Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aß pathology.

Accumulation of amyloid-beta (Aß) can lead to the formation of aggregates that contribute to neurodegeneration in Alzheimer's disease (AD). Despite globally reduced neural activity during AD onset, recent studies have suggested that Aß induces hyperexcitability and seizure-like activity during the early stages of the disease that ultimately exacerbate cognitive decline. However, the underlying mechanism is unknown. Here, we reveal an Aß-induced elevation of postsynaptic density protein 95 (PSD-95) in cultured neurons in vitro and in an in vivo AD model using APP/PS1 mice at 8 weeks of age. Elevation of PSD-95 occurs as a result of reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). The elevation of PSD-95 is consistent with the facilitation of excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induced by Aß. Inhibition of PSD-95 corrects these Aß-induced synaptic defects and reduces seizure activity in APP/PS1 mice. Our results demonstrate a mechanism underlying elevated seizure activity during early-stage Aß pathology and suggest that PSD-95 could be an early biomarker and novel therapeutic target for AD.

Cysteine-rich 61 inhibition attenuates hepatic insulin resistance and improves lipid metabolism in high-fat diet fed mice and HepG2 cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with insulin resistance development. Hepatic lipid accumulation and inflammation are considered the main drivers of hepatic insulin resistance in MASLD. Cysteine-rich 61 (Cyr61 also called CCN1), a novel secretory matricellular protein, is implicated in liver inflammation, and its role in MASLD is not clearly understood. Therefore, we investigated the role of Cyr61 in hepatic insulin resistance and lipid metabolism as major factors in MASLD pathogenesis. In high-fat diet (HFD)-fed C57BL/6J mice, Cyr61 was downregulated or upregulated via viral transduction. Measurements of glucose homeostasis, histological assessment of liver tissues, and gene expression and signaling pathways of lipogenesis, fatty acid oxidation, and inflammation were performed using liver samples from these mice. Cyr61 levels in HepG2 cells were reduced using RNAi-mediated gene knockdown. Inflammation and insulin resistance were evaluated using real-time polymerase chain reaction and western blotting. HFD/AAV-shCyr61 mice exhibited enhanced glucose tolerance via the protein kinase B pathway, reduced hepatic inflammation, decreased lipogenesis, and increased fatty acid oxidation. Notably, HFD/AAV-shCyr61 mice showed elevated protein expression of sirtuin 6 and phosphorylated-AMP-activated protein kinase. In vitro experiments demonstrated that inhibition of Cyr61 downregulated pro-inflammatory cytokines such as interleukin-1 beta, IL-6, and tumor necrosis factor-alpha via the nuclear factor kappa B/c-Jun N-terminal kinase pathway, and alleviated insulin resistance. Cyr61 affected hepatic inflammation, lipid metabolism, and insulin resistance. Inhibition of Cyr61 reduced inflammation, recovered insulin resistance, and altered lipid metabolism in vivo and in vitro. Therefore, Cyr61 is a potential therapeutic target in MASLD.

Imeglimin attenuates NLRP3 inflammasome activation by restoring mitochondrial functions in macrophages.

Imeglimin is a novel oral antidiabetic drug for treating type 2 diabetes. However, the effect of imeglimin on NLRP3 inflammasome activation has not been investigated yet. Here, we aimed to investigate whether imeglimin reduces LPS-induced NLRP3 inflammasome activation in THP-1 macrophages and examine the associated underlying mechanisms. We analyzed the mRNA and protein expression levels of NLRP3 inflammasome components and IL-1ß secretion. Additionally, reactive oxygen species (ROS) generation, mitochondrial membrane potential, and mitochondrial permeability transition pore (mPTP) opening were measured by flow cytometry. Imeglimin inhibited NLRP3 inflammasome-mediated IL-1ß production in LPS-stimulated THP-1-derived macrophages. In addition, imeglimin reduced LPS-induced mitochondrial ROS production and mitogen-activated protein kinase phosphorylation. Furthermore, imeglimin restored the mitochondrial function by modulating mitochondrial membrane depolarization and mPTP opening. We demonstrated for the first time that imeglimin reduces LPS-induced NLRP3 inflammasome activation by inhibiting mPTP opening in THP-1 macrophages. These results suggest that imeglimin could be a promising new anti-inflammatory agent for treating diabetic complications.

