Incremental prognostic value of 18F-FDG myocardial ischemic memory imaging for major adverse cardiovascular events in patients with suspected unstable angina.

BACKGROUND: The additional prognostic value of 18F-FDG PET myocardial ischemic memory imaging for patients with suspected unstable angina (UA) is not well established. This study aimed to determine whether 18F-FDG PET imaging provides incremental prognostic information for predicting major adverse cardiac events (MACE) compared to clinical risk factors, GRACE score, and coronary artery calcium score (CACS) in suspected UA patients. METHODS: In this post-hoc analysis of a prospective study, 265 suspected UA patients (62.3% male, mean age 65.0±9.4 years) were enrolled. 18F-FDG positive was defined as focal or focal on diffuse uptake patterns. MACE included cardiovascular death, acute myocardial infarction, heart failure, rehospitalization for UA, and stroke. Multivariable Cox regression was used to identify predictors of MACE, and the incremental prognostic value of 18F-FDG PET imaging was assessed using C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: Over a median follow-up of 25 months, 51 patients (19.2%) experienced MACE. 18F-FDG positive (HR=3.220, 95% CI: 1.630-6.360, P<0.001) , as well as 18F-FDG standardized uptake ratio (SUR) (HR=1.330, 95%CI: 1.131-1.564, P=0.0006) and Extent (HR=1.045, 95%CI: 1.028-1.062, P<0.0001), were independent predictors of MACE. The addition of 18F-FDG PET imaging significantly improved risk stratification beyond clinical factors, the GRACE score, and CACS, with improved C-index (0.769 vs 0.688, P=0.045), NRI (0.324, P=0.020), and IDI (0.055, P=0.027). CONCLUSION: 18F-FDG PET myocardial ischemic memory imaging significantly improves prognostic assessment for suspected UA patients, providing valuable additional risk stratification beyond clinical risk factors, GRACE score, and CACS.

Prognostic value of transient ischemic dilatation by 13N-ammonia PET MPI for short-term outcomes in patients with non-obstructive CAD.

OBJECTIVE: Transient ischaemic dilatation (TID) had incremental diagnostic and prognostic value in obstructive coronary artery disease (CAD), but its clinical significance in patients with non-obstructive CAD remains unknown. We aimed to explore the prognostic value of TID in patients with non-obstructive CAD by 13N-ammonia PET imaging. METHODS: We retrospectively studied 131 consecutive patients with non-obstructive CAD undergoing one-day rest-stress 13N-ammonia PET myocardial perfusion imaging (MPI). TID was automatically generated using CardIQ Physio software. The receiver operative characteristic (ROC) curve was used to determine the optimal threshold of TID. The follow-up outcome was major adverse cardiac events (MACE), a composite of re-hospitalization for heart failure or unstable angina, late revascularization, non-fatal myocardial infarction, and cardiac death. Cardiac event-free survivals for normal and abnormal TID were compared using Kaplan-Meier plots and log-rank tests. RESULTS: During a median follow-up of 42.08 ± 17.67 months, 22 (16.7%) patients occurred MACE. The optimal cut-off value of TID was 1.03 based on MACE. Our preliminary outcome analysis suggests that TID-abnormal subjects had a lower overall survival probability. Furthermore, our multivariate analysis reveals abnormal TID was the only independent predictor for MACE in non-obstructive CAD. In the subgroup analysis, an abnormal TID was an independent predictor for MACE in patients with abnormal perfusion patterns. CONCLUSION: Among patients with non-obstructive CAD, PET-derived TID ≥ 1.03 may identify those with a high risk of subsequent MACE independently. It was also an independent risk factor for poor prognosis in patients with abnormal perfusion.

Effects of Minor Zn Dopants in Sn-10Bi Solder on Interfacial Reaction and Shear Properties of Solder on Ni/Au Surface Finish.

