Recent Failures Research Articles

Novel antiseizure medications in the development pipeline: promising candidates and recent failures

AbstractIn the past decade, we have observed a paradigm shift in the discovery of novel antiseizure medications (ASMs), which is a consequence of significant progress in epilepsy genetics, the availability of novel disease models, drug-screening technologies, the discovery of new mechanisms of action, expanding existing drugs into new populations, or new routes of delivery. This resulted in a very rich pipeline of potential future treatments for epilepsy, including gene-modifying treatments for rare genetic epilepsies and mechanistically guided precision treatments. Hopes are high that this pipeline may bring therapeutic breakthroughs similar to those recently achieved with cenobamate for the common drug-resistant focal epilepsy and fenfluramine for seizures in Dravet syndrome. Furthermore, we stand at the beginning of a new era of epilepsy treatment expansion, from traditional seizure suppression to disease prevention and modification. This review discusses the most advanced and promising candidates in the clinical development pipeline but also describes recent failures in the development of novel ASMs.

Liability Mechanisms and Dispute Resolution in Crypto Exchange Contracts: Balancing Code-Based Execution and Legal Enforceability

This paper examines the tension between code-based execution and legal enforceability in smart contracts used by cryptocurrency exchanges. As decentralized finance grows in prominence, there is an increasing need to balance the immutability and automation of blockchain-based agreements with traditional legal protections and dispute resolution mechanisms. We analyze current approaches to liability allocation and conflict resolution in major crypto exchanges, identifying key challenges in harmonizing algorithmic governance with existing contract law. Case studies of recent exchange hacks and failures are used to illustrate the limitations of purely code-based systems. We then propose a hybrid model that preserves the efficiency of automated execution while incorporating safeguards for human intervention in exceptional circumstances. This framework aims to enhance user protections, regulatory compliance, and overall trust in decentralized financial infrastructure. Our findings have implications for exchange operators, regulators, and contract law as it evolves to address blockchain-enabled agreements.

Residual post-infarct myocardial inflammation detected by 68Ga-DOTATATE PET/MRI predicts long-term adverse cardiac remodelling

Abstract Background Maladaptive inflammatory responses are associated with adverse cardiac remodelling after myocardial infarction (MI), but clinical methods for detecting residual myocardial inflammation post-MI are lacking. Purpose To investigate somatostatin receptor subtype 2 (SST2) positron emission tomography (PET)/magnetic resonance imaging (MRI) using 68Ga-DOTATATE after MI. Methods In a prospective observational cohort study, infarct-related myocardial inflammation detected by 68Ga-DOTATATE PET at 2wk and 3mo post-MI was compared with MRI characteristics including left ventricular (LV) volumetric changes at 1yr, as well circulating immune cell phenotyping and serum proteomic markers. Patients with a prior history of MI or heart failure were excluded. Histological SST2 expression was assessed in myocardial biopsies. Results 38 participants (mean age 60 [SD 9] years; 84% male) with recent MI were enrolled, of whom 58% had an ST-segment elevation MI. Mean peak Troponin I was 16,665 (range 408 to >25,000) ng/L and mean post-infarct LV ejection fraction was 51 (SD 9) %. 68Ga-DOTATATE maximum standardized uptake values (SUVmax) at 10 (SD 4) days accurately localised infarcted myocardial segments defined by late-gadolinium enhancement MRI (LGE; Fig. 1); were 14.2% higher in akinetic/hypokinetic vs. normo-kinetic segments (p<0.0001); and were correlated both with peak segmental strain (r=0.47, p=0.003) and segmental T1 values (r=0.51, p=0.02). Mean infarct SUVmax was 19.7% lower on repeat PET/MRI after a mean 102 (SD 22) days (p<0.0001), and this change was in keeping with parallel reductions in T2-weighted oedema signal on MRI and serum biomarkers of cardiac injury and systemic inflammation. Residual inflammation assessed by mean infarct SUVmax at 3mo was correlated with ΔLV indexed end-diastolic volume at 369 (SD 14) days, after adjustment for baseline infarct size and other clinical variables (p=0.038). The 3mo:2wk ratio of mean infarct SUVmax was an even stronger predictor of adverse myocardial remodelling (p=0.0025). Circulating SST2+ classical monocytes were correlated with infarct 68Ga-DOTATATE signal (r=0.47, p=0.02), and SST2 was co-expressed with CD68+ macrophages in inflamed myocardial specimens of patients with recent MI and ischaemic heart failure. After statistical feature selection and multiple comparisons adjustments, among the blood markers associated with 3mo:2wk infarct SUVmax was CCL25, a chemokine involved in macrophage recruitment which has been implicated in adverse cardiac remodelling. Conclusions Here, in the first prospective clinical study of serial SST2 PET/MRI after MI, we show that 68Ga-DOTATATE can identify and track resolving infarct-related myocardial inflammation. Moreover, residual inflammation detected by 68Ga-DOTATATE is associated with long-term adverse myocardial remodelling and could provide a potential future imaging biomarker to help stratify high-risk patients for emerging immunomodulatory therapies.Figure 1.68Ga-DOTATATE PET-MRI after MI