Impact of residual microcalcifcations on prognosis after neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: Residual microcalcifications after neoadjuvant chemotherapy (NAC) are challenging for deciding extent of surgery and questionable for impact on prognosis. We investigated changes in the extent and patterns of microcalcifications before and after NAC and correlated them with pathologic response. We also compared prognosis of patients depending on presence of residual microcalcifications after NAC. METHODS: A total of 323 patients with invasive breast carcinoma treated with neoadjuvant chemotherapy at Kangbuk Samsung Hospital and Samsung Medical center from March 2015 to September 2018 were included. Patients were divided into four groups according to pathologic response and residual microcalcifications. Non-pCRw/mic group was defined as breast non-pCR with residual microcalcifications. Non-pCRw/o mic group was breast non-pCR without residual microcalcifications. pCRw/mic group was breast pCR with residual microcalcifications. pCRw/o mic group was breast pCR without residual microcalcifications. The first aim of this study is to investigate changes in the extent and patterns of microcalcifications before and after NAC and to correlate them with pathologic response. The second aim is to evaluate oncologic outcomes of residual microcalcifications according to pathologic response after NAC. RESULTS: There were no statistical differences in the extent, morphology, and distribution of microcalcifications according to pathologic response and subtype after NAC (all p > 0.05). With a median follow-up time of 71 months, compared to pCRw/o mic group, the hazard ratios (95% confidence intervals) for regional recurrence were 5.190 (1.160-23.190) in non-pCRw/mic group and 5.970 (1.840-19.380) in non-pCRw/o mic group. Compared to pCRw/o mic group, the hazard ratios (95% CI) for distant metastasis were 8.520 (2.130-34.090) in non-pCRw/mic group, 9.120 (2.850-29.200) in non-pCRw/o mic group. Compared to pCRw/o mic, the hazard ratio (95% CI) for distant metastasis in pCRw/mic group was 2.240 (0.230-21.500) without statistical significance (p = 0.486). CONCLUSIONS: Regardless of residual microcalcifications, patients who achieved pCR showed favorable long term outcome compared to non-pCR group.

Optical Coherence Tomography in the Assessment and Management of Cardiac Allograft Vasculopathy.

PURPOSE OF REVIEW: Cardiac Allograft vasculopathy (CAV) is a major barrier to improving outcomes after heart transplantation. Coronary angiography has very low sensitivity to detect early CAV and intravascular ultrasound (IVUS) only improves it to some extent. In this article, we detail the current evidence surrounding use of Optical Coherence tomography (OCT) in patients with CAV. RECENT FINDINGS: OCT has the ability to recognize CAV at earlier stages with intimal thickness < 150 µm, can characterize CAV in almost pathologic / microscopic detail - plaque characteristics are better visualized and novel early features such as layered fibrotic plaques and microchannels have been identified. Progression of CAV can be monitored also, with promise shown in automated serial measurements also. OCT has significantly advanced our understanding of the pathophysiology-as well as permits precise monitoring and surveillance of the disease. Potential treatment options could also be evaluated using OCT.

Adsorptive removal of micropollutants by natural and faujasite zeolites: Structural effect of micropollutants on adsorption.

To effectively characterize natural zeolite powder (ZP) and faujasite zeolite (FAU) as adsorbents to remove a wide variety of organic micropollutants, quantitative structure-activity relationship (QSAR) models for the adsorption of zeolites were developed. For this purpose, batch isotherms were performed to measure the adsorption affinity (Kd) between zeolite and organic micropollutants, and the measured Kd values were used as a dependent variable in the QSAR modeling. In the modeling, the concept of a linear free energy relationship (LFER) was employed and used either empirically measured or in silico calculated descriptors. Modeling results based on empirical descriptors showed that log Kd values for ZP could be predicted with R2 = 0.949 and standard error (SE) = 0.137 log units, and for FAU, R2 = 0.895 and SE = 0.144 log units. A test set was used to validate the models developed by the training set. The predictabilities of the models for the test set were R2 = 0.907 and SE = 0.209 log units for ZP and R2 = 0.784 and SE = 0.236 log units for FAU, indicating that the models have reasonable robustness and predictability. Also, we showed that in silico-based descriptors could be applied to the prediction. These findings may help determine the general coverage of ZP and FAU zeolites and identify suitable applications.

