AGILE's potential in expediting the development of customized LNPs, addressing the complex needs of mRNA delivery in clinical practice, thereby broadening the scope and efficacy of mRNA therapies.

A folding motif formed with an expanded genetic alphabet.

Adding synthetic nucleotides to DNA increases the linear information density of DNA molecules. Here we report that it also can increase the diversity of their three-dimensional folds. Specifically, an additional nucleotide (dZ, with a 5-nitro-6-aminopyridone nucleobase), placed at twelve sites in a 23-nucleotides-long DNA strand, creates a fairly stable unimolecular structure (that is, the folded Z-motif, or fZ-motif) that melts at 66.5 °C at pH 8.5. Spectroscopic, gel and two-dimensional NMR analyses show that the folded Z-motif is held together by six reverse skinny dZ-:dZ base pairs, analogous to the crystal structure of the free heterocycle. Fluorescence tagging shows that the dZ-:dZ pairs join parallel strands in a four-stranded compact down-up-down-up fold. These have two possible structures: one with intercalated dZ-:dZ base pairs, the second without intercalation. The intercalated structure would resemble the i-motif formed by dC:dC+-reversed pairing at pH ≤ 6.5. This fZ-motif may therefore help DNA form compact structures needed for binding and catalysis.

Balloon Spacer Implant Is an "Intermediate Value" Innovation Relative to Partial Repair for Full-Thickness Massive Rotator Cuff Repairs: A Cost-Utility Analysis.

PURPOSE: To evaluate the cost-utility of a balloon spacer implant relative to partial repair (PR) for the surgical treatment of full-thickness massive rotator cuff tears (MRCTs). METHODS: A decision-analytic model comparing balloon spacer with PR was developed using data from a prospective, randomized, single-blinded, multicenter-controlled trial of 184 randomized patients. Our model was constructed on the basis of the various event pathways a patient could have after the procedure. The probability that each patient progressed to a given outcome and the quality-adjusted life years (QALY) associated with each outcome were derived from the clinical trial data. Incremental cost utility ratio (ICUR) and incremental net monetary benefit were calculated on the basis of a probabilistic sensitivity analysis using Monte Carlo simulations of 1,000 hypothetical patients progressing through the decision-analytic model. One-way sensitivity and threshold analyses were performed by varying cost, event probability, and QALY estimates. RESULTS: The balloon spacer had an ICUR of $106,851 (95% confidence interval $96,317-$119,143) relative to PR for surgical treatment of MRCT. Across all patients, the balloon spacer was associated with greater 2-year QALY gain compared with PR (0.20 ± 0.02 for balloon spacer vs 0.18 ± 0.02 for PR), but with substantially greater total 2-year cost ($9,701 ± $939 for balloon spacer vs $6,315 ± $627 for PR). PR was associated with a positive incremental net monetary benefit of $1,802 (95% confidence interval $1,653-$1,951) over balloon spacer at the $50,000/QALY willingness-to-pay threshold. CONCLUSIONS: Compared with PR, the balloon spacer is an "intermediate-value" innovation for treatment of MRCT over a 2-year postoperative period with an ICUR value that falls within the $50,000 to $150,000 willingness-to-pay threshold. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Socioeconomic Factors Including Patient Income, Education Level, and Health Insurance Influence Postoperative Secondary Surgery and Hospitalization Rates Following Hip Arthroscopy.