Sn-10Bi low-bismuth-content solder alloy provides a potential alternative to the currently used Sn-Ag-Cu series due to its lower cost, excellent ductility, and strengthening resulting from the Bi solid solution and precipitation. This study primarily investigates the interfacial evolution and shear strength characteristics of Sn-10Bi joints on a Ni/Au surface finish during the as-soldered and subsequent isothermal aging processes. To improve the joint performance, a 0.2 or 0.5 wt.% dopant of Zn was incorporated into Sn-10Bi solder. The findings demonstrated that a 0.2 or 0.5 wt.% Zn dopant altered the composition of the intermetallic compound (IMC) formed at the interface between the solder and Ni/Au surface finish from Ni3Sn4 to Ni3(Sn, Zn)4. The occurrence of this transformation is attributed to the diffusion of Zn atoms into the Ni3Sn4 lattice, resulting in the substitution of a portion of the Sn atoms by Zn atoms, thereby forming the Ni3(Sn, Zn)4 IMC during the soldering process, which was also verified by calculations based on first principles. Furthermore, a 0.2 or 0.5 wt.% Zn dopant in Sn-10Bi significantly inhibited the Ni3(Sn, Zn)4 growth after both the soldering and thermal aging processes. Zn addition can enhance the shear strength of solder joints irrespective of the as-soldered or aging condition. The fracture mode was determined by the aging durations-with the brittle mode occurring for as-soldered joints, the ductile mode occurring for aged joints after 10 days, and again the brittle mode for joints after 40 days of aging.

Sex difference in human diseases: mechanistic insights and clinical implications.

Sex characteristics exhibit significant disparities in various human diseases, including prevalent cardiovascular diseases, cancers, metabolic disorders, autoimmune diseases, and neurodegenerative diseases. Risk profiles and pathological manifestations of these diseases exhibit notable variations between sexes. The underlying reasons for these sex disparities encompass multifactorial elements, such as physiology, genetics, and environment. Recent studies have shown that human body systems demonstrate sex-specific gene expression during critical developmental stages and gene editing processes. These genes, differentially expressed based on different sex, may be regulated by androgen or estrogen-responsive elements, thereby influencing the incidence and presentation of cardiovascular, oncological, metabolic, immune, and neurological diseases across sexes. However, despite the existence of sex differences in patients with human diseases, treatment guidelines predominantly rely on male data due to the underrepresentation of women in clinical trials. At present, there exists a substantial knowledge gap concerning sex-specific mechanisms and clinical treatments for diverse diseases. Therefore, this review aims to elucidate the advances of sex differences on human diseases by examining epidemiological factors, pathogenesis, and innovative progress of clinical treatments in accordance with the distinctive risk characteristics of each disease and provide a new theoretical and practical basis for further optimizing individualized treatment and improving patient prognosis.

The ventromedial prefrontal cortex plays an important role in implicit emotion regulation: A focality-optimized multichannel tDCS study in anxiety individuals.

The regulation of emotions is a crucial facet of well-being and social adaptability, with explicit strategies receiving primary attention in prior research. Recent studies, however, emphasize the role of implicit emotion regulation, particularly implicating the ventromedial prefrontal cortex (VMPFC) in association with its implementation. This study delves into the nuanced role of the VMPFC through focality-optimized multichannel transcranial direct current stimulation (tDCS), shedding light on its causal involvement in implicit reappraisal. The primary goal was to evaluate the effectiveness of VMFPC-targeted tDCS and elucidate its role in individuals with high trait anxiety. Participants engaged in implicit and explicit emotion regulation tasks during multichannel tDCS targeting the VMPFC. The outcome measures encompassed negative emotion ratings, pupillary diameter, and saccade count, providing a comprehensive evaluation of emotion regulation efficiency. The intervention exhibited a notable impact, resulting in significant reductions in negative emotion ratings and pupillary reactions during implicit reappraisal, highlighting the indispensable role of the VMPFC in modulating emotional responses. Notably, these effects demonstrated sustained efficacy up to 1 day postintervention. This study underscores the potency of VMPFC-targeted multichannel tDCS in augmenting implicit emotion regulation. This not only contributes insights into the neural mechanisms of emotion regulation but also suggests innovative therapeutic avenues for anxiety disorders. The findings present a promising trajectory for future mood disorder interventions, bridging the gap between implicit emotion regulation and neural stimulation techniques.

