Major Risk Research Articles

Design and Methods of the Early Age-Related Hearing Loss Investigation Randomized Controlled Trial.

Hearing loss has been identified as a major modifiable risk factor for cognitive decline. The Early Age-Related Hearing Loss Investigation (EARHLI) study will assess the mechanisms linking early age-related hearing loss (ARHL) and cognitive impairment. Randomized, controlled, single-site, early phase II, superiority trial. Tertiary academic medical center. One hundred fifty participants aged 55 to 75 years with early ARHL (severity defined as borderline to moderate) and amnestic mild cognitive impairment will be included. Participants will be randomized 1:1 to a best practice hearing intervention or a health education control. The primary study outcome is cognition measured by the Alzheimer Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite. Secondary outcomes include additional measures of cognition, social engagement, and brain organization/connectivity. Trial enrollment will begin in early 2024. After its completion in 2028, the EARHLI trial should offer evidence on the effect of hearing treatment versus a health education control on cognitive performance, social engagement, and brain organization/connectivity in 55- to 75-year-old community-dwelling adults with early ARHL and amnestic mild cognitive impairment.

Occurrence, Isolation, Pharmacological Potential, Metabolism, and Toxicity of Myristicin: A Naturally Occurring Alkoxy-Substituted Allylbenzene

Background: Natural products are secondary metabolites obtained from plants, animals, and microorganisms with diverse chemical structures resulting in diverse biological functions and drug-like properties. Objective: This review article summarizes in detail the occurrence, detection, isolation, various pharmacological properties, metabolism, and toxicity of a natural compound i.e., 5-Allyl-1-methoxy- 2,3-methylenedioxybenzene commonly known as Myristicin. Methods: A relevant literature search was made using the keywords essential oil, mace, myristicin, nutmeg, and pharmacological activities from different databases such as PubMed, Sci Finder, Science Direct, and Google Scholar. The literature search results presented articles from 1963 to 2022. Thereafter, the articles were carefully screened and selected for review. Results: Myristicin, an alkoxy-substituted allylbenzene is present in major to minor amounts in the essential oils obtained from different plant parts and exhibits various pharmacological properties such as antimicrobial, antioxidant, antiproliferative, anti-inflammatory, insecticidal, and hepatoprotective. It forms 10 metabolites by reduction, demethylation, hydroxylation, ring formation, ring-opening, and conjugate formation. In the liver, myristicin has been metabolized by Cytochrome P450 complex enzymes to generate active metabolite (1ˈ hyroxymyristicin) responsible for cytotoxic, genotoxic and apoptotic effects (150 μM). But, myristicin at 600 μM does not produce enough 1ʼ-hydroxymyristicin to give the final toxicant. Conclusion: Myristicin poses no major risk to human health through the consumption of herbs and spices due to its presence in low amounts. It has great potential to be used in the traditional system of medicine. We hope that this review will provide complete knowledge about myristicin on a single platform.

Epidemiology and demographic patterns of cardiovascular diseases and neoplasms deaths in Western Europe: a 1990–2019 analysis

ObjectivesCardiovascular diseases (CVDs) and neoplasms have been considered as public health concerns worldwide. This study aimed to estimate the epidemiological patterns of death burden on CVDs and neoplasms and its attributable risk factors in Western Europe from 1990 to 2019 to discuss the potential causes of the disparities. Study design and methodsWe collected data on CVDs and neoplasm deaths in 24 Western European countries from the Global Burden of Disease Study. We analyzed patterns by age, sex, country, and associated risk factors. The results include percentages of total deaths, age-standardized death rates per 100,000 population, and uncertainty intervals (UIs). Time trends were assessed using annual percent change. ResultsIn 2019, CVDs and neoplasms accounted for 33.54% and 30.15% of Western Europe's total deaths, with age-standardized death rates of 128.05 and 137.51 per 100,000. Over 1990–2019, CVD rates decreased by 54.97%, and neoplasm rates decreased by 19.54%. Top CVD subtypes were ischemic heart disease and stroke; top cancers for neoplasms were lung and colorectal. Highest CVD death burdens were in Finland, Greece, Austria; neoplasm burdens in Monaco, San Marino, Andorra. The major risk factors were metabolic (CVDs) and behavioral (neoplasms). Gender differences revealed higher CVD death burden in males, while neoplasm burden varied by risk factors and age groups. ConclusionIn 2019, CVDs and neoplasms posed significant health risks in Western Europe, with variations in death burdens and risk factors across genders, age groups, and countries. Future interventions should target vulnerable groups to lessen the impact of CVDs and neoplasms in the region.

