Recent publications
Background. Systemic sclerosis (SSc) is an autoimmune disease (AD), that receives less attention compared to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren’s syndrome (pSS). This study aims to analyze transcriptional profiles and immune cell composition in peripheral blood mononuclear cells (PBMC) from SSc patients compared to other ADs.
Methods. RNA-seq data from 119 untreated patients (eight with SSc, 42 with RA, 41
with pSS, 28 with SLE) and 20 healthy controls were analyzed. Bioinformatics tools
were employed to identify differentially expressed genes (DEGs), biological functions and immune cell profiles unique to SSc and shared with other ADs.
Results. 1,148 DEGs were found in SSc, with upregulated genes associated with
megakaryocyte processes and downregulated genes associated with neutrophil function and immune response. DEGs, including ALDH1A1 and MEGF9, were associated with neutropenia. Upregulated transcription factors (TFs) were linked to embryonic hematopoiesis and downregulated TFs were involved in leukocyte differentiation and immune regulation. Comparative analysis with other ADs revealed common pathogenic pathways, emphasizing megakaryocyte proliferation. Neutrophils count was significantly decreased in ADs (p < 0.001) compared to healthy controls. Comparative analysis highlighted common pathways, particularly in megakaryocyte proliferation, and unique genes (MEGF9, MMP8, and KRT family members) in SSc, suggesting roles in neutrophil function, skin integrity, and fibrosis.
Conclusions. This study identifies dysregulated gene expression (KRT and MMP8) as�sociated with neutrophil function and increased megakaryocytes in SSc, highlighting common patterns across autoimmune diseases. These findings offer new insights into the potential pathogenesis of SSc, and help to explore new targets for the treatment.
With the emergence of AI generated content, cross-modal retrieval of 2D and 3D data has obtained increasing research attention. In practical applications, massive amounts of 2D and 3D data need expensive annotation, which would make labels scarce. Even worse, complicated heterogeneous relationships between 2D and 3D data make the problem more challenging. In this research, we study the problem of semi-supervised 2D and 3D cross-modal retrieval and provide a novel method named
H
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ling (HOPE) for this problem. The core of HOPE is to align two modalities in the common space from a hierarchical perspective. Specifically, HOPE not only enforces each sample to approach its respective modality-invariant anchors from an individual view, but also measures both prototypes and distribution for both modalities for discrepancy reduction from a group view. To handle label scarcity with limited error accumulation, HOPE employs two branches of perturbed networks to generate ambiguous candidates, which guides the cross-branch supervision using a margin-based ranking objective. In addition, we retrieve reliable unlabeled samples for each anchor with curriculum learning and class balance, which are added into labeled datasets to clear ambiguity. Extensive experiments on various benchmark datasets validate the superiority of the proposed HOPE.
Hybrid arrays enable millimeter-wave (mmW) base stations and users to steer multiple beams simultaneously. However, in dense mmW networks with small inter-site distances and many users, a large number of serving beams can lead to significant inter- and intra-cell interference that prevents data-hungry users from satisfying their rate requirements. In this work, we address this problem by designing a linear multi-step optimization framework for user association and beam scheduling with interference management. In the first step, the framework aims to maximize the number of users with fully satisfied rate requirements by scheduling a minimal number of non-interfering beams. In the second step, any remaining non-interfering beams are distributed among other users to maximize the number of them with at least partially satisfied requirements. Hybrid precoders and combiners are then designed to remove any excess sidelobe interference among the scheduled beams. Finally, power allocation is optimized on a network level to boost the data rates of the partially satisfied users. Given that the framework includes NP-hard optimization problems, we propose an algorithm that attains a sub-optimal solution in polynomial-time. The proposed framework is numerically evaluated in realistic mmW channels and the results reveal its advantages over the baseline user association schemes.
BACKGROUND
Patients with premorbid dementia have been generally excluded from trials of stroke therapies, and their dementia diagnosis may affect the care received. There are few data on the quality of stroke care and outcomes in these patients.
METHODS
We compared the quality of care and outcomes for acute ischemic stroke patients with versus without premorbid dementia using national data from the Get With The Guidelines-Stroke registry between July 1, 2020, and December 31, 2021. Process outcomes included receiving intravenous thrombolysis, endovascular thrombectomy, and additional national quality measures. Clinical outcomes included ambulatory status at discharge, discharge destination, and mortality. The analyses were adjusted for patient and hospital characteristics.