Causal association between blood leukocyte counts and vascular dementia: a two-sample bidirectional Mendelian randomization study.

While previous observational studies have suggested a link between leukocyte counts and vascular dementia (VD), the causal relationship between leukocyte counts and various subtypes of VD remains elusive. This study aimed to investigate the causal relationship between five types of leukocyte counts and VD, with the goal of improving prevention and treatment strategies. In this study, leukocyte counts were used as the exposure variable, with genome-wide association study (GWAS) data sourced from both the UK Biobank and the Blood Cell Consortium. Additionally, GWAS data for five subtypes of vascular dementia were obtained from the FinnGen database. We conducted rigorous statistical analysis and visualization using Mendelian randomization (MR) to elucidate the potential causal relationship between leukocyte counts and vascular dementia. This study, utilizing MR analysis with data from the UK Biobank and Blood Cell Consortium, identified significant causal associations between increased lymphocyte counts and VD. Specifically, lymphocyte counts were found to be causally related to multiple and mixed VD subtypes. Sensitivity analyses, including MR-Egger regression and MR-PRESSO tests, confirmed the robustness of these findings, with no evidence of reverse causality or significant horizontal pleiotropy detected. The results underscore a potential inflammatory or immunological mechanism in the pathogenesis of VD, highlighting lymphocytes as a key component in their etiology. This investigation establishes a robust association between elevated lymphocyte and leukocyte counts and an increased risk of VD, emphasizing the roles of inflammation, immune activation, and hematological factors in disease pathogenesis.

Prognostic Value of Resting Left Ventricular Sphericity Indexes in Coronary Artery Disease With Preserved Ejection Fraction.

BACKGROUND: Adverse left ventricular remodeling is a significant cardiovascular predictor for patients with coronary artery disease and preserved left ventricular ejection fraction (LVEF). However, the remodeling indexes reflecting left ventricular spherization by myocardial perfusion imaging are underexplored. METHODS AND RESULTS: 727 patients (mean age 59.8±13.5 years, 329 women) diagnosed or suspected coronary artery disease with preserved LVEF who underwent resting myocardial perfusion imaging were retrospectively enrolled. The myocardial perfusion imaging findings including the total perfusion deficit and sphericity indexes (shape index (SI) and eccentricity index (EI) obtained from gated (QGS) and non-gated (QPS) images) were collected. Major adverse cardiovascular events (MACE) were followed up for 45.1±22.0 months. All patients were divided into 4 subgroups based on total perfusion deficit at 10% and LVEF at 65%. Univariable comparative analyses were performed in 5 cohorts (all patients and 4 subgroups). Patients who experienced MACE displayed higher SI and/or lower EI (all P<0.05). Kaplan-Meier survival analyses suggested significant differences for SIQPS in all 5 cohorts, for EIQPS and EIQGS in 4 cohorts, and for end-systolic and end-diastolic SIQGS in 3 cohorts (all P<0.05). Multivariate Cox analysis showed that abnormal SI and EI remained statistically significant predictors for MACE after adjusting for total perfusion deficit, LVEF, and other confounding factors. CONCLUSIONS: For patients diagnosed or suspected of coronary artery disease with preserved or supra-normal LVEF, resting sphericity indexes by myocardial perfusion imaging displayed incremental long-term prognostic value. Among these indicators, SIQPS is particularly promising across different perfusion or preserved functional conditions.

Novel 131-iodine labeled and ultrasound-responsive nitric oxide and reactive oxygen species controlled released nanoplatform for synergistic sonodynamic/nitric oxide/chemodynamic/radionuclide therapy.

