Therapeutic Gene Editing in Dyslipidemias.

Dyslipidemia, characterized by abnormal lipid levels in the blood, significantly escalates the risk of atherosclerotic cardiovascular disease and requires effective treatment strategies. While existing therapies can be effective, long-term adherence is often challenging. There has been an interest in developing enduring and more efficient solutions. In this context, gene editing, particularly clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology, emerges as a groundbreaking approach, offering potential long-term control of dyslipidemia by directly modifying gene expression. This review delves into the mechanistic insights of various gene-editing tools. We comprehensively analyze various pre-clinical and clinical studies, evaluating the safety, efficacy, and therapeutic implications of gene editing in dyslipidemia management. Key genetic targets, such as low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C3 (APOC3), and lipoprotein (a) (Lp(a)), known for their pivotal roles in lipid metabolism, are scrutinized. The paper highlights the promising outcomes of gene editing in achieving sustained lipid homeostasis, discusses the challenges and ethical considerations in genome editing, and envisions the future of gene therapy in revolutionizing dyslipidemia treatment and cardiovascular risk reduction.

Exploring the Effect of Thyroid Hormone on Serum Lipoprotein (a) Levels in Patients With Thyroid Hormone Dysfunction: A Systematic Review.

Genetic variations among people mainly determine the blood levels of lipoprotein (a) (Lp(a)), and it is relatively stable throughout one's lifetime. Nevertheless, there could still be other factors that control the Lp(a) level. Thyroid hormones are known to influence the serum lipid level by regulating the expression of key enzymes that are involved in lipid metabolism. Both hypo and hyperthyroidism are associated with changes in lipid levels. Even though thyroid hormone abnormalities have been shown to alter traditional lipid parameters like low-density lipoprotein (LDL-C), its influence on Lp(a) has not been established. This review aims to identify the relationship between Lp(a) and thyroid hormones by reviewing data from correlative studies and observing treatment-related Lp(a) level changes in thyroid disorders from interventional studies. We searched MEDLINE, Cochrane, and Google Scholar databases with predefined search criteria and search strategies for paper identification. Individual reviewers reviewed identified papers for selection. Finalized papers were reviewed for Lp(a) levels and their responses to treatment in patients with thyroid disorders to establish the relationship between Lp(a) and thyroid hormone. We concluded that the data were limited and sometimes contradicted one another to establish a clear relationship between Lp(a) and thyroid hormones. Even though correlative studies data showed strong indications that overt-hypothyroidism was associated with high Lp(a) levels, thyroid hormone replacement studies did not show any significant changes in Lp(a) levels compared to pre-treatment in patients with both overt-hypothyroidism and subclinical hypothyroidism. More clinical trials focusing on Lp(a) with longer periods of treatment and follow-up in thyroid patients are needed to establish the relationship between the two. The possibility of dose-related Lp(a) responses to thyroid hormone treatment should also be explored.

Local-Peak Scale-Invariant Feature Transform for Fast and Random Image Stitching.

Image stitching aims to construct a wide field of view with high spatial resolution, which cannot be achieved in a single exposure. Typically, conventional image stitching techniques, other than deep learning, require complex computation and are thus computationally expensive, especially for stitching large raw images. In this study, inspired by the multiscale feature of fluid turbulence, we developed a fast feature point detection algorithm named local-peak scale-invariant feature transform (LP-SIFT), based on the multiscale local peaks and scale-invariant feature transform method. By combining LP-SIFT and RANSAC in image stitching, the stitching speed can be improved by orders compared with the original SIFT method. Benefiting from the adjustable size of the interrogation window, the LP-SIFT algorithm demonstrates comparable or even less stitching time than the other commonly used algorithms, while achieving comparable or even better stitching results. Nine large images (over 2600 × 1600 pixels), arranged randomly without prior knowledge, can be stitched within 158.94 s. The algorithm is highly practical for applications requiring a wide field of view in diverse application scenes, e.g., terrain mapping, biological analysis, and even criminal investigation.

