Risk Of Failure Research Articles

Impact of the inoculum size on the in vivo activity of the aztreonam-avibactam combination in a murine model of peritonitis due to Escherichia coli expressing CTX-M-15 and NDM-1.

The combination of aztreonam (ATM) and avibactam (AVI) is an attractive option to treat infections caused by extended spectrum β-lactamase plus NDM-1-producing Enterobacteriaceae. Since ATM activity was shown to be severely impacted by an increase in the inoculum size in vitro, we wondered whether ATM-AVI activity could be impaired in high-inoculum infections. We analyzed the impact of the inoculum size on ATM-AVI activity in vitro and in a murine model of peritonitis due to susceptible Escherichia coli CFT073-pTOPO and its isogenic derivatives producing NDM-1 (E. coli CFT073-NDM1) and CTX-M-15 plus NDM-1 (E. coli CFT073-CTXM15-NDM1). The impact of the inoculum size on bacterial morphology was studied by microscopic examination. In vitro, at standard (105) inoculum, E. coli CFT073-CTXM15-NDM1 was resistant to ATM but susceptible to the ATM-AVI combination. At high (107) inoculum, MICs of ATM alone and of the ATM-AVI combination reached >512 and 64 mg/L, respectively, against all tested strains. ATM led to bacterial filamentation when active against the bacteria, i.e., in monotherapy or in combination with AVI against susceptible E. coli CFT073-pTOPO and only in combination with AVI against E. coli CFT073-CTXM15-NDM1. In vivo, increase in the inoculum led to a drastic decrease in the activity of ATM alone against E. coli CFT073-pTOPO and ATM-AVI against E. coli CFT073-CTXM15-NDM1. Our results suggest a high in vivo impact of the inoculum increase on the activity of ATM alone against ATM-susceptible E. coli and of ATM-AVI against CTX-M-15 plus NDM-1 producing E. coli. Clinicians must be aware of the risk of failures when using ATM-AVI in high-inoculum infections.

Agricultural Insurance Premium Determination Model for Risk Mitigation Based on Rainfall Index: Systematic Literature Review

Rainfall is significantly essential in the agricultural sector to increase productivity. However, rainfall instability serves as a potential source of risk, causing crop failure and negatively impacting the welfare of farmers. To mitigate this risk, rainfall index-based agricultural insurance offers financial protection to farmers. There is no information on how to set a reasonable premium in index-based agricultural insurance. Therefore, this research aimed to systematically explore a model for determining a rainfall index-based agricultural insurance premium, focusing on the methods used and their effectiveness in mitigating the risk of harvest failure in the agricultural sector. The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) method and a bibliometric analysis were used to collect and analyze articles from Scopus, ScienceDirect, and Dimensions databases. The results showed that there were 15 articles on determining a rainfall index-based agricultural insurance premium, where 4 used the Black–Scholes method and 11 applied other main methods. Meanwhile, no articles applied the fractional Black–Scholes method in determining agricultural insurance premiums based on the rainfall index, providing new opportunities for further research. The results contributed to the development of a model for agricultural insurance premium determination that could generate more diverse and flexible premium estimates as a sustainable method to mitigate the risk of harvest failure. This research is expected to serve as a reference for developing rainfall index-based agricultural insurance in the future and contribute to the Government of the Agriculture Department’s policy formulation regarding insurance programs for farmers.

Impact of weight change on kidney transplantation outcomes: A systematic review and meta-analysis.

