Cellular Mechanisms of NETosis.

Neutrophils are critical to innate immunity, including host defense against bacterial and fungal infections. They achieve their host defense role by phagocytosing pathogens, secreting their granules full of cytotoxic enzymes, or expelling neutrophil extracellular traps (NETs) during the process of NETosis. NETs are weblike DNA structures decorated with histones and antimicrobial proteins released by activated neutrophils. Initially described as a means for neutrophils to neutralize pathogens, NET release also occurs in sterile inflammation, promotes thrombosis, and can mediate tissue damage. To effectively manipulate this double-edged sword to fight a particular disease, researchers must work toward understanding the mechanisms driving NETosis. Such understanding would allow the generation of new drugs to promote or prevent NETosis as needed. While knowledge regarding the (patho)physiological roles of NETosis is accumulating, little is known about the cellular and biophysical bases of this process. In this review, we describe and discuss our current knowledge of the molecular, cellular, and biophysical mechanisms mediating NET release as well as open questions in the field.

Epigenomic profiling of the infrapatellar fat pad in osteoarthritis.

Osteoarthritis is a prevalent, complex disease of the joints, and affects multiple intra-articular tissues. Here, we have examined genome-wide DNA methylation profiles of primary infrapatellar fat pad and matched blood samples from 70 osteoarthritis patients undergoing total knee replacement surgery. Comparing the DNA methylation profiles between these tissues reveal widespread epigenetic differences. We produce the first genome-wide methylation quantitative trait locus (mQTL) map of fat pad, and make the resource available to the wider community. Using two-sample Mendelian randomization and colocalization analyses, we resolve osteoarthritis GWAS signals and provide insights into the molecular mechanisms underpinning disease aetiopathology. Our findings provide the first view of the epigenetic landscape of infrapatellar fat pad primary tissue in osteoarthritis.

Mitochondrial respiration in peripheral arterial disease depends on stage severity.

Peripheral arterial disease (PAD) is an increasing cause of morbidity and its severity is graded based on clinical manifestation. To investigate the influence of the different stages on myopathy of ischemic muscle we analysed severity-dependent effects of mitochondrial respiration in PAD. Eighteen patients with severe PAD, defined as chronic limb-threatening ischemia, 47 patients with intermittent claudication (IC) and 22 non-ischemic controls were analysed. High-resolution respirometry (HRR) was performed on muscle biopsies of gastrocnemius and vastus lateralis muscle of patients in different PAD stages to investigate different respiratory states. Results from HRR are given as median and interquartile range and were normalized to citrate synthase activity (CSA), a marker for mitochondrial content. In order to account for inter-individual differences between patients and controls, we calculated the ratio of O2-flux in gastrocnemius muscle over vastus muscle ('GV ratio'). CSA of the gastrocnemius muscle as a proxy for mitochondrial content was significantly lower in critical ischemia compared to controls. Mitochondrial respiration normalized to CSA was higher in IC compared to controls. Likewise, the GV ratio was significantly higher in IC compared to control. Mitochondrial respiration and CSA of PAD patients showed stage-dependent modifications with greater changes in the mild PAD stage group (IC).

Sex-specific effects of injury and beta-adrenergic activation on metabolic and inflammatory mediators in a murine model of post-traumatic osteoarthritis.