Susceptibility to recombinant SARS-CoV-2 spike protein entry in the lungs of high-fat diet-induced obese mice.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Obesity is a major risk factor for the development of COVID-19. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2. The receptor-binding domain of the S1 subunit (S1-RBD protein) in the SARS-CoV-2 spike glycoprotein binds to ACE2 on host cells, through which the virus enters several organs, including the lungs. Considering these findings, recombinant ACE2 might be utilized as a decoy protein to attenuate SARS-CoV-2 infection. Here, we examined whether obesity increases ACE2 expression in the lungs and whether recombinant ACE2 administration diminishes the entry of S1-RBD protein into lung cells. We observed that high-fat diet-induced obesity promoted ACE2 expression in the lungs by increasing serum levels of LPS derived from the intestine. S1-RBD protein entered the lungs specifically through ACE2 expressed in host lungs and that the administration of recombinant ACE2 attenuated this entry. We conclude that obesity makes hosts susceptible to recombinant SARS-CoV-2 spike proteins due to elevated ACE2 expression in lungs, and this model of administering S1-RBD protein can be applied to new COVID-19 treatments.

Loneliness is associated with more trust but worse trustworthiness expectations.

Subjective feelings of loneliness emerge due to unsatisfactory social relationships, representing a major risk for mental and physical well-being. Despite its social nature, evidence on how loneliness affects social behaviours and expectations is lacking. Using Bayesian analyses and economic games, we show in three different studies that lonelier individuals trusted their partners to a greater extent despite less favourable trustworthiness expectations, showing a greater discrepancy between their trusting behaviours and their expectations of others' trustworthiness. Such discrepancy was reversed in extravert individuals who also reported to be less lonely. These results provide evidence on two opposing effects of loneliness as a motivator for social connections and promoter of social withdrawal, and demonstrate the moderating role of personality traits. This work contributes to a better understanding of how loneliness impacts social behaviour and social expectations, with important downstream clinical implications for varying health conditions associated with heightened feelings of loneliness.

Identification of a functional missense variant in the matrix metallopeptidase 10 (MMP10) gene in two families with premature myocardial infarction

A positive family history is a major independent risk factor for atherosclerosis, and genetic variation is an important aspect of cardiovascular disease research. We identified a heterozygous missense variant p.L245P in the MMP10 gene in two families with premature myocardial infarction using whole-exome sequencing. The aim of this study was to investigate the consequences of this variant using in-silico and functional in-vitro assays. Molecular dynamics simulations were used to analyze protein interactions, calculate free binding energy, and measure the volume of the substrate-binding cleft of MMP10-TIMP1 models. The p.L245P variant showed an altered protein surface, different intra- and intermolecular interactions of MMP10-TIMP1, a lower total free binding energy between MMP10-TIMP1, and a volume-minimized substrate-binding cleft of MMP10 compared to the wild-type. For the functional assays, human THP-1 cells were transfected with plasmids containing MMP10 cDNA carrying the p.L245P and wild-type variant and differentiated into macrophages. Macrophage adhesion and migration assays were then conducted, and pro-inflammatory chemokine levels were evaluated. The p.L245P variant led to macrophages that were more adherent, less migratory, and secreted higher levels of the pro-inflammatory chemokines CXCL1 and CXCL8 than wild-type macrophages. Thus, the p.L245P variant in MMP10 may influence the pathogenesis of atherosclerosis in families with premature myocardial infarction by altering protein - protein interactions, macrophage adhesion and migration, and expression of pro-inflammatory chemokines, which may increase plaque rupture. These results could contribute to the development of selective MMP10 inhibitors and reduce the risk of atherosclerosis in families with a history of premature myocardial infarction.