Kidney transplant recipients frequently experience a wide range of metabolic complications, including weight changes, which significantly impact patient outcomes and graft function, yet the relationship between weight gain and transplant outcomes remains poorly understood. This systematic review and meta-analysis aimed to synthesise existing evidence on the influence of weight gain on patient and graft outcomes following kidney transplantation to enhance clinical practice and optimise post-transplant care strategies. A literature search was conducted across databases such as PubMed and Scopus for peer-reviewed studies published up to 8 August 2024. We included adult kidney transplant recipients (ages 18 years and older) with substantial and clinically relevant post-transplant weight gain and a control group without such changes, focusing on outcomes including all-cause mortality, graft survival, cardiovascular events and acute rejection. The pooled analysis, which included data from 11 studies, indicated no significant association between post-transplant weight gain and the risk of all-cause mortality (hazard ratio [HR] 1.21, 95% confidence interval [CI] 0.69 to 2.10, p = 0.51; I2 = 28%), cardiovascular events (HR 0.93, 95% CI 0.43 to 2.01, p = 0.85; I2 = 32%) or acute rejection (HR 1.13, 95% CI 0.76 to 1.68, p = 0.55; I2 = 9%). However, weight gain was significantly associated with an increased risk of graft failure (HR 1.58, 95% CI 1.22 to 2.05, p < 0.001; I2 = 0%). Substantial and clinically relevant weight gain after kidney transplant was associated with a higher risk of graft failure. Within the timeframes of study observation, risks of all-cause mortality, cardiovascular events or acute rejection were not increased by weight gain in kidney transplant recipients.

Current Advances and Future Directions of Pluripotent Stem Cells-Derived Engineered Heart Tissue for Treatment of Cardiovascular Diseases

Cardiovascular diseases resulting from myocardial infarction (MI) remain a leading cause of death worldwide, imposing a substantial burden on global health systems. Current MI treatments, primarily pharmacological and surgical, do not regenerate lost myocardium, leaving patients at high risk for heart failure. Engineered heart tissue (EHT) offers a promising solution for MI and related cardiac conditions by replenishing myocardial loss. However, challenges like immune rejection, inadequate vascularization, limited mechanical strength, and incomplete tissue maturation hinder clinical application. The discovery of human-induced pluripotent stem cells (hiPSCs) has transformed the EHT field, enabling new bioengineering innovations. This review explores recent advancements and future directions in hiPSC-derived EHTs, focusing on innovative materials and fabrication methods like bioprinting and decellularization, and assessing their therapeutic potential through preclinical and clinical studies. Achieving functional integration of EHTs in the heart remains challenging due to the need for synchronized contraction, sufficient vascularization, and mechanical compatibility. Solutions such as genome editing, personalized medicine, and AI technologies offer promising strategies to address these translational barriers. Beyond MI, EHTs also show potential in treating ischemic cardiomyopathy, heart valve engineering, and drug screening, underscoring their promise in cardiovascular regenerative medicine.

Pathological Q waves at presentation of anterior ST segment elevation myocardial infarction predict heart failure: a Southeast Asian perspective.

Pathological Q waves at presentation in ST segment elevation myocardial infarction (STEMI) have been associated with poorer clinical outcomes including heart failure. This observational study highlights the prognostic value of pathological Q waves at presentation in the Southeast Asian population. Multiethnic Asian patients presenting with STEMI and treated with primary coronary intervention were recruited from 2015 to 2019. The presenting ECG was reviewed for pathological Q waves and patients were divided into groups with and without Q waves. The confirmatory multivariate analyses concerning the presence of Q wave, occurrence of heart failure, time to heart failure at 1 year, and the mortality status were performed with generalized structural equation model. A total of 1385 patients were included. Patients with pathological Q waves were more likely to suffer from anterior myocardial infarction (55.6 vs. 43.6%) and classified as Killip class >2 (13.5 vs. 8.0%). Among them, fewer reported ST segment resolution >50% (66.5 vs. 79.7%). They reported significantly lower LVEF (45.5 vs. 51.1%), longer symptom onset to ECG (168 vs. 111 min), and longer symptom-onset-to-balloon time (228 vs. 176 min). In addition, patients with Q waves were likely to stay longer in hospital (6.4 vs. 6.1 days) and faced a higher risk of heart failure (5.2 vs. 2.5%) in a year. We highlight the important morbidity associated with Q waves at presentation and found not only that heart failure occurrence was higher in the Q wave group, but there was also an acceleration of and shorter onset to heart failure.