OBJECTIVE: Metabolic processes are intricately linked to the resolution of innate inflammation and tissue repair, two critical steps for treating post-traumatic osteoarthritis (PTOA). Based on lipolytic and immunoregulatory actions of norepinephrine, we hypothesized that intra-articular ß-adrenergic receptor (ßAR) stimulation would suppress PTOA-associated inflammation in the infrapatellar fat pad (IFP) and synovium. DESIGN: We used the ßAR agonist isoproterenol to perturb intra-articular metabolism 3.5 weeks after applying a non-invasive single-load compression injury to knees of 12-week-old male and female mice. We examined the acute effects of intra-articular isoproterenol treatment relative to saline on IFP histology, multiplex gene expression of synovium-IFP tissue, synovial fluid metabolomics, and mechanical allodynia. RESULTS: Injured knees developed PTOA pathology characterized by heterotopic ossification, articular cartilage loss, and IFP atrophy and fibrosis. Isoproterenol suppressed the upregulation of pro-fibrotic genes and downregulated the expression of adipose genes and pro-inflammatory genes (Adam17, Cd14, Icam1, Csf1r, and Casp1) in injured joints of female (but not male) mice. Analysis of published single-cell RNA-seq data identified elevated catecholamine-associated gene expression in resident-like synovial-IFP macrophages after injury. Injury substantially altered synovial fluid metabolites by increasing amino acids, peptides, sphingolipids, phospholipids, bile acids, and dicarboxylic acids, but these changes were not appreciably altered by isoproterenol. Intra-articular injection of either isoproterenol or saline increased mechanical allodynia in female mice, whereas neither substance affected male mice. CONCLUSIONS: Acute ßAR activation altered synovial-IFP transcription in a sex and injury-dependent manner, suggesting that women with PTOA may be more sensitive than men to treatments targeting sympathetic neural signaling pathways.

Disentangling the detrimental effects of local from systemic adipose tissue dysfunction on articular cartilage in the knee.

OBJECTIVE: Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee. METHODS: Intra-articular adipose tissue development was studied using reporter mice. Mice with selective lipodystrophy of intra-articular adipose tissue were generated by conditional knockout (cKO) of Bscl2 in Gdf5-lineage cells, and compared with congenital Bscl2 knockout (KO) mice with generalised lipodystrophy and associated systemic metabolic dysfunction. OA was induced by surgically destabilising the medial meniscus (DMM) and obesity by high-fat diet (HFD). Gene expression was analysed by quantitative RT-PCR and tissues were analysed histologically. RESULTS: The infrapatellar fat pad (IFP), in contrast to overlying subcutaneous adipose tissue, developed from a template established from the Gdf5-expressing joint interzone during late embryogenesis, and was populated shortly after birth by adipocytes stochastically arising from Pdgfrα+ Gdf5-lineage progenitors. While female Bscl2 KO mice with generalised lipodystrophy developed spontaneous knee cartilage damage, Bscl2 cKO mice with intra-articular lipodystrophy did not, despite synovial hyperplasia and inflammation of the residual IFP. Furthermore, male Bscl2 cKO mice showed no worse cartilage damage after DMM. However, female Bscl2 cKO mice with intra-articular lipodystrophy showed increased susceptibility to the cartilage-damaging effects of HFD-induced obesity. CONCLUSION: Our findings emphasise the prevalent role of systemic metabolic and inflammatory effects in impairing cartilage homeostasis, with a modulatory role for intra-articular adipose tissue.

Effect of isometric quadriceps exercise on local microcirculation of the infrapatellar fat pad in female patients with knee osteoarthritis.

OBJECTIVE: To elucidate the local microcirculation of the infrapatellar fat pad (IFP) in patients with knee osteoarthritis (KOA) by determining the changes in IFP hardness and hemoglobin concentration during isometric quadriceps exercise (IQE). DESIGN: In this observational cross-sectional study, patients diagnosed with bilateral KOA were included in the KOA group (30 knees), healthy older adults in the control group (20 knees), and younger adults in the young group (20 knees). Ultrasonography was performed at rest and during IQE to measure IFP hardness based on shear wave velocity. Near-infrared spectroscopy was performed to measure oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), and total hemoglobin (cHb) in the IFP before (Baseline), during (IQE task), and after IQE (Post). IFP hardness and O2Hb, HHb, and cHb concentration were analyzed using a linear mixed model for the groups and measurement points. RESULTS: During IQE, IFP hardness changes were significantly less in the KOA group than in the other groups (KOA: 95 % confidence intervals (CIs) [-0.854, 0.028]; control: 95 % CI [-0.941, -0.341]; and young: 95 % CI [-2.305, -1.706]). In the KOA group, O2Hb concentration exhibited no significant changes at Post compared with Baseline; however, significant changes were observed in the other groups (KOA: 95 % CI [-1.176, 0.423]; control: 95 % CI [-1.452, -0.276]; and young: 95 % CI [-4.062, -2.102]). CONCLUSIONS: During IQE, changes in hardness and hemoglobin concentration in the IFP were not significant in the KOA group, suggesting impaired local microcirculation of the IFP.