Rural-urban stroke mortality gaps in the United States.

INTRODUCTION: Disparities in stroke outcomes, influenced by the use of systemic thrombolysis, endovascular therapies, and rehabilitation services, have been identified. Our study assesses these disparities in mortality after stroke between rural and urban areas across the United States (US). METHODS: We analyzed the CDC data on deaths attributed to cerebrovascular disease from 1999 to 2020. Data was categorized into rural and urban regions for comparative purposes. Age-adjusted mortality rates (AAMR) were computed using the direct method, allowing us to examine the ratios of rural to urban deaths for the cumulative population and among demographic subpopulations. Linear regression models were used to assess temporal changes in mortality ratios over the study period, yielding beta-coefficients (ß). RESULTS: There was a total of 628,309 stroke deaths in rural regions and 2,556,293 stroke deaths within urban regions. There were 1.13 rural deaths for each one urban death per 100,000 population in 1999 and 1.07 in 2020 (ß = -0.001, ptrend = 0.41). The rural-urban mortality ratio in Hispanic populations decreased from 1.32 rural deaths for each urban death per 100,000 population in 1999 to 0.85 in 2020 (ß = -0.011, ptrend < 0.001). For non-Hispanic populations, mortality remained stagnant with 1.12 rural deaths for each urban death per 100,000 population in 1999 and 1.07 in 2020 (ß = -0.001, ptrend = 0.543). Regionally, the Southern US exhibited the highest disparity with a urban-rural mortality ratio of 1.19, followed by the Northeast (1.13), Midwest (1.04), and West (1.01). CONCLUSIONS: Our findings depict marked disparities in stroke mortality between rural and urban regions, emphasizing the importance of targeted interventions to mitigate stroke-related disparities.

Analysis of Clinical Characteristics of Tuberculosis Patients with Dementia in Gyeongsangbuk-do, Republic of Korea.

(1) Background: Among Korean research papers there have been studies on the correlation between tuberculosis-hypertension and diabetes and the correlation between dementia-hypertension and diabetes, but there were no analysis data specifically on tuberculosis and dementia. (2) Methods: A total of 2992 tuberculosis patients in the Gyeongbuk region were analyzed through a final analysis of integrated disease and health management system data collected from 2021 to 2022. In this selection, patients with tuberculosis under 50 years of age and 368 people diagnosed with tuberculosis were excluded. (3) Results: From 2021 to 2022, among the 2992 tuberculosis patients in Gyeongsangbuk-do aged 50 or older, 2722 (91.0%) belonged to the general tuberculosis patient group, while 270 (9.0%) belonged to the dementia-tuberculosis patient group. The average age in the dementia-tuberculosis group was 81.4 years, significantly higher than the general group's average of 75.7 years. Within the dementia-tuberculosis patient group, 235 patients (87.0%) had underlying medical conditions in addition to dementia and tuberculosis. The tuberculosis treatment cure rate was 56.3% (1477 patients) in the general group and 38.9% (105 patients) in the dementia-tuberculosis patient group. (4) Conclusions: The cure rate was notably higher in the general group. Similarly, the mortality rate (deaths due to tuberculosis) was significantly higher in the dementia-tuberculosis patient group (7.0%, 19 patients) compared to the normal group (3.0%, 81 patients). The mortality rate in the dementia group was more than twice that of the general group.

Frequency-Dependent Neural Modulation of Dorsal Horn Neurons by Kilohertz Spinal Cord Stimulation in Rats.

Kilohertz high-frequency spinal cord stimulation (kHF-SCS) is a rapidly advancing neuromodulatory technique in the clinical management of chronic pain. However, the precise cellular mechanisms underlying kHF-SCS-induced paresthesia-free pain relief, as well as the neural responses within spinal pain circuits, remain largely unexplored. In this study, using a novel preparation, we investigated the impact of varying kilohertz frequency SCS on dorsal horn neuron activation. Employing calcium imaging on isolated spinal cord slices, we found that extracellular electric fields at kilohertz frequencies (1, 3, 5, 8, and 10 kHz) induce distinct patterns of activation in dorsal horn neurons. Notably, as the frequency of extracellular electric fields increased, there was a clear and significant monotonic escalation in neuronal activity. This phenomenon was observed not only in superficial dorsal horn neurons, but also in those located deeper within the dorsal horn. Our study demonstrates the unique patterns of dorsal horn neuron activation in response to varying kilohertz frequencies of extracellular electric fields, and we contribute to a deeper understanding of how kHF-SCS induces paresthesia-free pain relief. Furthermore, our study highlights the potential for kHF-SCS to modulate sensory information processing within spinal pain circuits. These insights pave the way for future research aimed at optimizing kHF-SCS parameters and refining its therapeutic applications in the clinical management of chronic pain.