Temporal Trends of Dry Spells in Indian Meteorological Subdivisions During Southwest Monsoon 1951–2023

ABSTRACTAmidst the backdrop of climate change, the monsoon rainfall pattern is experiencing alterations over time. A precise evaluation of monsoon rainfall distribution throughout the season is crucial for effective water management in agriculture, conducting drought assessments, and evaluating associated risks. Our study focused on analysing dry and wet spells within the Indian meteorological subdivisions over the past 73 years (1951–2023). It examines the spatial distribution of southwest monsoon rainfall and dry days, revealing a correlation between limited rainfall and extended dry periods, especially noticeable in regions like Western Rajasthan and Jammu &amp; Kashmir. Vulnerability to drought is evident in regions with moderate monsoon rainfall and a high frequency of dry days. The study reveals that 65% of meteorological subdivisions experience over 60 dry days during the monsoon season, underscoring the need for a detailed analysis of dry day patterns. July and August are vital for Indian agriculture, as crop growth relies on consistent monsoonal rainfall; extended dry spells during this period cause moisture stress, affecting key stages like flowering and grain filling. The study reveals an alarming trend, with 44% of meteorological subdivisions showing an increase in dry days during August, and 29% exhibiting a similar trend for the overall monsoon season. The study also investigated the relationship between dry days and ENSO events, finding that Central and Northwest India are predominantly affected by moderate to strong events, resulting in a high probability of increased dry days. This increase in dry spells, driven by shifts in monsoon variability and intensity, reduces water availability during the growing season and raises the risk of crop failure. These findings emphasise the importance of implementing effective mitigation strategies to address the challenges posed by prolonged dry spells and their detrimental impact on crop yields.

Circulating microRNA as promising biomarkers in hypertrophic cardiomyopathy: can advanced cardiac magnetic resonance unlock new insights in research?

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder associated with an increased risk of arrhythmias, heart failure, and sudden cardiac death. Current imaging and clinical markers are not fully sufficient in accurate diagnosis and patient risk stratification. Although known cardiac biomarkers in blood are used, they lack specificity for HCM and primarily stratify for death due to heart failure in overt cases. Non-coding RNAs, particularly microRNAs, have emerged as promising biomarkers due to their role in regulating gene expression in both healthy and pathological hearts. Circulating microRNA signatures may dynamically reflect the progression of HCM, offering potential utility in diagnosis and disease monitoring as well as inform biologic pathways for innovative therapeutic strategies. However, studying microRNAs in cardiovascular diseases is still in its early stages and poses many challenges. This review focuses on emerging research perspectives using advanced cardiac magnetic resonance techniques. We presume, that the search for circulating miR signatures associated with specific adverse myocardial features observed on cardiac magnetic resonance imaging - such as fibrosis, disarray, and microvascular disease - represents a promising direction in HCM research.

Biomarkers of cellular senescence and major health outcomes in older adults.

The geroscience hypothesis proposes that underlying biological processes, such as the accumulation of senescent cells, have deleterious effects on multiple tissues and increase the risk of many chronic conditions with aging. Senescent cells produce heterogenous biomarkers, also called senescence-associated secretory phenotype (SASP). Circulating concentrations of senescence biomarkers may reflect an underlying burden of senescent cells in various tissues. Plasma levels of these proteins have been associated with increased mortality and poorer physical function. The associations of them with the incidence of major age-related conditions including heart failure, cardiovascular disease, stroke, and dementia, have not been studied. We measured 35 senescence biomarkers in baseline plasma samples from 1678 participants aged 70-79years old in the longitudinal Health ABC cohort study. Clinical outcomes were ascertained and validated over an average 11.5year follow-up. In models adjusted for age, sex, and race, higher levels of most of senescence biomarkers were associated with increased risk of all-cause mortality, mobility limitation, and heart failure. Several were also associated with an increased risk of coronary heart disease, stroke, and dementia. Very few were associated with the risk of cancer. Proteins that were selected by Lasso regression for each outcome that commonly included GDF15 and IL6, significantly improved the prediction of mortality, mobility limitation, and heart failure compared with age, sex, and race alone. These results indicate that levels of senescence biomarkers predict an increased risk of several age-related clinical outcomes and may identify individuals most likely to benefit from senotherapeutics.

