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OBJECTIVES: Patients with congenital heart disease (CHD) are increasingly pursuing pregnancy, highlighting the need for data on late cardiovascular events (more than 6 months after delivery). We aimed to determine the incidence of late cardiovascular events in postpartum patients with CHD and evaluate the accuracy of the existing risk scores in predicting these events. STUDY DESIGN: We identified patients with CHD who delivered between 2008 and 2020 at a tertiary centre and had follow-up data for greater than 6 months post partum. Late cardiovascular events were defined as heart failure, arrhythmia, thromboembolic events, endocarditis, urgent cardiovascular interventions or death. Survival analysis and Cox proportional model were used to estimate the incidence of late cardiovascular events and determine the hazard ratio of factors associated with these events. RESULTS: Of 117 patients, 19% had 36 late cardiovascular events over a median follow-up of 3.8 years. Annual incidence of any late cardiovascular event was 5.7%. Hazards of late cardiovascular events were significantly higher among those with higher Cardiac Disease in Pregnancy Study (CARPREG) II and Zwangerschap bij Aangeboren HARtAfwijking-Pregnancy in Women With Congenital Heart Disease (ZAHARA) risk scores and among patients with prepregnancy New York Heart Association class≥II. C-statistic to predict the late cardiovascular events was highest for ZAHARA (0.7823), followed by CARPREG II (0.6902) and prepregnancy New York Heart Association class≥ II (0.6677). CONCLUSIONS: Currently available risk tools designed for prognostication during the peripartum period can also be used to determine risks of late maternal cardiovascular events among those with CHD. These findings provide important new information for counselling and risk modification.

Abstract Background Metabolic syndrome (MetS) is a significant epidemiological problem worldwide. It is a pre-morbid, chronic and low-grade inflammatory disorder that precedes many chronic diseases. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) could be used to treat MetS because they express high regenerative capacity, strong immunomodulatory properties and allogeneic biocompatibility. This study aims to investigate WJ-MSCs as a therapy against MetS in a rat model. Methods Twenty-four animals were fed with high-fat high-fructose (HFHF) diet ad libitum. After 16 weeks, the animals were randomised into treatment groups (n = 8/group) and received a single intravenous administration of vehicle, that is, 3 × 106 cells/kg or 10 × 106 cells/kg of WJ-MSCs. A healthy animal group (n = 6) fed with a normal diet received the same vehicle as the control (CTRL). All animals were periodically assessed (every 4 weeks) for physical measurements, serum biochemistry, glucose tolerance test, cardiovascular function test and whole-body composition. Post-euthanasia, organs were weighed and processed for histopathology. Serum was collected for C-reactive protein and inflammatory cytokine assay. Results The results between HFHF-treated groups and healthy or HFHF-CTRL did not achieve statistical significance (α = 0.05). The effects of WJ-MSCs were masked by the manifestation of different disease subclusters and continuous supplementation of HFHF diet. Based on secondary analysis, WJ-MSCs had major implications in improving cardiopulmonary morbidities. The lungs, liver and heart show significantly better histopathology in the WJ-MSC-treated groups than in the untreated CTRL group. The cells produced a dose-dependent effect (high dose lasted until week 8) in preventing further metabolic decay in MetS animals. Conclusions The establishment of safety and therapeutic proof-of-concept encourages further studies by improving the current therapeutic model.

Background With improving survival of patients with single ventricle physiology who underwent Fontan palliation, there is also an increase in the prevalence of overweight and obesity in these patients. This tertiary care single-center study aims to determine the association of body mass index (BMI) with the clinical characteristics and outcomes in adults with Fontan. Methods and Results Adult patients (aged ≥18 years) with Fontan who were managed at a single tertiary care center between January 1, 2000, and July 1, 2019, and had BMI data available were identified via retrospective review of medical records. Univariate and multivariable (after adjusting for age, sex, functional class, and type of Fontan) linear and logistic regression, as appropriate, were utilized to evaluate associations between BMI and diagnostic testing and clinical outcomes. A total of 163 adult patients with Fontan were included (mean age, 29.9±9.08 years), with a mean BMI of 24.2±5.21 kg/m2 (37.4% of patients had BMI ≥25 kg/m2). Echocardiography data were available for 95.7% of patients, exercise testing for 39.3% of patients, and catheterization for 53.7% of patients. Each SD increase in BMI was significantly associated with decreased peak oxygen consumption (P=0.010) on univariate analysis and with increased Fontan pressure (P=0.035) and pulmonary capillary wedge pressure (P=0.037) on multivariable analysis. In addition, BMI ≥25 kg/m2 was independently associated with heart failure hospitalization (adjusted odds ratio [AOR], 10.2; 95% CI, 2.79-37.1 [P