RESULTS
Among 609 350 patients with acute ischemic stroke, 29 751 of 546 407 (5.4%) had documented prestroke dementia (median age, 84 [interquartile range, 78–89]; 62.8% female). Patients with versus without premorbid dementia were more likely to arrive via emergency medical services (70.5% versus 46.8%) and had more severe strokes (median National Institutes of Health Stroke Scale score, 7 [interquartile range, 3–15] versus 3 [interquartile range, 1–8]). They were less likely to be admitted to a comprehensive stroke center (17.9% versus 22.7%; P <0.0001), to receive intravenous thrombolysis (9.6% versus 11.1%; adjusted odds ratio [aOR], 0.91 [95% CI, 0.87–0.95]) or endovascular thrombectomy (4.5% versus 7.4%; aOR, 0.62 [95% CI, 0.56–0.68]), attain each of the Get With The Guidelines-Stroke Achievement Measures and Quality Measures, or attain defect-free stroke care (92.0% versus 95.0%; aOR, 0.75 [95% CI, 0.71–0.78]). Patients with premorbid dementia had longer door-to-needle times (adjusted difference, 3.17 minutes [95% CI, 1.34–5.01]), lower odds of being discharged home (43.8% versus 60.1%; aOR, 0.96 [95% CI, 0.93–1.00]), and higher odds of being nonambulatory at discharge (25.8% versus 9.3%; aOR, 1.62 [95% CI, 1.54–1.69]), and of in-hospital mortality or hospice admission (23.3% versus 8.6%; aOR, 1.38 [95% CI, 1.32–1.43]). Symptomatic intracranial hemorrhage after intravenous thrombolysis/endovascular thrombectomy did not differ (5.3% versus 3.7%; aOR, 1.13 [95% CI, 0.97–1.31]).
CONCLUSIONS
Patients with premorbid dementia experienced slightly poorer quality of stroke care across multiple measures, were less likely to receive acute stroke interventions, and had worse poststroke outcomes than patients without dementia in a large nationwide registry. Our findings underscore the need for concerted efforts to further improve care quality and outcomes in this population.
Aim
To explore descriptions of normalcy among individuals who have lived with mechanical circulatory support for a long time.
Design
Reflexive thematic analysis was used for this qualitative research.
Methods
A parent study, utilising constructivist grounded theory, was conducted to explore the experiences of advance care planning among mechanical circulatory support individuals. Participants spontaneously shared their experiences of normalcy, which was outside the scope of the primary study. Thus, a secondary analysis using reflexive thematic analysis was performed to explore experiences of normalcy among individuals living with mechanical circulatory support for long‐term use.
Results
Twelve transcripts were purposively sampled and analysed. Three major themes were derived from the data: acquiescence, adapting to the device and restructuring family roles.
Conclusion
Normalcy continued to evolve years after device implantation because individuals were not prepared to face ongoing psychosocial challenges. Clinicians and researchers must address the complex emotional and social needs related to changes in goal therapy and unanticipated transplant delays. This includes the development of support groups that are aligned with the various stages of the MCS trajectory.
Implications for the Profession and/or Patient Care
Clinicians need to engage patients in conversations about disruptions to their perceived ‘normal’ lifestyle and how they plan to adapt to complex changes. Future support groups can be organised according to individuals' duration of implantation and goal therapy to reduce social withdrawal. Additionally, clinicians should assess bridge to transplant individuals' attitudes before connecting them with transplanted volunteers. Finally, clinicians can support resilience by recognising and discussing the ongoing work required to adapt to the complex changes throughout the mechanical circulatory support trajectory.
Impact
Perceptions of normalcy among mechanical circulatory support individuals are subject to ongoing change. Findings will inform clinicians of the social, emotional and familial challenges that require ongoing support and resources for long‐term mechanical circulatory support individuals.
Reporting Method
Reporting adhered to the COREQ checklist.
Patient Contribution
Participants contributed to this study by sharing their experiences of normalcy after living with mechanical circulatory support for 2 years or more.
BACKGROUND
Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition’s role in poststroke epilepsy (PSE) remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises poststroke survivor’s risk of PSE.