Cardiovascular Outcomes in Patients with Atrial Flutter and Oral Anticoagulation: The Predictive Role of Left Atrial Appendage Thrombus in a Long-Term, Prospective, Observational Cohort Study

Background/Objectives: The risks of blood clot formation, stroke, heart failure (HF), and cardiovascular death are enhanced in individuals with atrial flutter (AFL). However, it remains unclear whether left atrial appendage thrombus (LAAT) in individuals with AFL with anticoagulation enhances the risk of cardiovascular morbidity and mortality. Thus, in the current trial, we aimed to evaluate the predictive role of LAAT for cardiovascular outcomes in individuals with AFL who were receiving anticoagulation and admitted for electrical cardioversion. Methods: Ninety patients were included in this prospective observational cohort study. The primary endpoint was the identification of LAAT by transesophageal echocardiographic examination. All participants were observed for a median of 2114.5 (interquartile range, 1487.5–2591) days to identify the secondary endpoints: cardiovascular death, transient ischemic attack (TIA), stroke, systemic thromboembolic complications, hospitalization due to HF, or myocardial infarction. Results: LAAT was identified in nine (10%) patients. No differences in cardiovascular outcomes between patients with and without LAAT were documented. However, a higher CHA2DS2-VASc score, previous myocardial infarction, and previous stroke/TIA/systemic thromboembolism were associated with significantly higher rates of hospitalization due to HF. Decreased left ventricular ejection fraction (LVEF) was associated with significantly higher rates of cardiovascular death, underscoring the significance of this marker in disease prognosis. Conclusions: The impact of LAAT on cardiovascular outcomes was insignificant. Higher CHA2DS2-VASc scores, previous myocardial infarction, previous stroke/TIA/systemic thromboembolism, and lower LVEF significantly affected long-term prognosis and were associated with a poor prognosis.

Cardiac evaluation of renal transplant candidates with heart failure.

Patients with advanced kidney disease are at elevated risk of developing heart failure and appropriate risk stratification is important to permit them to receive kidney transplantation. The American Heart Association and American College of Cardiology joint statement provides guidance on risk stratification for the major cause of heart failure for these patients in its recommendations for coronary heart disease. Herein we provide an overview of the available literature on risk stratification for nonischemic heart failure and functional heart disease states such as pulmonary hypertension. Many of these options for optimizing these patients before transplant include optimizing their volume status, often with more aggressive ultrafiltration. Kidney transplantation remains the treatment of choice for patients with advanced kidney disease and cardiac disease, the correction of the azotemic substances with kidney transplantation has been associated with improved survival than remaining on dialysis long-term. The findings in the studies reviewed here are expected to help clinicians refine current strategies for evaluating potential kidney transplant recipients.

Predictive factors for arteriovenous fistula maturation: A prospective study.

Arteriovenous fistula (AVF) maturation failure remains common despite preoperative ultrasound mapping. Identifying predictive biomarkers can help anticipate primary failure and reducing invasive procedures. Our study aimed to identify clinical and analytical risk factors for primary AVF failure or delay. A prospective study (October 2022-March 2023) included adult patients scheduled for AVF creation. In all patients, a preoperative ultrasound mapping was conducted and AVF maturation assessed at least 6 weeks post-surgery. Clinical, analytical, and demographic data were collected. Eighty patients were included, 62.5% male, and mean age 66.3 years. For distal anastomosis, preoperative vein (3.8 ± 1.2 vs. 2.8 ± 0.6 mm; p 0.002) and supply artery (2.5 ± 0.4 vs. 2.0 ± 0.3 mm; p 0.001) diameters were significant factors impacting primary failure. Also, for proximal anastomosis, the artery diameter (2.4 ± 0.4 vs. 2.0 ± 0.4 mm; p 0.01) had an impact on AVF maturation. ROC curves established for distal AVF a vein diameter cutoff of 3.25 mm (AUC 77.2%) and artery cut-off of 2.35 mm (AUC 74.6%) and for proximal AVF an artery cutoff of 2.25 mm (AUC 76.5%). Distal AVF creation correlated with higher primary failure risk (p < 0.001). No correlation was found between the primary failure rate and the presence of central venous catheter or serum results. In a sub analysis, we found that patients with central venous catheter had higher levels of inflammatory markers. Our study highlights the importance of preoperative evaluation, ultrasound mapping, and careful AVF site selection. Recognizing vein and artery diameter thresholds for optimal outcomes is crucial. Avoiding central venous catheters in suitable patients can positively impact AVF results.