Abstract Impaired respiratory variation of right atrial pressure (RAP) in severe pulmonary hypertension (PH) suggests difficulty tolerating increased preload during inspiration. Our study explores whether this impairment links to specific factors: right ventricular (RV) diastolic function, elevated RV afterload, systolic RV function, or RV-pulmonary arterial (PA) coupling. We retrospectively evaluated respiratory RAP variation in all participants enrolled in the EXERTION study. Impaired respiratory variation was defined as end-expiratory RAP − end-inspiratory RAP ≤ 2 mm Hg. RV function and afterload were evaluated using conductance catheterization. Impaired diastolic RV function was defined as end-diastolic elastance (Eed) ≥ median (0.19 mm Hg/mL). Seventy-five patients were included; PH was diagnosed in 57 patients and invasively excluded in 18 patients. Of the 75 patients, 31 (41%) had impaired RAP variation, which was linked with impaired RV systolic function and RV-PA coupling and increased tricuspid regurgitation and Eed as compared to patients with preserved RAP variation. In backward regression, RAP variation associated only with Eed. RAP variation but not simple RAP identified impaired diastolic RV function (area under the receiver operating characteristic curve [95% confidence interval]: 0.712 [0.592, 0.832] and 0.496 [0.358, 0.634], respectively). During exercise, patients with impaired RAP variation experienced greater RV dilatation and reduced diastolic reserve and cardiac output/index compared with patients with preserved RAP variation. Preserved RAP variation was associated with a better prognosis than impaired RAP variation based on the 2022 European Society of Cardiology/European Respiratory Society risk score (chi-square P = 0.025) and survival free from clinical worsening (91% vs 71% at 1 year and 79% vs 50% at 2 years [log-rank P = 0.020]; hazard ratio: 0.397 [95% confidence interval: 0.178, 0.884]). Subgroup analyses in patients with group 1 and group 4 PH demonstrated consistent findings with those observed in the overall study cohort. Respiratory RAP variations reflect RV diastolic function, are independent of RV-PA coupling or tricuspid regurgitation, are associated with exercise-induced haemodynamic changes, and are prognostic in PH. Trial registration. NCT04663217.

Abstract The PEGASUS study is the first multicentric and prospective assessment of the safety of air travel flying in pulmonary hypertension (PH) (NCT03051763). Data of air travel from 60 patients with PH was available. No severe adverse events occurred. Nine patients self‐reported mild adverse events during flight (13%), while after landing, 12 patients reported events (20%). Solely one patient (2%) had an adverse event leading to medical consultation. In patients with PH and World Health Organization functional classes II and III, air travel was safe.

Abstract Background Female condoms protect against unplanned pregnancies and sexually transmitted infections (STIs) including HIV; however, their uptake is very low in South Africa. Nurses are frontline healthcare workers and are uniquely positioned to promote their use to their clients. This study assesses nurses’ knowledge of, attitudes to, and practices regarding the promotion of female condoms at selected primary healthcare facilities in the King Sabata Dalindyebo sub-district of the Eastern Cape, South Africa. Methods A descriptive cross-sectional study was conducted from April to May 2021 at five community health centres in the King Sabata Dalindyebo sub-district, South Africa. A total of 139 nurses completed a self-administered questionnaire. Data were analysed using simple descriptive statistics. Results The majority of the participants (82.7%) were knowledgeable about the female condom. Some participants did not have a good attitude and willingness to promote female condom use to their clients. Junior nurses (enrolled nursing assistants and newly qualified professional nurses) were less knowledgeable about the female condom than more qualified and older nurses. There was no significant association between level of knowledge and attitude or willingness to promote the use of the female condom. Conclusion This study found good knowledge of the female condom among the nurses; however, the knowledge did not translate into a willingness to promote the device at their health facilities. Capacity building of the junior nurses will fill the knowledge gaps identified. Studies exploring the sociocultural issues around the female condom are needed in the region.