Sponsor Reputation and Capital Structure Dynamics in Leveraged Buyouts

We examine whether leveraged buyout (LBO) sponsors’ reputations as borrowers affect the refinancing terms of their portfolio companies. In 510 U.S. LBOs for which we can reconstruct debt financing activity, 67% of financing events occur one quarter before the earliest existing debt maturity. These On Time events generally improve borrowing terms, whereas Early events feature more dividends, leverage, and higher cost. In each case, dividend issuance decreases and cost increases with the proportion of the sponsors’ recent exits that are failures. Effects are absent for matched firms and prior to the LBO and are procyclical; sponsors with recent failures miss opportunities to decrease financing costs in good times. This paper was accepted by Bo Becker, finance. Supplemental Material: The data files are available at https://doi.org/10.1287/mnsc.2023.00971 .

Increasing dam failure risk in the USA due to compound rainfall clusters as climate changes

A changing climate, with intensifying precipitation may contribute to increasing failures of dams by overtopping. We present the first analysis of rainfall sequences and events associated with recent hydrologic failures of 552 dams in the United States. We find that the maximum 1-day rainfall associated with failure was often not extreme compared to dam spillway design criteria, even when accounting for rainfall statistics changing with time at each site. However, the combination of the total rainfall 5 to 30 days prior and the maximum 1-day rainfall associated with dam failure is rare. Persistent atmospheric circulation patterns that lead to recurrent rainfall events, rather than just more moisture in the atmosphere is a possible reason. The probability of these compound precipitation risks has increased across much of the country. With over 90,000 aging dams still in service, the increasing likelihood of intense rainfall sequences raises concerns about future dam failures.

Validating brain activity measures as reliable indicators of individual diagnostic group and genetically mediated sub-group membership in Fragile X Syndrome

Recent failures translating preclinical behavioral treatment effects to positive clinical trial results in humans with Fragile X Syndrome (FXS) support refocusing attention on biological pathways and associated measures, such as electroencephalography (EEG), with strong translational potential and small molecule target engagement. This study utilized guided machine learning to test promising translational EEG measures (resting power and auditory chirp oscillatory variables) in a large heterogeneous sample of individuals with FXS to identify best performing EEG variables for reliably separating individuals with FXS, and genetically-mediated subgroups within FXS, from typically developing controls. Best performing variables included resting relative frontal theta power, all combined posterior-head resting power bands, posterior peak alpha frequency (PAF), combined PAF across all measured regions, combined theta, alpha, and gamma power during the chirp, and all combined chirp oscillatory variables. Sub-group analyses for resting EEG best discriminated non-mosaic FXS males via frontal theta resting relative power (AUC = 0.8759), even with data reduced to a 20-channel clinical montage (AUC = 0.9062). In the chirp task, FXS females and non-mosaic males were nearly perfectly discriminated by combined theta, alpha, and gamma power (AUC = 0.9444) and a combination of all variables (AUC = 0.9610), respectively. Results support use of resting and auditory oscillatory tasks to reliably identify neural deficit in FXS, and to identify specific translational targets for genetically-mediated sub-groups, supporting potential points for stratification.

A recent catastrophic submarine slope failure in the Krishna-Godavari basin, Bay of Bengal, India

A recent catastrophic submarine slope failure in the Krishna-Godavari basin, Bay of Bengal, India

Gender differences in skilled performance under failure competitive environments: evidence from elite archers.

Psychologists are particularly interested in how people operate in stressful settings. The sporting arena is a "natural laboratory" for studying how people behave and perform in high-pressure situations. This study explores the gender differences in archers' ability to cope with adversity, highlighting the significant cold-hand effect observed in both male and female archers, with notable differences in the last arrow performance under pressure. Our method is a Poisson general linear model -based test for the cold hand that examines how the performance of the last arrow per set depends on the performance of the previous two shots. We also interact the player's gender with performance on the previous two arrows and game status to test for gender differences in response to past performance and intermediate game status. The Poisson regression analysis reveals that male and female archers' performance dropped significantly after experiencing two consecutive missing bullseyes, which means a cold-hand effect exists. However, although there was no significant difference in the performance of male and female archers on the third arrow, female archers have significantly lower last arrow per set scores than male archers after near poor performance or being in a situation where losing can only be avoided by winning the current set. This finding suggests that female archers are more vulnerable to the potentially negative effects of adversity caused by trailing or recent failures than their male counterparts. We attempt to explain the reasons behind the results above from both psychological and physiological perspectives.