Design and Uncertainty Evaluation of a Calibration Setup for Turbine Blades Vibration Measurement

Turbomachinery engines face significant failure risks due to the combination of thermal loads and high-amplitude vibrations in turbine and compressor blades. Accurate stress distribution measurements are critical for enhancing the performance and safety of these systems. Blade tip timing (BTT) has emerged as an advanced alternative to traditional measurement methods, capturing blade dynamics by detecting deviations in blade tip arrival times through sensors mounted on the stator casing. This research focuses on developing an analytical model to quantify the uncertainty budget involved in designing a calibration setup for BTT systems, ensuring targeted performance levels. Unlike existing approaches, the proposed model integrates both operational variability and sensor performance characteristics, providing a comprehensive framework for uncertainty quantification. The model incorporates various operating and measurement scenarios to create an accurate and reliable calibration tool for BTT systems. In the broader context, this advancement supports the use of BTT for qualification processes, ultimately extending the lifespan of turbomachinery through condition-based maintenance. This approach enhances performance validation and monitoring in power plants and aircraft engines, contributing to safer and more efficient operations.

Risk of Incident Heart Failure and Heart Failure Subtypes in Patients with Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease (CVD) including heart failure (HF). However, little is known regarding the relative risks of heart failure subtypes such as HF with preserved (HFpEF) or reduced ejection fraction (HFrEF) in RA compared to non-RA. We identified RA patients and matched non-RA comparators among participants consenting to broad research from two large academic centers. We identified incident HF and categorized HF subtypes based on ejection fraction (EF) closest to the HF incident date. Covariates included age, sex, and established CVD risk factors. Cox proportional hazards models were used to estimate the hazard ratios (HR) for incident HF and HF subtypes. We studied 1445 RA patients and 4335 matched non-RA comparators (mean age 51.4 and 51.7 years, 78.7% female). HFpEF was the most common HF subtype in both groups (65% in RA vs. 59% in non-RA). RA patients had a HR of 1.79 (95% CI: 1.38-2.32) for incident HF compared to those without RA after adjusting for CVD risk factors. RA patients had a higher rate of HFpEF (HR 1.99, 95% CI: 1.43 - 2.77), but there was no statistical difference in HFrEF rate (HR 1.45, 95% CI 0.81 - 2.60). RA was associated with higher rate of HF overall compared to non-RA, even after adjustment for established CVD risk factors. The elevated risk was driven by HFpEF, supporting a role for inflammation in HFpEF and highlighting potential opportunities to address this excess risk in RA.

Factors for Treatment Failure After Fecal Microbiota Transplantation in Clostridioides difficile Infection

Recently, fecal microbiota transplantation (FMT) has been introduced as an effective treatment option for Clostridioides difficile infection (CDI). However, the risk factors associated with FMT treatment failure have not been well demonstrated. Therefore, we aimed to investigate the risk factors of treatment failure or recurrence after FMT for CDI. This retrospective study included 124 patients with CDI who underwent FMT at Inha University Hospital between November 2017 and August 2021 and were followed up for 8 weeks after FMT for symptoms of CDI. FMT failure was defined as diarrhea recurrence or a positive stool test. We assessed the risk factors for treatment failure, including comorbidities, antibiotic use pre- and post-FMT, and the number of CDI episodes before FMT. Ninety-three patients (75%) experienced symptom improvement &lt;7 days after FMT, while treatment failure occurred in 40 patients (32.3%). Multivariate analysis revealed that males had a lower symptom improvement rate &lt;7 days after FMT (p = 0.049). Patients using antibiotics after FMT showed a higher rate of recurrence or treatment failure in &lt;8 weeks (p = 0.032). Patients requiring antibiotics after FMT should be considered at higher risk of treatment failure. Careful antibiotic stewardship, particularly minimizing non-essential antibiotic use before and after FMT, may significantly enhance treatment outcomes. Further large-scale prospective studies are warranted to confirm these findings and develop targeted antibiotic management protocols for improving the efficacy of FMT in CDI treatment.