METHODS
We conducted a case-control genetic association study nested within the UK Biobank, a large UK-based prospective cohort. Our exposures of interest were 2 distinct polygenic risk scores—generalized and focal epilepsy—modeled as deciles and constructed using genetic variants identified in the latest International League Against Epilepsy genome-wide association study meta-analysis. We aimed to evaluate the association between these polygenic risk scores and their corresponding subtype of PSE—generalized and focal. In sensitivity analyses, we evaluated participants of European ancestry separately and considered focal and generalized epilepsy outcomes in participants without a history of stroke. In secondary analyses, we evaluated the polygenic risk of PSE by stroke subtype (ischemic, hemorrhagic, or any stroke). Multivariable logistic regression models were fitted, adjusting for age, sex, genetic ancestry, and the first 5 principal genetic components.
RESULTS
Among 17 549 UK Biobank stroke survivors with available genetic information (mean age, 61; 43% female), 185 (1%) developed generalized PSE, while 124 (0.7%) developed focal PSE. Multivariable logistic regression results showed that, when compared against the lowest decile, participants within the highest PRS decile for generalized PSE had 5-fold higher odds of developing generalized PSE (OR, 5.05 [95% CI, 2.37–12.5]; P trend<0.001). Similarly, when compared against the lowest decile, participants within the highest polygenic risk score decile for focal PSE had 3-fold higher odds of developing focal PSE (OR, 3.20; [5% CI, 1.25–9.82]; P trend=0.024). Sensitivity analyses among participants of European ancestry yielded similar results.
CONCLUSIONS
Our findings suggest that, like other forms of epilepsy, genetic predisposition plays an essential role in PSE. These results underscore the need for future studies to elucidate the mechanisms underlying PSE development and to identify novel therapeutic avenues.
Consensus recommendation published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation to enable appropriate intervention for affected patients. To this end, we assembled a multi-institutional expert pathology working group as part of a “Symposium on Atypical Neurofibroma: State of the Science”. Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling, and recommend molecular profiling for clinically or radiologically worrisome non-cutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. We also propose renaming “low-grade MPNST” to “ANNUBP with increased proliferation” to avoid the use of the “malignant” term in this group of tumors with persistent unknown biologic potential. This refined integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors should continue to evolve in concert with our understanding of these neoplasms.
BACKGROUND
A polypill containing all 4 classes of guideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF) has been proposed to change the heart failure treatment paradigm. The acceptability, appropriateness, and feasibility of a HFrEF polypill-based strategy are unknown. The purpose of this study was to elicit patients’ and providers’ priorities in the design of HFrEF polypills.
METHODS
From April 2023 to December 2023, we conducted a convergent parallel mixed-methods study at Washington University in St. Louis, the University of California, San Francisco, and the American College of Cardiology. We administered physician surveys containing adapted implementation outcome measures to elicit physicians’ perspectives on the acceptability, feasibility, and appropriateness of a HFrEF polypill (Likert scale ranging from 1 [low] to 5 [high]). We used a purposive sampling frame to select patients and physicians for in-depth interviews. Using semi-structured interview guides, we elicited participants’ perspectives on current HFrEF care, HFrEF polypill design, and supportive strategies. The Consolidated Framework for Implementation Research v2.0 guided thematic analysis.
RESULTS
Of the 214 survey respondents across the United States, physicians agreed that HFrEF polypills are highly acceptable (mean [SD], 4.2 [0.7]), highly appropriate (4.1 [0.8]), and highly feasible (4.1 [0.7]). Key themes from 9 patient and 22 provider interviews included the following: (1) current determinants of HFrEF care, including medication adherence, variations in clinical practice, and health care access, (2) provider-level differences in preferred HFrEF polypill design, (3) cost and equity considerations in the implementation of HFrEF polypills, and (4) research priorities for evaluating polypill effectiveness and implementation.
CONCLUSIONS
A HFrEF polypill-based strategy was viewed as highly acceptable, appropriate, and feasible by patients and physicians. Participants described key priorities in HFrEF polypill design, titratability, and potential impacts on health equity that will directly inform future randomized controlled trials.