[Lipoprotein-associated phospholipase A2 (Lp-PLA2): Relevant biomarker and therapeutic target?] / La phospholipase A2 associée aux lipoprotéines (Lp-PLA2) : biomarqueur pertinent et cible thérapeutique ?

Over the last fifteen years, numerous studies have sought to decipher the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in vascular inflammation-related diseases, notably atherosclerosis. Despite the disappointing results of clinical trials using the Lp-PLA2 inhibitor darapladib, new pathophysiological, epidemiological and genetic data have enabled the development of new inhibitors. Recent studies also show that Lp-PLA2 is involved in vascular inflammation-related diseases other than atherosclerosis (ischemic stroke, Alzheimer's disease and vascular dementia, diabetes, cancers…), and inhibition of Lp-PLA2 could have beneficial therapeutic in these diseases. This review aims to present new data on Lp-PLA2 and to evaluate its current interest as a biomarker but also as a therapeutic target.

Depletion of monocytic myeloid-derived suppressor cells in LP-BM5 murine retroviral infection has a positive impact on virus-induced host immunodeficiency.

We have shown the induction of CD11b+Ly6C+ monocytic myeloid-derived suppressor cells (M-MDSCs) during infection of B6 mice by LP-BM5 immunodeficiency-inducing retrovirus. We published that the molecular mechanisms of these M-MDSCs vary, and depend on the cell type targeted by the suppression -defined by use of biochemical inhibitors, mouse M-MDSCs knock-out strains and blocking antibodies. These M-MDSCs suppressed proliferation and function of T cells, via nitric oxide synthase/nitric oxide; and that of B cells, ∼50% via INOS/NO along with the negative checkpoint regulator VISTA, reactive nitrogen and oxygen species, and other soluble mediators. Here, LP-BM5 infected mice were treated weekly with 5-Fluorouracil (5-FU), resulting in depletion of peripheral blood and splenic M-MDSCs, reduced MDSC activity, and significantly decreased standard disease parameters of: splenomegaly, impaired B-and T-cell ex vivo polyclonal responses, and viral load. In addition, 5-FU treatment significantly increased percentages of CD4+ and CD8+ T cells.

Probiotic Lactobacillus plantarum 299v supplementation in patients with major depression in a double-blind, randomized, placebo-controlled trial: A metabolomics study.

BACKGROUND: Understanding the multifactorial nature of major depressive disorder (MDD) is crucial for tailoring treatments. However, the complex interplay of various factors underlying the development and progression of MDD poses significant challenges. Our previous study demonstrated improvements in cognitive functions in MDD patients undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) supplemented with Lactobacillus plantarum 299v (LP299v). METHODS: To elucidate the biochemical mechanisms underlying cognitive functions improvements, we explored underlying metabolic changes. We employed multi-platform metabolomics, including LC-QTOF-MS and CE-TOF-MS profiling, alongside chiral LC-QqQ-MS analysis for amino acids. RESULTS: Supplementation of SSRI treatment with LP299v intensified the reduction of long-chain acylcarnitines, potentially indicating improved mitochondrial function. LP299v supplementation reduced N-acyl taurines more than four times compared to the placebo, suggesting a substantial impact on restoring biochemical balance. The LP299v-supplemented group showed increased levels of oxidized glycerophosphocholine (oxPC). Additionally, LP299v supplementation led to higher levels of sphingomyelins, L-histidine, D-valine, and p-cresol. LIMITATIONS: This exploratory study suggests potential metabolic pathways influenced by LP299v supplementation. However, the need for further research hinders the ability to draw definitive conclusions. CONCLUSIONS: Observed metabolic changes were linked to mitochondrial dysfunction, inflammation, oxidative stress, and gut microbiota disruption. Despite the subtle nature of this alterations, our research successfully detected these differences and connected them to the metabolic disruptions associated with MDD. Our findings emphasise the intricate relationship between metabolism, gut microbiota, and mental health prompting further research into the mechanisms of action of probiotics in MDD treatment.

Modified dorsal recumbent position versus lithotomy position for flexible ureteroscopic lithotomy: a multicenter prospective randomized controlled clinical trial.