Nitric oxide (NO) and reactive oxygen species (ROS) embody excellent potential in cancer therapy. However, as a small molecule, their targeted delivery and precise, controllable release are urgently needed to achieve accurate cancer therapy. In this paper, a novel US-responsive bifunctional molecule (SD) and hyaluronic acid-modified MnO2 nanocarrier was developed, and a US-responsive NO and ROS controlled released nanoplatform was constructed. US can trigger SD to release ROS and NO simultaneously at the tumor site. Thus, SD served as acoustic sensitizer for sonodynamic therapy and NO donor for gas therapy. In the tumor microenvironment, the MnO2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H2O2 to produce .OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. The high concentration of ROS and NO in cancer cell can induce cancer cell apoptosis ultimately. In addition, toxic ONOO-, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. The 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. In -vitro and -vivo experiments showed that the nanoplatform has enhanced biocompatibility, and efficient anti-tumor potential, and it achieves synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer.

Metabolomics-based study on the significance of differential metabolite binding IgG isoforms in Hemolytic disease of newborn.

BACKGROUND: Hemolytic disease of the newborn (HDN) is a common condition that can have a severe impact on the health of newborns due to the hemolytic reactions it triggers. Although numerous studies have focused on understanding the pathogenesis of HDN, there are still many unanswered questions. METHODS: In this retrospective study, serum samples were collected from 15 healthy newborns and 8 infants diagnosed with hemolytic disease. The relationship between different metabolites and various IgG subtypes in Healthy, HDN and BLI groups was studied by biochemical technique and enzyme-linked immunosorbent assay (ELISA). Metabolomics analysis was conducted to identify the differential metabolites associated with HDN. Subsequently, Pearson's correlation analysis was used to determine the relation of these differential metabolites with IgG isoforms. The relationship between the metabolites and IgG subtypes was observed after treatment. RESULTS: The study results revealed that infants with hemolytic disease exhibited abnormal elevations in TBA, IgG1, IgG2a, IgG2b, IgG3, and IgG4 levels when compared to healthy newborns. Additionally, differences in metabolite contents were also observed. N, N-DIMETHYLARGININE showed negative correlations with TBA, IgG1, IgG2a, IgG2b, IgG3, and IgG4, while 2-HYDROXYBUTYRATE, AMINOISOBUTANOATE, Inosine, and ALLYL ISOTHIOCYANATE exhibited positive correlations with TBA, IgG1, IgG2a, IgG2b, IgG3, and IgG4. Through metabolomics-based research, we have discovered associations between differential metabolites and different IgG isoforms during the onset of HDN. CONCLUSION: These findings suggest that changes in metabolite and IgG isoform levels are linked to HDN. Understanding the involvement of IgG isoforms and metabolites can provide valuable guidance for the diagnosis and treatment of HDN.

Cystathionine γ-lyase contributes to exacerbation of periodontal destruction in experimental periodontitis under hyperglycemia.

BACKGROUND: Diabetes is one of the major inflammatory comorbidities of periodontitis via 2-way interactions. Cystathionine γ-lyase (CTH) is a pivotal endogenous enzyme synthesizing hydrogen sulfide (H2S), and CTH/H2S is crucially implicated in modulating inflammation in various diseases. This study aimed to explore the potential role of CTH in experimental periodontitis under a hyperglycemic condition. METHODS: CTH-silenced and normal human periodontal ligament cells (hPDLCs) were cultured in a high glucose and Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) condition. The effects of CTH on hPDLCs were assessed by Cell Counting Kit 8 (CCK8), real-time quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The model of experimental periodontitis under hyperglycemia was established on both Cth-/- and wild-type (WT) mice, and the extent of periodontal destruction was assessed by micro-CT, histology, RNA-Seq, Western blot, tartrate-resistant acid phosphatase (TRAP) staining and immunostaining. RESULTS: CTH mRNA expression increased in hPDLCs in response to increasing concentration of P.g-LPS stimulation in a high glucose medium. With reference to WT mice, Cth-/- mice with experimental periodontitis under hyperglycemia exhibited reduced bone loss, decreased leukocyte infiltration and hindered osteoclast formation, along with reduced expression of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in periodontal tissue. RNA-seq-enriched altered NF-κB pathway signaling in healthy murine gingiva with experimental periodontitis mice under hyperglycemia. Accordingly, phosphorylation of p65 (P-p65) was alleviated in CTH-silenced hPDLCs, leading to decreased expression of IL6 and TNF. CTH knockdown inhibited activation of nuclear factor kappa-B (NF-κB) pathway and decreased production of proinflammatory cytokines under high glucose and P.g-LPS treatment. CONCLUSION: The present findings suggest the potential of CTH as a therapeutic target for tackling periodontitis in diabetic patients.