Background: Proteins are commonly used in the healthcare industry to treat various health conditions, and most proteins are sensitive to physical and chemical changes. Lyophilization, also known as freeze-drying, involves sublimating water in the form of ice from a substance at low pressure, forming a freeze-dried powder that increases its shelf life. Extreme pressure and varying temperatures in the freeze-drying process may damage the protein’s structural integrity. Lyoprotectants are commonly used to protect protein conformations. It is important to choose a suitable lyoprotectant to ensure optimal effectiveness. Method: Twenty articles screened from Scopus, Web of Science, and PubMed were included in this review that discussed potential lyoprotectants and their effectiveness with different protein models. Results: Lyoprotectants were categorized into sugars, polyols, surfactants, and amino acids. Lyoprotectants can exhibit significant protective effects towards proteins, either singularly or in combination with another lyoprotectant. They exert various interactions with the protein to stabilize it, such as hydrogen bonding, hydrophobic interactions, electrostatic interactions, and osmoprotection. Conclusions: This review concludes that disaccharides are the most effective lyoprotectants, while other groups of lyoprotectants are best used in combination with other lyoprotectants.

Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants that pose significant environmental and health risks. These compounds originate from both natural phenomena, such as volcanic activity and wildfires, and anthropogenic sources, including vehicular emissions, industrial processes, and fossil fuel combustion. Their classification as carcinogenic, mutagenic, and teratogenic substances link them to various cancers and health disorders. PAHs are categorized into low-molecular-weight (LMW) and high-molecular-weight (HMW) groups, with HMW PAHs exhibiting greater resistance to degradation and a tendency to accumulate in sediments and biological tissues. Soil serves as a primary reservoir for PAHs, particularly in areas of high emissions, creating substantial risks through ingestion, dermal contact, and inhalation. Coastal and aquatic ecosystems are especially vulnerable due to concentrated human activities, with PAH persistence disrupting microbial communities, inhibiting plant growth, and altering ecosystem functions, potentially leading to biodiversity loss. In plants, PAH contamination manifests as a form of abiotic stress, inducing oxidative stress, cellular damage, and growth inhibition. Plants respond by activating antioxidant defenses and stress-related pathways. A notable aspect of plant defense mechanisms involves plant-derived extracellular vesicles (PDEVs), which are membrane-bound nanoparticles released by plant cells. These PDEVs play a crucial role in enhancing plant resistance to PAHs by facilitating intercellular communication and coordinating defense responses. The interaction between PAHs and PDEVs, while not fully elucidated, suggests a complex interplay of cellular defense mechanisms. PDEVs may contribute to PAH detoxification through pollutant sequestration or by delivering enzymes capable of PAH degradation. Studying PDEVs provides valuable insights into plant stress resilience mechanisms and offers potential new strategies for mitigating PAH-induced stress in plants and ecosystems.

The newly synthesized imidazole derivative namely, 4,5-bis[(E)-2-phenylethenyl]-1H,1′H-2,2′-biimidazole (KA1), was studied for its molecular geometry, docking studies, spectral analysis and density functional theory (DFT) studies. Experimental vibrational frequencies were compared with scaled ones. The reactivity sites were determined using average localized ionization analysis (ALIE), electron localized function (ELF), localized orbital locator (LOL), reduced density gradient (RDG), Fukui functions and frontier molecular orbital (FMO). Due to the solvent effect, a lower gas phase energy gap was observed. Through utilization of the noncovalent interaction (NCI) method, the hydrogen bond interaction, steric effect and Vander Walls interaction were investigated. Molecular docking simulations were employed to determine the specific atom inside the molecules that exhibits a preference for binding with protein. The parameters for the molecular electrostatic potential (MESP) and global reactivity descriptors were also determined. The thermodynamic characteristics were determined through calculations employing the B3LYP/cc-pVDZ basis set. Antimicrobial activity was carried out using the five different microorganisms like Escherichia coli, Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae and Candida albicans.

