Acute coronary events continue to represent a threat to aviation safety and mission completion and comprise a significant cause of loss of medical certification in both military and civilian aircrew. In the age range of active aircrew, coronary events often present as a plaque rupture event with acute incapacitation as the initial manifestation. The identification of asymptomatic aircrew with a high risk for an acute coronary event remains a major challenge to aviation medical practitioners. For aircrew who have had a coronary event or are have significant atherosclerosis, the challenge is to guide the appropriate evaluations to allow a risk assessment for consideration for continuing flight duties.

Using a series of four case studies, this article will explore the evaluation, treatment, and proper aeromedical disposition of coronary artery disease (CAD). Cases will include CAD screening, asymptomatic non-obstructive CAD, asymptomatic obstructive/ischemic CAD, and symptomatic CAD with myocardial infarction.

This paper presents the current benchmark for assessing aircrew for occult coronary disease and for assessment and disposition of aircrew with known coronary disease with data derived from current aeromedical and clinical literature, as well as the expert consensus of the North Atlantic Treaty Organization Working Group on Occupational Cardiology (HFM WG 251, 316). Gray G, Holdsworth D, Guettler N, Broekhuizen L, Syburra T, D'Arcy J, Bron D, Manen O, Davenport E. Coronary artery disease detection and disposition in aircrew. Aerosp Med Hum Perform. 2026; 97(3):210-217.

AbstractThis study explores tensions between rarity, research, and clinical decision-making in surgical diseases through a case study of pediatric pulmonary vein stenosis (PVS), an extremely rare and severe pediatric cardiopulmonary disease. We first examine the history of PVS treatment and illustrate how the field has been characterized by rapid clinical changes that outpace evidence. Through this context, we characterize patients and their ability to contribute to research as a limited resource that future patients depend on. We argue that this establishes future patients as legitimate stakeholders in decisions regarding current-day clinical management. Exploring this tension, we ask, to what extent should just resource utilization and research priorities shape clinical decisions, and can the dual role of patients-both as care recipients and as a limited resource-be ethically balanced? The article interrogates these questions through two proposals: standardizing care across centers, and regionalizing PVS treatment. We argue that regionalization is ethically justifiable, whereas standardization is not. Ultimately, we conclude that while a patient's primary role is as a recipient of care, research and resource considerations can and should still inform clinical management of rare diseases. Importantly, this is ethically possible only under conditions that preserve patient welfare and the accepted standard of care.

Current guidelines recommend frailty assessment for risk stratification of candidates for transcatheter mitral and tricuspid valve repair (TMTVR), but it remains unclear which frailty score is most appropriate.

In a retrospective monocentric analysis of patients who received TMTVR, a modified version of the essential frailty toolset (EFT) was calculated from four categories: gait speed, cognitive impairment, hemoglobin, and serum albumin. Cox proportional hazards models were used to examine the association between EFT frailty and all-cause mortality.

A total of 206 patients were analyzed; median age was 76 [72-82] years, and 55% were male. According to the EFT, 49 patients (24%) were non-frail, 127 patients (62%) were pre-frail, and 30 patients (15%) were frail. Estimated survival at 2 years was 88 ± 5% for non-frail patients, 74 ± 5% for pre-frail patients, and 62 ± 10% for frail patients, with a hazard ratio of 1.54 (95% CI 1.16-2.04; p = 0.003) per standard deviation of EFT score. This association remained virtually unchanged when adjusted for other risk factors and Fried physical frailty, but disappeared when adjusted for the multidimensional prognostic index (MPI), which is based on a comprehensive geriatric assessment. A stepwise approach using EFT in all patients and MPI only in pre-frail EFT patients resulted in two risk categories with a 4.4-fold (95% CI 2.3-9.4) difference in 2-year mortality between categories.

The EFT has prognostic value for patients undergoing TMTVR. Due to its simplicity, the EFT could serve as a first-line frailty assessment tool to guide therapeutic decision-making, potentially in a stepwise approach with MPI.

