Peripheral Events Research Articles

Factors associated with major adverse cardiovascular events among Arabs and Jews in Israel: a population-based cohort study

Abstract Introduction Arabs in Israel are at higher risk of cardiovascular mortality; however, there are no data on factors associated with disparities in major adverse cardiovascular events (MACE) incidence among Arabs and Jews. Purpose To study factors associated with MACE incidence among Arabs and Jews in Israel. Materials and Methods This is a cohort study carried out in urban localities of Hadera District in Israel. The study sample included 1,100 participants, stratified in equal numbers by ethnicity (Arab and Jewish), sex, and five 10-year age group (mean age: 51 years, range: 26-77). Data collected via in-person interviews conducted between 2001-2006 included socio-demographic characteristics and health-related behaviors (smoking, physical activity, and diet). Data on baseline diabetes, hypertension, dyslipidemia, and cardiovascular disease were collected from interviews and participants' health records. Information on MACE occurring during follow-up was determined based on hospital discharge diagnoses, recorded in the Israel Ministry of Health hospital admission database. MACE was defined as an acute coronary, cerebrovascular or peripheral artery event, or invasive procedure for its treatment. Factors associated with the time to first MACE were tested in Cox proportional hazards models. Sensitivity analysis included death from any cause as a competing risk, using Fine and Gray’s model. Results During a median follow-up period of 20 years, there were 221 first MACE during follow-up; 91 among Jewish participants and 130 among Arab participants, hazard ratio (HR) Arab vs. Jewish: 1.59; 95% confidence interval (CI) 1.22, 2.09, adjusted for age and sex. Arab ethnicity was no longer significantly associated with MACE, following further adjustment for years of education; HR: 1.32; 95%CI 0.95, 1.84. The HR (95%CI) associated with ethnicity after additional adjustment for health-related behaviors, body weight and baseline chronic morbidity was 1.02 (95%CI: 0.73, 1.42). A subgroup analysis among 950 participants, who did not have a baseline diagnosis of cardiovascular disease, produced similar results. These participants experience 147 first MACE during follow-up. The age and sex-adjusted HR (95%CI) associated with Arab ethnicity was 1.72 (1.23, 2.40), compared to 1.08 (0.72, 1.64) in a fully adjusted model. Competing risk analysis did not materially change these results. Conclusions Arabs in Israel are at higher risk for MACE. Lower socioeconomic position and higher prevalence of unhealthy lifestyle and cardiovascular risk factors may explain the excess risk of MACE among Arabs. Improving cardiovascular health among Arabs should consider social determinants of health and cultural aspects.

A comprehensive approach combining FFR, CFR, and IMR in order to predict adverse cardiovascular events in patients with non-obstructive coronary artery disease

Abstract Background Abnormal coronary circulation is linked to poor patient outcomes. The predictive values of comprehensive physiological assessments in patients with non-obstructive coronary artery disease (NOCAD) have not been fully investigated. Objectives The study aimed to evaluate the predictive value of a comprehensive approach that combines fractional flow reserve (FFR), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR) in patients with NOCAD. Methods FFR, CFR, and IMR were measured in the left anterior descending artery of 226 patients with NOCAD. The primary endpoint was defined as adverse cardiovascular events including cardiovascular death, heart failure, coronary revascularization, cerebral infarction, and peripheral vascular events. Results Optimal cutoffs predicting the endpoint were 0.89 for FFR, 2.3 for CFR and 18.0U for IMR. Among the patients, 53 were negative for all indices, 80 positive for one, and 93 positive for two or three. During a median follow-up period of two years, 29 adverse events occurred, with the distribution as follows: 1 (1.9%) in patients with all negative indices, 5 (6.2%) in those with one positive index, and 23 (24.7%) in those with two or three positive indices. Kaplan-Meier curve analysis demonstrated significantly worse event-free survival in patients with an increasing number of positive indices (χ2=18.5, P<0.001). The presence of two or three positive indices was an independent predictor of the endpoint (hazard ratio 7.280, p<0.001). Conclusions Combining FFR, CFR, and IMR is an effective method for predicting cardiovascular events in patients with NOCAD.

