Error traps in patients with congenital heart disease undergoing noncardiac surgery.

Patients with congenital heart disease are living longer due to improved medical and surgical care. Congenital heart disease encompasses a wide spectrum of defects with varying pathophysiology and unique anesthetic challenges. These patients often present for noncardiac surgery before or after surgical repair and are at increased risk for perioperative morbidity and mortality. Although there is no singular safe anesthetic technique, identifying potential error traps and tailoring perioperative management may help reduce morbidity and mortality. In this article, we discuss five error traps based on the collective experience of the authors. These error traps can occur when providing perioperative care to patients with congenital heart disease for noncardiac surgery and we present potential solutions to help avoid adverse outcomes.

Does one size really fit all? The case for personalized antiplatelet therapy in interventional cardiology.

Cardiovascular disease is the leading cause of death worldwide. Dual antiplatelet therapy (DAPT), with aspirin plus a P2Y12 inhibitor, is currently recommended as a default for patients after acute coronary syndrome (ACS) and following percutaneous coronary intervention (PCI). However, controversies arise over the role of aspirin, the optimal duration of DAPT after drug-eluting stent (DES) implantation, the choice of P2Y12 inhibitor and the variability in individual responses to antiplatelet agents. Recent data indicate that monotherapy with a P2Y12 inhibitor may have adequate anti-ischemic effects with lower bleeding risk. Additionally, discrepancies in DAPT duration recommendations and the optimal P2Y12 inhibitor, provides more uncertainty. We ask the question "does one size really fits all?" or should a more personalized strategy should be implemented.

Diseases affecting the heart and blood circulation are the leading cause of death worldwide. Treatment with drugs that prevents platelets from clumping (called antiplatelets) like aspirin plus another drug group (called P2Y12 inhibitors) like clopidogrel, ticagrelor and prasugrel, is currently recommended as a default for patients after heart attack and/or in whom coronary stents are inserted. However, it is very well documented that the response of any individual to these drugs is highly variable, and that the patients who don't respond as well to them are at increased risk of having clot events in their coronary arteries. On the other hand, people who respond to the drugs very sensitively have a higher bleeding risk. Despite these observations, there is no attempt to test the response of individuals patients to their antiplatelet drugs in routine practice. This review article looks in detail and whether the currently used strategy of "One size fits all" should be changed, given that there may well now be the chance to perform routine testing on everyone, and personalize their treatment accordingly.

Prelacrimal-Transmaxillary Approach to Lateral Sphenoid Recess Skull Base Defects.

The lateral recess of a well-pneumatized sphenoid sinus is challenging to access surgically. Traditional methods require the use of multiple angled endoscopes and curved instruments which may limit visualization. We describe a prelacrimal-transpterygoid/maxillary approach which offers direct access to this region with a 0° endoscope. Laryngoscope, 2024.

The role of attention and verbal rehearsal in remembering more valuable item-colour binding.

Selectively remembering more valuable information can improve memory efficiency. Such value effects have been observed on long-term memory for item-colour binding, but the possible contributory factors are unclear. The current study explored contributions from attention (Experiment 1) and verbal rehearsal (Experiment 2). Across two experiments, memory was superior for item-colour bindings that were associated with high (relative to low) point values at encoding, both in an immediate test and a delayed re-test. When availability of attentional resources was reduced during encoding, value only influenced immediate and not delayed memory (Experiment 1). This indicates that a transient value effect can be obtained with little attentional resources, but attentional resources are involved in creating a longer lasting effect. When articulatory suppression was implemented during encoding (Experiment 2), value effects were somewhat reduced in the immediate test and abolished in the delayed re-test, suggesting a role for verbal rehearsal in value effects on item-colour binding memory. These patterns of value effects did not interact with encoding presentation format (i.e., sequential vs. simultaneous presentation of objects). Together, these results suggest that attentional resources and verbal rehearsal both contribute to value effects on item-colour binding memory, with varying impacts on the durability of these effects.

Contamination in Trypophobia: investigating the role of disgust.

Trypophobia is a relatively common aversion to clusters of holes. There is no consensus yet on which emotions are involved in Trypophobia nor in its functional utility. This report investigates the role of disgust using contamination tasks in two studies, which contrast people with an aversion to trypophobic stimuli to those without. In Study 1, participants reported their emotional reactions to imagined contamination of trypophobic images. In Study 2, participants evaluated physically present trypophobic, disgust, fear, and control stimuli. The capacity of these stimuli to contaminate other objects was established using a chain of contagion task. Across both studies, contamination was present, however, only those with an aversion to trypophobic stimuli evidenced contamination on the chain of contagion task, a hallmark of disgust responding. Elevated levels were not only reported for disgust, but also alongside fear/anxiety. Participant reports suggest an underlying disease avoidance mechanism in Trypophobia, with trypophobic participants demonstrating an exaggerated response to such stimuli involving disgust and fear/anxiety, which is also seen in small animal phobia, BII, and C-OCD. Implications, particularly for treatment are discussed.