Risk Factors for the Recurrence of Distal Anterior Cerebral Artery Aneurysms After Endovascular Treatment.

OBJECTIVE: We aimed to investigate risk factors for the recurrence of distal anterior cerebral artery (DACA) aneurysms after endovascular treatment (EVT). METHODS: The clinical and radiologic outcomes of DACA aneurysms treated with endovascular methods at a single tertiary hospital from September 2008 to December 2021 were retrospectively reviewed. We measured the angle between 2 distal branches of DACA aneurysms and categorized the angle as follows: 1) wide-angle (≥180°), and 2) narrow-angle type configuration (<180°). Univariate and multivariate analyses were performed to demonstrate the relationships between characteristics of DACA aneurysm and recurrence risk. RESULTS: In total, 132 DACA aneurysms were treated in our institution. Among these, 47 DACA aneurysms after EVT were included in this study. Forty patients underwent coil embolization without stent, 7 for stent-assisted coil embolization. At the last follow-up (mean 30.2 ± 24.2 months), overall recurrence rate was 23.4% (n = 11). Recurrence rate of the wide-angle type (9 of 23, 39.1%) was significantly greater than narrow-angle type (2 of 24, 8.3%) (P = 0.041; odds ratio 8.174, 95% confidence interval 1.094-61.066). Irregular shape of the DACA aneurysm also showed significantly greater recurrence rate (P = 0.011; odds ratio 10.663, 95% confidence interval 1.701-66.838) after endovascular treatment. CONCLUSIONS: The wide-angle between 2 distal branches of DACA aneurysm and irregular shape might be independent risk factors for the recurrence after endovascular treatment for DACA aneurysms.

Sex Differences and Clinical Outcomes in Patients With Myocardial Infarction With Nonobstructive Coronary Arteries: A Meta-Analysis.

BACKGROUND: Although myocardial infarction with nonobstructive coronary arteries (MINOCA) is more common in women, it is unknown whether sex is a risk factor for adverse outcomes in patients with MINOCA. We aimed to investigate the relationship between sex differences and outcomes of patients with MINOCA. METHODS AND RESULTS: A systematic literature search was performed in PubMed, Embase, and Cochrane databases from their inception until August 2023 for relevant studies. End points were pooled using the Hartung-Knapp-Sidik-Jonkman random-effects model as odds ratio (OR) with 95% CIs. Nine studies, involving 30 281 patients with MINOCA (comprising 18 079 women and 12 202 men), were included in the study. Women were older and had a higher prevalence of hypertension, diabetes, and stroke compared with men. The median duration of follow-up was 3.5 years, with an interquartile range of 2.2 to 4.2 years. Pooled analysis revealed no statistically significant difference in the risk of all-cause mortality (OR, 1.03 [95% CI, 0.87-1.22]), major adverse cardiovascular events (OR, 1.18 [95% CI, 0.89-1.58]), heart failure (OR, 1.32 [95% CI, 0.57-3.03]), stroke (OR, 1.13 [95% CI, 0.56-2.26]), and myocardial infarction (OR, 1.04 [95% CI, 0.29-3.76]) between the 2 groups. Regarding short-term outcomes, women had a significantly higher risk of in-hospital major adverse cardiovascular events compared with men (OR, 1.33 [95% CI, 1.16-1.53]) whereas there was no significant difference in the risk of in-hospital mortality (OR, 0.90 [95% CI, 0.64-1.28]) between the 2 patient groups. CONCLUSIONS: Despite the differences in demographics and comorbidity profiles, there was no significant difference in the long-term outcomes for patients with MINOCA between sexes. However, it is noteworthy that women experienced a higher risk of in-hospital major adverse cardiovascular events compared with men.