Impact of indoor air pollution on DNA damage and chromosome stability: a systematic review.

Indoor air pollution is becoming a rising public health problem and is largely resulting from the burning of solid fuels and heating in households. Burning these fuels produces harmful compounds, such as particulate matter regarded as a major health risk, particularly affecting the onset and exacerbation of respiratory diseases. As exposure to polluted indoor air can cause DNA damage including DNA sd breaks as well as chromosomal damage, in this paper, we aim to provide an overview of the impact of indoor air pollution on DNA damage and genome stability by reviewing the scientific papers that have used the comet, micronucleus, and γ-H2AX assays. These methods are valuable tools in human biomonitoring and for studying the mechanisms of action of various pollutants, and are readily used for the assessment of primary DNA damage and genome instability induced by air pollutants by measuring different aspects of DNA and chromosomal damage. Based on our search, in selected studies (in vitro, animal models, and human biomonitoring), we found generally higher levels of DNA strand breaks and chromosomal damage due to indoor air pollutants compared to matched control or unexposed groups. In summary, our systematic review reveals the importance of the comet, micronucleus, and γ-H2AX assays as sensitive tools for the evaluation of DNA and genome damaging potential of different indoor air pollutants. Additionally, research in this particular direction is warranted since little is still known about the level of indoor air pollution in households or public buildings and its impact on genetic material. Future studies should focus on research investigating the possible impact of indoor air pollutants in complex mixtures on the genome and relate pollutants to possible health outcomes.

Leveraging interindividual variability in threat conditioning of inbred mice to model trait anxiety.

Trait anxiety is a major risk factor for stress-induced and anxiety disorders in humans. However, animal models accounting for the interindividual variability in stress vulnerability are largely lacking. Moreover, the pervasive bias of using mostly male animals in preclinical studies poorly reflects the increased prevalence of psychiatric disorders in women. Using the threat imminence continuum theory, we designed and validated an auditory aversive conditioning-based pipeline in both female and male mice. We operationalised trait anxiety by harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy. While sustained freezing during prolonged retrieval sessions was identified as an anxiety-endophenotype biomarker in both sexes, females were consistently associated with an increased freezing response. RNA-sequencing of CeA, BLA, ACC, and BNST revealed massive differences in phasic and sustained responders' transcriptomes, correlating with transcriptomic signatures of psychiatric disorders, particularly post-traumatic stress disorder (PTSD). Moreover, we detected significant alterations in the excitation/inhibition balance of principal neurons in the lateral amygdala. These findings provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility in a sex-specific manner.

First-trimester uterine artery Doppler and hypertensive disorders in twin pregnancies: Use of twin versus singleton references.

To determine the association of first-trimester uterine artery Doppler with hypertensive disorders of pregnancy in twin pregnancies. This was a retrospective cohort study of twin pregnancies followed at the University Hospital Center of Central Lisbon, Portugal, between January 2010 and December 2022. First-trimester uterine artery pulsatility index (UtA-PI) was determined and compared between twin pregnancies (n = 454) and singleton pregnancies (n = 908), matched to maternal and pregnancy characteristics. Maternal characteristics and mean UtA-PI were analyzed for gestational age, birth weight, gestational hypertension, early- and late-onset pre-eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and preterm birth. Univariable and multivariable logistic regression models were used. The mean first-trimester UtA-PI was significantly lower in dichorionic twins than in singletons (P < 0.001). To study hypertensive disorders of pregnancy in twins, 390 pregnancies were included: 311 (79.7%) dichorionic and 79 (20.3%) monochorionic twins. The observed rates of early- and late-onset pre-eclampsia, gestational hypertension, and HELLP syndrome were 1.0%, 4.4%, 7.4%, and 1.5%, respectively. We achieved a 100% detection rate for early-onset pre-eclampsia using the UtA-PI 90th centile for twins. However, when singleton references were considered, the detection rate decreased to 50%. UtA-PI at or above the 95th centile was associated with increased odds for preterm birth before 32 weeks (adjusted odds ratio 4.1, 95% confidence interval 1.0-16.7, P = 0.043). Unless other major risk factors for hypertensive disorders are present, women with low UtA-PI will probably not benefit from aspirin prophylaxis. Close monitoring of all twin pregnancies for hypertensive disorders is still recommended.