Nrf2 Ameliorates Atrial Fibrosis During Antithrombotic Therapy for Atrial Fibrillation by Modulating CYP2C9 Activity.

Anticoagulant therapy can significantly reduce the incidence of stroke and peripheral embolism events in patients with atrial fibrillation (AF). Although warfarin is widely used as an anticoagulant drug, a wrong dose can lead to increased risks of bleeding or blood clots. The aim of this study was to assess whether nuclear factor-erythroid-2-related factor 2 (Nrf2) can improve the efficacy of warfarin through the regulation of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) using a rat model of AF. Results showed that AF significantly reduced Nrf2 in myocardial tissue of sham-operated rats. Furthermore, Nrf2 overexpression effectively reduced AF-induced atrial fibrosis by reducing collagen in the left atrium, inhibiting the expression of the fibrosis-related genes collagen I and transforming growth factor-β1 in rats with AF. Nrf2 overexpression can activate CYP2C9, decrease the serum concentration of warfarin, and decrease prothrombin time and international normalized ratio in AF rats. In this article, Nrf2 overexpression protects against fibrosis, increased survival in AF rats, and activated CYP2C9 expression, thus broadening the therapeutic range of warfarin in AF rats.

A comparison of recall methods for high-stress critical incidents in police training

Police officers often face critical incidents involving armed offenders, requiring the use of force to ensure safety. Eyewitness accounts, including those from officers, are crucial in the justice system but can be unreliable. Techniques such as self-authored statements and structured interviews are used to gather information, but their efficacy in high-stress situations is unclear. Previous research suggests that heightened arousal during memory encoding enhances recall, particularly for central details. This study compares recall methods (statements vs. interviews) for police officers in high-stress versus no-stress situations, focusing on central and peripheral event details. Officers participated in a simulated high-stress incident, providing memory data through both methods. Overall, no significant difference was found in memory scores between the techniques. However, analysis revealed significant differences favoring structured interviews for peripheral information. Recall that central information remained consistent across methods. These findings highlight the need for careful methodology when examining memories formed in stressful contexts.

Peripheral nervous system immune-related adverse events due to checkpoint inhibition.

Immune checkpoint inhibitors have revolutionized cancer therapy and are increasingly used to treat a wide range of oncological conditions, with dramatic benefits for many patients. Unfortunately, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), which can involve any organ system, including the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs involve the PNS in two-thirds of affected patients. Muscle involvement (immune-related myopathy) is the most common PNS irAE and can be associated with neuromuscular junction involvement. Immune-related peripheral neuropathy most commonly takes the form of polyradiculoneuropathy or cranial neuropathies. Immune-related myopathy (with or without neuromuscular junction involvement) often occurs along with immune-related myocarditis, and this overlap syndrome is associated with substantially increased mortality. This Review focuses on PNS adverse events associated with immune checkpoint inhibition. Underlying pathophysiological mechanisms are discussed, including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells. An overview of current approaches to clinical management is provided, including cytokine-directed therapies that aim to decouple anticancer immunity from autoimmunity and emerging treatments for patients with severe (life-threatening) presentations.

CD34+ Hematopoietic Stem Cell Count as a Novel Predictor of Vascular Event in Sickle Cell Disease Patients

Abstract Background Sickle cell disease (SCD) is one of the most common genetic disorders, it not only has hematological pathophysiological consequences, but also has systemic pathological manifestations such as vascular events (VEs). Prior studies have described that VEs are associated with poor outcomes in the short term and decreased quality of life in patients over the long term. There is no standardized method for predicting vascular injury in Sickle cell disease patients. Aim of the Work Our aim is to evaluate circulating CD34 as a novel predictive marker of occurrence of vascular event in Children with Sickle Cell Disease in their steady state and relate levels to severity of VEs in the following 6 months. Patient and Methods This study was an exploratory study, conducted at Pediatrics Hematology- Oncology Unit at Ain Shams University Children’s Hospital, where 50 children with sickle cell disease were enrolled at their steady state (defined as 2 months free from any Vascular Event prior to the study), aged 6 months - 16 years. Flow cytometry was done for quantification of circulating CD34+ at inclusion and compared to age and sex matched control and patients were followed up for 6 months for vascular events. Results There is statistically significant higher level of CD34+ among SCD patients compared to age and sex matched control with p value < 0.001.Circulating CD34+ showed significantly higher level in patients who developed systemic vascular events after 6 months of follow up with p value 0.022. There was no statistically significant correlation between circulating CD34+ and severity of peripheral vascular events (or any need for hospitalization) on follow up. Conclusion CD34+ cell count at steady state may be a promising biomarker of further vascular event in children with SCD.