PURPOSE: To evaluate a large cross-sectional sample of patients utilizing administrative database records and analyze the effects of income, insurance type, and education level on outcomes after hip arthroscopy, including 2-year revision surgery, conversion to total hip arthroplasty (THA), and 90-day hospitalizations. METHODS: Current Procedural Terminology codes were used to query the PearlDiver Mariner database from October 2015 to January 2020 for patients undergoing hip arthroscopy with a minimum 2-year follow-up. Patients were categorized by mean family income in their zip code of residence (MFIR), health insurance type, and educational attainment in their zip code of residence (EAR). Two-year revision arthroscopy, conversion to THA, and 90-day hospital readmissions or emergency department (ED) visits were analyzed along socioeconomic strata. RESULTS: Multivariate analysis of 33,326 patients revealed that patients with MFIR between $30,000 and $70,000 had lower odds of 2-year revision arthroscopy (odds ratio [OR], 0.63; P < .001), THA conversion (OR, 0.76; P = .050), and 90-day readmission (OR, 0.53; P = .007) compared to MFIR >$100,000. Compared to patients with commercial insurance, patients with Medicare had lower odds of revision arthroscopy (OR, 0.60; P = .035) and THA conversion (OR, 0.46, P < .001) but greater odds of 90-day readmission (OR, 1.74; P = .007). Patients with Medicaid had higher odds of 90-day ED visits (OR, 1.84; P < .001). Patients with low EAR had higher odds of revision arthroscopy (OR, 1.42; P = .005) and THA conversion (OR, 1.58; P = .002) compared to those with high EAR. CONCLUSIONS: Following hip arthroscopy, patients residing in areas with lower mean family income were less likely to undergo reoperations and readmissions. Medicare patients showed lower reoperation but higher readmission odds, while Medicaid patients showed higher odds of ED visits. Additionally, higher educational attainment in the zip code of residence is protective against future reoperation. LEVEL OF EVIDENCE: Level III, retrospective case series.

Super-enhancer interactomes from single cells link clustering and transcription.

Regulation of gene expression hinges on the interplay between enhancers and promoters, traditionally explored through pairwise analyses. Recent advancements in mapping genome folding, like GAM, SPRITE, and multi-contact Hi-C, have uncovered multi-way interactions among super-enhancers (SEs), spanning megabases, yet have not measured their frequency in single cells or the relationship between clustering and transcription. To close this gap, here we used multiplexed imaging to map the 3D positions of 376 SEs across thousands of mammalian nuclei. Notably, our single-cell images reveal that while SE-SE contacts are rare, SEs often form looser associations we termed "communities". These communities, averaging 4-5 SEs, assemble cooperatively under the combined effects of genomic tethers, Pol2 clustering, and nuclear compartmentalization. Larger communities are associated with more frequent and larger transcriptional bursts. Our work provides insights about the SE interactome in single cells that challenge existing hypotheses on SE clustering in the context of transcriptional regulation.

Sexual Orientation, Gender Identity, and Experiences During, Awareness of, and Attitudes Toward Research for People With Parkinson Disease.

Background and Objectives: Presentation, progression, and treatment of Parkinson disease (PD) can differ based on sex and gender. However, knowledge on PD is limited by the characteristics of research participants, and most of the participants are men. In this study, we aimed to identify the attitudes toward and barriers to research participation for people with PD (PwP) based on their sexual orientation and gender identity. Methods: Data were obtained from the Fox Insight on March 16, 2023, for PwP who completed the Attitudes and Beliefs Regarding Research and Genetic Testing for PD. Responses were compared between sexual and gender minorities (SGM) (n = 136), cisgender heterosexual women (n = 1,479), and cisgender heterosexual men (n = 1,445). Associations between age, socioeconomic variables, and the responses that differed between the groups were assessed with linear models. Results: More than 68% of the participants were willing to participate in research; only 43.7% heard about research opportunities, and 52.3% knew where to find a study. Approximately 86.8% of the participants reported hearing about a study from their doctor would make them more likely to participate. A higher percentage of SGM were concerned about transportation and researchers not understanding or respecting their beliefs; a higher percentage of cisgender heterosexual women were concerned about transportation, data privacy, and their family's reaction to genetic results; and a higher percentage of cisgender heterosexual men were concerned about time required for research activities and complex forms. Age and socioeconomic variables were significantly associated with approach toward research that differed between the groups. Discussion: PwP are willing to participate in research, and health care providers can facilitate their participation. Barriers to research participation related to sexual and gender identity exist and must be addressed to increase our understanding of PD in underrepresented populations.

Clinical Warburg Effect in a Patient With Mantle Cell Lymphoma: A Case Report.

The clinical Warburg effect is a rare occurrence in cancer biology where tumor cells primarily utilize glycolysis for energy production, leading to significant hypoglycemia and lactate formation. This presentation is associated with a poor prognosis for the patient. In this context, we describe the case of a 53-year-old woman with stage IV mantle cell lymphoma who developed the clinical Warburg effect with solely arrhythmia and without neurological symptoms. She received prompt treatment for glucose stabilization and underwent inpatient chemotherapy. This case underscores the importance of early intervention to reduce tumor burden and highlights the effectiveness of hemodialysis in stabilizing metabolic acidosis. Further investigation into this approach is warranted.