Extrahepatic Malignancies Are the Leading Cause of Death in Patients with Chronic Hepatitis B without Cirrhosis: A Large Population-Based Cohort Study.

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis.

Adverse Events in Total Artificial Heart for End-Stage Heart Failure: Insight From the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE).

Background and Objectives: Real-world clinical data, outside of clinical trials and expert centers, on adverse events related to the use of SyncCardia total artificial heart (TAH) remain limited. We aim to analyze adverse events related to the use of SynCardia TAH reported to the Food and Drug Administration (FDA)'s Manufacturers and User Defined Experience (MAUDE) database. Methods: We reviewed the FDA's MAUDE database for any adverse events involving the use of SynCardia TAH from 1/01/2012 to 9/30/2020. All the events were independently reviewed by three physicians. Results: A total of 1,512 adverse events were identified in 453 "injury and death" reports in the MAUDE database. The most common adverse events reported were infection (20.2%) and device malfunction (20.1%). These were followed by bleeding events (16.5%), respiratory failure (10.1%), cerebrovascular accident (CVA)/other neurological dysfunction (8.7%), renal dysfunction (7.5%), hepatic dysfunction (2.2%), thromboembolic events (1.8%), pericardial effusion (1.8%), and hemolysis (1%). Death was reported in 49.4% of all the reported cases (n=224/453). The most common cause of death was multiorgan failure (n=73, 32.6%), followed by CVA/other non-specific neurological dysfunction (n=44, 19.7%), sepsis (n=24, 10.7%), withdrawal of support (n=20, 8.9%), device malfunction (n=11, 4.9%), bleeding (n=7, 3.1%), respiratory failure (n=7, 3.1%), gastrointestinal disorder (n=6, 2.7%), and cardiomyopathy (n=3, 1.3%). Conclusions: Infection was the most common adverse event following the implantation of TAH. Most of the deaths reported were due to multiorgan failure. Early recognition and management of any possible adverse events after the TAH implantation are essential to improve the procedural outcome and patient survival.

mGluR7 allosteric modulator AMN082 corrects protein synthesis and pathological phenotypes in FXS.

Fragile X syndrome (FXS) is the leading cause of inherited autism and intellectual disabilities. Aberrant protein synthesis due to the loss of fragile X messenger ribonucleoprotein (FMRP) is the major defect in FXS, leading to a plethora of cellular and behavioral abnormalities. However, no treatments are available to date. In this study, we found that activation of metabotropic glutamate receptor 7 (mGluR7) using a positive allosteric modulator named AMN082 represses protein synthesis through ERK1/2 and eIF4E signaling in an FMRP-independent manner. We further demonstrated that treatment of AMN082 leads to a reduction in neuronal excitability, which in turn ameliorates audiogenic seizure susceptibility in Fmr1 KO mice, the FXS mouse model. When evaluating the animals' behavior, we showed that treatment of AMN082 reduces repetitive behavior and improves learning and memory in Fmr1 KO mice. This study uncovers novel functions of mGluR7 and AMN082 and suggests the activation of mGluR7 as a potential therapeutic approach for treating FXS.

CRISPR/Cas12a antifouling nanocomposite electrochemical biosensors enable amplification-free detection of Monkeypox virus in complex biological fluids.

The escalating global threat of infectious diseases, including monkeypox virus (MPXV), necessitates advancements in point-of-care diagnostics, moving beyond the constraints of conventional methods tethered to centralized laboratories. Here, we introduce multiple CRISPR RNA (crRNA)-based biosensors that can directly detect MPXV within 35 minutes without pre-amplification, leveraging the enhanced sensitivity and antifouling attributes of the BSA-based nanocomposite. Multiple crRNAs, strategically targeting diverse regions of the F3L gene of MPXV, are designed and combined to amplify Cas12a activation and its collateral cleavage of reporter probes. Notably, our electrochemical sensors exhibit the detection limit of 669 fM F3L gene without amplification, which is approximately a 15-fold improvement compared to fluorescence detection. This sensor also shows negligible changes in peak current after exposure to complex biological fluids, such as whole blood and serum, maintaining its sensitivity at 682 fM. This sensitivity is nearly identical to the conditions when only the F3L gene was present in PBS. In summary, our CRISPR-based electrochemical biosensors can be utilized as a high-performance diagnostic tool in resource-limited settings, representing a transformative leap forward in point-of-care testing. Beyond infectious diseases, the implications of this technology extend to various molecular diagnostics, establishing itself as a rapid, accurate, and versatile platform for detection of target analytes.

