Clinical and pathophysiologic determinants of catheter ablation outcome in hypertrophic cardiomyopathy with atrial fibrillation.

Background: Hypertrophic cardiomyopathy (HCM) is frequently associated with atrial fibrillation (AF). We compared clinical, echocardiographic, and electrophysiological parameters between HCM subtypes and those without HCM at AF catheter ablation (AFCA) and analyzed post-AFCA reverse remodeling and AF recurrence based on HCM presence and subtype. Methods: Among 5161 consecutive patients who underwent de novo AFCA, we included HCM patients and control patients who were age-, gender-, and AF type-matched. Between AF-HCM patients and controls, we compared baseline values for left atrium (LA) wall thickness (LAWT), reverse remodeling at 1-year follow-up, and procedural outcomes over the course of follow-up between two groups. Results: A total of 122 AF-HCM patients and 318 control patients were included. AF-HCM patients had more frequent heart failure and higher LA diameter, E/Em, and LA pressure (all, p < .001). However, LAWT did not differ from control group. A year after AFCA, degree of LA reverse remodeling was significantly lower in AF-HCM than in control group (ΔLA dimension, p = .025). Nonapical HCM (HR 1.71; 95% CI 1.05-2.80), persistent AF (HR 1.46; 95% CI 1.05-2.04), and LA dimension (HR 1.04; 95% CI 1.01-1.06) were independent risk factors for AF recurrence. During 78.0 months of follow-up, nonapical HCM patients showed higher AF recurrence rate than both apical HCM (log-rank p = .005) and control patients (log-rank p = .002). Conclusions: The presence of HCM, particularly nonapical HCM, displayed increased LA hemodynamic loading with diastolic dysfunction and had poorer rhythm outcomes after AFCA compared to both apical HCM and control group.

Unveiling a common phase transition pathway of high-density amorphous ices through time-resolved x-ray scattering.

Here, we investigate the hypothesis that despite the existence of at least two high-density amorphous ices, only one high-density liquid state exists in water. We prepared a very-high-density amorphous ice (VHDA) sample and rapidly increased its temperature to around 205 ± 10 K using laser-induced isochoric heating. This temperature falls within the so-called "no-man's land" well above the glass-liquid transition, wherein the IR laser pulse creates a metastable liquid state. Subsequently, this high-density liquid (HDL) state of water decompresses over time, and we examined the time-dependent structural changes using short x-ray pulses from a free electron laser. We observed a liquid-liquid transition to low-density liquid water (LDL) over time scales ranging from 20 ns to 3 µs, consistent with previous experimental results using expanded high-density amorphous ice (eHDA) as the initial state. In addition, the resulting LDL derived both from VHDA and eHDA displays similar density and degree of inhomogeneity. Our observation supports the idea that regardless of the initial annealing states of the high-density amorphous ices, the same HDL and final LDL states are reached at temperatures around 205 K.

Dynamic Changes in Soluble Triggering Receptor Expressed on Myeloid Cells-1 in Sepsis with Respect to Antibiotic Susceptibility.

Purpose: Proper antibiotic administration is crucial for sepsis management. Given the escalating incidence of antimicrobial resistance, there is a pressing need for indicators of antimicrobial susceptibility with short turnaround times. This study aimed to investigate the potential of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as an early biomarker for in vivo antibiotic susceptibility in patients with sepsis. Patients and Methods: We conducted a retrospective analysis of plasma samples from patients enrolled in a pre-established study designed to investigate prognostic biomarkers in patients with sepsis or septic shock. Baseline and 6 h sTREM-1 levels were examined using enzyme-linked immunosorbent assays. The primary outcome of the study was the comparison of percentage changes in sTREM-1 levels at the 6 h relative to baseline with respect to antibiotic susceptibility. Results: Of the 596 patients enrolled in the pre-established study, 29 with a median age of 75.8 and a 28-day mortality rate of 17.2% were included in the present analysis. Among these patients, 24 were classified into the susceptible group, whereas the remaining five were classified into the resistant group. The trend in plasma sTREM-1 levels differed with respect to antibiotic susceptibility. Moreover, percentage change in sTREM-1 levels at the 6 h relative to baseline was significantly higher in the resistant group (P = 0.028). Conclusion: The trend in plasma sTREM-1 levels in patients with sepsis differed with respect to antibiotic susceptibility, with a higher percentage change in patients treated with inappropriate antibiotics. These findings indicate the potential utility of sTREM-1 as an early biomarker of antibiotic susceptibility.