The role of CT in acute bowel obstruction due to a supravesical hernia, a case report from Nepal

Introduction and importance: Supravesical hernias are rare internal hernias but potential cause of small bowel obstruction. The clinical features are often non-specific, preoperative diagnosis is very difficult and is often diagnosed intraoperatively. The exact pathogenesis is unclear with the major risk factors of prematurity, a positive family history, male gender, smoking habits leading to decreased collagen production, advancing age, and conditions characterized by defective collagen synthesis Case presentation: We are reporting a case of small bowel obstruction secondary to a supravesical hernia, in a 78-year-old male presented with central abdominal pain, vomiting and obstipation. Ultrasonography of the abdomen and pelvis identified a marked dilation of the small bowel loop with multiple loops of dilated jejunum and ileum in contrast-enhanced CT scan of the abdomen and pelvis with lead point from the terminal ileum. Exploratory laparotomy was done with the diagnosis of left posterior a left posterior superior vesical hernia with small bowel obstruction. Clinical discussion: The case focuses supravesical hernia as a rare yet life-threatening etiology of small bowel obstruction, emphasizing the importance of clinical suspicion when patients present with signs and symptoms of bowel obstruction. While diagnosis often occurs intraoperatively, the utilization of computed tomography (CT) scans in emergency settings can provide valuable insights into the location, potential causes, and condition of the herniated bowel sac. The case highlights the pivotal role of computed tomography (CT) scans in diagnosis and emphasizes the need for multidisciplinary cooperation among clinicians, radiologists, and surgeons. Conclusion: Early intervention ensures better outcomes and prevents irreversible bowel damage, underscoring the importance of a comprehensive approach to patient care.

Total knee arthroplasty and periprosthetic distal femoral fracture: looking beyond the osteoporosis to previous osteoporotic fracture.

Osteoporosis is a risk factor for fractures, including those of the hip, vertebrae, and distal radius; however, the association between osteoporosis and periprosthetic fractures after total knee arthroplasty (TKA) has not been much investigated. Therefore, we aimed to investigate the association of the presence of systemic osteoporosis with periprosthetic fractures after TKA. This study included 34 patients with periprosthetic fractures following primary TKA and 106 controls matched for age and sex. Bone mineral density was evaluated at the femoral neck, total hip, and lumbar spine using dual X-ray absorptiometry. Medical records were reviewed for age; sex; body mass index; smoking; rheumatoid arthritis, endocrine diseases, and cardiovascular diseases; history of glucocorticoid use; medication for osteoporosis; and history of previous osteoporotic fracture. In addition, anterior femoral notching after TKA was evaluated. Univariable and multivariable logistic regression analysis were used to determine factors associated with periprosthetic fracture. The prevalence of osteoporosis in the fracture group was higher than that in the control group (61.8% vs. 40.6%, p=0.045). The rate of medication for osteoporosis was significantly low in the fracture group (47.6 % vs 76.7%, p=0.026). History of previous osteoporotic fracture (odds ratio [OR], 9.1; p=0.015) and osteoporosis (OR, 3.6; p=0.013) were significant risk factors for periprosthetic fractures after TKA. Medication for osteoporosis could decrease the risk of periprosthetic fracture (OR 0.3; p=0.020). Osteoporosis is a major risk factor for periprosthetic distal femoral fractures after TKA. Therefore, careful assessment and proper treatment of osteoporosis need and the importance of taking osteoporotic medication needs to be recognized to the patients following primary TKA, especially in patients with a history of osteoporotic fracture. Prognostic study, level III.