Abstract Aims Commercially available integrated software for echocardiographic measurement of stroke work (SW) is increasingly used for the right ventricle, despite a lack of validation. We sought to assess the validity of this method [echo‐based myocardial work (MW) module] vs. gold‐standard invasive right ventricular (RV) pressure–volume (PV) loops. Methods and results From the prospectively recruiting EXERTION study (NCT04663217), we included 42 patients [34 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) and 8 patients with absence of cardiopulmonary disease] with RV echocardiography and invasive PV catheterization. Echocardiographic SW was assessed as RV global work index (RVGWI) generated via the integrated pressure–strain MW software. Invasive SW was calculated as the area bounded by the PV loop. An additional parameter derived from the MW module, RV global wasted work (RVGWW), was correlated with PV loop measures. RVGWI significantly correlated with invasive PV loop‐derived RV SW in the overall cohort [rho = 0.546 (P

Platelet-derived extracellular vesicles (pEVs) are emerging as pivotal players in numerous physiological and pathological processes, extending beyond their traditional roles in hemostasis and thrombosis. As one of the most abundant vesicle types in human blood, pEVs transport a diverse array of bioactive molecules, including growth factors, cytokines, and clotting factors, facilitating crucial intercellular communication, immune regulation, and tissue healing. The unique ability of pEVs to traverse tissue barriers and their biocompatibility position them as promising candidates for targeted drug delivery and regenerative medicine applications. Recent studies have underscored their involvement in cancer progression, viral infections, wound healing, osteoarthritis, sepsis, cardiovascular diseases, rheumatoid arthritis, and atherothrombosis. For instance, pEVs promote tumor progression and metastasis, enhance tissue repair, and contribute to thrombo-inflammation in diseases such as COVID-19. Despite their potential, challenges remain, including the need for standardized isolation techniques and a comprehensive understanding of their mechanisms of action. Current research efforts are focused on leveraging pEVs for innovative anti-cancer treatments, advanced drug delivery systems, regenerative therapies, and as biomarkers for disease diagnosis and monitoring. This review highlights the necessity of overcoming technical hurdles, refining isolation methods, and establishing standardized protocols to fully unlock the therapeutic potential of pEVs. By understanding the diverse functions and applications of pEVs, we can advance their use in clinical settings, ultimately revolutionizing treatment strategies across various medical fields and improving patient outcomes.

Traumatic damage to the spinal cord (SCI) frequently leads to irreversible neurological deficits, which may be related to apoptotic neurodegeneration in nerve tissue. The MLC901 treatment possesses neuroprotective and neuroregenerative activity. This study aimed to explore the regenerative potential of MLC901 and the molecular mechanisms promoting neurogenesis and functional recovery after SCI in rats. A calibrated forceps compression injury for 15 s was used to induce SCI in rats, followed by an examination of the impacts of MLC901 on functional recovery. The Basso, Beattie, and Bresnahan (BBB) scores were utilized to assess neuronal functional recovery; H&E and immunohistochemistry (IHC) staining were also used to observe pathological changes in the lesion area. Somatosensory Evoked Potentials (SEPs) were measured using the Nicolet® Viking Quest™ apparatus. Additionally, we employed the Western blot assay to identify PI3K/AKT/GSK-3β pathway-related proteins and to assess the levels of GAP-43 and GFAP through immunohistochemistry staining. The study findings revealed that MLC901 improved hind-limb motor function recovery, alleviating the pathological damage induced by SCI. Moreover, MLC901 significantly enhanced locomotor activity, SEPs waveform, latency, amplitude, and nerve conduction velocity. The treatment also promoted GAP-43 expression and reduced reactive astrocytes (GFAP). MLC901 treatment activated p-AKT reduced p-GSK-3β expression levels and showed a normalized ratio (fold changes) relative to β-tubulin. Specifically, p-AKT exhibited a 4-fold increase, while p-GSK-3β showed a 2-fold decrease in T rats compared to UT rats. In conclusion, these results suggest that the treatment mitigates pathological tissue damage and effectively improves neural functional recovery following SCI, primarily by alleviating apoptosis and promoting neurogenesis. The underlying molecular mechanism of this treatment mainly involves the activation of the PI3K/AKT/GSK-3β pathway.