Effect of Intravenous Push and Piggyback Administration of Ceftriaxone on Mortality in Sepsis.

BACKGROUND: There is a lack of evidence-based guidelines for the administration methods of ceftriaxone in emergency departments (EDs), resulting in the reliance on individual institutional protocols for decision-making. OBJECTIVE: This study was performed to compare the effects of administering ceftriaxone via intravenous push (IVP) and intravenous piggyback (IVPB) on 28-day mortality in patients with sepsis. METHODS: This was a retrospective study of patients aged 18 years or older with sepsis or septic shock who visited an ED and were treated with ceftriaxone as an initial antibiotic between March 2010 and February 2019. Patients were divided into the IVP group and the IVPB group based on the administration method. The primary outcome was 28-day mortality, and multivariable Cox proportional hazards regression analysis was performed to evaluate the relationship between antibiotic administration methods and 28-day mortality. RESULTS: During the study period, a total of 939 patients were included in the final analysis, and the overall mortality rate was 12.2%. The antibiotic administration time was significantly lower in the IVP group than in the IVPB group, and the rates of antibiotic administration within 1 h and within 3 h were higher in the IVP group than in the IVPB group (p < 0.05). However, there was no significant difference in 28-day mortality between the two groups (hazard ratio 1.07, 95% confidence interval 0.69-1.65). CONCLUSIONS: IVP administration of ceftriaxone reduced the time of antibiotic administration compared with IVPB, but there was no difference in 28-day mortality.

Feasibility of intraoperative pathologic examination for sentinel lymph nodes during sentinel node navigation surgery in early gastric cancer: results of pathologic protocol for SENORITA trial.

BACKGROUND: During sentinel node navigation surgery in patients with gastric cancer, intraoperative pathologic examination of sentinel nodes is crucial in determining the extent of surgery. In this study, we evaluated the feasibility and accuracy of intraoperative pathologic protocols using data from a prospective, multicenter, randomized trial. METHODS: A retrospective analysis was conducted using data from the SEntinel Node ORIented Tailored Approach trials from 2013 to 2016. All sentinel lymph nodes were evaluated during surgery with hematoxylin-eosin (HE) staining using a representative section at the largest plane for lymph nodes. For permanent histologic evaluation, sentinel basin nodes were stained with HE and cytokeratin immunohistochemistry in formalin-fixed, paraffin-embedded (FFPE) sections and examined with HE for three deeper-step sections at 200-µm intervals. The failure rate of identification by frozen section and the metastasis rate in non-sentinel basins were investigated. RESULTS: Of the 237 patients who underwent sentinel node basin dissection, 30 had lymph node metastases on permanent pathology. Thirteen patients had macrometastasis confirmed in frozen sections as well as FFPE sections (failure rate: 0%). Patients with negative sentinel nodes in frozen sections but micrometastasis in FFPE sections had no lymph node recurrence during the follow-up period (0%, 0/6). However, in cases with tumor-positive nodes in frozen sections, metastases in non-sentinel basins were detected in the paraffin blocks (8.3%, 2/24). CONCLUSIONS: The single-section HE staining method is sufficient for detecting macrometastasis via intraoperative pathological examination. If a negative frozen-section result is confirmed, sentinel basin dissection can be performed safely. Otherwise, standard surgery is required.

Targeting Heme Oxygenase 2 (HO2) with TiNIR, a Theragnostic Approach for Managing Metastatic Non-Small Cell Lung Cancer.

Despite notable advancements in cancer therapeutics, metastasis remains a primary obstacle impeding a successful prognosis. Our prior study has identified heme oxygenase 2 (HO2) as a promising therapeutic biomarker for the aggressive subsets within tumor. This study aims to systematically evaluate HO2 as a therapeutic target of cancer, with a specific emphasis on its efficacy in addressing cancer metastasis. Through targeted inhibition of HO2 by TiNIR (tumor-initiating cell probe with near infrared), we observed a marked increase in reactive oxygen species. This, in turn, orchestrated the modulation of AKT and cJUN activation, culminating in a substantial attenuation of both proliferation and migration within a metastatic cancer cell model. Furthermore, in a mouse model, clear inhibition of cancer metastasis was unequivocally demonstrated with an HO2 inhibitor administration. These findings underscore the therapeutic promise of targeting HO2 as a strategic intervention to impede cancer metastasis, enhancing the effectiveness of cancer treatments.