Incidence and outcomes of ventilator associated pneumonia in pediatric patients: an observational study

Background: Ventilator associated pneumonia (VAP) is very common in pediatric intensive care unit (PICU) intubated patients and also responsible for major morbidity and mortality. Usually, it develops after 48 hours of mechanically ventilated patients, its incidence increases as the duration of time increases and it is a major risk factor for VAP. The present study was carried out to know the overall incidence of VAP in mechanically ventilated patients in PICU. Methods: The study was carried out in PICU of the department of pediatrics, B. R. D. Medical College, Gorakhpur from October 2020 to October 2021. Patients aged between 1 year to 15 years were included in the study. Results: There were 50 (59.5%) patients’ male and 34 (40.5%) patients’ female under investigation. The clinical pulmonary infection score (CPIS) values ranged from the mean value of 4.38±2.30 at 36th hours to 7.33±1.92 at 96th hours of intubation. VAP was present in 23 (27.3%) patients while 62 (73.8%) patients were having no VAP. Among VAP associated patients, 14.3% were Acinetobacter positive, 5.95% were Klebsiella positive and 3.57% were E. coli positive. Conclusions: Parameters of CPIS associated with VAP revealed that Acinetobactor was comparative more common organism and the age group of 1 to 5 years was more sensitive. VAP can be reduced by decreasing the duration of mechanical ventilation.

Genetic risk of second malignant neoplasm after childhood cancer treatment: A systematic review.

Second malignant neoplasm (SMN) is one of the most severe long-term risks for childhood cancer survivors (CCS), significantly impacting long-term patient survival. While radiotherapy and chemotherapy are known risk factors, the observed inter-individual variability suggests a genetic component contributing to the risk of SMN. This article aims to conduct a systematic review of genetic factors implicated in the SMN risk among CCS. Searches were performed in PubMed, Scopus, and Web of Sciences. Eighteen studies were included (eleven candidate gene studies, three genome-wide association studies, and four whole exome/genome sequencing studies). The included studies were based on different types of first cancers, investigated any or specific types of SMN, and focused mainly on genes involved in drug metabolism and DNA repair pathways. These differences in study design and methods used to characterize genetic variants limit the scope of the results and highlight the need for further extensive and standardized investigations. However, this review provides a valuable compilation of SMN risk-associated variants and genes, facilitating efficient replication and advancing our understanding of the genetic basis for this major risk for CCS.

Physical activity change after early rhythm control after new-onset atrial fibrillation and major adverse cardiovascular event risk

Abstract Background There is paucity of information about major adverse cardiovascular event (MACE) related to physical activity change after early rhythm control (ERC) after new-onset atrial fibrillation (AF). We investigated the association between physical activity after ERC and clinical outcomes in new-onset AF patients. Methods This study was performed based on the Korean National Health Insurance Service database. We included adults with new-onset AF between 2009 and 2018. Patients who received national health screening examination before and after AF diagnosis within 2-year were finally included (n=161,379). Among these, 48,243 patients were received rhythm control within 2-year after AF diagnosis. Patients were categorized into 4 groups as follows: persistent non-exerciser, new exerciser (after AF diagnosis and ERC), exercise maintainer, and exercise quitter (after AF diagnosis and ERC). The primary outcome was MACE defined as the composite of ischemic stroke, myocardial infarction, and hospitalization for heart failure. Multivariable Cox analysis was performed. Results Among 48,243 patients receiving ERC, 63% (n=30,540) was persistent non-exerciser, 13% (n=6260) was new exerciser, 11% (n=5102) was exercise maintainer, and 13% (n=6341) was exercise quitter. After multivariable adjustment, compared to persistent non-exerciser, new exerciser and exercise maintainer with ERC showed lower risk of MACE by 10% and 19%, respectively (adjusted hazard ratio [aHR], 95% confidence interval [95% CI], 0.903 [0.802-0.994] for new exerciser, and 0.810 [0.725-0.906] for exercise maintainer) (Table 1). However, exercise quitter did not show significant benefit compared to persistent non-exerciser (Table 1). To assess the synergistic effect of ERC and starting or maintaining physical activity, we performed exploratory analysis including patients who did not receive ERC. Compared to persistent non-exerciser without ERC, persistent non-exerciser with ERC was associated with a significantly lower risk of MACE (0.832 [0.797-0.868], Table 2). Patients who received ERC and started or maintained physical activity with ERC showed greatest risk reduction for MACE by 27% and 36%, respectively (0.732 [0.668-0.802] for new exerciser and 0.641 [0.576-0.713] for exercise maintainer) (Table 2). Conclusion Even in context with beneficial effect of ERC in patients with new-onset AF, maintaining or starting regular physical activity after ERC might bring greater reduction on the risk of MACE. Physician should emphasize healthy lifestyle behavior with rhythm control in patients with new-onset AF.