Nicotinamide adenine dinucleotide (NAD⁺) is a vital molecule, serving as a redox cofactor and the limiting substrate for numerous enzymes. NAD⁺ decline is a key feature of aging, while supplementation with NAD⁺ precursors can efficiently counteract aging traits and prevent age-associated conditions in preclinical models. However, clinical translation remains challenging, likely due to the limited NAD⁺ boosting capacity of classical precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). This has brought attention to their reduced forms, reduced NMN (NMNH) and reduced NR (NRH), which are more potent NAD⁺ boosters but remain poorly characterized. Here, we performed a comprehensive comparative analysis using RNA sequencing, proteomics, and metabolomics on cultured murine hepatocytes treated with NMN, NMNH, NR, or NRH. Global metabolic profiling revealed that NRH and NMNH induced substantially broader metabolic alterations than NR and NMN, with NRH uniquely suppressing metabolites involved in energy metabolism. The pronounced metabolic effects were reflected at a transcriptional level, with reduced precursors triggering a significantly higher number of differentially expressed genes than oxidized ones. Shared differentially expressed genes between NMNH and NRH revealed upregulation of stress-related glutathione-S-transferases (Gsts) which furthermore were reflected in our proteomic profiling. However, the upregulation of Gsts did not cause a depletion of glutathione or oxiglutathione, suggesting a pseudo-stress response to reduced NAD⁺ precursors. Together, our data demonstrate that reduced NAD⁺ precursors are unique and distinct from the market-available NAD⁺ precursors NR and NMN, not only as more potent NAD⁺ boosters, but also as compounds influencing a broader range of cellular processes.

Acute chest pain poses a substantial burden on health care systems and is a common reason for emergency department visits worldwide. Although diagnostic pathways are available to triage patients-distinguishing those needing immediate intervention from those safe for discharge-accurately diagnosing acute coronary syndrome (ACS) remains challenging. ACS is present in only 5%-10% of acute chest pain cases; however, most patients undergo extensive investigations to rule it out due to the clinical and legal consequences of misdiagnosis. In response, coronary CT angiography (CCTA) has emerged as a promising diagnostic tool, gaining support from international societies over the past decade. The 2023 European Society of Cardiology guidelines recommend considering CCTA or functional imaging tests for the initial evaluation of patients without electrocardiographic changes and with uncertain high-sensitivity cardiac troponin levels (class IIa, level A). Similarly, U.S. guidelines support the use of CCTA or functional tests to exclude clinically significant coronary artery disease in patients with intermediate risk of ACS after inconclusive evaluations (class I, level A). This article examines the role of CCTA in managing different risk populations; the potential for CCTA to optimize resource utilization while maintaining diagnostic accuracy; and the impact of other diagnostic resources, such as high-sensitivity troponins, on established diagnostic pathways.

Licorice (Glycyrrhiza spp.), a traditional Chinese herb, contains glycyrrhetinic acid derivatives with neuroprotective properties but limited bioavailability.

YCY-20 is a novel derivative synthesized by structural modification of 18β-glycyrrhetinic acid. The aim of this study is to explore its therapeutic effect and potential molecular mechanism on cerebral ischemia-reperfusion injury (CIRI).

Pharmacokinetic profiling was performed to compare plasma exposure and brain distribution of YCY-20 and its parent compound 18β-GA. Neuroprotection was assessed using middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced HT22 cells. Evaluations included infarct volume (TTC staining), apoptosis (TUNEL, flow cytometry), and protein dynamics (Western blot). Network pharmacology identified potential targets, and in vivo experiments are conducted to validate the relevant molecular pathways.

YCY-20 exhibited improved pharmacokinetic properties, with higher and more stable plasma concentrations and detectable brain levels after oral administration, compared with 18β-GA. YCY-20 administration significantly attenuated body weight loss, cerebral infarct volume, and neuronal apoptosis in MCAO/R rats. Mechanistically, YCY-20 suppressed the MCAO/R-induced upregulation of pro-apoptotic proteins (Bax, caspase-3, cleaved caspase-3) while restoring anti-apoptotic Bcl-2 expression. In vitro OGD/R models corroborated these anti-apoptotic effects. Network analysis identified AGE-RAGE/MAPK signaling as the predominant pathway modulated by YCY-20, with subsequent in vivo validation demonstrating its capacity to downregulate key mediators in this pathway.

YCY-20 confers protection against CIRI, at least partially through apoptosis inhibition mediated by AGE-RAGE/MAPK signaling pathway modulation. This study provides preclinical evidence for developing licorice-derived agents in stroke management.

Tobacco smoking induces persistent DNA methylation (DNAm) changes in blood that can serve as long-term biomarkers for smoking exposure. We aimed to develop and validate a DNAm classifier of smoking status using Illumina EPIC array data.

We built Epigenetic Smoking status Estimator2 (EpiSmokEr2), a Least Absolute Shrinkage and Selection Operator (LASSO) regression-based DNAm classifier using 511 CpGs from Illumina Infinium MethylationEPIC array (EPIC) data. The model was trained on 1343 samples from the Young Finns Study cohort and validated across six independent datasets from four cohorts and two array platforms (EPIC and EPICv2).

EpiSmokEr2 achieved an average sensitivity of 0.87 and specificity of 0.86 in distinguishing current from never smokers. Predicted smoking status correlated strongly with established DNAm smoking scores and GrimAge, indicating its ability to capture biologically relevant smoking effects. Simulation analysis showed EpiSmokEr2 was robust for up to 10% missing CpGs.