Investigating the Mechanisms of Intradermal Injection for Easier "Skin Booster" Treatment: A Fluid Mechanics Approach to Determine Optimal Delivery Method.

Background: The use of "skin boosters" for rejuvenating aged skin is widely used. However, the accurate injection of the skin booster into the dermal layer remains a challenge due to the density of the dermis. The purpose of this study was to investigate the optimal mechanical variables of delivery that enabled correct targeting of the product to the dermis for optimal results. Methods: We investigated the impact of mechanical variables (syringe diameter, needle diameter and length, and viscosity of the skin booster) on the force required for intradermal injection in porcine skin. The correlation between these variables and the injection force was examined as well. Results: The results show that smaller syringe diameters, larger needle diameters, shorter needle lengths, and lower viscosity of the skin boosters reduce the injection force needed for intradermal injections. Conclusions: During the administration of skin booster injections, clinicians should take into account optimal conditions that facilitate intradermal injections, thus maximizing rejuvenating outcomes. Furthermore, manufacturers of skin boosters should formulate the products with decreased viscosity and provide the product in conjunction with appropriate needles and syringes, designed to optimize ease of injection.

Dynamic three-dimensional structures of a metal-organic framework captured with femtosecond serial crystallography.

Crystalline systems consisting of small-molecule building blocks have emerged as promising materials with diverse applications. It is of great importance to characterize not only their static structures but also the conversion of their structures in response to external stimuli. Femtosecond time-resolved crystallography has the potential to probe the real-time dynamics of structural transitions, but, thus far, this has not been realized for chemical reactions in non-biological crystals. In this study, we applied time-resolved serial femtosecond crystallography (TR-SFX), a powerful technique for visualizing protein structural dynamics, to a metal-organic framework, consisting of Fe porphyrins and hexazirconium nodes, and elucidated its structural dynamics. The time-resolved electron density maps derived from the TR-SFX data unveil trifurcating structural pathways: coherent oscillatory movements of Zr and Fe atoms, a transient structure with the Fe porphyrins and Zr6 nodes undergoing doming and disordering movements, respectively, and a vibrationally hot structure with isotropic structural disorder. These findings demonstrate the feasibility of using TR-SFX to study chemical systems.

Development of the multiplex imaging chamber at PAL-XFEL.

Various X-ray techniques are employed to investigate specimens in diverse fields. Generally, scattering and absorption/emission processes occur due to the interaction of X-rays with matter. The output signals from these processes contain structural information and the electronic structure of specimens, respectively. The combination of complementary X-ray techniques improves the understanding of complex systems holistically. In this context, we introduce a multiplex imaging instrument that can collect small-/wide-angle X-ray diffraction and X-ray emission spectra simultaneously to investigate morphological information with nanoscale resolution, crystal arrangement at the atomic scale and the electronic structure of specimens.

Ensemble Deep Learning Model to Predict Lymphovascular Invasion in Gastric Cancer.

Lymphovascular invasion (LVI) is one of the most important prognostic factors in gastric cancer as it indicates a higher likelihood of lymph node metastasis and poorer overall outcome for the patient. Despite its importance, the detection of LVI(+) in histopathology specimens of gastric cancer can be a challenging task for pathologists as invasion can be subtle and difficult to discern. Herein, we propose a deep learning-based LVI(+) detection method using H&E-stained whole-slide images. The ConViT model showed the best performance in terms of both AUROC and AURPC among the classification models (AUROC: 0.9796; AUPRC: 0.9648). The AUROC and AUPRC of YOLOX computed based on the augmented patch-level confidence score were slightly lower (AUROC: -0.0094; AUPRC: -0.0225) than those of the ConViT classification model. With weighted averaging of the patch-level confidence scores, the ensemble model exhibited the best AUROC, AUPRC, and F1 scores of 0.9880, 0.9769, and 0.9280, respectively. The proposed model is expected to contribute to precision medicine by potentially saving examination-related time and labor and reducing disagreements among pathologists.

Inappropriate use of intravenous epinephrine leading to atrial fibrillation during prehospital anaphylaxis treatment: A case report.