Association of muscle health impairment and atherosclerosis with major osteoporotic fracture risk in Taiwanese Vegetarians

ABSTRACT Objectives: Despite the beneficial effects of “vegetarian style” diet on atherosclerosis, it is also proven potentially detrimental to bone health. The influence of muscle health or atherosclerosis on major osteoporotic fracture (MOF) risk in vegetarians has rarely been explored. This prospective study aimed to investigate an association of MOF risk with muscle health and atherosclerosis in vegetarians. Materials and Methods: We conducted a questionnaire survey with the Mini-Nutritional Assessment (MNA) on 39 vegetarians. The 10-year probability of MOF was determined using the Taiwanese Fracture Risk Assessment (FRAX®) calculator. Appendicular skeletal muscle (ASM) mass and bone mineral density were measured with dual-energy X-ray absorptiometry. Physical performance was evaluated using the 6-min walk test (6MWT). Common carotid artery intima–media thickness (ccIMT) was determined using sonography. Serum levels of parathyroid hormone (PTH), Vitamin D, adiponectin, and leptin were measured. Results: Eleven (28.2%) of 39 vegetarians had a moderate-high risk of MOF, defined by FRAX-calculated risk ≥10%. These subjects had lower ASM (P &lt; 0.005) and 6MWT distances (P &lt; 0.01) but greater ccIMT than those with low risk. The MOF risk was negatively correlated with ASM (r = −0.51, P &lt; 0.001) and 6MWT distances (r = −0.62, P &lt; 0.001) but positively correlated with ccIMT (r = 0.56, P &lt; 0.001). Linear regression analysis revealed that MOF risk scores were negatively associated with ASM and 6MWT distance while positively associated with ccIMT. There was no significant association of MOF risk with MNA scores, serum levels of PTH, Vitamin D, adiponectin, or leptin. Conclusion: Decreased ASM mass, reduced physical performance, and atherosclerosis are significantly associated with MOF risk in vegetarians.

Prophylactic treatment of FSGS recurrence in patients who relapsed in a previous kidney graft.

Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between December 31, 2004, and December 31, 2020, and who had a history of FSGS recurrence on a previous graft. We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT+group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT+group, P=0.54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% (95% CI: 53.4 to 78.4%): 65.1% (95%CI: 48.7 to 77.4%) in patients with FSGS recurrence vs. 77.3% (95% CI: 43.8 to 92.3%) in patients without recurrence (P=0.48). Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.

Outcomes of leadless pacemaker in chronic kidney disease patients: real-world data from the i-LEAPER registry