Ischemic heart disease mortality in individuals with inflammatory bowel disease: A nationwide analysis of disparities in the United States.

INTRODUCTION: Inflammatory bowel disease (IBD) is linked to immune-mediated pathogenesis and a pro-inflammatory state, leading to accelerated atherosclerosis. This earlier onset of clinical cardiovascular disease poses significant morbidity and mortality. We sought to identify IHD mortality trends in individuals with IBD in the United States (US). METHODS: Mortality due to ischemic heart diseases (IHD) as the underlying cause of death with the IBD as a contributor of death were queried from death certificates using the CDC database from 1999 to 2020. Yearly crude mortality rates (CMR) were estimated by dividing the death count by the respective population size, reported per 100,000 persons. Mortality rates were adjusted for age using the Direct method and compared by demographic subpopulations. Log-linear regression models were utilized to assess temporal variation (annual percentage change [APC]) in mortality. RESULTS: Age-adjusted mortality rates (AAMR) decreased from 0.11 in 1999 to 0.07 in 2020, primarily between 1999 and 2018 (APC -4.41, p < 0.001). AAMR was higher among male (AAMR 0.08) and White (AAMR 0.08) populations compared to female populations (AAMR 0.06) and Black (AAMR 0.04) populations, respectively. No significant differences were seen when comparing mortality between urban (AAMR 0.07) and rural (AAMR 0.08) regions. Southern US regions (AAMR 0.06) had the lowest mortality rates when compared to the other US census regions: Northeastern (AAMR 0.08), Midwestern (AAMR 0.08), and Western (AAMR 0.08). CONCLUSION: Disparities in IHD mortality exist among individuals with IBD in the US based on demographic factors, with an overall decline in mortality during the 22-year period. Further investigation is warranted to confirm these findings and evaluate for contributors to the observed disparities.

EXPRESS: Dual Versus Triple Antithrombotic Therapy in Atrial Fibrillation and Acute Coronary Syndrome: An Updated Meta-Analysis of Randomized Controlled Trials.

Antithrombotic treatment in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) poses a dilemma. We compared outcomes of dual thrombotic therapy (DAT) (direct oral anticoagulants [DOACs]/warfarin + antiplatelets) versus triple antithrombotic therapy (TAT) (DOACs/warfarin, aspirin, and P2Y12 inhibitor) in this population. Multiple databases were searched from inception to 12/17/2023 to identify randomized controlled trials (RCTs) comparing DAT versus TAT in patients with AF and ACS. Outcomes included major adverse cardiac events (MACE), bleeding events, stroke, stent thrombosis, and myocardial infarction (MI). Relative risk (RR) and 95% confidence intervals were estimated with a random-effects model using the inverse-variance technique. We assigned I2>50% as an indicator of statistical heterogeneity. P-value <0.05 was considered significant. Ten RCTs comprising 6186 patients on TAT (female 26%, mean age 71±9 yrs) and 6,800 patients on DAT (female 27%, mean age 71±9 yrs) were included. Patients receiving DAT experienced lower rates of bleeding events compared to those receiving TAT, with relative risks of 0.69 [0.55-0.87] (p<0.001), 0.65 [0.40-1.06] (p=0.09), and 0.62 [0.46-0.84] (p<0.001) for TAT durations of 3, 6, and 12 months, respectively. No difference was seen in the occurrence of MACE, MI, stroke, or stent thrombosis between DAT and TAT across all 3 durations of TAT therapy. This is the largest pooled analysis comparing TAT to DAT stratified by duration of antithrombotic therapy. Our results revealed that DAT was associated with reduced bleeding risk despite no difference in other outcomes.

Impact of diabetes distress on glycemic control and diabetic complications in type 2 diabetes mellitus.