Four metalloporphyrinic metal-organic frameworks (MOFs) were successfully synthesized and exhibited enhanced activities for the photooxidation of a sulfur mustard simulant, 2-chloroethyl ethyl sulfide (CEES). Among them, a Sn-porphyrin functionalized 2D...
Objectives: Approximately 10% of patients with syncope have serious or life-threatening causes that may not be apparent during the initial emergency department
(ED) assessment. Consequently, researchers have developed clinical decision rules
(CDRs) to predict adverse outcomes and risk stratify ED syncope patients. This
systematic review and meta-analysis (SRMA) aims to cohere and synthesize the best
current evidence regarding the methodological quality and predictive accuracy of
CDRs for developing an evidence-based ED syncope management guideline.
Methods: We conducted a systematic literature search according to the patient–
intervention–control–outcome question: In patients 16 years of age or older who
present to the ED with syncope for whom no underlying serious/life-threatening
condition was found during the index ED visit (population), are risk stratification tools
(intervention), better than unstructured clinical judgment (i.e., usual care; comparison),
for providing accurate prognosis and aiding disposition decision for outcomes within
30 days (outcome)? Two reviewers independently assessed articles for inclusion and
methodological quality. We performed statistical analysis using Meta-DiSc. We used
GRADEPro GDT software to determine the certainty of the evidence and create a
summary of the findings (SoF) tables.
Results: Of 2047 publications obtained through the search strategy, 31 comprising 13
CDRs met the inclusion criteria. There were 13 derivation studies (17,578 participants)
and 24 validation studies (14,845 participants). Only three CDRs were validated in more than two studies. The San Francisco Syncope Rule (SFSR) was validated in 12 studies: positive likelihood ratio (LR+) 1.15–4.70 and negative likelihood ratio (LR−) 0.03–0.64. The Canadian Syncope Risk Score (CSRS) was validated in five studies: LR+ 1.15–2.58 and LR− 0.05–0.50. The Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) risk score was validated in five studies: LR+ 1.16–3.32 and LR− 0.14–0.46.
Conclusions: Most CDRs for ED adult syncope management have low-quality
evidence for routine clinical practice use. Only three CDRs (SFSR, CSRS, OESIL)
are validated by more than two studies, with significant overlap in operating
characteristics.
Two-thirds of all glaciers worldwide are projected to disappear by 2100 CE. Large uncertainties however remain in maritime settings, where some glaciers have recently gained mass in response to increased snowfall. One of these regions is southern Patagonia, where increased precipitation since the 1980s seems to have attenuated glacier retreat. Whether this exceptional behavior will continue in a warmer future is unclear. Here, we use a numerical ice-flow model constrained by paleoglaciological data to simulate how climate variability influenced the evolution of three maritime outlet glaciers of the Southern Patagonian Icefield during the last 6000 years. Our experiments suggest that precipitation drove 67% of the centennial-scale fluctuations in the volume of the modeled glaciers. When applied to the temperature projected by 2100 CE, our simulations show that precipitation needs to increase by 10–50% to maintain present-day glacier volumes, depending on the climate scenario (SSP1-2.6 to SSP5-8.5). This implies that if greenhouse-gas emission cuts fail, these glaciers will enter a warmer regime unseen over the last 6000 years, where precipitation cannot offset glacier mass loss. Conversely, if emissions are curtailed, increased precipitation could halt mass loss of some of Patagonia’s largest glaciers, and potentially of other maritime glaciers worldwide.
- Binbin Jiang
- Han Xiao
- Jiayi Li
- [...]
- Konglin Wu
Seawater electrolysis is an ideal approach to generating green hydrogen. Nevertheless, the sluggish kinetics of water dissociation and the detrimental chlorine chemistry environment are serious obstructions for industrial applications. Herein, constructing unique (Co) Lewis acid and (Ru–P) base pair sites in Ru‐Co2P decorated on nitrogen and phosphorus co‐doped carbon (Ru‐Co2P/NPC) significantly optimizes the energy barrier of water dissociation and enhances the anti‐corrosive ability for alkaline seawater splitting. As expected, the optimal Ru‐Co2P/NPC‐2 exhibits exceptional hydrogen evolution reaction (HER) performances with overpotentials as low as 22.0 and 26.0 mV to derive 10 mA cm⁻² and operate steadily (@ 50 mA cm⁻²) over 30 h in alkaline and alkaline seawater electrolytes. The experimental and theoretical results elucidate that Co acting as Lewis acid sites prompts the water adsorption and breakage of the H─O bond, whereas Ru–P as Lewis base sites facilitates the hydrogen desorption in alkaline media. Furthermore, modulated chemical microenvironments can be beneficial to hinder chloride corrosion on the active sites of catalysts. This work sheds light on the rational construction of a highly efficient electrocatalyst for alkaline HER in seawater.