Background: The lithotomy position (LP) may pose limitations and discomfort for elderly patients and those with a history of lower limb surgery, potentially leading to an increased risk of complications. And the LP is the conventional position during flexible ureteroscopic lithotomy for the treatment of ureteral calculi. However, it has some disadvantages, such as peripheral nerve injury and deep venous thrombosis in the lower limbs, etc. Therefore, we performed a new approach, which is named as modified dorsal recumbent position (MDRP). Currently, there is a lack of systematic analysis and standardization regarding the surgical positioning for flexible ureteroscopic lithotripsy. The objective of the study was to assess whether there were any disparities in the overall duration of the procedure when comparing the MDRP with the LP. The investigation of the optimal position for flexible ureteroscopic lithotomy is essential for enhancing patient safety and comfort. Methods: This is a prospective, multicenter, randomized clinical trial. A total of 144 patients with renal or ureteral calculi from April 2021 to June 2022 were enrolled. Eligible patients were randomized to the MDRP group (n=72) or LP group (n=72). The patient's demographics, the placement of the surgical position (time of position placement, time of disinfection and towel laying, time of position return, degree of medical fatigue) and the operation safety (time of operation, time of ureteroscope from bladder neck to ureteral orifice, heart rate, blood pressure) of two groups were compared and analyzed. Results: Between the two groups, the body positioning time (93.8±31.6 vs. 134.8±40.1 s, P=0.02), operation time (71.8±36.7 vs. 77.7±48.6 min, P=0.04), the time from the bladder neck to the ureteral orifice of the flexible ureteroscope spent by the doctors (3.4±4.7 vs. 10.3±14.7 s, P<0.001) and incidence rate of patient's lower limb soreness (19.4% vs. 49.7%, P=0.01) in the MDRP group were significantly shorter than those in the LP group. However, there was no significant difference in the stone removal rate (87.6% vs. 85.4%, P=0.09) or postoperative hospitalization days (4.3±1.4 vs. 4.1±1.6 d, P=0.08) between the two groups. Conclusions: This trial showed that the MDRP could not only effectively shorten the operation time, shorten the time from the bladder neck to the ureteral orifice of the ureteroscopic lithotripsy, but also place the patient's body in a functional position, stabilize the blood pressure during the operation, improve the comfort of the patient. Trial Registration: Chinese Clinical Trial Registry (No. ChiCTR2100053416).

Light-Up Fluorescence and Circularly Polarized Luminescence in Achiral Interlocked Framework via Adaptive Lone Pair-π Interaction Confinement.

Interactions between lone pairs and aromatic π systems are significant across biology and self-assembled materials. Herein, employing an achiral confinement metal-organic framework (MOF) encapsulates guest molecules, it is successfully realized that lone pair (lp)-π interaction induces fluorescence "turn-on" and circularly polarized luminescence for the first time. The MOFs synthesized based on naphthalenediimide show nearly non-emissive, which can be light-up by introducing acetone or ester guests containing lone pairs-π interaction. Furthermore, the introduction of a series of lp-rich chiral esters induces supramolecular chirality as well as circularly polarized luminescence in achiral MOFs, while also observing chiral adaptability. This work first demonstrates the luminescence and chiral induction via lone pair electrons-π interactions, presenting a fresh paradigm for the advancement of chiroptical materials.

Assessing Stroke Recurrence Risk by Using a Lipoprotein-Associated Phospholipase A2 and Platelet Count-Based Nomogram.