Diagnostic values, association with disease activity and possible risk factors of anti-PAD4 in rheumatoid arthritis: a meta-analysis.

OBJECTIVE: Anti-peptidyl arginine deaminase 4 (anti-PAD4) antibody has been a subject of investigation in RA in the last two decades. This meta-analysis investigated the diagnostic values, association with disease activity and possible risk factors of anti-PAD4 antibody in rheumatoid arthritis. METHOD: We searched studies from five databases up to 1 December 2022. Bivariate mixed-effect models were used to pool the diagnostic accuracy indexes, and the summary receiver operating characteristics (SROC) curve was plotted. The quality of diagnostic studies was assessed using QUADAS-2. Non-diagnostic meta-analyses were conducted using the random-effects model. Sensitivity analysis, meta-regression, subgroup analyses and Deeks' funnel plot asymmetry test were used to address heterogeneity. RESULT: Finally, 24 journal articles and one letter were included. Anti-PAD4 antibody had a good diagnostic value between RA and healthy individuals, but it might be lower between RA and other rheumatic diseases. Moreover, anti-PAD4 could slightly enhance RA diagnostic sensitivity with a combination of ACPA or ACPA/RF. Anti-PAD4 antibody was positively correlated with HLA-SE and negatively correlated with ever or current smoking in patients with RA. RA patients with anti-PAD4 antibody had higher DAS28, ESR, swollen joint count (SJC) and the possibility of having interstitial lung disease (ILD) and pulmonary fibrosis compared with those without. CONCLUSION: Our study suggests that anti-PAD4 antibody is a potentially useful diagnostic biomarker and clinical indicator for RA. Further mechanistic studies are required to understand the impact of HLA-SE and smoking on the production of anti-PAD4 antibody.

Nonpharmacologic rate control of postoperative atrial fibrillation in the canine sterile pericarditis model.

INTRODUCTION: Postoperative atrial fibrillation (POAF) is common following open heart surgery, and is associated with significant morbidity. Medications used for ventricular rate control of POAF may not be effective in controlling rapid ventricular rates during the postoperative period because of increased sympathetic tone. The purpose of this study was to develop nonpharmacologic rate control of POAF by atrioventricular node (AVN) fat pad stimulation using clinically available temporary pacing wires in the canine sterile pericarditis model. METHODS: We studied 10 sterile pericarditis dogs in the closed-chest state on postoperative days 1-3. The AVN fat pad stimulation (amplitude 2-15 mA; frequency 20 Hz; pulse width 0.03-0.2 ms) was performed during sustained POAF (>5 min). We measured ventricular rate and inefficient ventricular contractions during sustained POAF and compared it with and without AVN fat pad stimulation. Also, the parameters of AVN fat pad stimulation to achieve a rate control of POAF were measured over the postoperative days. RESULTS: Eleven episodes of sustained POAF were induced in 5/10 sterile pericarditis dogs in the closed-chest state on postoperative days 1-2. During POAF, the AVN fat pad stimulation decreased the ventricular rate from 178 ± 52 bpm to 100 ± 8 bpm in nine episodes. Nonpharmacologic rate control therapy successfully controlled the ventricular rate and eliminated inefficient ventricular contractions during POAF for the duration of the AVN fat pad stimulation. The AVN fat pad stimulation output remained relatively stable over the postoperative days. CONCLUSION: During sustained POAF, nonpharmacologic rate control by AVN fat pad stimulation effectively and safely controlled rapid ventricular rates throughout the postoperative period.

The suprapatellar fat pad: A histotopographic comparative study.