Tisotumab vedotin in head and neck squamous cell carcinoma: Updated analysis from innovaTV 207 Part C.

6012 Background: Recurrent or metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) is treated in the first-line with an immunotherapy-based approach, including in combination with platinum-based chemotherapy or as monotherapy, or platinum-based combination plus targeted therapy. Still, most pts experience disease progression, and the efficacy of subsequent line treatment options is limited. Tisotumab vedotin (TV) is an investigational antibody-drug conjugate directed to tissue factor. TV at 1.7 mg/kg IV Q2W has demonstrated encouraging antitumor activity in 2L-4L r/m HNSCC from the innovaTV 207 (NCT03485209) study. Here, we present data from the full cohort, Part C. Methods: innovaTV 207 is an open-label, global, phase 2, multicohort, multicenter study evaluating TV monotherapy or in combination for advanced solid tumors. In Part C, pts with r/m HNSCC received TV monotherapy (1.7 mg/kg IV Q2W). All pts were required to have received a platinum-based regimen, either in the r/m setting, or have persistent disease following platinum-based chemoradiation and a checkpoint inhibitor (CPI), if eligible. Primary endpoint was confirmed objective response rate (cORR) per investigator. Secondary endpoints included duration of response (DOR), time-to-response (TTR), and safety. Results: As of 6 Sept 2023, 40 pts with HNSCC were treated. 39 (97.5%) pts received prior platinum-based therapy. In the r/m setting, 25 (62.5%) pts received ≤2 prior lines of systemic therapy (median: 2; range: 1-3), 40 (100%) pts received prior CPI, 23 (57.5%) pts received prior taxane, and 27 (67.5%) pts received prior cetuximab. The most common subsites at diagnosis were oropharynx (n=16, of which 12 were p16 positive), larynx (n=10), and oral cavity (n=9). In the full cohort, cORR was 32.5% (95% CI, 18.6-49.1), with 1 complete response and 12 partial responses. Median DOR was 5.6 mo (95% CI, 3.0-NR) and median TTR was 1.4 mo. Among pts with ≤2 prior lines (n=25), cORR was 40.0% (95% CI, 21.1-61.3). In this subgroup, DOR is not yet mature (range: 1.2+ to 7.9+ mo), and among the 10 responders, 6 pts remain in response; median TTR was 1.5 mo. In the full cohort, 85.0% of pts had at least 1 treatment-related adverse event (TRAE). Grade ≥3 TRAEs occurred in 25.0% of pts, of which the most common were peripheral neuropathy events (12.5%). Adverse events of special interest were prespecified for ocular, peripheral neuropathy, and bleeding events, and occurred in 21 (52.5%), 19 (47.5%), and 15 (37.5%) pts, respectively. Updated efficacy and safety data are planned. Conclusions: TV demonstrated encouraging antitumor activity in a heavily pretreated r/m HNSCC population with a manageable safety profile consistent with previous TV monotherapy data. The study is ongoing; TV represents a promising treatment option for pts with r/m HNSCC who have progressed after prior platinum-based therapy and immunotherapy. Clinical trial information: NCT03485209 .