Abstract Background Chronic kidney disease (CKD) represents a major risk factor for patients requiring transvenous pacemaker (TV-PM), resulting in a high rate of operative complications and PM-related infection rate (21.9% and 12.5%, respectively), with both complications parallels to severity of CKD. Moreover, TV leads represent an important concern for end-stage CKD patients, often needing vascular access patency for renal replacement therapy. In this setting leadless pacemakers (LPMs) represent an attractive alternative to TV-PM for their lower device-related infection rate and the absence of TV leads. To date, limited data on LPM safety and efficacy profile in CKD patients are available. Purpose to assess operative and long-term safety and efficacy of LPMs implantation in patients with different stages of CKD in the real-world setting. Methods Consecutive patients who underwent LPM implantation in 12 European centers joining the i-LEAPER registry were retrospectively enrolled. CKD stage was assessed according to CKD-EPI equation for eGFR. Patients with CKD stage G3a/b (N=245) and stage G4/G5 (N=67) were compared with patients with normal kidney function (NKF) (N=867). Primary safety endpoint was LPM-related major complications rate at implant and during follow-up (FU). Additionally, the rate of patients showing sub-optimal electrical performance (pacing threshold [PT] &amp;gt;1V@0.24ms) was compared between groups. Results 1179 patients were enrolled and followed for a median of 33 [IQR 24-47] months. When compared with the NKF group, patients with CKD stage G3a/b and stage G4/G5 showed a higher burden of cardiovascular comorbidities (Table 1). The choice of a LPM was mainly due to vascular concern in the CKD stage G4/G5 group, while a perceived highest infective risk was reported in CKD stage G3a/b group (Table 1). Major complication rate at implant and during FU did not differ between groups, regardless of renal impairment stage (Table 2). All-cause mortality incidence resulted higher in CKD stage G4/G5 group when compared with NKF group (17.9% vs 6.8%; HR 4.24; 95%CI 4.25-7.94, p&amp;lt;0.001) (Figure A). The rate of patients with PT&amp;gt;V1@0.24ms during FU did not differ between groups, not exceeding 13.8%, and therefore remaining consistent with historical data for LPM (Figure B). Conclusion In the real-world setting, LPM showed a remarkable safety and efficacy profile in CKD patients regardless of renal impairment stage that was comparable to NKF population. LPM should be considered as first choice in CKD patients requiring a PM.

Senolysis ameliorates increased susceptibility to ventricular arrhythmias in prediabetes

Abstract Background Obesity and associated prediabetes are major risk factors for cardiovascular disease that promote cellular senescence and predispose to ventricular arrhythmias (VA). In consequence, targeting cellular senescence may represent a feasible therapeutical approach that can decrease VA susceptibility in aged hearts. The aim of the present study was to characterize the impact of senolysis on glucose control, left ventricular function (LVF) and VA susceptibility in a prediabetic mouse model. Methods Ten – 12 week-old C57Bl/6J mice were fed a high-fat diet over a period of 12 weeks to generate diet-induced-obesity (DIO). Afterwards, mice were treated with dasatinib (5 mg/kg) and quercetin (50 mg/kg) (DQ) or vehicle (10 % DMSO) by oral gavage three times in 7 days. Cardiac senescence was assessed by measuring Cdkn1a mRNA expression levels. Glucose control was monitored by glucose tolerance testing. LVF was evaluated by echocardiography and myocardial contractility was assessed by sarcomere length measurements in paced single cardiomyocytes. VA susceptibility testing was performed by programmed ventricle stimulation combined with an epicardial fluorescence imaging of the LV anterior wall in isolated hearts. VA susceptibility was quantified by an established scoring system. Results Cardiac senescence, as assessed by expression of Cdkn1a mRNA (encoding p21), was increased in DIO mice (P=0.0004, Figure 1A), whereas DQ reduced cardiac senescence (P&amp;lt;0.0001, Figure 1A). Glucose control was impaired in DIO mice (P&amp;lt;0.0001) and could be partially restored by DQ (P=0.003). LVF was ameliorated by DQ in DIO mice (P=0.018). In agreement, contractility in single cardiomyocytes was improved (Amplitude of sarcomere contraction: P=0.0003, figure 1B; speed of sarcomere contraction: P=0.046). VA susceptibility was increased in DIO mice (number of inducible VAs: P=0.001, figure 1C; VA score: P=0.0002; VT inducibility: P=0.001) whereas DQ limited VA susceptibility (number of induced VAs: P=0.004, Figure 1C; VA score: P=0.004; VT inducibility: P=0.025) in isolated hearts. Conclusions Our findings demonstrate that senolysis ameliorates glucose tolerance and LVF while reducing VA susceptibility in obesity and prediabetes. In consequence, senolysis may offer a perspective therapeutical approach for obese patients at risk for VAs. Further experiments will address underlying molecular mechanisms to identify potential therapeutical targets.