Stroke recurrence remains a critical challenge in clinical neurology, necessitating the identification of reliable predictive markers for better management and treatment strategies. This study investigates the interaction between lipoprotein-associated phospholipase A2 (Lp-PLA2) and platelets as a potential predictor for stroke recurrence, aiming to refine risk assessment and therapeutic approaches. In a retrospective cohort of 580 ischemic stroke patients, we analyzed clinical data with a focus on Lp-PLA2 and platelet levels. By using multivariable logistic regression, we identified independent predictors of stroke recurrence. These predictors were then used to develop a comprehensive nomogram. The study established diabetes mellitus, hypertension, low-density lipoprotein (LDL), Lp-PLA2 levels, and platelet counts as independent predictors of stroke recurrence. Crucially, the interaction parameter Lp-PLA2 * platelet (multiplication of Lp-PLA2 and platelet count) exhibited superior predictive power over each factor considered separately. Our nomogram incorporated diabetes mellitus, cerebral infarction causes, hypertension, LDL, and the Lp-PLA2 * platelet count interaction and demonstrated enhanced accuracy in predicting stroke recurrence compared to traditional risk models. The interaction between Lp-PLA2 and platelets emerged as a significant predictor for stroke recurrence when integrated with traditional risk factors. The developed nomogram offers a novel and practical tool in molecular neurobiology for assessing individual risks, facilitating personalized treatment strategies. This approach underscores the importance of multifactorial assessment in stroke management and opens avenues for targeted interventions to mitigate recurrence risks.

Diet affordability: a key dimension in the assessment of sustainable food systems and healthy diets.

A promulgated global shift toward a plant-based diet is largely in response to a perceived negative environmental impact of animal food production, but the nutritional adequacy and economic implications of plant-sourced sustainable healthy dietary patterns need to be considered. This paper reviews recent modeling studies using Linear Programming to determine the respective roles of animal- and plant-sourced foods in developing a least-cost diet in the United States and New Zealand. In both economies, least-cost diets were found to include animal-based foods, such as milk, eggs, fish, and seafood, to meet the energy and nutrient requirements of healthy adults at the lowest retail cost. To model a solely plant-based least-cost diet, the prevailing costs of all animal-sourced foods had to be increased by 1.1 to 11.5 times their original retail prices. This led to the inclusion of fortified plant-based foods, such as fortified soymilk, and a plant-based diet that was considerably (34-45%) more costly. The first-limiting essential nutrients were mostly the vitamins and minerals, with special focus on pantothenic acid, zinc, and vitamin B-12, when transitioning from an animal- and plant-containing least-cost diet to a plant-only based least-cost diet. Modeled least-cost diets based on contemporary food costs include animal-sourced foods, at least for developed high-income US and NZ food economies, and potentially for developing low- and middle-income countries, such as Indonesia. Modeling of least-cost diets that consist exclusively of plant-based foods is feasible, but at a higher daily diet cost, and these diets are often close to limiting for several key nutrients. Diet affordability, as a key dimension of sustainable healthy diets, and the respective economic roles of animal- and plant-sourced foods need to be considered.

Effects of Weight Loss and Weight Maintenance on Lipoprotein Insulin Resistance Scores in Adults with Overweight and Obesity.

Background: An elevated lipoprotein insulin resistance (LP-IR) score corresponds to insulin resistance in adults with overweight and obesity, yet data are lacking regarding the impact of exercise interventions on LP-IR. The purpose of this secondary analysis was to evaluate the effects of a weight loss and weight maintenance intervention on LP-IR score in adults with overweight and obesity. Methods: Thirty sedentary adults with overweight and obesity completed a 10-week OPTIFAST® weight loss program with supervised aerobic exercise to achieve clinical weight loss (CWL) (≥7% from baseline). Aerobic exercise volume increased weekly until 700 MET min/week was reached. Participants who reached CWL were randomized to groups at volumes at either physical activity (PA-REC) or weight maintenance (WM-REC) recommendations (weeks 11-28). Plasma blood samples were analyzed via nuclear magnetic resonance spectroscopy at baseline, after weight loss (week 10), and following weight maintenance (week 28). Results: Following the weight loss phase, on average, participants significantly (p < 0.001) reduced LP-IR score (-12.1 ± 13.5), body weight (-8.9 ± 2.7%), and waist circumference (-7.7 ± 4.1 cm). During the weight maintenance phase, there were no changes in LP-IR score between exercise groups (PA-REC: 4.1 ± 13.6; WM-REC: -2.0 ± 11.2; P = 0.7). The PA-REC group had improvements in LP-IR score from baseline (49.8 ± 24.6 to 36.6 ± 27.6, P < 0.001), yet there were no within-group changes during the weight maintenance phase (P > 0.05). Conclusion: LP-IR score improved during weight loss in adults with overweight and obesity and were sustained during the weight maintenance phase in the PA-REC group. Aerobic exercise at least at minimum guidelines following CWL can preserve LP-IR score improvements and may indicate a reduced T2DM risk in adults with overweight and obesity.