EpiSmokEr2 provides a reliable DNAm-based estimator of smoking status. It is available as an open-source R package on GitHub, facilitating broad use in epidemiological and clinical research.

Cerebral hemodynamics and metabolism are central to neurosurgical decision-making and directly influence management in cerebrovascular disease, revascularization, and perioperative care. Powers'classification offers a physiological basis for hemodynamic ischemia, and quantitative positron emission tomography remains the gold standard for evaluating cerebral blood flow, cerebral blood volume, oxygen extraction fraction, and the cerebral metabolic rate of oxygen. Single photon emission computed tomography with acetazolamide, computed tomography/magnetic resonance perfusion, and arterial spin labeling have improved clinical accessibility and allow assessment of cerebrovascular reserve, time-to-peak, mean transit time, and time-to-maximum. In acute ischemic stroke, perfusion imaging has advanced treatment selection from a time-based to a tissue-based paradigm, supporting thrombectomy in patients with large ischemic cores. Post-recanalization phenomena, including hyperperfusion and no-reflow, illustrate the complexity of microcirculatory dynamics. Perfusion studies also inform decisions in bypass surgery and carotid revascularization. For neurosurgeons, understanding these modalities and their complementary interpretations is essential for safe and effective practice. Future integration of imaging metrics with physiological data through artificial intelligence may facilitate patient-specific strategies, standardized protocols, multicenter validation, and ultimately reduce complications while improving outcomes.

Post-stroke movement disorders consisting of complex involuntary movement patterns with parkinsonism, dystonia, hemiballismus/hemichorea, and tremor represent a therapeutical challenge. Deep brain stimulation has been considered an effective treatment option, although it remains unclear which DBS targets should be approached.

An individual participant data meta-analysis was conducted analyzing the efficacy (Burke Fahn Marsden Dystonia Rating Scale (BFM)-motor/-disability and the Fahn-Tolosa-Marín Scale for tremor (FTMTRS)) of pallidal (GPi) deep brain stimulation versus thalamic (VIM) versus GPi + VIM. PubMed, Embase, Cochrane Library, Ovid Medline, and Scopus were searched from 2000 to 2025. Additionally, correlation/regression analyses (age, duration of disease, stimulation parameters) were performed.

Sixteen studies including 32 patients (34.4% male; 65.6% female) were enrolled targeting the GPi (63.2%) versus VIM (23.6%) versus GPi/VIM-DBS (13.2%). Dystonia with tremor was found in 53%, dystonia with hemichorea/choreoathetosis in 50% (age at disease onset: 10 ± 18 years, age at DBS surgery: 37 ± 15 years, disease duration: 28 ± 19 years). GPi-DBS improved dystonia (BFM-motor: 6-12 months p < 0.005 and >12 months p = 0.038; BFM-disability 6-12 months p = 0.038) with no significant/relevant changes for VIM and GPi/VIM. No correlations were determined between DBS outcome and stimulation protocol and demographic characteristics. Adverse events occurred in 19%.

DBS is effective for treating post-stroke movement disorders of various etiologies. Given the heterogeneity, selection, and reporting bias, the published data is limited in providing high-quality evidence. Hence, the authors advocate a multifocal DBS approach along with trial stimulation determined under a rigorous study protocol.

Autonomic dysfunction post-stroke negatively affects the cardiovascular system's ability to regulate heart rate and blood pressure response to exercise. While high-intensity interval exercise (HIIE) is prescribed for stroke recovery, limited knowledge exists regarding how HIIE impacts autonomic function post-stroke. Characterize autonomic nervous system response to HIIE post-stroke. Heart rate and blood pressure were recorded during a 10-min recumbent stepper HIIE bout, cool-down, immediately post-exercise, and 30-min post-exercise. Fast Fourier Transformation was used to determine low and high frequency beat-to-beat blood pressure and heart rate power spectral density at all timepoints and baseline baroreflex sensitivity. We tested for differences in spectral data between timepoints using Friedman's test. The influence of arterial stiffness, age, and beta-blocker use on autonomic function was explored using linear regression. Twenty-seven participants completed HIIE. The autonomic nervous system response to HIIE was blunted with neither low nor high frequency blood pressure or heart rate variability exhibiting significant changes from baseline during exercise (p > 0.05). Baroreflex sensitivity was impaired, with age (p = 0.03), arterial stiffness (p < 0.01), and beta-blocker use (p = 0.03) affecting sensitivity. Autonomic function is blunted during HIIE post-stroke and likely attributed to impaired baroreflex sensitivity and arterial stiffness.