Mind the GAHP: A novel protocol for improved vascular access in the hypotensive patient.

Background: Obtaining intravenous access in hypotensive patients is challenging and may critically delay resuscitation. The Graduated Vascular Access for Hypotensive Patient (GAHP) protocol leverages intraosseous fluid boluses to specifically dilate proximal veins. This study aims to evaluate the efficacy of GAHP in maximizing venous targets through early distal intraosseous access and a small fluid bolus. Methods: This was a prospective randomized cadaveric pilot study to evaluate extremity venous engorgement during intraosseous infusion. Cadavers (n = 23) had an intraosseous needle inserted into four sites: distal radius, proximal humerus, distal femur, and distal tibia. Intraosseous saline was rapidly infused, venous optimization was measured using real-time ultrasound. Primary outcome was maximum vessel circumference increase with intraosseous infusion. Secondary outcomes were: time to maximum circumference, and infusion volume required. Statistical analyses included Levene's test for equality of variances, Wilcoxon signed-rank test, and generalized estimating equation. Results: There was a significant mean increase of 1.03 cm (95% CI 0.86, 1.20), representing a difference of 102%. We found no significant difference in time to optimize vessel circumference across sites, but volume required significantly differed. Conclusion: GAHP quickly and effectively increased the circumference of anatomically adjacent veins. Anatomical sites did not differ on time to reach maximum enlargement of vessels following intraosseous infusion but did differ in terms of volume required to maximize vessel circumference. Further research is needed using live, hypotensive patients.

Feasibility of Wearable Sensors to Assess Cognitive Load During Clinical Performance: Lessons Learned and Blueprint for Success.

INTRODUCTION: Cognitive load (CogL) is increasingly recognized as an important resource underlying operative performance. Current innovations in surgery aim to develop objective performance metrics via physiological monitoring from wearable digital sensors. Surgeons have access to consumer technology that could measure CogL but need guidance regarding device selection and implementation. To realize the benefits of surgical performance improvement these methods must be feasible, incorporating human factors usability and design principles. This paper aims to evaluate the feasibility of using wearable sensors to assess CogL, identify the benefits and challenges of implementing devices, and develop guidance for surgeons planning to implement wearable devices in their research or practice. METHODS: We examined the feasibility of wearable sensors from a series of empirical studies that measured aspects of clinical performance relating to CogL. Across four studies, 84 participants and five sensors were involved in the following clinical settings: (i) real intraoperative surgery; (ii) simulated laparoscopic surgery; and (iii) medical team performance outside the hospital. RESULTS: Wearable devices worn on the wrist and chest were found to be comfortable. After a learning curve, electrodermal activity data were easily and reliably collected. Devices using photoplethysmography to determine heart rate variability were significantly limited by movement artifact. There was variable success with electroencephalography devices regarding connectivity, comfort, and usability. CONCLUSIONS: It is feasible to use wearable sensors across various clinical settings, including surgery. There are some limitations, and their implementation is context and device dependent. To scale sensor use in clinical research, surgeons must embrace human factors principles to optimize wearability, usability, reliability, and data security.

Association between adolescent alcohol use and cognitive function in young adulthood: A co-twin comparison study.

BACKGROUND AND AIMS: Studies on adolescent alcohol use and cognition are often unable to separate the potential causal effects of alcohol use on cognition from shared etiological influences, including genetic influences or other substance use comorbidities also known to be associated with cognition, such as nicotine use. The present study aimed to fill this gap and clarify the relationship between adolescent alcohol use and young adult cognition by accounting for both measured and unmeasured confounders. DESIGN: A random effects model accounting for nesting in families was used to control for measured confounders. Next, co-twin comparisons were conducted within the full sample and in monozygotic twin pairs (MZ) to control for unmeasured genetic and environmental confounders shared by co-twins. PARTICIPANTS/SETTING: Participants were 812 individuals (58.6% female, 361 complete pairs, 146 MZ pairs) from the longitudinal FinnTwin12 study in Finland. MEASUREMENTS: Adolescent alcohol use was indexed with measures of frequency of use and intoxication averaged across ages 14 and 17. Cognitive outcomes were measured at average age 22 and included Trail Making Test, California Stroop test, Wechsler Adult Intelligence subtests (Vocabulary, Block Design, Digit Symbol), Digit Span subtest of Wechsler Memory Scale, Mental Rotation Test and Object Location Memory test. Covariates included sex, parental education, general cognitive ability, current alcohol use and nicotine use. FINDINGS: Greater frequency of alcohol use and frequency of intoxication across adolescence was associated with decreased vocabulary scores in the co-twin control [freq: stnd beta = -0.12, 95% confidence interval (CI) = -0.234, -0.013] and MZ only co-twin control models (freq: stnd beta = -0.305, 95% CI = -0.523, -0.087; intox: stnd beta = -0.301, 95% CI = -0.528, -0.074). CONCLUSIONS: In Finland, there appears to be little evidence that adolescent alcohol use causes cognitive deficits in young adulthood, except modest evidence for association of higher adolescent alcohol use with lower young adult vocabulary scores.