In a prehospital setting, the narrow therapeutic window of epinephrine necessitates its cautious administration for anaphylaxis. In this case, a 46-year-old man presented severe anaphylactic symptoms. Following standard protocol, the emergency medical technician (EMT) administered intramuscular epinephrine; however, symptoms persisted. Under the oversight of the emergency medical service (EMS) medical director, an additional intravenous bolus of epinephrine was administered, unfortunately leading to atrial fibrillation. This case underscores the potential risks of intravenous epinephrine, which isn't typically recommended for anaphylaxis without continuous monitoring. Since 2019, South Korea has initiated a pilot program to expand the EMT's scope of practice, which gives them the authority to administer epinephrine for anaphylaxis. The ultimate decision regarding epinephrine use for anaphylaxis, emphasizing patient safety, rests with the EMS medical director. Proper training for EMTs, coupled with the EMS medical director's comprehensive knowledge and meticulous protocol adherence, can ensure patient safety and optimal outcomes.

Risk of non-thyroidal autoimmune diseases in patients with Graves' disease: a nationwide retrospective cohort study.

OBJECTIVE: Graves' disease (GD) is a major autoimmune thyroid disorder and associated with non-thyroidal autoimmune disease (NTAD). We aimed to investigate the risk of NTAD in patients with GD compared with age- and sex-matched controls and to evaluate whether the risk differs between individuals with or without Graves' ophthalmopathy (GO). METHODS: This was a retrospective cohort study using data from the Korean National Health Claims database. We included 77 401 patients with GD (2,310 with GO) and 77 401 age- and sex-matched controls. Risk of NTAD were compared between the entire cohort and within the GD cohort. RESULTS: During a mean follow-up period of 9 years, NTAD developed in 12 341 (16.1%) patients in the GD cohort. Risk for systemic lupus erythematosus (SLE) [adjusted hazard ratio (aHR):1.15, 95% confidence interval (CI): 1.02-1.29], vitiligo (aHR: 1.24, 95% CI: 1.10-1.40), and alopecia areata (aHR: 1.11, 95% CI: 1.10-1.40) were higher in the GD cohort than in the control cohort. In the GD cohort, risk for SLE (aHR: 1.60, 95% CI: 1.11-2.33), Sjogren's syndrome (aHR: 1.89, 95% CI: 1.30-2.74), and ankylosing spondylitis (aHR: 1.53, 95% CI: 1.08-2.17) were higher in the GO group than in the non-GO group. CONCLUSION: This study demonstrated an increased risk of SLE, vitiligo and alopecia areata in patient with GD. In the GD cohort, patients with GO had an increased risk of SLE, Sjogren's syndrome and ankylosing spondylitis. These findings suggest that importance of implementing a strategy for early detection of NTAD based on the presence of GO.

Cumulative exposure to hypertriglyceridemia and risk of type 2 diabetes in young adults.

AIM: This study aimed to examine whether cumulative exposure to hypertriglyceridemia is associated with an increased risk of developing type 2 diabetes in young adults. METHODS: The study included 1,840,251 participants aged 20-39 years who had undergonefourconsecutiveannualhealth checkups and had no history of type 2 diabetes. Participants werecategorized into five groups (exposure score 0-4) based on the frequencies of hypertriglyceridemia diagnosis over a four-year period. The primary outcome was newly diagnosed type 2 diabetes. Exploratory analyses were performed for the different subgroups. RESULTS: During a follow-up period of 6.53 years, 40,286 participants developed type 2 diabetes. The cumulative incidence of type 2 diabetes significantly increased with higher exposure scores for hypertriglyceridemia (log-rank test, P < 0.001). The multivariable-adjusted hazard ratios for incident diabetes were 1.674 (95 % CI, 1.619, 1.732), 2.192 (95 % CI, 2.117, 2.269), 2.637 (95 % CI, 2.548, 2.73), and 3.715 (95 % CI, 3.6, 3.834) for participants with scores of 1-4, respectively, compared with those with an exposure score of 0. CONCLUSIONS: In this large-scale prospective cohort study of young adults, cumulative exposure to hypertriglyceridemia was significantly associated with an increased risk of type 2 diabetes, independent of lifestyle-related factors.

Blood failure: traumatic hemorrhage and the interconnections between oxygen debt, endotheliopathy, and coagulopathy.