The effect of diabetes distress on glycemic control and its association with diabetes complications is still poorly understood. We aimed to study the clinical features of patients with high diabetes distress, focusing on changes in glycemic control and risk of diabetic complications. From the Korean National Diabetes Program data, we investigated 1862 individuals with type 2 diabetes mellitus (T2DM) who completed diabetic complication studies and the Korean version of the Problem Areas in Diabetes Survey (PAID-K). A total score of PAID-K ≥ 40 was considered indicative of high distress. Individuals with high distress (n = 589) had significantly higher levels of glycated hemoglobin than those without distress (7.4% vs. 7.1%, p < 0.001). This trend persisted throughout the 3-year follow-up period. Higher PAID-K scores were associated with younger age, female gender, longer duration of diabetes, and higher carbohydrate intake (all p < 0.05). There was a significant association between high distress and diabetic neuropathy (adjusted odds ratio, 1.63; p = 0.002), but no significant association was found with other complications, including retinopathy, albuminuria, and carotid artery plaque. In conclusion, high diabetes distress was associated with uncontrolled hyperglycemia and higher odds of having diabetic neuropathy.

Sex-based outcomes on unguided de-escalation from ticagrelor to clopidogrel in stabilized patients with acute myocardial infarction undergoing percutaneous coronary intervention: a post-hoc analysis of the TALOS-AMI.

Background: The TALOS-AMI study highlighted the effectiveness of a de-escalation strategy shifting from ticagrelor to clopidogrel 1 month after percutaneous coronary intervention (PCI), resulting in significant reduction in clinical events, primarily attributed to a substantial decrease in bleeding events. Nevertheless, the impact of this strategy on outcomes based on sex remains unclear. Methods: This was a post-hoc analysis of the TALOS-AMI study. At 1 month after PCI, patients who remained adherent to aspirin and ticagrelor without experiencing major adverse events were randomized into either the de-escalation group (clopidogrel plus aspirin) or the active control group (ticagrelor plus aspirin) for an additional 12 months. The primary endpoint encompassed a composite of cardiovascular death, myocardial infarction, stroke, and Bleeding Academic Research Consortium bleeding type 2 or greater at 12 months after randomization. Results: Among the 2,697 patients included in this study, 454 (16.8%) were women. Women, characterized by older age and a higher prevalence of hypertension, diabetes, impaired renal function, and non-ST-segment myocardial infarction, exhibited a lower primary endpoint at 12 months compared to men [adjusted hazards ratio (HR), 0.60; 95% confidence interval (CI), 0.37-0.95; P = 0.03]. Compare to the active control group, the de-escalation group demonstrated a reduced risk of the primary endpoint in both women (adjusted HR, 0.38; 95% CI, 0.15-0.95; P = 0.039) and men (adjusted HR, 0.56; 95% CI, 0.40-0.79; P = 0.001) (interaction P = 0.46). Conclusions: In stabilized patients post-PCI with drug-eluting stents for acute myocardial infarction, the primary endpoint was lower among women compared to men. In this cohort, the benefits of an unguided de-escalation strategy from ticagrelor to clopidogrel were comparable in women and men.

Extrinsic hydrophobicity-controlled silver nanoparticles as efficient and stable catalysts for CO2 electrolysis.

To realize economically feasible electrochemical CO2 conversion, achieving a high partial current density for value-added products is particularly vital. However, acceleration of the hydrogen evolution reaction due to cathode flooding in a high-current-density region makes this challenging. Herein, we find that partially ligand-derived Ag nanoparticles (Ag-NPs) could prevent electrolyte flooding while maintaining catalytic activity for CO2 electroreduction. This results in a high Faradaic efficiency for CO (>90%) and high partial current density (298.39 mA cm‒2), even under harsh stability test conditions (3.4 V). The suppressed splitting/detachment of Ag particles, due to the lipid ligand, enhance the uniform hydrophobicity retention of the Ag-NP electrode at high cathodic overpotentials and prevent flooding and current fluctuations. The mass transfer of gaseous CO2 is maintained in the catalytic region of several hundred nanometers, with the smooth formation of a triple phase boundary, which facilitate the occurrence of CO2RR instead of HER. We analyze catalyst degradation and cathode flooding during CO2 electrolysis through identical-location transmission electron microscopy and operando synchrotron-based X-ray computed tomography. This study develops an efficient strategy for designing active and durable electrocatalysts for CO2 electrolysis.