Non-invasive efficacy assessment of pulsed dye laser and photodynamic therapy for port-wine stain.

Port wine stain (PWS) is a congenital vascular malformation that commonly occurs on the face and neck. Currently, the main treatments for port wine stain are pulsed dye laser (PDL) and photodynamic therapy (PDT). However, the efficacy evaluation of PWS mostly relies on the subjective judgement of clinicians, and it is difficult to accurately respond to many small changes after treatment. Therefore, some non-invasive and efficient efficacy assessment methods are also needed. With the continuous development of technology, there are currently many visualisation instruments to evaluate PWS, including dermoscopy, VISIA-CR™ system, reflectance confocal microscopy (RCM), high-frequency ultrasound (HFUS), optical coherence tomography (OCT), Photoacoustic imaging (PAI), laser speckle imaging (LSI) and laser Doppler imaging (LDI). Among them, there are simple and low-cost technologies such as dermoscopy and the VISIA-CR™ system, but they may not be able to observe the deeper structures of PWS. At this time, combining techniques such as HFUS and OCT to increase penetration depth is crucial to evaluate PWS. In the future, the combination of these different technologies could help overcome the limitations of a single technology. This article provides a systematic overview of non-invasive methods for evaluating treatment efficacy in port wine stains and summarises their advantages and disadvantages.

Fluorescent probes for imaging: a focus on atherosclerosis.

Atherosclerosis, as a chronic cardiovascular disease driven by inflammation, can lead to arterial stenosis and thrombosis, which seriously threatens human life and health. Achieving the timely monitoring of atherosclerosis is an important measure to reduce acute cardiovascular diseases. Compared with other imaging platforms, fluorescence imaging technology has the characteristics of excellent sensitivity, high spatiotemporal resolution and real-time imaging, which is very suitable for direct visualization of molecular processes and abnormalities of atherosclerosis. Recently, researchers have strived to design a variety of fluorescent probes, from single-mode fluorescent probes to fluorescent-combined dual/multimode probes, to enrich the imaging and detection of atherosclerosis. Therefore, this review aims to provide an overview of currently investigated fluorescent probes in the context of atherosclerosis, summarize relevant published studies showing applications of different types of fluorescent probes in the early-stage and other stages to detect atherosclerosis, give effective biological targets and discuss the latest progress and some limitations. Finally, some insights are provided for the development of a new generation of more accurate and efficient fluorescent probes.

Asynchronous Involvement of VLPFC and DLPFC During Negative Emotion Processing: An Online Transcranial Magnetic Stimulation Study.

The ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC) have been found to play important roles in negative emotion processing. However, the specific time window of their involvement remains unknown. This study addressed this issue in three experiments using single-pulse transcranial magnetic stimulation (TMS). We found that TMS applied over the VLPFC at 400 ms after negative emotional exposure significantly enhanced negative feelings compared to the vertex condition. Furthermore, TMS applied over the DLPFC at both 0 ms and 600 ms after negative emotional exposure also resulted in deteriorated negative feelings. These findings provide potential evidence for the VLPFC-dependent semantic processing (∼400 ms) and the DLPFC-dependent attentional and cognitive control (∼0/600 ms) in negative emotion processing. The asynchronous involvement of these frontal cortices not only deepens our understanding of the neural mechanisms underlying negative emotion processing but also provides valuable temporal parameters for neurostimulation therapy targeting patients with mood disorders.

Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps".

Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap".

Synthesis and evaluation of a 68Ga-labeled spermine derivative for tumor PET imaging.