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development.

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5-8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy-related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo-controlled adjunctive-therapy trial. For the other compounds, adequately powered placebo-controlled efficacy trials have not been completed to date.

A Novel Compound with Kokumi Properties: Enzymatic Preparation and Taste Presentation Evaluation of N-Lauroyl Phenylalanine.

To satisfy the demands of the food industry, innovative flavor enhancers need to be developed urgently to increase the food flavor. In our work, N-lauroyl phenylalanine (LP) was prepared from phenylalanine (l-Phe) and lauric acid (Lau) in water through the use of commercial enzymes (Promatex, Sumizyme FP-G, and Trypsin), and its flavor-presenting properties and mechanism were investigated. The highest LP yields obtained under one-factor optimized conditions were 61.28, 63.43, and 77.58%, respectively. Sensory assessment and an e-tongue test revealed that 1 mg/L LP enhanced the kokumi, saltiness, and umami of the simulated chicken broth solution and attenuated the bitterness of the l-isoleucine solution. The molecular simulation results suggested that the mechanisms of LP enhancement of kokumi and umami were related to hCaSR and hT1R1-hT1R3, and that hydrophobic forces and hydrogen bonds were involved in the binding of LP to taste receptors. The results implied that LP is a potential flavor enhancer for food applications.

The Ubiquitin Ligase Adaptor NDFIP1 Interacts with TRESK and Negatively Regulates the Background K+ Current.

The TRESK (K2P18.1, KCNK18) background potassium channel is expressed in primary sensory neurons and has been reported to contribute to the regulation of pain sensations. In the present study, we examined the interaction of TRESK with NDFIP1 (Nedd4 family-interacting protein 1) in the Xenopus oocyte expression system by two-electrode voltage clamp and biochemical methods. We showed that the coexpression of NDFIP1 abolished the TRESK current under the condition where the other K+ channels were not affected. Mutations in the three PPxY motifs of NDFIP1, which are responsible for the interaction with the Nedd4 ubiquitin ligase, prevented a reduction in the TRESK current. Furthermore, the overexpression of a dominant-negative Nedd4 construct in the oocytes coexpressing TRESK with NDFIP1 partially reversed the down-modulating effect of the adaptor protein on the K+ current. The biochemical data were also consistent with the functional results. An interaction between epitope-tagged versions of TRESK and NDFIP1 was verified by co-immunoprecipitation experiments. The coexpression of NDFIP1 with TRESK induced the ubiquitination of the channel protein. Altogether, the results suggest that TRESK is directly controlled by and highly sensitive to the activation of the NDFIP1-Nedd4 system. The NDFIP1-mediated reduction in the TRESK component may induce depolarization, increase excitability, and attenuate the calcium dependence of the membrane potential by reducing the calcineurin-activated fraction in the ensemble background K+ current.

The prevalence, patients' characteristics, and hyper-Lp(a)-emia risk factors in the Polish population. The first results from the PMMHRI-Lp(a) Registry.