Low-dose intravitreal injection of 4 mg preservative-free gentamicin and superficial lamellar keratectomy combined with modified Gundersen grafts to control chronic heterochromic iridocyclitis and secondary keratitis in horses.

OBJECTIVE: To describe a combined treatment approach for heterochromic iridocyclitis and secondary keratitis (HIK) in horses. ANIMAL STUDIED: A total of 15 horses (16 eyes). PROCEDURES: Sixteen eyes from 15 horses (mean age 14.1 years, range 6-26 years) received low-dose (4 mg) intravitreal preservative-free gentamicin injection (IVGI) and modified Gundersen grafts with standing sedation and local anesthesia following a clinical diagnosis of HIK. Additional therapies of suprachoroidal triamcinolone (8 mg) injection, episcleral bromfenac implants, and suprachoroidal cyclosporine implants were performed in individual cases. Leptospira titers were also reported when available. RESULTS: The most frequent ophthalmic findings were pigmented keratic precipitates (n = 15/16 eyes, 94%), corneal edema (n = 14/16 eyes, 88%), and pigmented cells suspended in the anterior chamber (n = 7/16 eyes, 44%). Postoperative treatment generally consisted of topical and systemic NSAIDs, topical antibiotics, and a topical mydriatic agent. Complications included persistent corneal edema (7/16, 44%), corneal ulceration (6/16, 38%), graft failure requiring revision (2/16, 13%), stromal abscess (1/16, 6%), surgery site infection (1/16, 6%), and suspected retinal degeneration following IVGI (1/16, 6%). One case was enucleated 6 months after treatment (1/16, 6%). Of the 12 eyes with at least 3 months of post-treatment follow-up, 10 were comfortable and visual with static or improved symptoms of HIK. CONCLUSIONS: This multimodal treatment approach aims to address both the anterior uveitis and endothelial decompensation frequently seen in horses with HIK. The surgery can be performed under standing sedation. Continued evaluation and long-term follow-up is necessary in all horses with HIK.

Global Leadership Initiative on Malnutrition cachexia: an inflammation-first approach for the diagnosis of disease-related malnutrition.

PURPOSE OF REVIEW: The following article examines the rationale for an inflammation-first approach for diagnosing cachexia and how the current Global Leadership Initiative on Malnutrition (GLIM) framework may be adapted to facilitate this. RECENT FINDINGS: Recently, the GLIM have published guidance on the measurement of inflammation in the context of cachexia, advocating that C-reactive protein (CRP) should be utilized for quantification. The inclusion of a systemic inflammatory biomarker for the diagnosis of cachexia questions whether it may be more aptly considered a systemic inflammatory syndrome. SUMMARY: The current consensus of the GLIM is that cachexia is 'disease-related malnutrition with inflammation'. In line with this definition, the GLIM proposed a two-step diagnostic framework: screening for malnutrition using validated screening tools and then confirming the presence of disease-related malnutrition with phenotypic (nonvolitional weight loss, low BMI, and reduced muscle mass) and aetiologic criterion reduced food intake/assimilation, and inflammation or disease burden). The GLIM are to be commended for guidance on the measurement of systemic inflammation in their current proposal, given the relative importance to clinical outcomes in patients with cancer. However, the use of CRP is somewhat rudimentary and contrasts other cancer cachexia guidelines and contemporary clinical cancer research.

Sustaining village malaria worker programmes with expanded roles: Perspectives of communities, healthcare workers, policymakers, and implementers in Vietnam.