The wound healing mechanism is dynamic and well-orchestrated; yet, it is a complicated process. The hallmark of wound healing is to promote wound regeneration in less time without invading skin pathogens at the injury site. This study developed a sodium–carboxymethylcellulose (Na-CMC) bilayer scaffold that was later integrated with silver nanoparticles/graphene quantum dot nanoparticles (AgNPs/GQDs) as an acellular skin substitute for future use in diabetic wounds. The bilayer scaffold was prepared by layering the Na-CMC gauze onto the ovine tendon collagen type 1 (OTC-1). The bilayer scaffold was post-crosslinked with 0.1% (w/v) genipin (GNP) as a natural crosslinking agent. The physical and chemical characteristics of the bilayer scaffold were evaluated. The results demonstrate that crosslinked (CL) groups exhibited a high-water absorption capacity (>1000%) and an ideal water vapour evaporation rate (2000 g/m2 h) with a lower biodegradation rate and good hydrophilicity, compression, resilience, and porosity than the non-crosslinked (NC) groups. The minimum inhibitory concentration (MIC) of AgNPs/GQDs presented some bactericidal effects against Gram-positive and Gram-negative bacteria. The cytotoxicity tests on bilayer scaffolds demonstrated good cell viability for human epidermal keratinocytes (HEKs) and human dermal fibroblasts (HDFs). Therefore, the Na-CMC bilayer scaffold could be a potential candidate for future diabetic wound care.

Regenerative medicine represents a paradigm shift in healthcare, aiming to restore tissue and organ function through innovative therapeutic strategies. Among these, bioprinting and extracellular vesicles (EVs) have emerged as promising techniques for tissue rejuvenation. EVs are small lipid membrane particles secreted by cells, known for their role as potent mediators of intercellular communication through the exchange of proteins, genetic material, and other biological components. The integration of 3D bioprinting technology with EVs offers a novel approach to tissue engineering, enabling the precise deposition of EV-loaded bioinks to construct complex three-dimensional (3D) tissue architectures. Unlike traditional cell-based approaches, bioprinted EVs eliminate the need for live cells, thereby mitigating regulatory and financial obstacles associated with cell therapy. By leveraging the synergistic effects of EVs and bioprinting, researchers aim to enhance the therapeutic outcomes of skin regeneration while addressing current limitations in conventional treatments. This review explores the evolving landscape of bioprinted EVs as a transformative approach for skin regeneration. Furthermore, it discusses the challenges and future directions in harnessing this innovative therapy for clinical applications, emphasizing the need for interdisciplinary collaboration and continued scientific inquiry to unlock its full therapeutic potential.

Colorectal cancer (CRC) is a significant public health challenge, with 5-fluorouracil (5-FU) resistance being a major obstacle to effective treatment. Despite advancements, resistance to 5-FU remains formidable due to complex mechanisms such as alterations in drug transport, evasion of apoptosis, dysregulation of cell cycle dynamics, tumor microenvironment (TME) interactions, and extracellular vesicle (EV)-mediated resistance pathways. Traditional chemotherapy often results in high toxicity, highlighting the need for alternative approaches with better efficacy and safety. Phytochemicals (PCs) and EVs offer promising CRC therapeutic strategies. PCs, derived from natural sources, often exhibit lower toxicity and can target multiple pathways involved in cancer progression and drug resistance. EVs can facilitate targeted drug delivery, modulate the immune response, and interact with the TME to sensitize cancer cells to treatment. However, the potential of PCs and engineered EVs in overcoming 5-FU resistance and reshaping the immunosuppressive TME in CRC remains underexplored. Addressing this gap is crucial for identifying innovative therapies with enhanced efficacy and reduced toxicities. This review explores the multifaceted mechanisms of 5-FU resistance in CRC and evaluates the synergistic effects of combining PCs with 5-FU to improve treatment efficacy while minimizing adverse effects. Additionally, it investigates engineered EVs in overcoming 5-FU resistance by serving as drug delivery vehicles and modulating the TME. By synthesizing the current knowledge and addressing research gaps, this review enhances the academic understanding of 5-FU resistance in CRC, highlighting the potential of interdisciplinary approaches involving PCs and EVs for revolutionizing CRC therapy. Further research and clinical validation are essential for translating these findings into improved patient outcomes.