FAILURE OF CARE STANDARD IN RELATION TO PFIZER BNT162b2 modRNA

This article explains two core physician competencies required for licensure, and the recent widespread failure of physicians to provide safe medical care for the communities which they serve.

Taking a Nosedive: Can Boeing’s Image be Saved? Application of Image Repair Theory

Boeing’s leadership faced significant criticism for its mishandling of the two 737 Max plane crashes that occurred within a six-month span. Since then, Boeing has been grappling with ongoing quality control issues with its 737 Max series, including a recent door plug failure on a 737 Max 9 mid-flight, and production flaws in the 787 Dreamliner, such as gaps between fuselage sections.This case study applies image repair theory (IRT) to explore Boeing’s crisis communication strategies in response to the 737 Max plane crashes. This study further investigates the application of the concepts of stealing thunder, framing hypothesis, and ethical apology, and their application in Boeing's crisis management. The findings reveal that Boeing's leadership employed both denial and mortification strategies; however, the timing and execution of these communications were flawed, leading to long-term reputational damage.Boeing’s failure to employ stealing thunder, effective framing, and delivering sincere apologies has hindered its ability to control the crisis narrative. Theoretical implications for IRT are discussed.

FAILURE OF CARE STANDARD IN RELATION TO PFIZER BNT162b2 modRNA

This article explains two core physician competencies required for licensure, and the recent widespread failure of physicians to provide safe medical care for the communities which they serve.

Cultural Heritage Work in Turkey: a Roundtable

Abstract This round table highlights the experiences and perspectives of individuals engaged in projects of cultural preservation in Turkey. Its participants work on, what might be called, the heritage of “minority” cultures – including that of Armenia, but also those of Alevi, Chaldean, Georgian, Greek, Syrian, and other communities that run counter to mainstream political narratives about indigeneity and autochthony. It addresses the challenges of heritage preservation in Turkey, the role of state policy and that of the public, questions of intangible versus tangible heritage, concepts of minority/majority cultures, and reflects on recent successes and failures of conservation in Turkey.

Surgical management of giant cell arteritis of the proximal aorta

ObjectiveGiant cell arteritis (GCA) may present as proximal aortic pathology requiring surgical intervention. We present our experience with surgical management of GCA in patients presenting with proximal aortic disease. MethodsFrom January 1993 to May 2020, 184 adult patients were diagnosed with GCA on histopathology after undergoing cardiac surgery. Survival was estimated with Kaplan-Meier method. Reoperation rates were estimated with cumulative incidence accounting for competing risks of death. ResultsThe most common indication for surgery was ascending aortic aneurysm (n = 179, 97.3%). Stroke occurred in 6 (3.3%), pneumonia in 8 (4.4%), and dialysis in 3 (1.6%) patients. Multivariable analysis found advanced age (hazard ratio [HR], 1.054; 95% confidence interval [CI], 1.026-1.082, P < .001), recent heart failure (HR, 1.890; 95% CI, 1.016-3.516, P = .04), peripheral vascular disease (HR, 2.229; 95% CI, 1.458-3.624, P < .001), and cerebrovascular disease (HR, 1.762; 95% CI, 1.035-3.000, P = .03) as predictors of late mortality. Median follow-up was 13.7 years, and 30-day mortality was 1.5%. Nineteen patients underwent 24 aortic reinterventions including aortic arch reconstruction (n = 4), descending thoracic aorta aneurysm repair (n = 8), thoracoabdominal aortic aneurysm repair (n = 11), and pseudoaneurysm repair (n = 1). Rate of reintervention on the aorta was 3.9% (95% CI, 1.9%-8.1%), 7.1% (95% CI, 4.1%-12.3%), 12.8% (95% CI, 8.3%-19.6%), and 12.8% (95% CI, 8.3%-19.6%) at 1, 5, 10, and 15 years, respectively. ConclusionsSurgery in patients with GCA can be performed with acceptable early and late outcomes. Advancing age, heart failure, peripheral vascular disease, and cerebrovascular disease are risk factors for worse survival. Postoperative surveillance is important as need for aortic reintervention is not uncommon.