This review explores the concept of "blood failure" in traumatic injury, which arises from the interplay of oxygen debt, the endotheliopathy of trauma (EoT), and acute traumatic coagulopathy (ATC). Traumatic hemorrhage leads to the accumulation of oxygen debt, which can further exacerbate hemorrhage by triggering a cascade of events when severe. Such events include EoT, characterized by endothelial glycocalyx damage, and ATC, involving platelet dysfunction, fibrinogen depletion, and dysregulated fibrinolysis. To manage blood failure effectively, a multifaceted approach is crucial. Damage control resuscitation strategies such as use of permissive hypotension, early hemorrhage control, and aggressive transfusion of blood products including whole blood aim to minimize oxygen debt and promote its repayment while addressing endothelial damage and coagulation. Transfusions of red blood cells, plasma, and platelets, as well as the use of tranexamic acid, play key roles in hemostasis and countering ATC. Whole blood, whether fresh or cold-stored, is emerging as a promising option to address multiple needs in traumatic hemorrhage. This review underscores the intricate relationships between oxygen debt, EoT, and ATC and highlights the importance of comprehensive, integrated strategies in the management of traumatic hemorrhage to prevent blood failure. A multidisciplinary approach is essential to address these interconnected factors effectively and to improve patient outcomes.

Extracorporeal Blood Treatment Using Functional Magnetic Nanoclusters Mitigates Organ Dysfunction of Sepsis in Swine.

Mitigating sepsis-induced severe organ dysfunction with magnetic nanoparticles has shown remarkable advances in extracorporeal blood treatment. Nevertheless, treating large septic animals remains challenging due to insufficient magnetic separation at rapid blood flow rates (>6 L h-1) and limited incubation time in an extracorporeal circuit. Herein, superparamagnetic nanoclusters (SPNCs) coated with red blood cell (RBC) membranes are developed, which promptly capture and magnetically separate a wide range of pathogens at high blood flow rates in a swine sepsis model. The SPNCs exhibited an ultranarrow size distribution of clustered iron oxide nanocrystals and exceptionally high saturation magnetization (≈ 90 emu g-1) close to that of bulk magnetite. It is also revealed that CD47 on the RBCs allows the RBC-SPNCs to remain at a consistent concentration in the blood by evading innate immunity. The uniform size distribution of the RBC-SPNCs greatly enhances their effectiveness in eradicating various pathogenic materials in extracorporeal blood. The use of RBC-SPNCs for extracorporeal treatment of swine infected with multidrug-resistant E. coli is validated and found that severe bacteremic sepsis-induced organ dysfunction is significantly mitigated after 12 h. The findings highlight the potential application of RBC-SPNCs for extracorporeal therapy of severe sepsis in large animal models and potentially humans.

High blood viscosity in acute ischemic stroke.

Background: The changes in blood viscosity can influence the shear stress at the vessel wall, but there is limited evidence regarding the impact on thrombogenesis and acute stroke. We aimed to investigate the effect of blood viscosity on stroke and the clinical utility of blood viscosity measurements obtained immediately upon hospital arrival. Methods: Patients with suspected stroke visiting the hospital within 24 h of the last known well time were enrolled. Point-of-care testing was used to obtain blood viscosity measurements before intravenous fluid infusion. Blood viscosity was measured as the reactive torque generated at three oscillatory frequencies (1, 5, and 10 rad/sec). Blood viscosity results were compared among patients with ischemic stroke, hemorrhagic stroke, and stroke mimics diagnosed as other than stroke. Results: Among 112 enrolled patients, blood viscosity measurements were accomplished within 2.4 ± 1.3 min of vessel puncture. At an oscillatory frequency of 10 rad/sec, blood viscosity differed significantly between the ischemic stroke (24.2 ± 4.9 centipoise, cP) and stroke mimic groups (17.8 ± 6.5 cP, p < 0.001). This finding was consistent at different oscillatory frequencies (134.2 ± 46.3 vs. 102.4 ± 47.2 at 1 rad/sec and 39.2 ± 11.5 vs. 30.4 ± 12.4 at 5 rad/sec, Ps < 0.001), suggesting a relationship between decreases in viscosity and shear rate. The area under the receiver operating curve for differentiating cases of stroke from stroke mimic was 0.79 (95% confidence interval, 0.69-0.88). Conclusion: Patients with ischemic stroke exhibit increases in whole blood viscosity, suggesting that blood viscosity measurements can aid in differentiating ischemic stroke from other diseases.