BACKGROUND: The knowledge on the prevalence of elevated lipoprotein(a) (Lp(a)), patients' characteristics, and nongenetic risk factors is scarce in some regions including Poland, the largest Central and Eastern European country. Thus, we aimed to present the results from the Lp(a) registry established in Poland's 2nd largest, supra-regional hospital - the Polish Mother's Memorial Hospital Research Institute (PMMHRI). METHODS: The PMMHRI-Lp(a)-Registry was established in January 2022. Since that time all consecutive patients of the Departments of Cardiology, Endocrinology, and outpatient cardiology, diabetology and metabolic clinics have been included. The indications for Lp(a) measurement in the registry are based on the 2021 Polish Lipid Guidelines and new Polish recommendations on the management of elevated Lp(a) (2024). Lp(a) was determined using Sentinel's Lp(a) Ultra, an Immunoturbidimetric quantitative test (Sentinel, Milan, Italy), and the results are presented in mg/dL. RESULTS: 511 patients were included in the registry between Jan 2022 and 15th May 2024. The mean age of patients was 48.21 years. Female patients represented 53.42 % of the population. Elevated Lp(a) levels above 30 and 50 mg/dL were detected in 142 (27.79 %), and 101 (19.8 %) patients, respectively. The mean Lp(a) level was 30.45 ± 42.50 mg/dL, with no significant sex differences [mean for men: 28.80 mg/dL; women: 31.89 mg/dL]. There were also no significant differences between those with and without: coronary artery disease (CAD), dyslipidemia, stroke, heart failure, cancer, diabetes, chronic kidney disease, and thyroid disease. The significant Lp(a) level difference was observed in those with a history of myocardial infarction (MI) vs those without (51.47 ± 55.16 vs 28.09 ± 37.51 mg/dL, p < 0.001). However, when we divided those with premature vs no premature MI, no significant difference in Lp(a) level was observed (51.43 ± 57.82 vs 51.52 ± 53.18 mg/dL, p = 0.95). Lipid-lowering therapy (LLT) at baseline did not significantly affect Lp(a) level, with only significant differences for the highest doses of rosuvastatin (p < 0.05) and in those treated with ezetimibe (as a part of the combination therapy; 44.73 ± 54.94 vs 26.84 ± 37.11 mg/dL, p < 0.001). For selected patients (n = 43; 8.42 %) with at least two Lp(a) measurements (mean time distance: 7 ± 5 months, range 1-20 months) we did not observe statistically significant visit-to-visit variability (mean difference: 3.25 mg/dL; r = 0.079, p = 0.616). While dividing the whole population into those with Lp(a) ≤30 mg/dL and > 30 mg/dL, the only hyper-Lp(a)-emia prevalence differences were seen for FH diagnosis (12.88 vs 21.43; p = 0.017), MI prevalence (6.52 vs 16.90 %; p < 0.001), thyroid disease diagnosis (18.14 vs 26.76 %; p = 0.033) and ezetimibe treatment (18.58 vs 30.77 %, p = 0.036). A similar pattern was observed while dividing the whole population on those with Lp(a) ≤50 mg/dL (125 nmol/L) and > 50 mg/dL (125 nmol/L) except for no statistical difference for thyroid disease. CONCLUSIONS: These results strongly emphasize that Lp(a) should be measured commonly, as its high level is highly prevalent (even every 3rd patient) in patients at cardiovascular disease (CVD) risk in primary and secondary prevention, requiring risk re-stratification and optimization of the treatment. This is especially important in the regions that characterize baseline high CVD risk, which refers to most CEE countries, including Poland.

Predictive value of initial Lp-PLA2, NT-proBNP, and peripheral blood-related ratios for heart failure after early onset infarction in patients with acute myocardial infarction.