BackgroundLower income is associated with high incident cardiovascular disease (CVD) and mortality. CVD is an important cause of morbidity and mortality in cancer survivors. However, there is limited research on the association between income, CVD, and mortality in this population.MethodsThis study utilized nationally representative data from the National Health and Nutrition Examination Survey (NHANES), a cross-sectional survey evaluating the health and nutritional status of the US population. Our study included NHANES participants aged ≥20 years from 2003-2014, who self-reported a history of cancer. We evaluated the association between income level, prevalence of CVD, and all-cause mortality. All-cause mortality data was obtained through public use mortality files. Income level was assessed by poverty-income ratio (PIR) that was calculated by dividing family (or individual) income by poverty guideline. We used multivariable-adjusted Cox proportional hazard models through a backward elimination method to evaluate associations between PIR, CVD, and all-cause mortality in cancer survivors.ResultsThis cohort included 2,464 cancer survivors with a mean age of 62 (42% male) years. Compared with individuals with a higher PIR tertiles, those in the lowest PIR tertile had a higher rate of pre-existing CVD and post-acquired CVD. In participants with post-acquired CVD, the lowest PIR tertile had over two-fold increased risk mortality (Hazard Ratio (HR) = 2.17; 95% CI: 1.27-3.71) when compared to the highest PIR tertile. Additionally, we found that PIR was as strong a predictor of mortality in cancer survivors as CVD. In patients with no CVD, the lowest PIR tertile continued to have almost a two-fold increased risk of mortality (HR = 1.72; 95% CI: 1.69-4.35) when compared to a reference of the highest PIR tertile.ConclusionsIn this large national study of cancer survivors, low PIR is associated with a higher prevalence of CVD. Low PIR is also associated with an increased risk of mortality in cancer survivors, showing a comparable impact to that of pre-existing and post-acquired CVD. Urgent public health resources are needed to further study and improve screening and access to care in this high-risk population.

Abstract Right ventricular (RV) function and its adaptation to increased afterload [RV–pulmonary arterial (PA) coupling] are crucial in various types of pulmonary hypertension, determining symptomatology and outcome. In the course of disease progression and increasing afterload, the right ventricle undergoes adaptive remodelling to maintain right‐sided cardiac output by increasing contractility. Exhaustion of compensatory RV remodelling (RV–PA uncoupling) finally leads to maladaptation and increase of cardiac volumes, resulting in heart failure. The gold‐standard measurement of RV–PA coupling is the ratio of contractility [end‐systolic elastance (Ees)] to afterload [arterial elastance (Ea)] derived from RV pressure–volume loops obtained by conductance catheterization. The optimal Ees/Ea ratio is between 1.5 and 2.0. RV–PA coupling in pulmonary hypertension has considerable reserve; the Ees/Ea threshold at which uncoupling occurs is estimated to be ~0.7. As RV conductance catheterization is invasive, complex, and not widely available, multiple non‐invasive echocardiographic surrogates for Ees/Ea have been investigated. One of the first described and best validated surrogates is the ratio of tricuspid annular plane systolic excursion to estimated pulmonary arterial systolic pressure (TAPSE/PASP), which has shown prognostic relevance in left‐sided heart failure and precapillary pulmonary hypertension. Other RV–PA coupling surrogates have been formed by replacing TAPSE with different echocardiographic measures of RV contractility, such as peak systolic tissue velocity of the lateral tricuspid annulus (S′), RV fractional area change, speckle tracking‐based RV free wall longitudinal strain and global longitudinal strain, and three‐dimensional RV ejection fraction. PASP‐independent surrogates have also been studied, including the ratios S′/RV end‐systolic area index, RV area change/RV end‐systolic area, and stroke volume/end‐systolic volume. Limitations of these non‐invasive surrogates include the influence of severe tricuspid regurgitation (which can cause distortion of longitudinal measurements and underestimation of PASP) and the angle dependence of TAPSE and PASP. Detection of early RV remodelling may require isolated analysis of single components of RV shortening along the radial and anteroposterior axes as well as the longitudinal axis. Multiple non‐invasive methods may need to be applied depending on the level of RV dysfunction. This review explains the mechanisms of RV (mal)adaptation to its load, describes the invasive assessment of RV–PA coupling, and provides an overview of studies of non‐invasive surrogate parameters, highlighting recently published works in this field. Further large‐scale prospective studies including gold‐standard validation are needed, as most studies to date had a retrospective, single‐centre design with a small number of participants, and validation against gold‐standard Ees/Ea was rarely performed.