Enhanced Tailings Dam Beach Line Indicator Observation and Stability Numerical Analysis: An Approach Integrating UAV Photogrammetry and CNNs

Tailings ponds are recognized as significant sources of potential man-made debris flow and major environmental disasters. Recent frequent tailings dam failures and growing trends in fine tailings outputs underscore the critical need for innovative monitoring and safety management techniques. Here, we propose an approach that integrates UAV photogrammetry with convolutional neural networks (CNNs) to extract beach line indicators (BLIs) and conduct enhanced dam safety evaluations. The significance of real 3D geometry construction in numerical analysis is investigated. The results demonstrate that the optimized You Only Look At CoefficienTs (YOLACT) model outperforms in recognizing the beach boundary line, achieving a mean Intersection over Union (mIoU) of 72.63% and a mean Pixel Accuracy (mPA) of 76.2%. This approach shows promise for future integration with autonomously charging UAVs, enabling comprehensive coverage and automated monitoring of BLIs. Additionally, the anti-slide and seepage stability evaluations are impacted by the geometry shape and water condition configuration. The proposed approach provides more conservative seepage calculations, suggesting that simplified 2D modeling may underestimate tailings dam stability, potentially affecting dam designs and regulatory decisions. Multiple numerical methods are suggested for cross-validation. This approach is crucial for balancing safety regulations with economic feasibility, helping to prevent excessive and unsustainable burdens on enterprises and advancing towards the goal of zero harm to people and the environment in tailings management.

A semi-analytical time-domain model with explicit fluid force expressions for streamwise fluidelastic instability of a single and multiple flexible tube array

Fluidelastic instability (FEI) within steam generator tube arrays poses a significant safety concern for nuclear power plants. Traditionally assumed to manifest in the transverse direction, recent failures at the San Onofre Nuclear Generating Station have underscored the importance of understanding streamwise FEI (SFEI). These incidents have spurred analytical investigations into SFEI, but progress has been hindered by the lack of explicit fluid force formulations, particularly in semi-analytical SFEI models. This paper presents a novel semi-analytical time-domain SFEI model featuring an ideal geometry-based decay function and meticulously derived explicit fluid elastic force expressions. The proposed model supports both frequency-domain stability analysis and true time-domain response analysis, and it is applicable to configurations featuring either a single elastic tube in a rigid array or multiple flexible tubes in an array. Additionally, the tube motion phases are obtained by comparing time-domain responses and employing modified multi-tube frequency-domain SFEI analyses. The stability thresholds predicted for a parallel triangular array using our theoretical model closely align with reported experimental data, thereby validating its accuracy. Our work supplements and advances semi-analytical modeling, alleviating implementation challenges for analyzing SFEI phenomena.

Major recent failures in Brazilian mine waste containment facilities, current cases of maximum emergency level and imminent risk of rupture, and a brief sustainability analysis.

Wasteisthe materials left over after the processing of ores. Significant disasters involving waste disposal structures have occurred in Brazil in recent years and caused severe damage by contaminating soil, rivers and coastal areas, destroying native fauna and flora, interrupting the water supply and compromising its potability, putting the population's health, livelihoods and economy at risk, as well as causing 289 irreparable human deaths. Regulatory laws have become stricter, and since 2019, after the tailings dam tragedies occurred in 2015 and 2019 in Mariana and Brumadinho, in Minas Gerais, the operation of upstream-raised tailings dams has been prohibitedin Brazil. In 2022, a waste slide from a sterile pile at the Pau Branco Mine in Nova Lima promoted a dike overflow. There was the death of five people whose car was buried by a landslide on a hillside. New strategies and technologies, such as reprocessing and recycling, can be tested to ascertain whether they can help improve practices in tailings management. Indeed, mining companies' corporate responsibility and sustainability practices need to be evaluated toverify whether they better match expectations. On the other hand, more specific and detailed regulations and resolutions are required to ensure the safe monitoring and management of sterile waste piles. This paper presents a review of the facts, a discussion of the literature (mainly on recent tailings dam disasters), the current situation of mining-containingwaste structures in Brazil, a brief sustainability analysisand perspectives aimed at preventing/minimising catastrophes in the future.

Clinicians' viewpoints on current paradigms of care and research in Parkinson's disease.

Aim of this review is to discuss the value of current ongoing research initiatives in Parkinson's disease from the clinicians' point of view. The repeat, recent failures on progress slowing reflect the drifting apart between initially promising experimental and then disappointing clinical outcomes in the translational trials with well selected Parkinson's disease patients. A similar development concerns the emerging gap between novel developed drugs with improved pharmacokinetic behaviour and their limited use in the clinical practice following approval. Restricted regional different worldwide availability and direct, respectively indirect budget limitations for neurologists in private practice are essential hurdles. They prevent the widespread prescription of these compounds. As a result return of investment for the pharmaceutical industry becomes more and more uncertain. The interest for research on novel treatment approaches for the amelioration of motor and non motor symptoms declines. Clinicians crucially scrutinize the claim for an optimum patient care by payers and regulators.