Metabolic processes in living organisms depend on the synergistic actions of enzymes working in proximity and in concert, catalyzing reactions effectively while regulating the formation of metabolites. This enzyme synergy offers promising therapeutic application for diseases such as alcohol intoxication, cancer, and hyperinflammation. Despite their potential, the clinical translation of enzyme cascades is restricted by challenges including poor enzyme stability, short half‐life, and a lack of delivery strategies that maintain enzyme proximity. In this study, multi‐enzyme nanocascades synthesized are developed through in situ atom transfer radical polymerization using a zwitterionic monomer. This method markedly enhances enzyme stability and proximity, thereby prolonging their circulation half‐life after systemic administration. It is demonstrated that the nanocascades of uricase and catalase effectively reduce uric acid levels without excessive hydrogen peroxide production, providing a potential antidote for hyperuricemia. Moreover, in a murine breast cancer model, the nanocascades of glucose oxidase and catalase inhibited tumor progression and enhanced the therapeutic efficacy of doxorubicin. The prolonged circulation and promoted reaction efficacy of these nanocascades underscore their substantial potential in enzyme replacement therapy and the treatment of various diseases.
In patients with out‐of‐hospital cardiac arrest (OHCA) who attain return of spontaneous circulation (ROSC), rearrest while in the prehospital setting represents a significant barrier to survival. To date, there are limited data to guide prehospital emergency medical services (EMS) management immediately following successful resuscitation resulting in ROSC and prior to handoff in the emergency department. Post‐ROSC care encompasses a multifaceted approach including hemodynamic optimization, airway management, oxygenation, and ventilation. We sought to develop an evidenced‐based, goal‐directed bundle of care targeting specified vital parameters in the immediate post‐ROSC period, with the goal of decreasing the incidence of rearrest and improving survival outcomes. Here, we describe the rationale and development of this goal‐directed bundle of care, which will be adopted by several EMS agencies within California. We convened a group of EMS experts, including EMS Medical Directors, quality improvement officers, data managers, educators, EMS clinicians, emergency medicine clinicians, and resuscitation researchers to develop a goal‐directed bundle of care to be applied in the field during the period immediately following ROSC. This care bundle includes guidance for prehospital personnel on recognition of impending rearrest, hemodynamic optimization, ventilatory strategies, airway management, and diagnosis of underlying causes prior to the initiation of transport.
Objectives
To understand the extent of racial disparities in SARS-CoV-2 vaccination among PWH and those vulnerable to HIV infection and to estimate the contributions of medical mistrust and vaccine-hesitant attitudes to these disparities.
Design
Quantitative data analyses in a racially and gender diverse, mixed-serostatus prospective cohort, the MACS/WIHS Combined Cohort Study.
Methods
Interviewer-assisted questionnaires assessed SARS-CoV-2 vaccination, medical mistrust, and vaccine-hesitant attitudes from March 2021—September 2022 (n=3948). Longitudinal analyses assessed effects of sociodemographics on medical mistrust and vaccine-hesitant attitudes. A hierarchical multivariable logistic regression assessed effects of these co-factors on SARS-CoV-2 vaccination. Causal mediation models assessed whether a) medical mistrust mediated the relationship between Black identity and vaccine-hesitant attitudes, and b) vaccine-hesitant attitudes mediated the relationship between Black identity and SARS-CoV-2 non-vaccination.
Results
Participants’ mean age was 56.7; 55.3% were Black, 52.6% cisgender female, 62.6% PWH. 10.1% reported never receiving SARS-CoV-2 vaccinations (13.4% of Black and 4.5% of white participants). Black-identified participants had higher odds of non-vaccination than white participants (aOR = 1.72; 95% CI: 1.08, 2.72). Medical mistrust mediated the relationship between Black identity and vaccine-hesitant attitudes, accounting for 46.0% of the effect ( p < 0.0001). Vaccine-hesitant attitudes mediated the relationship between Black identity and SARS-CoV-2 non-vaccination to the extent that 57.7% (95% CI: 25.3%, 90.1%) of the disparity would be eliminated if vaccine-hesitant attitudes among Black respondents were reduced to levels reported among other racial groups.