SAFETY AND EFFICACY OF A LIGHT ANTITHROMBOTIC REGIMEN AFTER LEFT ATRIAL APPENDAGE OCCLUSION: INSIGHTS FROM THE LOGIC (LEFT ATRIAL APPENDAGE OCCLUSION IN PATIENTS WITH GASTROINTESTINAL OR INTRACRANIAL BLEEDING) INTERNATIONAL MULTICENTER REGISTRY

Abstract Background Antithrombotic therapy (AT) after left atrial appendage occlusion (LAAO) in patients with non–valvular atrial fibrillation (NVAF) has the purpose of preventing device related thrombosis (DRT), avoiding embolic events; nevertheless, the correct antithrombotic regimen after LAAO is still under debate. Aims Aim of this substudy of the observational LOGIC registry was to describe the efficacy and safety of a light antithrombotic regimen, comprising single antiplatelet therapy or none, compared to a standard antithrombotic regimen, after a successful LAAO. Methods Patients with NVAF that underwent LAAO were previously included in the LOGIC registry. Patients receiving single or no AT were considered as light therapy group, while other regimen were considered as standard regimen group. Outcomes of interest were: death from any causes and cardiovascular death, ischemic stroke, transient ischemic attack and systemic embolization, any bleeding and major bleeding at 12 months. Results. Six hundred and twenty–eight patients were considered in the analysis, 31.4% received a light antithrombotic regimen. There were no differences in overall and cardiovascular mortality (5.1% Vs 6.7%, p=0.426 and 2.0% Vs 1.4%, p=0.553 respectively). Cerebrovascular stroke and transient ischemic attack were similar between the two groups (1.5% Vs 1.4%, p=0.898 and 1.5% Vs 1.3%, p=0.847). Light regimen was not associated with an increased rate of systemic embolism (1.0% Vs 0.7%, p=0.447 and HR 0.88 [95% CI: 0.34 – 2.27; p=0.79]). Conclusions An AT regimen based on single or no antithrombotic therapy after LAAO seems to be safe in patients with high–bleeding risk, without increasing cerebrovascular or peripheral ischemic events.

Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for transplant-ineligible myeloma: AMaRC 03-16

AbstractIn newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369).

Interactive exploration of adverse events and multimorbidity in CKD.

Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. Over a median of 6.5 years, 10271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

Factors Associated With Physical Inactivity of Recipients of a Kidney Transplant: Results From the ADHERE BRAZIL Multicenter Study.

Physical activity is recommended for recipients of a kidney transplant. However, ADHERE BRAZIL study found a high prevalence (69%) of physical inactivity in Brazilian recipients of a kidney transplant. To tackle this behavior, a broad analysis of barriers is needed. This study aimed to identify factors (patient and transplant center levels) associated with physical inactivity among recipients of a kidney transplant. This was a subproject of the ADHERE BRAZIL study, a cross-sectional, multicenter study of 1105 recipients of a kidney transplant from 20 kidney transplant centers. Using a multistage sampling method, patients were proportionally and randomly selected. Applying the Brief Physical Activity Assessment questionnaire, patients were classified as physically active (≥150min/wk) or physically inactive (<150min/wk). On the basis of an ecological model, 34 factors associated with physical inactivity were analyzed by sequential logistic regression. At the patient level, physical inactivity was associated with smoking (odds ratio = 2.43; 95% CI = 0.97-6.06), obesity (odds ratio = 1.79; 95% CI = 1.26-2.55), peripheral vascular disease (odds ratio = 3.18; 95% CI = 1.20-8.42), >3 posttransplant hospitalizations (odds ratio = 1.58; 95% CI = 1.17-2.13), family income of >1 reference salary ($248.28 per month; odds ratio = 0.66; 95% CI = 0.48-0.90), and student status (odds ratio = 0.58; 95% CI = 0.37-0.92). At the center level, the correlates were having exercise physiologists in the clinical team (odds ratio = 0.54; 95% CI = 0.46-0.64) and being monitored in a teaching hospital (undergraduate students) (odds ratio = 1.47; 95% CI = 1.01-2.13). This study identified factors associated with physical inactivity after kidney transplantation that may guide future multilevel behavioral change interventions for physical activity. In a multicenter sample of recipients of a kidney transplant with a prevalence of physical inactivity of 69%, we found associations between this behavior and patient- and center-level factors. At the patient level, the chance of physical inactivity was positively associated with smoking, obesity, and patient morbidity (peripheral vascular disease and hospitalization events after kidney transplantation). Conversely, a high family income and a student status negatively correlated with physical inactivity. At the center level, the presence of a dedicated professional to motivate physical activity resulted in a reduced chance of physical inactivity. A broad knowledge of barriers associated with physical inactivity can allow us to identify patients at a high risk of not adhering to the recommended levels of physical activity.