OBJECTIVE: To analyze the predictive value of lipoprotein-associated phospholipase A2 (Lp-PLA2), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and peripheral blood-related ratios at the initial diagnosis for heart failure (HF) after early-onset infarction in patients with acute myocardial infarction (AMI). METHODS: This retrospective analysis included 151 patients first diagnosed with AMI at Xianyang Central Hospital from February 2020 to February 2023. Patients were classified into two groups: those who developed HF during hospitalization (HF group, n=45) and those who did not (non-HF group, NHF, n=106). Differences in Lp-PLA2, NT-proBNP, and peripheral blood ratios at initial diagnosis were compared between the groups. Binary logistic regression was used to identify independent risk factors for HF, and a nomogram model was developed based on these factors. RESULTS: HR (P=0.032), C-reactive protein (CRP) (P<0.001), alanine aminotransferase (ALT) (P=0.015), coronary artery lesion score (CALDS) (P<0.001), D-dimer (D-D) (P=0.021), neutrophil-to-lymphocyte ratio (NLR) (P<0.001), Lp-PLA2 (P<0.001), and NT-proBNP (P<0.001) were significantly higher in the HF group than in the NHF group. Left ventricular end-systolic diameter (LVESD) (P<0.001) and left ventricular end-diastolic diameter (LVEDD) (P<0.001) were significantly lower in the HF group. Multifactorial logistic regression identified HR (P=0.034), CRP (P=0.028), CALDS (P=0.007), NLR (P=0.001), Lp-PLA2 (P=0.001), and NT-proBNP (P=0.002) as independent predictors of HF. The AUCs for NLR, Lp-PLA2, and NT-proBNP were 0.806, 0.849, and 0.780, respectively. The nomogram model achieved an AUC of 0.964, significantly outperforming individual indicators per Delong's test, highlighting its superior predictive efficacy. CONCLUSION: HR, CRP, CALDS, NLR, Lp-PLA2, and NT-proBNP were identified as independent predictors of HR post-AMI myocardial infarction. The constructed nomogram model provides an effective tool for early clinical identification of high-risk patients, potentially improving prognosis and guiding therapeutic strategies.

Perspective: Timely diagnosis and repair of intraoperative thoracic/lumbar cerebrospinal fluid (CSF) leaks.

Background: Our review of 12 articles for this perspective showed the frequency of intraoperative thoracic and/or lumbar CSF fistulas/dural tears (DT) ranged from 2.6% - 8% for primary surgical procedures. Delayed postoperative CSF leak/DT were also diagnosed in 0.83% (17/2052 patients) to 14.3% (2/14 patients) of patients undergoing thoracic and/or lumbar procedures. Further, the rate of recurrent postoperative CSF leaks/DT varied from 13.3% (2/15 patients) to 33.3% (4/12 patients). Methods: Intraoperative, postoperative delayed, and recurrent postoperative traumatic postsurgical thorac CSF leaks/DT can be limited by performing initially sufficient operative decompressions and/or decompressions/fusions (i.e., utilizing adequate open exposures vs. inadequate minimally invasive (MI) approaches). The incidence of CSF leaks/DT can be further reduced by spine surgeons' utilization of operating microscopes, and their avoiding routine attempts at total synovial cyst excision and/or complete resection of hypertrophied/ossified yellow ligament in the presence of significant dural adhesions. Results: Multiple CSF leak/CT repair techniques included; using interrupted, non-resorbable sutures for direct dural repairs (i.e. 7-0 Gore-Tex sutures where the suture is larger than the needle thus plugging needle holes), and adding where needed muscle patch grafts, microfibrillar collagen, the rotation of Multifidus muscle pedicle flaps, fibrin sealants (FS)/fibrin glues (FG), lumbar drains (LD), and/or lumbo-peritoneal (LP) shunts. Conclusion: Intraoperative, postopertive delayed, and/or recurrent postoperative thorac and/or lumbar traumatic surgical CSF leaks can be reduced by choosing to initially perform the appropriately extensive open operative decompressions and/or decompresssions/fusions. It is critical to use an operating microscope, non-resorbable interrupted sutures, and where necessary, muscle patch grafts, microfibrillar collagen, the rotation of Multifidus Muscle Pedicle Flaps, FS/FG, LD, and/or LP shunts.

Clinical Impact of Lipoprotein (a) and Cumulative Low-Density Lipoprotein Cholesterol Exposure on Coronary Artery Disease in Patients with Heterozygous Familial Hypercholesterolemia.