The suprapatellar fat pad is an adipose tissue located in the anterior knee whose role in osteoarthritis is still debated. Considering that anatomy drives function, the aim of this histotopographic study was to investigate the specific morphological features of the suprapatellar fat pad versus the infrapatellar fat pad in the absence of osteoarthritis, for a broad comparative analysis. Suprapatellar fat pad and infrapatellar fat pad tissue samples (n = 10/group) underwent microscopical/immunohistochemical staining and transmission electron microscopy analysis; thus, tissue-specific characteristics (i.e., vessels and nerve endings presence, lobuli, adipocytes features, septa), including extracellular matrix proteins prevalence (collagens, elastic fibers), were focused. Multiphoton microscopy was also adopted to evaluate collagen fiber orientation within the samples by Fast Fourier Transform (coherency calculation). The absence of inflammation was confirmed, and comparable counted vessels and nerve endings were shown. Like the infrapatellar fat pad, the suprapatellar fat pad appeared as a white adipose tissue with lobuli and septa of comparable diameter and thickness, respectively. Tissue main characteristics were also proved by both semithin sections and transmission electron microscopy analysis. The suprapatellar fat pad adipocytes were roundish and with a smaller area, perimeter, and major axis than that of the infrapatellar fat pad. The collagen fibers surrounding them showed no significant difference in collagen type I and significantly higher values for collagen type III in the infrapatellar fat pad group. Regarding the septa, elastic fiber content was statistically comparable between the two groups, even though more represented by the suprapatellar fat pad. Total collagen was significantly higher in the infrapatellar fat pad and comparing collagen type I and type III they were similarly represented in the whole cohort despite collagen type I appearing to be higher in the infrapatellar fat pad than in the suprapatellar fat pad and vice versa for collagen type III. Second harmonic generation microscopy confirmed through coherency calculation an anisotropic distribution of septa collagen fibers. From a mechanical point of view, the different morphological characteristics determined a major stiffness for the infrapatellar fat pad with respect to the suprapatellar fat pad. This study provides, for the first time, a topographic description of the suprapatellar fat pad compared to the infrapatellar fat pad; differences between the two groups may be attributed to a different anatomical location within the knee; the results gathered here may be useful for a more complete interpretation of osteoarthritis disease, involving not only cartilage but the whole joint.

Role of long noncoding RNAs in diabetes-associated peripheral arterial disease.

Diabetes mellitus (DM) is a metabolic disease that heightens the risks of many vascular complications, including peripheral arterial disease (PAD). Various types of cells, including but not limited to endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages (MΦs), play crucial roles in the pathogenesis of DM-PAD. Long non-coding RNAs (lncRNAs) are epigenetic regulators that play important roles in cellular function, and their dysregulation in DM can contribute to PAD. This review focuses on the developing field of lncRNAs and their emerging roles in linking DM and PAD. We review the studies investigating the role of lncRNAs in crucial cellular processes contributing to DM-PAD, including those in ECs, VSMCs, and MΦ. By examining the intricate molecular landscape governed by lncRNAs in these relevant cell types, we hope to shed light on the roles of lncRNAs in EC dysfunction, inflammatory responses, and vascular remodeling contributing to DM-PAD. Additionally, we provide an overview of the research approach and methodologies, from identifying disease-relevant lncRNAs to characterizing their molecular and cellular functions in the context of DM-PAD. We also discuss the potential of leveraging lncRNAs in the diagnosis and therapeutics for DM-PAD. Collectively, this review provides a summary of lncRNA-regulated cell functions contributing to DM-PAD and highlights the translational potential of leveraging lncRNA biology to tackle this increasingly prevalent and complex disease.

High ankle-brachial index participants experienced similar long-term mortality as peripheral artery disease in a national sample of community-dwelling adults.