Development and evaluation of a prediction model for peripheral artery disease-related major adverse limb events using novel biomarker data

ObjectivePrognostic tools for individuals with peripheral artery disease (PAD) remain limited. We developed prediction models for 3-year PAD-related major adverse limb events (MALE) using demographic, clinical, and biomarker data previously validated by our group. MethodsWe performed a prognostic study using a prospectively recruited cohort of patients with PAD (n = 569). Demographic/clinical data were recorded including sex, age, comorbidities, previous procedures, and medications. Plasma concentrations of three biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], fatty acid binding protein 3 [FABP3], and FABP4) were measured at baseline. The cohort was followed for 3 years. MALE was the primary outcome (composite of open/endovascular vascular intervention or major amputation). We trained three machine learning models with 10-fold cross-validation using demographic, clinical, and biomarker data (random forest, decision trees, and Extreme Gradient Boosting [XGBoost]) to predict 3-year MALE in patients. Area under the receiver operating characteristic curve (AUROC) was the primary model evaluation metric. ResultsThree-year MALE was observed in 162 patients (29%). XGBoost was the top-performing predictive model for 3-year MALE, achieving the following performance metrics: AUROC = 0.88 (95% confidence interval [CI], 0.84-0.94); sensitivity, 88%; specificity, 84%; positive predictive value, 83%; and negative predictive value, 91% on test set data. On an independent validation cohort of patients with PAD, XGBoost attained an AUROC of 0.87 (95% CI, 0.82-0.90). The 10 most important predictors of 3-year MALE consisted of: (1) FABP3; (2) FABP4; (3) age; (4) NT-proBNP; (5) active smoking; (6) diabetes; (7) hypertension; (8) dyslipidemia; (9) coronary artery disease; and (10) sex. ConclusionsWe built robust machine learning algorithms that accurately predict 3-year MALE in patients with PAD using demographic, clinical, and novel biomarker data. Our algorithms can support risk stratification of patients with PAD for additional vascular evaluation and early aggressive medical management, thereby improving outcomes. Further validation of our models for clinical implementation is warranted.

Non-coronary peripheral arterial complications in people with type 2 diabetes: a Swedish retrospective cohort study

BackgroundFew studies have explored long-term trends and risk factors for peripheral arterial complications in type 2 diabetes compared to the general population. Our research focuses on identifying optimal risk factors, their significance, multifactorial control risks, and trends for these complications in diabetic patients versus general controls. MethodsThis study included persons with type 2 diabetes mellitus entered into the Swedish National Diabetes Register 2001-2019 and controls matched for age-, sex- and county of residence. Outcomes comprised of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity arterial disease and diabetes foot disease. Standardized incidence rates and Cox regression were used for analyses. FindingsThe study comprises 655,250 persons with type 2 diabetes mellitus; average age 64.2; 43.8% women. Among persons with type 2 diabetes mellitus, the incidence rates per 100,000 person years for each non-coronary peripheral arterial complication event changed between 2001 and 2019 as follows: extracranial large artery disease 170.0 to 84.9; aortic aneurysm 40.6 to 69.2; aortic dissection 9.3 to 5.6; lower extremity artery disease from 338.8 to 190.8; and diabetic foot disease from 309.8 to 226.8. Baseline hemoglobin A1c (HbA1c), systolic blood pressure (SBP), smoking status and lipid levels were independently associated with all outcomes in the type 2 diabetes mellitus cohort. Within the cohort with type 2 diabetes mellitus, the risk for extracranial large artery disease and lower extremity artery disease increased in a stepwise fashion for each risk factor not within target. Excess risk for non-coronary peripheral arterial complications in the entire cohort for persons with type 2 diabetes mellitus, compared to matched controls, were as follows: extracranial large artery disease adjusted hazard ratio (HR) 1.69 (95% confidence interval (CI), 1.65-1.73), aortic aneurysm HR 0.89 (95% CI, 0.87-0.92), aortic dissection HR 0.51 (95% CI, 0.46-0.57) and lower extremity artery disease HR 2.59 (95% CI, 2.55-2.64). InterpretationsThe incidence of non-coronary peripheral arterial complications has declined significantly among persons with type 2 diabetes mellitus, with the exception of aortic aneurysm. HbA1c, smoking and blood pressure demonstrated greatest relative contribution for outcomes and lower levels of cardiometabolic risk factors are associated with reduced relative risk of outcomes.Funding: Swedish governmental and the county support of research and education of doctors, the Swedish Heart and Lung Foundation and Åke-Wibergs grant.