BACKGROUND: In Vietnam, multiple types of community-based malaria workers are recruited to promote access to malaria testing and treatment for at-risk mobile and migrant populations. However, as the country approaches elimination, these roles are at risk from declining investment. This article characterises the different types of workers and relevant health policy in Vietnam, and explores stakeholder perspectives on sustaining and expanding the roles of these workers in the malaria elimination context. METHODS: We conducted a rapid policy document review to describe the policy background of community-based health care in Vietnam and identify key informants. In-depth interviews were conducted with policymakers and implementers (n = 11) in different government sectors, international, and civil society organizations. We also conducted interviews (n = 8) and two focus group discussions with community members (n = 12), and interviews with health workers (n = 9) in 18 communities in Phu Yen and Binh Thuan provinces in the central region. RESULTS: Our study identified three main types of malaria workers: village health workers (VHWs), malaria post workers (MPWs) and other groups of workers supported by civil society organisations (CSO). Workers reported being willing to maintain their current roles and potentially provide additional services that respond to community needs, although they were concerned about excess workload and inadequate income. Besides working in a variety of jobs to secure their incomes, mainly in agriculture, VHWs in particular were primarily tasked with supporting the delivery of a wide range of health services from commune health stations. Faced with reduced patients, MPWs and CSO-supported workers could be tasked with the following potential roles: case notification for infectious diseases, real-time data collection and reporting, and screening for non-malaria illnesses using other rapid test kits. There was agreement that the community-based health network is crucial to health care delivery in remote communities and to ensure comprehensive access to care among vulnerable populations. However, policymakers and implementers stressed concerns about their limited skillsets, the inadequate budget to support these workers, and the regulation constraining them from performing diagnosis and treatment activities, highlighting the priority to maintain the capacity of workers and funding allocation through provincial advocacy and multi-programme collaboration. CONCLUSIONS: This study highlights the crucial role of community-based health workers in eliminating malaria in Vietnam. Sustained efforts are needed to maintain accessible case detection and treatment while addressing local health concerns beyond malaria. Implementing these strategies requires prioritizing the mapping of groups most in need and developing enablers to raise community awareness and maintain the capacity of these workers. Ensuring political advocacy, financial resources, and coordination between multiple groups are key to maximizing impact and integrating malaria activities into the broader health system.

Effects of Single Low-Carbohydrate, High-Fat Meal Consumption on Postprandial Lipemia and Markers of Endothelial Dysfunction: A Systematic Review of Current Evidence.

CONTEXT: Postprandial lipemia (PPL) is associated with increased risk of endothelial dysfunction (ED), a precursor of atherosclerotic cardiovascular disease (ASCVD). The effects of low-carbohydrate, high-fat (LCHF) diets on ASCVD risk are uncertain; therefore, gaining a greater understanding of LCHF meals on PPL may provide valuable insights. OBJECTIVE: The current systematic review investigated the effects of single LCHF meal consumption on PPL and markers of ED. DATA SOURCES: CINAHL Plus, PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for key terms related to endothelial function, cardiovascular disease, glycemia, lipemia, and the postprandial state with no restriction on date. DATA EXTRACTION: Full-text articles were independently screened by 2 reviewers, of which 16 studies were eligible to be included in the current review. All trials reported a minimum analysis of postprandial triglycerides (PPTG) following consumption of an LCHF meal (<26% of energy as carbohydrate). Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. DATA ANALYSIS: Single-meal macronutrient composition was found to play a key role in determining postprandial lipid and lipoprotein responses up to 8 hours post-meal. Consumption of LCHF meals increased PPTG and may contribute to ED via reduced flow-mediated dilation and increased oxidative stress; however, energy and macronutrient composition varied considerably between studies. CONCLUSION: Consumption of an LCHF meal had a negative impact on PPL based on some, but not all, single-meal studies; therefore, the contribution of LCHF meals to cardiometabolic health outcomes remains unclear. Further research is needed on specific categories of LCHF diets to establish a causal relationship between postprandial modulation of lipids/lipoproteins and impaired vascular endothelial function. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD 42023398774.

Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS).

OBJECTIVE: To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS). METHODS: All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes. RESULTS: We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS. INTERPRETATION: DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024.

Deep Learning-based Modeling for Preclinical Drug Safety Assessment.

In drug development, assessing the toxicity of candidate compounds is crucial for successfully transitioning from preclinical research to early-stage clinical trials. Drug safety is typically assessed using animal models with a manual histopathological examination of tissue sections to characterize the dose-response relationship of the compound - a time-intensive process prone to inter-observer variability and predominantly involving tedious review of cases without abnormalities. Artificial intelligence (AI) methods in pathology hold promise to accelerate this assessment and enhance reproducibility and objectivity. Here, we introduce TRACE, a model designed for toxicologic liver histopathology assessment capable of tackling a range of diagnostic tasks across multiple scales, including situations where labeled data is limited. TRACE was trained on 15 million histopathology images extracted from 46,734 digitized tissue sections from 157 preclinical studies conducted on Rattus norvegicus. We show that TRACE can perform various downstream toxicology tasks spanning histopathological response assessment, lesion severity scoring, morphological retrieval, and automatic dose-response characterization. In an independent reader study, TRACE was evaluated alongside ten board-certified veterinary pathologists and achieved higher concordance with the consensus opinion than the average of the pathologists. Our study represents a substantial leap over existing computational models in toxicology by offering the first framework for accelerating and automating toxicological pathology assessment, promoting significant progress with faster, more consistent, and reliable diagnostic processes.