The Prognostic Value of the Modified Surprise Question in Critically Ill Emergency Department Patients.

Objective: The initiation of palliative care (PC) in the emergency department (ED) is effective in improving the quality of life for seriously ill patients. This study aimed to evaluate the prognostic value of the modified surprise question (mSQ), "Would you be surprised if this patient died in the next 30 days?" as a trigger for initiating PC in critically ill ED patients. Methods: We conducted a prospective cohort study over a 6-month period in an ED, during which 22 emergency residents answered the mSQ for critically ill ED patients (Korean Triage and Acuity Scale 1 or 2). The primary outcome was the accuracy of the positive mSQ (negative response to the mSQ) in predicting 30-day mortality, and logistic regression analysis was performed to identify the prognostic factors. Results: A total of 300 patients were enrolled, and the positive mSQ group included 118 (39.3%) patients. The 30-day mortality rate of the cohort was 10.0%. The sensitivity, specificity, positive predictive value, and negative predictive value of the positive mSQ were 83.3%, 65.6%, 21.2%, and 97.3%, respectively, with a c-statistic of 0.74 and a positive likelihood ratio of 2.42. In a multivariable analysis controlling for clinically relevant variables, the odds ratio for 30-day mortality of the positive mSQ was 4.76 (95% confidence interval, 1.61-14.09; P = .005). Conclusions: The mSQ may be valuable for identifying critically ill ED patients with an increased risk of 30-day mortality. Therefore, it may be utilized as a trigger for PC consultation in the ED.

Emergence of liquid following laser melting of gold thin films.

X-ray structural science is undergoing a revolution driven by the emergence of X-ray Free-electron Laser (XFEL) facilities. The structures of crystalline solids can now be studied on the picosecond time scale relevant to phonons, atomic vibrations which travel at acoustic velocities. In the work presented here, X-ray diffuse scattering is employed to characterize the time dependence of the liquid phase emerging from femtosecond laser-induced melting of polycrystalline gold thin films using an XFEL. In a previous analysis of Bragg peak profiles, we showed the supersonic disappearance of the solid phase and presented a model of pumped hot electrons carrying energy from the gold surface to scatter at internal grain boundaries. This generates melt fronts propagating relatively slowly into the crystal grains. By conversion of diffuse scattering to a partial X-ray pair distribution function, we demonstrate that it has the characteristic shape obtained by Fourier transformation of the measured F(Q). The diffuse signal fraction increases with a characteristic rise-time of 13 ps, roughly independent of the incident pump fluence and consequent final liquid fraction. This suggests the role of further melt-front nucleation processes beyond grain boundaries.

A Novel Interaction between MFN2/Marf and MARK4/PAR-1 Is Implicated in Synaptic Defects and Mitochondrial Dysfunction.

As cellular energy powerhouses, mitochondria undergo constant fission and fusion to maintain functional homeostasis. The conserved dynamin-like GTPase, Mitofusin2 (MFN2)/mitochondrial assembly regulatory factor (Marf), plays a role in mitochondrial fusion, mutations of which are implicated in age-related human diseases, including several neurodegenerative disorders. However, the regulation of MFN2/Marf-mediated mitochondrial fusion, as well as the pathologic mechanism of neurodegeneration, is not clearly understood. Here, we identified a novel interaction between MFN2/Marf and microtubule affinity-regulating kinase 4 (MARK4)/PAR-1. In the Drosophila larval neuromuscular junction, muscle-specific overexpression of MFN2/Marf decreased the number of synaptic boutons, and the loss of MARK4/PAR-1 alleviated the synaptic defects of MFN2/Marf overexpression. Downregulation of MARK4/PAR-1 rescued the mitochondrial hyperfusion phenotype caused by MFN2/Marf overexpression in the Drosophila muscles as well as in the cultured cells. In addition, knockdown of MARK4/PAR-1 rescued the respiratory dysfunction of mitochondria induced by MFN2/Marf overexpression in mammalian cells. Together, our results indicate that the interaction between MFN2/Marf and MARK4/PAR-1 is fine-tuned to maintain synaptic integrity and mitochondrial homeostasis, and its dysregulation may be implicated in neurologic pathogenesis.