BACKGROUND: Only a few small studies have shown the association between high ankle-brachial pressure index (ABI >1.4) and adverse cardiovascular (CV) events and mortality. Although there is abundant literature depicting the association between ABI and overall systemic atherosclerosis, it typically focuses on low ABI. Furthermore, historically, many studies focusing on peripheral artery disease have excluded high ABI participants. We aimed to study the mortality outcomes of persons with high ABI in the National Health and Nutrition Examination Survey (NHANES). METHODS: We obtained ABI from participants aged ≥40 years for survey years 1999 to 2004. We defined low a ABI as ≤0.9, normal ABI as 0.9 to 1.4, and high ABI as >1.4 or if the ankle pressures were >245 mm Hg. Demographics, various comorbidities, and laboratory test results were obtained at the time of the survey interview. Multivariable adjusted hazard ratios (HRs) along with 95% confidence intervals (CIs) were calculated for CV and all-cause mortality via Cox proportional hazards regression. Mortality was linked to all NHANES participants for follow-up through December 31, 2019, by the Centers for Disease Control and Prevention. RESULTS: We identified 7639 NHANES participants with available ABI. Of these, 6787 (89%) had a normal ABI, 646 (8%) had a low ABI, and 206 (3%) had elevated ABI. Of participants with high ABI, 50% were men, 15% were African Americans, 10% were current smokers, 56% had hypertension, 33% had diabetes, 15% had chronic kidney disease (CKD), and 18% had concomitant coronary artery disease (CAD). Diabetes (odds ratio [OR], 2.4; 95% CI, 1.7-3.2), CAD (OR, 1.6; 95% CI, 1.0-2.4), and CKD (OR, 1.5; 95% CI, 1.0-2.3) at baseline were associated with having a high ABI, respectively. A high ABI was associated independently with elevated CV (HR, 2.6; 95% CI, 2.1-3.1; P < .0001) and all-cause mortality (HR, 2.5; 95% CI, 2.2-2.8; P < .0001) after adjusting for covariates, including diabetes, CKD, CAD, current smoking, cancer, and hypertension. CONCLUSIONS: A high ABI is associated with an elevated CV and all-cause mortality, similar to patients with PAD. High ABI participants should receive the same attention and aggressive medical therapies as patients with PAD.

The association of comorbid depression with mortality and amputation risk in patients with chronic limb-threatening ischemia.

OBJECTIVE: There is increasing evidence that depression is a risk factor for worse outcomes in patients with peripheral artery disease. The association of depression in patients with chronic limb-threatening ischemia (CLTI) is not well described, nor is the impact of medical treatment for depression in this patient population. The objective of this study was to investigate the prevalence of depression in patients with CLTI, its association on major amputation and all-cause mortality, and whether medical antidepressant treatment is associated with improvement in these outcomes in patients with depression. METHODS: A retrospective review of all adult patients (≥18 years old) diagnosed with CLTI from January 1, 2007, to December 31, 2018, at a single academic medical center was performed. Collected data included patient demographics, comorbidities, and diagnosis of depression within 6 months of initial CLTI diagnosis. We also collected data on use of antidepressant medications. Outcomes evaluated were need for major lower extremity amputation and all-cause mortality. Multivariable logistic regression models estimated the adjusted effects of comorbid depression and antidepressant medication use on major amputation and all-cause mortality. Kaplan-Meier survival curves illustrated the probabilities of survival and limb salvage over time, stratified by diagnosis of comorbid depression. Multivariable Cox proportional hazards models estimated the adjusted effects of comorbid depression on time to major amputation and all-cause mortality, and the adjusted effect of antidepressant treatment on time to all-cause mortality. RESULTS: A total of 2987 patients with CLTI were identified. Mean age was 68.6 years (standard deviation, 12.9 years); 56.5% were male, and 43.5% were female. Comorbid depression within 6 months of CLTI diagnosis was present in 7.1% of the cohort (212 patients). In multivariable analysis, comorbid depression was associated with a 68% increase in the odds of major amputation (adjusted odds ratio [aOR], 1.68; 95% confidence interval [CI], 1.19-2.37; P < .01), a 164% increase in the odds of all-cause mortality among patients not taking antidepressants (aOR, 2.64; 95% CI, 1.31-5.32; P = .03), and only a 6% increase in the odds of all-cause mortality among patients taking antidepressants (aOR, 1.06; 95% CI, 0.72-1.55; P = .99). The effect of comorbid depression on mortality varied significantly by whether or not the patient was taking an antidepressant medication (P = .02). CONCLUSIONS: Comorbid depression in the patient population with CLTI is associated with a worse prognosis for major lower extremity amputation overall, and a worse prognosis for all-cause mortality among patients not taking an antidepressant. Furthermore, antidepressant treatment in the presence of comorbid depression in this patient population is associated with an improvement in the odds of all-cause mortality, illustrating the potential importance of medical management of depression.

Long-term patient-reported outcomes among patients undergoing revascularization vs medical therapy for intermittent claudication.