Allogeneic blood or marrow transplantation using haploidentical grandchildren donors and post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis.

BACKGROUND: High-dose post-transplant cyclophosphamide allows safe and effective use of allografts from haploidentical relatives (siblings, parents and children) in patients undergoing allogeneic blood or marrow transplant (alloBMT). More recently, second- and third-degree relatives have also been shown to be safe allograft donors. An increasing number of older patients undergoing alloBMT have been receiving allografts from haploidentical donors. However, older patients are more likely to have older siblings and children, and older donor age is associated with worse outcomes. OBJECTIVE: In the current study, we report the safety and utility of grandchildren as haploidentical donors and compared with children as donors in patients undergoing alloBMT. METHODS: We compared characteristics and outcomes of alloBMT patients aged 55 years and older with children older than 30 years as donors (C group; n = 276) and those with grandchildren as donors (GC group; n = 40). Because many important baseline characteristics predict outcomes after alloBMT, we performed propensity score matched analysis based on recipient age, alloBMT year, disease, graft source and haematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS: The median age of recipients was 67 years (range 55-79) in the C group and 73 years (range 57-78) in the GC group. More than 70% of recipients in the GC group were older than 70 years, compared with 27% in the C group. The median donor age was 37 years (range 31-52) in the C group and 20 years (range 14-34) in the GC group. More patients in the GC group had HCT-CI scores ≥3 than in the C group (32.5% vs. 23%, p = 0.27). Two-year overall survival did not differ between the two groups (GC 62% vs. C 60%, hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.53-1.75, p = 0.90) despite recipients of allografts from grandchildren being older. The 2-year RFS was 55% in the C group compared with 50% in the GC group (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Non-relapse mortality subdistribution [SD] (SDHR 1.36, 95% 0.70-2.63, p = 0.36), relapse (SDHR 0.72, 95% CI 0.33-1.58, p = 0.42) or relapse-free survival (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Propensity score matching analysis showed no significant differences in 2-year overall survival (GC 64% vs. C 53%; HR 0.77, 95% CI 0.42-1.42, p = 0.40), non-relapse mortality (SDHR 1.26, 95% 0.66-2.41, p = 0.48), relapse (SDHR 0.57, 95% CI 0.21-1.52, p = 0.26) or relapse-free survival (HR 0.94, 95% CI 0.57-1.54, p = 0.81). CONCLUSION: Our results indicate that outcomes of alloBMT patients with grandchild donors are similar to those with child donors, despite recipients' older age and higher comorbidities in the GC group. Grandchildren should be considered when selecting a donor for older alloBMT recipients.

AI-driven Discovery of Morphomolecular Signatures in Toxicology.

Early identification of drug toxicity is essential yet challenging in drug development. At the preclinical stage, toxicity is assessed with histopathological examination of tissue sections from animal models to detect morphological lesions. To complement this analysis, toxicogenomics is increasingly employed to understand the mechanism of action of the compound and ultimately identify lesion-specific safety biomarkers for which in vitro assays can be designed. However, existing works that aim to identify morphological correlates of expression changes rely on qualitative or semi-quantitative morphological characterization and remain limited in scale or morphological diversity. Artificial intelligence (AI) offers a promising approach for quantitatively modeling this relationship at an unprecedented scale. Here, we introduce GEESE, an AI model designed to impute morphomolecular signatures in toxicology data. Our model was trained to predict 1,536 gene targets on a cohort of 8,231 hematoxylin and eosin-stained liver sections from Rattus norvegicus across 127 preclinical toxicity studies. The model, evaluated on 2,002 tissue sections from 29 held-out studies, can yield pseudo-spatially resolved gene expression maps, which we correlate with six key drug-induced liver injuries (DILI). From the resulting 25 million lesion-expression pairs, we established quantitative relations between up and downregulated genes and lesions. Validation of these signatures against toxicogenomic databases, pathway enrichment analyses, and human hepatocyte cell lines asserted their relevance. Overall, our study introduces new methods for characterizing toxicity at an unprecedented scale and granularity, paving the way for AI-driven discovery of toxicity biomarkers.