Pseudopterygia in Fuchs Superficial Marginal Keratitis: Clinical Course and Surgical Outcome.

Surgery for pseudopterygia in Fuchs superficial marginal keratitis (FSMK) bears the risk of corneal perforation, as described in a few case reports. The aim of this case series was to understand the clinical course and surgical outcomes of pseudopterygia in FSMK. A retrospective case series included patients meeting FSMK criteria with pseudopterygia in at least 1 eye. The severity grading of pseudopterygia and peripheral infiltration events at follow-up were analyzed. Pseudopterygia involving corneal central 3 mm diameter (grade III) received surgery. Peripheral corneal infiltrate events within 1 week after surgery were recorded. Thirty-three eyes of 19 patients (8 men, 11 women; age 40-85 years; mean, 65 years) were included, with an average 48.1-month follow-up (range 0-188.8 months). At presentation, 7 eyes (21%) had grade III pseudopterygia. One patient showed corneal perforation 3 days after "pterygium" surgery elsewhere. The contralateral eye met the diagnosis of FSMK. During follow-up, 16 eyes (49%) exhibited peripheral corneal infiltrates, and 7 eyes (21%) showed progression of pseudopterygia to higher grades before or without any surgery. Ten eyes with grade III pseudopterygia underwent surgery. The best-corrected visual acuity in Logarithm of the Minimum Angle of Resolution improved from 0.34 ± 0.18 (range 0.05-0.52) to 0.13 ± 0.11 (range 0.05-0.4) (P = 0.0023). Six eyes (60%) developed peripheral corneal infiltrates within 1 week after surgery, which responded well to topical corticosteroids. Pseudopterygia in FSMK may progress to threaten visual acuity. Surgical excision can be safe and can effectively improve vision on the condition that the patients are closely followed in the early postoperative period to notice the corneal infiltrates.

Association of peripheral B cells and delirium: combined single-cell sequencing and Mendelian randomization analysis.

Delirium seriously affects the prognosis of patients and greatly reduces the ability to work and live. Peripheral inflammatory events may contribute to the development of delirium, the mechanism of which is still unclear. There is a lack of effective diagnostic and treatments for delirium in clinical practice. The study aims to investigate alterations in peripheral immune cell subsets under inflammatory stress and to explore causal associations with delirium. Single-cell transcriptional sequencing data of human peripheral blood mononuclear cells (PBMC) before and after lipopolysaccharide (LPS) intervention were processed by the Seurat package in R software. PBMC subsets and cellular markers were defined after downscaling and clustering by the Harmony algorithm to identify characteristic subsets in the context of inflammatory stress. Subsequently, a two-sample Mendelian randomization (MR) study was used to explore the causal associations of these inflammation-related PBMC subsets and their molecular phenotypes with delirium. Based on publicly available genetic data, the study incorporated 70 PBMC-associated immune traits, including 8 types of circulating immune cells, 33 B cell subsets and molecular phenotypes, 13 T cell subsets, and 16 B cell-associated cytokines. The results were also validated for robustness, heterogeneity, and horizontal pleiotropy. Under LPS-induced inflammatory stress, B cells, T cells, monocytes, and dendritic cells in human PBMC showed significant activation and quantitative changes. Of these, only lymphocyte and B cell counts were causally associated with delirium risk. This risk link is also seen in the TNF pathway. Further studies of B cells and their subsets revealed that this association may be related to unswitched memory B cells and CD27 expressed on memory B cells. Annotation of the screened SNPs revealed significant polymorphisms in CD27 and CD40 annotated by rs25680 and rs9883798, respectively. The functions of the key annotated genes may be related to the regulation of immune responses, cell differentiation, proliferation, and intercellular interactions. The present study revealed the potential possibility that B cell, memory B cell subset, and TNF-related molecules may be involved in the development of delirium due to peripheral inflammation, which can provide clues for further investigation of delirium prevention and treatment strategies.

Donepezil-Loaded Nanocarriers for the Treatment of Alzheimer's Disease: Superior Efficacy of Extracellular Vesicles Over Polymeric Nanoparticles.

Drug delivery across the blood-brain barrier (BBB) is challenging and therefore severely restricts neurodegenerative diseases therapy such as Alzheimer's disease (AD). Donepezil (DNZ) is an acetylcholinesterase (AChE) inhibitor largely prescribed to AD patients, but its use is limited due to peripheral adverse events. Nanodelivery strategies with the polymer Poly (lactic acid)-poly(ethylene glycol)-based nanoparticles (NPs-PLA-PEG) and the extracellular vesicles (EVs) were developed with the aim to improve the ability of DNZ to cross the BBB, its brain targeting and efficacy. EVs were isolated from human plasma and PLA-PEG NPs were synthesized by nanoprecipitation. The toxicity, brain targeting capacity and cholinergic activities of the formulations were evaluated both in vitro and in vivo. EVs and NPs-PLA-PEG were designed to be similar in size and charge, efficiently encapsulated DNZ and allowed sustained drug release. In vitro study showed that both formulations EVs-DNZ and NPs-PLA-PEG-DNZ were highly internalized by the endothelial cells bEnd.3. These cells cultured on the Transwell® model were used to analyze the transcytosis of both formulations after validation of the presence of tight junctions, the transendothelial electrical resistance (TEER) values and the permeability of the Dextran-FITC. In vivo study showed that both formulations were not toxic to zebrafish larvae (Danio rerio). However, hyperactivity was evidenced in the NPs-PLA-PEG-DNZ and free DNZ groups but not the EVs-DNZ formulations. Biodistribution analysis in zebrafish larvae showed that EVs were present in the brain parenchyma, while NPs-PLA-PEG remained mainly in the bloodstream. The EVs-DNZ formulation was more efficient to inhibit the AChE enzyme activity in the zebrafish larvae head. Thus, the bioinspired delivery system (EVs) is a promising alternative strategy for brain-targeted delivery by substantially improving the activity of DNZ for the treatment of AD.

The potency of time series outliers in volatile models: An empirical analysis of fintech, and mineral resources

Understanding the importance of sustainability, the increasing ecological concerns need resource management under the cumulative mineral dependency. In this vein, prices of financial technology and mineral resources influence environmental sustainability; hence, sudden price variations must be evaluated carefully. For this, detecting outliers in financial and economic variables is gaining attention as economies are regionally integrated and influenced by external factors. Such peripheral events highly influence the statistical properties of model parameters and error distributions. In this vein, the current study proposed the method of outlier detection in various time series volatile models by extending the procedure of Frances and Ghijselse (1999) based on the framework of Chen and Liu (1993). The method is based on three phases: First, the outliers are detected, then the outliers are removed and estimated using the linear interpolation method, and third, the data values are forecasted by re-estimating the model with a corrected series. Forecasting accuracy has also been compared with and without outlier series to observe the impact of outlier presence in the series. For empirical analysis, the S&P Kensho Democratized Banking Index (USD), S&P 500 Environmental and Socially Responsible Index, and Gold price per Troy Ounce from July 15, 2013, to July 14, 2023. The outcomes retrieved from the proposed method suggest that the error distribution of volatile models is affected by outliers and manifestly forecasting performance is better with outlier corrected series. The diagnostic of the model is also analyzed. The study presents robust policy implications for outlier detection procedures in volatile models.

Chinese herbal medicine Shenqi compound for early intervention in patients at high cardiovascular risk of type 2 diabetes mellitus: the protocol of a multicenter, randomized, double-blind, placebo-controlled trial.

Reducing multiple cardiovascular risk factors is a key link and a challenging clinical problem to reduce the risk of cardiovascular complications and death in patients with diabetes. Currently, there is a lack of clinical studies on patients with diabetes combined with multiple risk factors. Traditional Chinese medicine is believed to have therapeutic effects that contribute to the comprehensive control of multiple cardiovascular factors. This study aims to provide evidence for the efficacy and safety of Shenqi compound (SQC) for early intervention in diabetic patients at high cardiovascular risk. This study is a multicenter, randomized, double-blind, placebo-controlled trial. A total of 120 diabetic patients with high cardiovascular risk were enrolled in five research centers. After a 2-week run-in period, the intervention group received basic treatment and SQC granules, and the control group received basic treatment and placebo granules for a total of 24 weeks, with a 24-week follow-up. The endpoint outcomes are major adverse cardiovascular events and renal-related and peripheral vascular disease events. The primary efficacy outcome is carotid intima-media thickness, and the secondary efficacy outcomes are carotid shear stress, indicators of glucose and lipid metabolism, pancreatic islets function, hemorheology, traditional Chinese medicine syndrome score, and quality of life scale. Safety indicators and adverse events were used to assess the safety of SQC. This study comprehensively evaluated the efficacy and safety of SQC for early intervention in diabetic patients at high cardiovascular risk from the aspects of overall metabolic level, structure, and function of blood vessels, quality of life, and long-term follow-up of endpoint events, providing evidence-based evidence for the short-term efficacy and long-term benefits of early treatment to reduce the risk of diabetic cardiovascular complications.Trial Registration: This trial is registered in the Chinese Clinical Trial Registry on March 9, 2023, https://www.chictr.org.cn/showproj.html?proj=192803 (No. ChiCTR2300069219).

‘Inside the belly of the whale’: epistemology and aisthesis in the work of Aleksei German

ABSTRACT Considering the relative dearth of English-language scholarship on Aleksei Iu. German’s work, this essay attempts to provide a totalising account of German’s filmography, elaborating on the themes formulated by Nancy Condee (2009) and Alexander Graham (2012), both published before the release of German’s magnum opus Hard to be a God (2013). By encompassing German’s last film, this essay will consider German’s oeuvre as a single continuous text, gradually shifting from a politically subversive realism to a Dionysian formalism of endlessly proliferating time-images. Drawing from the work of Gilles Deleuze and Jacques Rancière, it is our argument that, rather than representing the ‘sensation of recall’, German gradually presents the aisthesis of his characters’ loss of control over symbolic reality. It is the surplus of realism effects, the sheer quantity of mimetic detail and the proliferation of peripheral events over narrative information that amounts to reality’s collapse: the stage of the carnival, the grotesque, where movement extends everywhere and nowhere.

Impact of genetic background as a risk factor for atherosclerotic cardiovascular disease: A protocol for a nationwide genetic case-control (CV-GENES) study in Brazil.

Atherosclerotic Cardiovascular Disease (ASCVD) represents the leading cause of death worldwide, and individual screening should be based on behavioral, metabolic, and genetic profile derived from data collected in large population-based studies. Due to the polygenic nature of ASCVD, we aimed to assess the association of genomics with ASCVD risk and its impact on the occurrence of acute myocardial infarction, stroke, or peripheral artery thrombotic-ischemic events at population level. CardioVascular Genes (CV-GENES) is a nationwide, multicenter, 1:1 case-control study of 3,734 patients in Brazil. Inclusion criterion for cases is the first occurrence of one of the ASCVD events. Individuals without known ASCVD will be eligible as controls. A core lab will perform the genetic analyses through low-pass whole genome sequencing and whole exome sequencing. In order to estimate the independent association between genetic polymorphisms and ASCVD, a polygenic risk score (PRS) will be built through a hybrid approach including effect size of each Single Nucleotide Polymorphism (SNP), number of effect alleles observed, sample ploidy, total number of SNPs included in the PRS, and number of non-missing SNPs in the sample. In addition, the presence of pathogenic or likely pathogenic variants will be screened in 8 genes (ABCG5, ABCG8, APOB, APOE, LDLR, LDLRAP1, LIPA, PCSK9) associated with atherosclerosis. Multiple logistic regression will be applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI), and population attributable risks will be calculated. Clinical trial registration: This study is registered in clinicaltrials.gov (NCT05515653).