Temporal trends of ischemic stroke rates in atrial fibrillation without anticoagulation: a nationwide cohort study from 2007 to 2018

Abstract Background Atrial fibrillation (AF) is a major risk factor for ischemic stroke (IS), but whether the magnitude of this risk has changed over time is unknown. Purpose To evaluate temporal trends in IS rates in patients with AF who have not initiated oral anticoagulant (OAC) therapy. Methods The registry-linkage Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) study covers all patients with incident AF in Finland from 2007 to 2018. A four-week quarantine period from AF diagnosis was applied and only follow-up time without OAC therapy was included. IS incidence rates were computed in four-year intervals. Results In total, 129 789 patients with new-onset AF (49.2% women; mean age 71.4 years) were identified. The IS incidence rate trends according to sex and the CHA2DS2-VA score are depicted in the Figure, along with the previously estimated treatment thresholds for direct oral anticoagulants (red broken line) and warfarin therapy (blue broken line). Between the calendar year intervals of 2007-2010 and 2015-2018, their mean CHA2DS2-VA score increased from 2.5 to 3.0, while concurrently the overall IS rate decreased by 25% from 36.7 (95% CI 34.5-39.0) to 27.6 (95% CI 26.1-29.0) events per 1000 patient years. This trend was driven by a 32% decrease in women, particularly among those with high CHA2DS2-VA scores. The overall IS rate in patients with a CHA2DS2-VA score of 1 was 8.2 (95% CI 7.2-9.4) events per 1000 patient years and it remained stable across the study period. Conclusions The IS rates in AF patients without OAC therapy have decreased by 25% between 2007 and 2018, despite their rising stroke risk scores. In patients with a CHA2DS2-VA score of 1 the IS rate appears to be lower than previously assumed and approximately at the threshold at which the potential benefits and harms of OAC therapy have been estimated to overlap.

Bioactive peptides as alternative treatment for Helicobacter pylori infection

The infection and chronic inflammatory response generated by Helicobacter pylori is a global health concern. This pathogen is characterized as a major risk factor in the development of gastric cancer and other diseases. Conventional eradication therapies are based on antibiotic regimens and as a consequence there is an increase in antimicrobial resistance of the pathogen strains, besides other potential side effects for the host. Therefore, it is necessary to explore new alternatives. This review delves into the realm of antimicrobial peptides, exploring their efficacy against H. pylori sourced from diverse origins. Furthermore, it sheds light on food-derived peptides exhibiting remarkable biological activity. These peptides exhibit promising effects on biomarkers associated with H. pylori infection, demonstrating anti-inflammatory and antioxidant properties validated through rigorous testing in both cell and animal models. Regarding the anti-inflammatory activity, the peptide VPY derived from soybean and the peptides derived from animal sources such as meat (β-Ala-His), egg (DEDTQAMPFR, DEDTQAMPF, MLGATSL, MSYSAGF, CR, FL, HC, LL, MK) and milk (IPAV) have reported a reduction of the cytokine IL-8, biomarker directly related to H. infection. For the antioxidant activity, peptides derived from milk (EAMAPK, AVPYPQ) and from Spirulina maxima (LDAVNR, MMLDF) have reduced ROS levels and could have a positive effect on the control of H. infection. Food-derived bioactive peptides with an anti-adhesive effect were also discussed. They derive from vegetable sources (corn, pea and wheat) and are capable of interacting with the host cells, interfering the adherence of H. pylori. Food-derived bioactive peptides have potential to avoid and/or mitigate undesired outcomes of infectious diseases due to the possibility of its application in nutraceuticals and food products, resulting in a preventive approach. Keywords: Helicobacter pylori, antibiotic resistance, bioactive peptides, antimicrobial peptides