Conclusions
Findings indicate a profound need to build trustworthy healthcare environments to combat medical mistrust and vaccine-hesitant attitudes in Black communities in the U.S, including those affected by HIV.
Background
Skin cancers are common post-transplant malignancies in solid organ transplant (SOT) recipients. The use of immune checkpoint inhibitors has improved outcomes in the general patient population but is associated with high risk of allograft rejection in transplant recipients. RP1 is a herpes simplex virus type 1 (HSV-1)–based oncolytic immunotherapy that expresses a fusogenic protein (gibbon ape leukemia virus glycoprotein with the R sequence deleted [GALV-GP-R−]) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This study is assessing the safety and efficacy of single-agent RP1 in SOT recipients with skin cancer.
Methods
The trial (NCT04349436) will enroll up to 65 transplant recipients with histologically confirmed advanced cutaneous squamous cell carcinoma (CSCC) and up to 10 patients with advanced non-CSCC skin cancer in 2 parts. Part A (completed) enrolled kidney and liver transplant recipients until safety was established, and Part B is enrolling kidney, liver, heart, and lung transplant recipients. Patients must have stable allograft function and Eastern Cooperative Oncology Group performance status ≤1. Patients with visceral metastases are excluded. Patients receive an initial RP1 dose at 1 x 10⁶ plaque-forming units (PFU)/mL followed by 1 x 10⁷ PFU/mL after 2 weeks that continues every 2 weeks for a maximum of 52 weeks, or until confirmed disease progression or unacceptable toxicity. Tumor biopsies are collected for biomarker analyses and HSV-1 serostatus is monitored.
Results
At the time of this analysis, 27 transplant recipients were enrolled (kidney, n = 22; liver, n = 4; lung, n = 1) with a median (range) age of 68 (48–86) years; 24 patients had CSCC and 3 had Merkel cell carcinoma. At study baseline, 56% of patients had locally advanced disease and 44% had metastatic disease. The investigator-assessed objective response rate for efficacy-evaluable patients was 35% (8/23); 22% of patients (5/23) had complete response. Most responses were ongoing. The most common (>20%) treatment-emergent adverse events were fatigue (33%), chills (26%), and pyrexia (26%). There was no evidence of allograft rejection. Eight deaths were reported; none were related to RP1. Immunohistochemistry from tumor biopsies and additional updated translational data will be presented.
Conclusions
This is the first trial assessing single-agent RP1 activity in SOT recipients with advanced cutaneous malignancies. RP1 monotherapy showed compelling antitumor activity in evaluable patients. RP1 monotherapy was well tolerated, with a safety profile similar to that reported in non-immunocompromised patients with advanced skin cancers (IGNYTE study).
Trial Registration
NCT04349436.
Ethics Approval
The study is conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Guidelines for Good Clinical Practice. The study protocol was approved by the institutional review board or ethics committee of each participating site. All participants provided written informed consent before study-related procedures were conducted.
Type 2 diabetes (T2D) is a risk factor for mucosal homeostasis and enhances the susceptibility to inflammation, in which neutrophils have been increasingly appreciated for their role. Here, barrier disruption and inflammation are observed at oral mucosa (gingiva) of T2D patients and mice. It is demonstrated that neutrophils infiltrate the gingival mucosa of T2D mice and expel obvious neutrophil extracellular traps (NETs), while removal of NETs alleviates the disruption of mucosal barrier. Mechanistically, gingival neutrophils released NETs are dependent of their metabolic reprogramming. Under hyperglycemic condition, neutrophils elevate both glucose incorporation and glycolysis via increased expression of GLUT1. Moreover, significantly increased levels of NETs are observed in local gingival lesions of patients, which are associated with clinical disease severity. This work elucidates a causative link between hyperglycemia and oral mucosal immunopathology, mediated by the altered immuno‐metabolic axis in neutrophil, thereby suggesting a potential therapeutic strategy.
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