Differential impacts of self-care behavior on clinical outcomes in patients with and without recent heart failure hospitalization

BackgroundAlthough clinical guidelines recommend self-care assessment for patients with chronic heart failure (CHF), its prognostic significance remains controversial. This study aimed to compare the prognostic significance of self-care behavior on mortality between patients with and without a history of recent hospitalization for heart failure (HF). MethodsWe analyzed consecutive 1907 CHF patients from a Japanese multicenter registry (January 2020–June 2023) using the 9-item European Heart Failure Self-care Behavior Scale (EHFScBS-9) at enrolment. Suboptimal self-care behavior was defined as a score < 70 on the EHFScBS-9. Patients were divided into recent (within 30 days post-discharge, n = 664) and no recent hospitalization for HF groups (n = 1263), respectively. The primary outcome was a composite of all-cause death and rehospitalization for HF. ResultsDuring a median follow-up period of 427 (interquartile range 273–630) days, the primary outcome occurred in 100 patients. Patients with suboptimal self-care behavior exhibited a higher incidence of the primary outcome in the recent hospitalization for HF group (p = 0.020) but not in the no recent hospitalization for HF group (P = 0.16). Multivariable regressions showed suboptimal self-care behavior was independently associated with the primary outcome in the recent hospitalization for HF group with a significant interaction (P = 0.029). ConclusionIn patients recently hospitalized for HF, but not in those without a recent hospitalization history for HF, suboptimal self-care behavior was associated with adverse events. This indicates the importance of self-care education for these patients.

Investigation of Fluidelastic Instability in Parallel Triangular Tube Arrays Subjected to Air Flow

Abstract One of the major considerations in the design and operation of heat exchangers is the flow-induced vibration (FIV). While there are multiple FIV excitation mechanisms, fluidelastic instability (FEI) is by far the most crucial mechanism as it can significantly compromise the structural integrity of the tube arrays. Traditionally, it was assumed that FEI could only happen in the transverse direction. However, recent tube failures in replacement steam generators have demonstrated that FEI can occur in the streamwise direction and be equally devastating. This new phenomenon has sparked intensive research to uncover its nature. An intensive experimental research program was launched to investigate the geometrical impact of various tube array types on the FEI in both the transverse and streamwise directions. To that end, the stability of a single flexible tube and multiple flexible tubes in tube arrays was tested. The study will focus on the stability behavior of parallel triangular arrays at pitch ratios in the range of 1.25–1.70. A comparison between the available experimental data and the current results was presented. The current results reveal that the stability threshold is sensitive to the pitch-to-diameter ratio of the array and the number of flexible tubes, especially in the streamwise direction.

Enhancing flood wave modelling of reservoir failure: a comparative study of structure-from-motion based 2D and 3D methodologies

Predicting flood wave propagation from reservoir failures is critical to practical flood hazard assessment and risk management. Flood waves are sensitive to topography, channel geometry, structures, and natural features along floodplain paths. Thus, the accuracy of flood wave modelling depends on how precisely those features are represented. This study introduces an enhancing approach to flood wave modelling by accurately representing three-dimensional objects in floodplains using the structure-from-motion (SfM). This method uses an unmanned aerial vehicle to capture topographic complexities and account for ground objects that impact flood propagation. Using the three-dimensional volume of fluid numerical approach significantly improves an enhanced representation of turbulent flow dynamics and computational efficiency, especially in handling large topography datasets. Reproductions from this enhanced three-dimensional approach were validated against recent reservoir failure observations and contrasted with traditional two-dimensional models. The results revealed that the suggested three-dimensional methodology achieved a significant 84.4% reproducibility when juxtaposed with actual inundation traces. It was 35.5%p more accurate than the two-dimensional diffusion wave equation (DWE) and 17.1%p more than the shallow water equation (SWE) methods in predicting flood waves. This suggests that the reproducibility of the DWE and SWE decreases compared to the three-dimensional approach when considering more complex floodplains. These results demonstrate that three-dimensional flood wave analysis with the SfM methodology is optimal for effectively minimising topographic and flood wave reproduction errors across extensive areas. This dual reduction in errors significantly enhances the reliability of flood hazard assessments and improves risk management by providing more precise and realistic predictions of flood waves.