OBJECTIVE: Society for Vascular Surgery guidelines recommend revascularization for patients with intermittent claudication (IC) if it can improve patient function and quality of life. However, it is still unclear if patients with IC achieve a significant functional benefit from surgery compared with medical management alone. This study examines the relationship between IC treatment modality (operative vs nonoperative optimal medical management) and patient-reported outcomes for physical function (PROMIS-PF) and satisfaction in social roles and activities (PROMIS-SA). METHODS: We identified patients with IC who presented for index evaluation in a vascular surgery clinic at an academic medical center between 2016 and 2021. Patients were stratified based on whether they underwent a revascularization procedure during follow-up vs continued nonoperative management with medication and recommended exercise therapy. We used linear mixed-effect models to assess the relationship between treatment modality and PROMIS-PF, PROMIS-SA, and ankle-brachial index (ABI) over time, clustering among repeat patient observations. Models were adjusted for age, sex, diabetes, Charlson Comorbidity Index, Clinical Frailty Score, tobacco use, and index ABI. RESULTS: A total of 225 patients with IC were identified, of which 40% (n = 89) underwent revascularization procedures (42% bypass; 58% peripheral vascular intervention) and 60% (n = 136) continued nonoperative management. Patients were followed up to 6.9 years, with an average follow-up of 5.2 ± 1.6 years. Patients who underwent revascularization were more likely to be clinically frail (P = .03), have a lower index ABI (0.55 ± 0.24 vs 0.72 ± 0.28; P < .001), and lower baseline PROMIS-PF score (36.72 ± 8.2 vs 40.40 ± 6.73; P = .01). There were no differences in patient demographics or medications between treatment groups. Examining patient-reported outcome trends over time; there were no significant differences in PROMIS-PF between groups, trends over time, or group differences over time after adjusting for covariates (P = .07, P = .13, and P =.08, respectively). However, all patients with IC significantly increased their PROMIS-SA over time (adjusted P = .019), with patients managed nonoperatively more likely to have an improvement in PROMIS-SA over time than those who underwent revascularization (adjusted P = .045). CONCLUSIONS: Patient-reported outcomes associated with functional status and satisfaction in activities are similar for patients with IC for up to 7 years, irrespective of whether they undergo treatment with revascularization or continue nonoperative management. These findings support conservative long-term management for patients with IC.

Clinical factors associated with ultrashort length of stay in patients undergoing lower extremity bypass for peripheral arterial disease.

BACKGROUND: Length of stay (LOS) is a major driver of cost and resource utilization following lower extremity bypass (LEB). However, the variable comorbidity burden and mobility status of LEB patients makes implementing enhanced recovery after surgery pathways challenging. The aim of this study was to use a large national database to identify patient factors associated with ultrashort LOS among patients undergoing LEB for peripheral artery disease. METHODS: All patients undergoing LEB for peripheral artery disease in the National Surgical Quality Improvement Project database from 2011 to 2018 were included. Patients were divided into two groups based on the postoperative length of stay : ultrashort (≤2 days) and standard (>2 days). Thirty-day outcomes were compared using descriptive statistics, and multivariable logistic regression was used to identify patient factors associated with ultrashort LOS. RESULTS: Overall, 17,510 patients were identified who underwent LEB, of which 2678 patients (15.3%) had an ultrashort postoperative LOS (mean, 1.8 days) and 14,832 (84.7%) patients had a standard LOS (mean, 7.1 days). When compared to patients with a standard LOS, patients with an ultrashort LOS were more likely to be admitted from home (95.9% vs 88.0%; P < .001), undergo elective surgery (86.1% vs 59.1%; P < .001), and be active smokers (52.1% vs 40.4%; P < .001). Patients with an ultrashort LOS were also more likely to have claudication as the indication for LEB (53.1% vs 22.5%; P < .001), have a popliteal revascularization target rather than a tibial/pedal target (76.7% vs 55.3%; P < .001), and have a prosthetic conduit (40.0% vs 29.9%; P < .001). There was no significant difference in mortality between the two groups (1.4% vs 1.8%; P = .21); however, patients with an ultrashort LOS had a lower frequency of unplanned readmission (10.7% vs 18.8%; P < .001) and need for major reintervention (1.9% vs 5.6%; P < .001). On multivariable analysis, elective status (odds ratio , 2.66; 95% confidence interval [CI], 2.33-3.04), active smoking (OR, 1.18; 95% CI, 1.07-1.30), and lack of vein harvest (OR, 1.55; 95% CI, 1.41-1.70) were associated with ultrashort LOS. Presence of rest pain (OR, 0.57; 95% CI, 0.51-0.63), tissue loss (OR, 0.30; 95% CI, 0.27-0.34), and totally dependent functional status (OR, 0.54; 95% CI, 0.35-0.84) were associated negatively with an ultrashort LOS. When examining the subgroup of patients who underwent vein harvest, totally dependent (OR, 0.38; 95% CI, 0.19-0.75) and partially dependent (OR, 0.53; 95% CI, 0.32-0.88) functional status were persistently negatively associated with ultrashort LOS. CONCLUSIONS: Ultrashort LOS (≤2 days) after LEB is uncommon but feasible in select patients. Preoperative functional status and mobility are important factors to consider when identifying LEB patients who may be candidates for early discharge.

Arabidopsis PHYTOALEXIN DEFICIENT 4 promotes the maturation and nuclear accumulation of immune-related cysteine protease RD19.

Arabidopsis PHYTOALEXIN DEFICIENT 4 (PAD4) has an essential role in pathogen resistance as a heterodimer with ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1). Here we investigated an additional PAD4 role in which it associates with and promotes the maturation of the immune-related cysteine protease RESPONSIVE TO DEHYDRATION 19 (RD19). We found that RD19 and its paralog RD19c promoted EDS1- and PAD4-mediated effector-triggered immunity to an avirulent Pseudomonas syringae strain, DC3000, expressing the effector AvrRps4 and basal immunity against the fungal pathogen Golovinomyces cichoracearum. Overexpression of RD19, but not RD19 protease-inactive catalytic mutants, in Arabidopsis transgenic lines caused EDS1- and PAD4-dependent autoimmunity and enhanced pathogen resistance. In these lines, RD19 maturation to a pro-form required its catalytic residues, suggesting that RD19 undergoes auto-processing. In transient assays, PAD4 interacted preferentially with the RD19 pro-protease and promoted its nuclear accumulation in leaf cells. Our results lead us to propose a model for PAD4-stimulated defense potentiation. PAD4 promotes maturation and nuclear accumulation of processed RD19, and RD19 then stimulates EDS1-PAD4 dimer activity to confer pathogen resistance. This study highlights potentially important additional PAD4 functions that eventually converge on canonical EDS1-PAD4 dimer signaling in plant immunity.

Role and intervention of PAD4 in NETs in acute respiratory distress syndrome.

BACKGROUND: Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Acute respiratory distress syndrome (ARDS) is a common sepsis-associated injury that can increase postoperative mortality but the mechanism is still unclear. MAIN TEXT: The role of neutrophils in the pathophysiology of sepsis was deeply challenged after the discovery of NETosis, a process resulting in neutrophil extracellular traps (NETs) release. NETs can support thrombin generation and the concept of immunothrombosis has emerged as a new innate response to infection. Immunothrombosis leads to thrombosis in microvessels and supports immune cells together with specific thrombus-related molecules. ARDS is a common sepsis-associated organ injury. Immunothrombosis participates in thrombosis in pulmonary capillaries. Intervention regarding immunothrombosis in ARDS is a key scientific problem. PAD4 is the key enzyme regulating the NET skeleton protein histone H3 to citrulline histone to form NETs in immune thrombosis. This review summarizes NETosis and immunohaemostasis, ARDS and therapeutic opportunities targeting PAD4 via PAD4 inhibitors and lncRNAs potentially, providing future therapies. CONCLUSIONS: We identified and summarized the fundamental definition of ARDS and the concept of immune thrombosis and its composition. NETs activation has become particularly relevant in the formation of immune thrombosis. The taskforce highlighted the intervention targets of PAD4, including noncoding RNAs, potentially providing future therapeutic targets to confront the high postoperative mortality of ARDS.

Omega-3 Polyunsaturated Fatty Acids are not associated with Peripheral Artery Disease in a Meta-Analysis from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study Cohorts.

BACKGROUND: Research suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. OBJECTIVES: We evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. METHODS: Omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. RESULTS: In the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. CONCLUSION: This study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.

Accelerated brain aging as a biomarker for staging in bipolar disorder: an exploratory study.

BACKGROUND: Two established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging. METHODS: In total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of both staging models were explored. RESULTS: A higher brain-PAD (higher biological age than chronological age) correlated with an increased likelihood of being in a higher stage of the inter-episodic functioning model, but not in the model based on number of mood episodes. However, after correcting for the confounding factors lithium-use and comorbid anxiety, the association lost significance. Global and (sub)cortical brain measures showed no significant association with the stages. CONCLUSIONS: These results suggest that brain-PAD may be associated with illness progression as defined by impaired inter-episodic functioning. Nevertheless, the significance of this association changed after considering lithium-use and comorbid anxiety disorders. Further research is required to disentangle the intricate relationship between brain-PAD, illness stages, and lithium intake or anxiety disorders. This study provides a foundation for potentially using brain-PAD as a biomarker for illness progression.

Mechanoecology: biomechanical aspects of insect-plant interactions.

Plants and herbivorous insects as well as their natural enemies, such as predatory and parasitoid insects, are united by intricate relationships. During the long period of co-evolution with insects, plants developed a wide diversity of features to defence against herbivores and to attract pollinators and herbivores' natural enemies. The chemical basis of insect-plant interactions is established and many examples are studied, where feeding and oviposition site selection of phytophagous insects are dependent on the plant's secondary chemistry. However, often overlooked mechanical interactions between insects and plants can be rather crucial. In the context of mechanoecology, the evolution of plant surfaces and insect adhesive pads is an interesting example of competition between insect attachment systems and plant anti-attachment surfaces. The present review is focused on mechanical insect-plant interactions of some important pest species, such as the polyphagous Southern Green Stinkbug Nezara viridula and two frugivorous pest species, the polyphagous Mediterranean fruit fly Ceratitis capitata and the monophagous olive fruit fly Bactrocera oleae. Their ability to attach to plant surfaces characterised by different features such as waxes and trichomes is discussed. Some attention is paid also to Coccinellidae, whose interaction with plant leaf surfaces is substantial across all developmental stages in both phytophagous and predatory species that feed on herbivorous insects. Finally, the role of different kinds of anti-adhesive nanomaterials is discussed. They can reduce the attachment ability of insect pests to natural and artificial surfaces, potentially representing environmental friendly alternative methods to reduce insect pest impact in agriculture.

The utility of Martius fat pad in the repair of urogenital fistulae: review of current evidence.

OBJECTIVE: To present the contemporary evidence on transvaginal urogenital fistulae (UGF) repair with Martius fat pad (MFP), compared to direct graftless fistula repair. METHODS: We reviewed all available studies reporting lower UGF repair via the transvaginal approach in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). The primary outcome of interest was the fistula closure rates. When available, patients' baseline characteristics, indications for surgery, and early and late postoperative complications with focus on MFP-related complications are reported. RESULTS AND DISCUSSION: In obstetric fistulae, tissue interposition has been almost completely abandoned, with contemporary large series reporting closure rates of >90% with graftless repair, even for complex fistulae. Similarly, most simple, non-irradiated iatrogenic fistulae can be closed safely without or with tissue interposition with success rates ranging between 86% and 100%. However, MFP is valuable in fistulae with difficulty achieving tension-free and layered closure, with significant tissue loss, urethral involvement and with poorly vascularised tissues after radiotherapy, with reported success rates between 80% and 97% in those challenging situations. CONCLUSION: A UGF repair should be individualised after considering the specific characteristics and complexity of the procedure. MFP interposition is probably unnecessary for the majority of low (obstetric) fistulae within otherwise healthy tissues. However, MFP may still have a place to maximise outcomes in low-income settings, in select cases with higher (iatrogenic) fistulae, and in most cases with radiotherapy.