Cardiometabolic Index is associated with heart failure: a cross-sectional study based on NHANES

IntroductionHeart failure is a complex syndrome characterized by impaired cardiac function. Despite improvements in treatment, the prevalence of heart failure continues to rise. The Cardiometabolic Index (CMI), a novel measure combining abdominal obesity and lipid levels, has emerged as a potential predictor of cardiac metabolic risk.MethodsWe analyzed data from the National Health and Nutrition Examination Survey (NHANES) involving 22,586 participants to investigate the association between CMI and heart failure. Multivariable logistic regression models and RCS analysis were used to explore the association between heart failure and CMI after adjusting for potential confounders. Subgroup analyses were performed among populations with different demographic and clinical characteristics.ResultsOur results revealed a significant positive correlation between CMI and heart failure, with odds ratios of 2.77 and 1.87 for the highest quartile after adjusting for confounders. Subgroup analyses indicated heightened risks among older adults and those with hypertension or diabetes. ROC curve analysis demonstrated that CMI offers good diagnostic value for heart failure, surpassing traditional measures like BMI.DiscussionOur findings suggest that CMI is a valuable tool for assessing the risk of heart failure, particularly in individuals with increased abdominal obesity or abnormal lipid profiles. This highlights the importance of addressing cardiac metabolic health in both prevention and treatment strategies for heart failure. Future research should focus on exploring causal relationships and refining predictive models that incorporate CMI to enhance early detection and intervention.

Patterns of failure after stereotactic radiosurgery for brain metastases from small cell lung cancer: outcomes in the immunotherapy era.

Small cell lung cancer (SCLC) is known to have high rates of development of brain metastases. Standard treatment has been whole brain radiation therapy (WBRT) but the role for more focused treatment and hippocampal avoidance has arisen in the past decade. In addition, with possible penetration of the central nervous system by more modern immunotherapies, the risk of distant failure may be lower. As such, we reviewed patients at our institution treated with stereotactic radiosurgery (SRS) to look at patterns, locations, and predictors of failure in the brain. A retrospective review and analysis of charts was done on 46 patients treated with SRS (no history of prior WBRT) for their brain metastases from SCLC. Multivariate analysis was used to determine significant prognostic factors influencing survival and local/distant failure. We tracked timing and type of immunotherapy, if any, as well as if patients failed in the hippocampus or required WBRT. There were 46 patients with 97 total brain metastases treated with SRS in this study. Median number of metastases was 2 (1-5). The median dose of radiation was 20Gy (20-30) in 3 fractions (1-5) for all 97 tumors. 11 patients did not receive immunotherapy, whereas 35 patients had immunotherapy of some sort. Median overall survival (OS) for the entire cohort was 13months, with a 12month OS of 59% and 2year OS of 30%. Cox regression did not reveal any significant predictors of OS, including age, sex, total volume, extracranial disease, KPS, immunotherapy, or number of metastases. 12month and 24month local control of disease was 95% and 80%, respectively. There were no significant predictors of local failure including volume, dose, or immunotherapy. 25 of the patients had distant brain failure, with a rate of distant failure of 38% and 64% for 6 and 12months, respectively. Immunotherapy, number of metastases, total target volume, nor presence of extracranial disease was predictive of distant brain failure. WBRT free survival was also measured and found to be 73% at 1year. There were no significant predictors for this measure. Lastly, five patients in this cohort showed failure in the hippocampus, where the rate of failure at 6 and 12months was 16%. Rates of distant brain failure in SCLC patients after SRS remain similar to those of NSCLC patients in the immunotherapy era. We did not show a decrease in distant failure rate based on immunotherapy use. The rate of hippocampal failure was quite low and should provide reassurance that SRS and techniques such as HA-IMRT can be reasonably used in these patients. Ongoing clinical trials will help provide more definitive answers in this arena.