BACKGROUND: The polyamine transporter system (PTS), which renders it a promising target for tumor therapy and imaging applications, facilitates the transmembrane transport of polyamines. We reported a novel derivative of spermine labeled with gallium-68 ([68Ga]Ga-NOTA-Spermine) for the imaging of the PTS in mouse models of tumor. RESULTS: The radiochemical yield of [68Ga]Ga-NOTA-Spermine was determined to be 64-69 %, demonstrating exceptional stability and radiochemical purity (>98 %). Cellular uptake experiments revealed that A549 cells exhibited peak uptake of [68Ga]Ga-NOTA-Spermine at 90 min (15.4 % ± 0.68 %). Biodistribution analysis demonstrated significant accumulation of [68Ga]Ga-NOTA-Spermine in kidneys and liver, while exhibiting low uptake levels in muscle, brain, and bones. Furthermore, Micro-PET/CT scans conducted on A549 tumor-bearing mouse models indicated substantial uptake of [68Ga]Ga-NOTA-Spermine, with maximum tumor/muscle (T/M) ratios reaching 3.71. CONCLUSION: These results suggest that [68Ga]Ga-NOTA-Spermine holds potential as a PET imaging agent for tumors with high levels of PTS.

Brain stimulation over the left DLPFC enhances motivation for effortful rewards in patients with major depressive disorder.

BACKGROUND: Amotivation is a typical feature in major depressive disorder (MDD), which produces reduced willingness to exert effort. The dorsolateral prefrontal cortex (DLPFC) is a crucial structure in goal-directed actions and therefore is a potential target in modulating effortful motivation. However, it remains unclear whether the intervention is effective for patients with MDD. METHODS: We employed transcranial magnetic stimulation (TMS), computational modelling and event-related potentials (ERPs) to reveal the causal relationship between the left DLPFC and motivation for effortful rewards in MDD. Fifty patients underwent both active and sham TMS sessions, each followed by performing an Effort-Expenditure for Rewards Task, during which participants chose and implemented between low-effort/low-reward and high-effort/high-reward options. RESULTS: The patients showed increased willingness to exert effort for rewards during the DLPFC facilitated session, compared with the sham session. They also had a trend in larger P3 amplitude for motivated attention toward chosen options, larger CNV during preparing for effort exertion, and larger SPN during anticipating a high reward. Besides, while behavior indexes for effortful choices were negatively related to depression severity in the sham session, this correlation was weakened in the active stimulation session. CONCLUSIONS: These findings provide behavioral, computational, and neural evidence for the left DLPFC on effortful motivation for rewards. Facilitated DLPFC improves motor preparation and value anticipation after making decisions especially for highly effortful rewards in MDD. Facilitated DLPFC also has a potential function in enhancing motivated attention during cost-benefit trade-off. This neuromodulation effect provides a potential treatment for improving motivation in clinics.

Enhancing ventrolateral prefrontal cortex activation mitigates social pain and modifies subsequent social attitudes: Insights from TMS and fMRI.

Social pain, a multifaceted emotional response triggered by interpersonal rejection or criticism, profoundly impacts mental well-being and social interactions. While prior research has implicated the right ventrolateral prefrontal cortex (rVLPFC) in mitigating social pain, the precise neural mechanisms and downstream effects on subsequent social attitudes remain elusive. This study employed transcranial magnetic stimulation (TMS) integrated with fMRI recordings during a social pain task to elucidate these aspects. Eighty participants underwent either active TMS targeting the rVLPFC (n = 41) or control stimulation at the vertex (n = 39). Our results revealed that TMS-induced rVLPFC facilitation significantly reduced self-reported social pain, confirming the causal role of the rVLPFC in social pain relief. Functional connectivity analyses demonstrated enhanced interactions between the rVLPFC and the dorsolateral prefrontal cortex, emphasizing the collaborative engagement of prefrontal regions in emotion regulation. Significantly, we observed that negative social feedback led to negative social attitudes, whereas rVLPFC activation countered this detrimental effect, showcasing the potential of the rVLPFC as a protective buffer against adverse social interactions. Moreover, our study uncovered the impact role of the hippocampus in subsequent social attitudes, a relationship particularly pronounced during excitatory TMS over the rVLPFC. These findings offer promising avenues for improving mental health within the intricate dynamics of social interactions. By advancing our comprehension of the neural mechanisms underlying social pain relief, this research introduces novel intervention strategies for individuals grappling with social distress. Empowering individuals to modulate rVLPFC activation may facilitate reshaping social attitudes and successful reintegration into communal life.

Recent developments in the use of nanocrystals to improve bioavailability of APIs.

Nanocrystals refer to materials with at least one dimension smaller than 100 nm, composing of atoms arranged in single crystals or polycrystals. Nanocrystals have significant research value as they offer unique advantages over conventional pharmaceutical formulations, such as high bioavailability, enhanced targeting selectivity and controlled release ability and are therefore suitable for the delivery of a wide range of drugs such as insoluble drugs, antitumor drugs and genetic drugs with broad application prospects. In recent years, research on nanocrystals has been progressively refined and new products have been launched or entered the clinical phase of studies. However, issues such as safety and stability still stand that need to be addressed for further development of nanocrystal formulations, and significant gaps do exist in research in various fields in this pharmaceutical arena. This paper presents a systematic overview of the advanced development of nanocrystals, ranging from the preparation approaches of nanocrystals with which the bioavailability of poorly water-soluble drugs is improved, critical properties of nanocrystals and associated characterization techniques, the recent development of nanocrystals with different administration routes, the advantages and associated limitations of nanocrystal formulations, the mechanisms of physical instability, and the enhanced dissolution performance, to the future perspectives, with a final view to shed more light on the future development of nanocrystals as a means of optimizing the bioavailability of drug candidates. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Machine-learning-based models to predict cardiovascular risk using oculomics and clinic variables in KNHANES.

BACKGROUND: Recent researches have found a strong correlation between the triglyceride-glucose (TyG) index or the atherogenic index of plasma (AIP) and cardiovascular disease (CVD) risk. However, there is a lack of research on non-invasive and rapid prediction of cardiovascular risk. We aimed to develop and validate a machine-learning model for predicting cardiovascular risk based on variables encompassing clinical questionnaires and oculomics. METHODS: We collected data from the Korean National Health and Nutrition Examination Survey (KNHANES). The training dataset (80% from the year 2008 to 2011 KNHANES) was used for machine learning model development, with internal validation using the remaining 20%. An external validation dataset from the year 2012 assessed the model's predictive capacity for TyG-index or AIP in new cases. We included 32122 participants in the final dataset. Machine learning models used 25 algorithms were trained on oculomics measurements and clinical questionnaires to predict the range of TyG-index and AIP. The area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, and F1 score were used to evaluate the performance of our machine learning models. RESULTS: Based on large-scale cohort studies, we determined TyG-index cut-off points at 8.0, 8.75 (upper one-third values), 8.93 (upper one-fourth values), and AIP cut-offs at 0.318, 0.34. Values surpassing these thresholds indicated elevated cardiovascular risk. The best-performing algorithm revealed TyG-index cut-offs at 8.0, 8.75, and 8.93 with internal validation AUCs of 0.812, 0.873, and 0.911, respectively. External validation AUCs were 0.809, 0.863, and 0.901. For AIP at 0.34, internal and external validation achieved similar AUCs of 0.849 and 0.842. Slightly lower performance was seen for the 0.318 cut-off, with AUCs of 0.844 and 0.836. Significant gender-based variations were noted for TyG-index at 8 (male AUC=0.832, female AUC=0.790) and 8.75 (male AUC=0.874, female AUC=0.862) and AIP at 0.318 (male AUC=0.853, female AUC=0.825) and 0.34 (male AUC=0.858, female AUC=0.831). Gender similarity in AUC (male AUC=0.907 versus female AUC=0.906) was observed only when the TyG-index cut-off point equals 8.93. CONCLUSION: We have established a simple and effective non-invasive machine learning model that has good clinical value for predicting cardiovascular risk in the general population.