AIMS: Elevated lipoprotein (a) (Lp[a]), predominantly determined by genetic variability, causes atherosclerotic cardiovascular disease (ASCVD), particularly in patients with familial hypercholesterolemia (FH). We aimed to elucidate the clinical impact of Lp(a) and cumulative exposure to low-density lipoprotein cholesterol (LDL-C) on CAD in patients with FH. METHODS: One hundred forty-seven patients clinically diagnosed with heterozygous familial hypercholesterolemia (HeFH) were retrospectively investigated. Patients were divided into 2 groups according to the presence of CAD. Their clinical characteristics and lipid profiles were evaluated. RESULTS: There were no significant differences in untreated LDL-C levels between the 2 groups (p=0.4), whereas the cumulative exposure to LDL-C and Lp(a) concentration were significantly higher in patients with CAD (11956 vs. 8824 mg-year/dL, p＜0.01; 40 vs. 14 mg/dL, p＜0.001, respectively). A receiver operating characteristic (ROC) curve analysis demonstrated that the cutoff values of Lp(a) and cumulative LDL-C exposure to predict CAD in patients with FH were 28 mg/dL (AUC 0.71) and 10600 mg-year/dL (AUC 0.77), respectively. A multivariate analysis revealed that cumulative LDL-C exposure ≥ 10600 mg-year/dL (p＜0.0001) and Lp(a) level ≥ 28 mg/dL (p＜0.001) were independent predictors of CAD. Notably, the risk of CAD remarkably increased to 85.7% with smoking, Lp(a) ≥ 28 mg/dL, and cumulative LDL-C exposure ≥ 10600 mg-year/dL (odds ratio: 46.5, 95%CI: 5.3-411.4, p＜0.001). CONCLUSIONS: This study demonstrated an additive effect of Lp(a) and cumulative LDL-C exposure on CAD in patients with HeFH. Interaction with traditional risk factors, particularly smoking and cumulative LDL-C exposure, enormously enhances the cardiovascular risk in this population.

An overview of S100 proteins and their functions in skin homeostasis, interface dermatitis conditions and other skin pathologies.

S100 proteins comprise a family of structurally related proteins that are calcium-sensitive. S100 proteins have been found to play various roles in regulation of cell apoptosis, cell proliferation and differentiation, cell migration and invasion, energy metabolism, calcium homeostasis, protein phosphorylation, anti-microbial activity and inflammation in a variety of cell types. While the specific function of many S100 proteins remains unknown, some of the S100 proteins serve as disease biomarkers as well as possible therapeutic targets in skin diseases. Interface dermatitis (ID) is a histopathological term that covers many different skin conditions including cutaneous lupus erythematosus, lichen planus, and dermatomyositis. These pathologies share similar histological features, which include basal cell vacuolization and lymphocytic infiltration at the dermal-epidermal junction. In this review, we summarize how the S100 protein family contributes to both homeostatic and inflammatory processes in the skin. We also highlight the role of S100 proteins in neuronal signalling, describing how this might contribute to neuroimmune interactions in ID and other skin pathologies. Last, we discuss what is known about the S100 family proteins as both biomarkers and potential treatment targets in specific pathologies.

Examining the lateralization of electrophysiological correlates of auditory awareness.

The neurological basis for perceptual awareness remains unclear, and theories disagree as to whether sensory cortices per se generate awareness. Critically, neural activity in the sensory cortices is only a neural correlate of consciousness (NCC) if it closely matches the contents of perceptual awareness. Research in vision and touch suggest that contralateral activity in sensory cortices is an NCC. Similarly, research in hearing with two sound sources (left and right) presented over headphones also suggests that a candidate NCC called the auditory awareness negativity (AAN) matches perceived location of sound. The current study used 13 different sound sources presented over loudspeakers for natural localization cues and measured event-related potentials to a threshold stimulus in a sound localization task. Preregistered Bayesian mixed models provided moderate evidence against an overall AAN and very strong evidence against its lateralization. Because of issues regarding data quantity and quality, exploratory analyses with aggregated data from multiple loudspeakers were conducted. Results provided moderate evidence for an overall AAN and strong evidence against its lateralization. Nonetheless, the interpretations of these results remain inconclusive. Therefore, future research should reduce the number of conditions and/or test over several sessions to procure a sufficient amount of data. Taken at face value, the results may suggest issues with AAN as an NCC of auditory awareness, as it does not laterally map onto experiences in a free-field auditory environment, in contrast to the NCCs of vision and touch.