The Causal Impact of Immune Cell Dynamics on liver failure: An Investigation via Mendelian Randomization (MR) Analysis

Background: Liver failure is a critical clinical condition with complex pathophysiology, where the role of immune cells has been increasingly recognized. However, establishing causality between immune cell activity and liver failure has been challenging. We aimed to investigate the causal role of specific immune cell populations in the development of liver failure using Mendelian randomization (MR) techniques. Methods: Genetic data from the Genome-wide association study (GWAS) database, focusing on 731 immunophenotypes and a liver failure dataset was utilised. Single nucleotide polymorphisms (SNPs) associated with immune cell exposures were identified and used as instrumental variables. MR analyses were performed using the TwoSampleMR package in R, employing various MR techniques, including weighted median, MR Egger, inverse-variance weighted (IVW), and others. The robustness of the MR findings was assessed through heterogeneity, pleiotropy, and leave-one-out sensitivity analyses. Results: Our MR study revealed significant causal associations between several immune cell populations and liver failure. Notably, genetic variants associated with CD28 on CD39+ CD4+ T cells and CD3 on CD39+ secreting T Reg cells were found to be causally linked to an increased risk of liver failure. The IVW MR method, which has been previously validated for its performance, provided the most consistent results across immune cell exposures. Conclusion: Our findings suggest a direct causal role for specific immune cells in liver failure, offering potential targets for future therapeutic strategies.

Recurrent Neural Network for Quantitative Time Series Predictions of Bridge Condition Ratings

Traditional forecasting models for bridge conditions, such as ARIMA and Markov chains, often fail to adequately capture nonlinear and dynamic relationships among critical variables like age, traffic patterns, and environmental factors, leading to suboptimal maintenance decisions, increased long-term maintenance costs, and heightened safety risks. This study addresses these limitations by developing recurrent neural network (RNN) models utilizing Long Short-Term Memory (LSTM) and Gated Recurrent Unit (GRU) architectures with a TimeDistributed output layer. This novel approach enables accurate forecasting of the Bridge Health Index (BHI) and condition ratings for key components—deck, superstructure, and substructure—while effectively modeling temporal dependencies. Applied to bridge data from Georgia, USA, the regression models (BHI) achieved R2 values exceeding 0.84, while the classification models (components condition ratings) demonstrated accuracy between 84.78% and 87.54%. By modeling complex temporal trends in bridge deterioration, our method processes time-dependent data from multiple bridges simultaneously, revealing intricate relationships that influence bridge performance within a state’s inventory. These results provide actionable insights for maintenance planning, optimized resource allocation, and reduced risks of unexpected failures. This research establishes a robust framework for bridge performance prediction, ensuring improved infrastructure safety and resilience amid aging assets and constrained maintenance budgets.

Cut-off value for the posterior tibial slope indicating the risk for retear of the anterior cruciate ligament.

The significance of the posterior tibial slope (PTS) has increasingly come into focus in anterior cruciate ligament (ACL) reconstruction being a risk factor for ACL graft failure. Nevertheless, inconsistent data on the critical value of the PTS exist. The purpose of this study was to define a cut-off value for the PTS in ACL surgery. In a retrospective cohort study, 350 revision ACL reconstructions (ACL-RR) with a failed ACL hamstring graft and 350 primary ACL reconstructions (ACL-R) were matched according to age, gender, concomitant injuries and graft characteristics and compared to a healthy control group. Using the proximal anatomic axis, lateral knee radiographs were evaluated for the PTS, interrater reliability was defined, ROC curves, Fischer's exact test and Baptista-Pike method were applied to define specificity and the odds ratio for a critical PTS value. Radiographic evaluation proved excellent interrater reliability (intraclass correlation coefficient 0.969). Evaluation of the PTS revealed 10.0 ± 2.2 (5-15) degrees in the ACL-RR group, 7.8 ± 1.8 (4.2-13) degrees in the ACL-R group and 6.6 ± 1.9 (3.6-12) degrees in the control group with significant differences between the groups (p < 0.001). A PTS value of 10.1 degrees proved a specificity of 98% for the prediction of an ACL graft failure and indicated an 11-fold risk for a retear of the ACL. A PTS exceeding 10.1 degrees carries an 11-fold risk for ACL graft failure and, therefore, should be considered in ACL reconstruction. These findings might serve as a cut-off value for the indication of a slope-reducing high tibial osteotomy in ACL surgery. Level III.

Endothelin receptor antagonists in chronic kidney disease.

Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ETA) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ETAreceptor andangiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice.