Examining the typical hemodynamic performance of nearly 3000 modern surgical aortic bioprostheses.

OBJECTIVES: The objective of this analysis was to assess the normal haemodynamic performance of contemporary surgical aortic valves at 1 year postimplant in patients undergoing surgical aortic valve replacement for significant valvular dysfunction. By pooling data from 4 multicentre studies, this study will contribute to a better understanding of the effectiveness of surgical aortic valve replacement procedures, aiding clinicians and researchers in making informed decisions regarding valve selection and patient management. METHODS: Echocardiograms were assessed by a single core laboratory. Effective orifice area, dimensionless velocity index, mean aortic gradient, peak aortic velocity and stroke volume were evaluated. RESULTS: The cohort included 2958 patients. Baseline age in the studies ranged from 70.1 ± 9.0 to 83.3 ± 6.4 years, and Society of Thoracic Surgeons risk of mortality was 1.9 ± 0.7 to 7.5 ± 3.4%. Twenty patients who had received a valve model implanted in fewer than 10 cases were excluded. Ten valve models (all tissue valves; n = 2938 patients) were analysed. At 1 year, population mean effective orifice area ranged from 1.46 ± 0.34 to 2.12 ± 0.59 cm2, and dimensionless velocity index, from 0.39 ± 0.07 to 0.56 ± 0.15. The mean gradient ranged from 8.6 ± 3.4 to 16.1 ± 6.2 mmHg with peak aortic velocity of 1.96 ± 0.39 to 2.65 ± 0.47 m/s. Stroke volume was 75.3 ± 19.6 to 89.8 ± 24.3 ml. CONCLUSIONS: This pooled cohort is the largest to date of contemporary surgical aortic valves with echocardiograms analysed by a single core lab. Overall haemodynamic performance at 1 year ranged from good to excellent. These data can serve as a benchmark for other studies and may be useful to evaluate the performance of bioprosthetic surgical valves over time. CLINICAL TRIAL REGISTRATION NUMBER: NCT02088554, NCT02701283, NCT01586910 and NCT01531374.

Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping-Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network­targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

The Prevalence of Coronary Artery Disease in Bicuspid Aortic Valve Patients: An Overview of the Literature.

The prevalence of coronary artery disease (CAD) in bicuspid aortic valve (BAV) patients is a debatable topic. Several studies have indicated that BAV patients have a lower prevalence of CAD compared with patients with a tricuspid aortic valve (TAV), but the effects of age and gender have not always been considered. This systematic review provides an overview of articles which report on CAD in BAV and TAV patients. Searches were executed in April 2021 and January 2022 according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines in three online databases: Medline, Embase, and Scopus. Screening and data extraction was done by two investigators separately. Primary and secondary outcomes were compared between BAV and TAV patients; a fixed effects model was used for correcting on confounders. Literature search yielded 1,529 articles with 44 being eligible for inclusion. BAV patients were younger (56.4 ± 8.3 years) than TAV patients (64 ± 10.3 years, p < 0.001). All CAD risk factors and CAD were more prevalent in TAV patients. No significant difference remained after correcting for age and gender as confounders. BAV patients have a lower prevalence of CAD and CAD risk factors compared with TAV patients. However, when the age differences between both groups are considered in the analyses, a similar prevalence of both CAD and CAD risk factors is found.

Comparative Analysis of Therapeutic Strategies in Post-Cardiotomy Cardiogenic Shock: Insight into a High-Volume Cardiac Surgery Center.

Background: Post-cardiotomy cardiogenic shock (PCCS), which is defined as severe low cardiac output syndrome after cardiac surgery, has a mortality rate of up to 90%. No study has yet been performed to compare patients with PCCS treated by conservative means to patients receiving additional mechanical circulatory support with veno-arterial extracorporeal membrane oxygenation (ECMO). Methods: A single-center retrospective analysis from January 2018 to June 2022 was performed. Results: Out of 7028 patients who underwent cardiac surgery during this time period, 220 patients (3%) developed PCCS. The patients were stratified according to their severity of shock based on the Stage Classification Expert Consensus (SCAI) group. Known risk factors for shock-related mortality, including the vasoactive-inotropic score (VIS) and plasma lactate levels, were assessed at structured intervals. In patients treated additionally with ECMO (n = 73), the in-hospital mortality rate was 60%, compared to an in-hospital mortality rate of 85% in patients treated by conservative means (non-ECMO; n = 52). In 18/73 (25%) ECMO patients, the plasma lactate level normalized within 48 h, compared to 2/52 (4%) in non-ECMO patients. The morbidity of non-ECMO patients compared to ECMO patients included a need for dialysis (42% vs. 60%), myocardial infarction (19% vs. 27%), and cerebrovascular accident (17% vs. 12%). Conclusions: In conclusion, the additional use of ECMO in PCCS holds promise for enhancing outcomes in these critically ill patients, more rapid improvement of end-organ perfusion, and the normalization of plasma lactate levels.

A precision functional atlas of personalized network topography and probabilities.

Although the general location of functional neural networks is similar across individuals, there is vast person-to-person topographic variability. To capture this, we implemented precision brain mapping functional magnetic resonance imaging methods to establish an open-source, method-flexible set of precision functional network atlases-the Masonic Institute for the Developing Brain (MIDB) Precision Brain Atlas. This atlas is an evolving resource comprising 53,273 individual-specific network maps, from more than 9,900 individuals, across ages and cohorts, including the Adolescent Brain Cognitive Development study, the Developmental Human Connectome Project and others. We also generated probabilistic network maps across multiple ages and integration zones (using a new overlapping mapping technique, Overlapping MultiNetwork Imaging). Using regions of high network invariance improved the reproducibility of executive function statistical maps in brain-wide associations compared to group average-based parcellations. Finally, we provide a potential use case for probabilistic maps for targeted neuromodulation. The atlas is expandable to alternative datasets with an online interface encouraging the scientific community to explore and contribute to understanding the human brain function more precisely.

MUC5AC concentrations in lung lavage fluids are associated with acute lung injury after cardiac surgery.

Heart surgery may be complicated by acute lung injury and adult respiratory distress syndrome. Expression and release of mucins MUC5AC and MUC5B in the lungs has been reported to be increased in acute lung injury. The aim of our study was to [1] investigate the perioperative changes of MUC5AC, MUC5B and other biomarkers in mini-bronchoalveolar lavage (minBAL), and [2] relate these to clinical outcomes after cardiac surgery. In this prospective cohort study in 49 adult cardiac surgery patients pre- and post-surgery non-fiberscopic miniBAL fluids were analysed for MUC5AC, MUC5B, IL-8, human neutrophil elastase, and neutrophils. All measured biomarkers increased after surgery. Perioperative MUC5AC-change showed a significant negative association with postoperative P/F ratio (p = 0.018), and a positive association with ICU stay (p = 0.027). In conclusion, development of lung injury after cardiac surgery and prolonged ICU stay are associated with an early increase of MUC5AC as detected in mini-BAL.

Do postoperative hemodynamic parameters add prognostic value for mortality after surgical aortic valve replacement?

Background: Although various hemodynamic parameters to assess prosthetic performance are available, prosthesis-patient mismatch (PPM) is defined exclusively by effective orifice area (EOA) index thresholds. Adjusting for the Society of Thoracic Surgeons predicted risk of mortality (STS PROM), we aimed to explore the added value of postoperative hemodynamic parameters for the prediction of all-cause mortality at 5 years after aortic valve replacement. Methods: Data were obtained from the Pericardial Surgical Aortic Valve Replacement (PERIGON) Pivotal Trial, a multicenter prospective cohort study examining the performance of the Avalus bioprosthesis. Candidate predictors were assessed at the first follow-up visit; patients who had no echocardiography data, withdrew consent, or died before this visit were excluded. Candidate predictors included peak jet velocity, mean pressure gradient, EOA, predicted and measured EOA index, Doppler velocity index, indexed internal prosthesis orifice area, and categories for PPM. The performance of Cox models was investigated using the c-statistic and net reclassification improvement (NRI), among other tools. Results: A total of 1118 patients received the study valve, of whom 1022 were eligible for the present analysis. In univariable analysis, STS PROM was the sole significant predictor of all-cause mortality (hazard ratio, 1.40; 95% confidence interval, 1.26-1.55). When extending the STS PROM with single hemodynamic parameters, neither the c-statistics nor the NRIs demonstrated added prognostic value compared to a model with STS PROM alone. Similar findings were observed when multiple hemodynamic parameters were added. Conclusions: The STS PROM was found to be the main predictor of patient prognosis. The additional prognostic value of postoperative hemodynamic parameters for the prediction of all-cause mortality was limited.

Cumulative Effects of Resting-State Connectivity Across All Brain Networks Significantly Correlate with Attention-Deficit Hyperactivity Disorder Symptoms.

Identification of replicable neuroimaging correlates of attention-deficit hyperactivity disorder (ADHD) has been hindered by small sample sizes, small effects, and heterogeneity of methods. Given evidence that ADHD is associated with alterations in widely distributed brain networks and the small effects of individual brain features, a whole-brain perspective focusing on cumulative effects is warranted. The use of large, multisite samples is crucial for improving reproducibility and clinical utility of brain-wide MRI association studies. To address this, a polyneuro risk score (PNRS) representing cumulative, brain-wide, ADHD-associated resting-state functional connectivity was constructed and validated using data from the Adolescent Brain Cognitive Development (ABCD, N = 5,543, 51.5% female) study, and was further tested in the independent Oregon-ADHD-1000 case-control cohort (N = 553, 37.4% female). The ADHD PNRS was significantly associated with ADHD symptoms in both cohorts after accounting for relevant covariates (p < 0.001). The most predictive PNRS involved all brain networks, though the strongest effects were concentrated among the default mode and cingulo-opercular networks. In the longitudinal Oregon-ADHD-1000, non-ADHD youth had significantly lower PNRS (Cohen's d = -0.318, robust p = 5.5 × 10-4) than those with persistent ADHD (age 7-19). The PNRS, however, did not mediate polygenic risk for ADHD. Brain-wide connectivity was robustly associated with ADHD symptoms in two independent cohorts, providing further evidence of widespread dysconnectivity in ADHD. Evaluation in enriched samples demonstrates the promise of the PNRS approach for improving reproducibility in neuroimaging studies and unraveling the complex relationships between brain connectivity and behavioral disorders.

A novel combination treatment for fragile X syndrome predicted using computational methods.

Fragile X syndrome is a neurodevelopmental disorder caused by silencing of the fragile X messenger ribonucleotide gene. Patients display a wide spectrum of symptoms ranging from intellectual and learning disabilities to behavioural challenges including autism spectrum disorder. In addition to this, patients also display a diversity of symptoms due to mosaicism. These factors make fragile X syndrome a difficult syndrome to manage and suggest that a single targeted therapeutic approach cannot address all the symptoms. To this end, we utilized Healx's data-driven drug discovery platform to identify a treatment strategy to address the wide range of diverse symptoms among patients. Computational methods identified the combination of ibudilast and gaboxadol as a treatment for several pathophysiological targets that could potentially reverse multiple symptoms associated with fragile X syndrome. Ibudilast is an approved broad-spectrum phosphodiesterase inhibitor, selective against both phosphodiesterase 4 and phosphodiesterase 10, and has demonstrated to have several beneficial effects in the brain. Gaboxadol is a GABAA receptor agonist, selective against the delta subunit, which has previously displayed encouraging results in a fragile X syndrome clinical trial. Alterations in GABA and cyclic adenosine monophosphate metabolism have long since been associated with the pathophysiology of fragile X syndrome; however, targeting both pathways simultaneously has never been investigated. Both drugs have a good safety and tolerability profile in the clinic making them attractive candidates for repurposing. We set out to explore whether the combination of ibudilast and gaboxadol could demonstrate therapeutic efficacy in a fragile X syndrome mouse model. We found that daily treatment with ibudilast significantly enhanced the ability of fragile X syndrome mice to perform a number of different cognitive assays while gaboxadol treatment improved behaviours such as hyperactivity, aggression, stereotypy and anxiety. Importantly, when ibudilast and gaboxadol were co-administered, the cognitive deficits as well as the aforementioned behaviours were rescued. Moreover, this combination treatment showed no evidence of tolerance, and no adverse effects were reported following chronic dosing. This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism.

A Nationwide Study on Mitral Valve Repair vs Replacement for Active Endocarditis.

BACKGROUND: Real-world evidence supporting the reproducibility and superiority of valve repair over replacement in active mitral valve infective endocarditis is lacking. METHODS: Data from a prospective nationwide database, including all cardiac surgical procedures in The Netherlands, were used. Adult patients undergoing primary mitral valve intervention who had a diagnosis of active infective endocarditis and who underwent surgery between 2013 and 2020 were included. Survival analysis was performed for the whole follow-up period as well as after applying the landmark of 90 days. RESULTS: Of 715 patients who met the inclusion criteria, 294 (41.1%) underwent valve repair. Mitral valve repair rates decreased slightly over the course of the study. The early mortality rate was 13.0%, and a trend of steadily declining early mortality rates over the course of the study, despite a steady increase in patient complexity, was observed. On risk-adjusted analysis, mitral valve replacement demonstrated inferior results when compared with valve repair (adjusted hazard ratio, 2.216; 95% CI, 1.425-3.448; P < .001), even after a landmark analysis was performed (adjusted hazard ratio 2.489; 95% CI, 1.124-5.516; P = .025). These results were confirmed by a propensity score-adjusted analysis (adjusted hazard ratio 2.251; 95% CI, 1.029-4.21; P = .042). CONCLUSIONS: Contemporary trends in mitral valve surgery for active infective endocarditis suggest growing patient complexity but slightly declining early mortality rates. A trend of decreasing mitral valve repair rates was seen. The results of this study suggest improved late outcomes of valve repair compared with valve replacement.

Oral Anticoagulation Versus Antiplatelet Treatment After Mitral Valve Repair: A Systematic Review and Meta-Analysis.

Oral anticoagulation with vitamin K antagonists is currently advised for a period of 3 months after surgical mitral valve repair, regardless of the rhythm status. The evidence supporting this recommendation is weak and recent studies have challenged the safety and efficacy of this recommendation. A systematic review of literature was conducted by searching PubMed, Embase, Web of Science, Emcare, and Cochrane Library databases for original publications comparing the efficacy and safety of oral anticoagulation with vitamin K antagonists to antiplatelet treatment early after mitral valve surgery in patients with no atrial fibrillation. Study end points included thromboembolic complications, bleeding complications and survival. A total of 5 studies, including 5,093 patients, met the inclusion criteria; 2,824 patients were included in the oral anticoagulation and 2,269 in the antiplatelet treatment group. Pooled analyses demonstrated no beneficial effect of oral anticoagulation on the incidence of thromboembolic complications (risk ratio 1.14, 95% confidence interval 0.76 to 1.70, p = 0.53, I2 = 8%). Moreover, oral anticoagulation did not result in a significantly increased risk of bleeding complications (risk ratio 0.89, 95% confidence interval 0.32 to 2.44, p = 0.81, I2 = 87%). When combining the efficacy and safety end points, no difference was observed between groups (risk ratio 1.01, 95% confidence interval 0.51 to 1.97, p = 0.99 I2 = 85%). Likewise, mortality did not differ between groups (risk ratio 0.89, 95% confidence interval 0.15 to 5.23, p = 0.90 I2 = 71%). Our results confirmed the safety but failed to confirm the efficacy of oral anticoagulation in patients who underwent mitral valve surgery. A randomized controlled trial would provide the evidence needed to support treatment recommendations.

Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers.

Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have a high frequency of CIN and TP53 mutations. Here, we show that inhibitors of the KIF18A motor protein activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells. Sensitivity to KIF18A inhibition is enriched in TP53-mutant HGSOC and TNBC cell lines with CIN features, including in a subset of CCNE1-amplified, CDK4-CDK6-inhibitor-resistant and BRCA1-altered cell line models. Our KIF18A inhibitors have minimal detrimental effects on human bone marrow cells in culture, distinct from other anti-mitotic agents. In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition.

Mitral regurgitation in atrial fibrillation: Is a simple repair enough to tackle a complex problem?

BACKGROUND: Clinical and echocardiographic results of valve repair for mitral regurgitation in the setting of atrial fibrillation are poorly studied. METHODS: Between January 2008 and December 2020, 89 patients underwent valve repair for mitral regurgitation in the setting of atrial fibrillation. Clinical and echocardiographic follow-up data were collected and studied. The primary composite endpoint consisted of all-cause mortality or hospitalization for heart failure. RESULTS: Valve repair with true-sized annuloplasty was performed in 83 (93 %) and restrictive annuloplasty in 6 (7 %) patients. Early mortality occurred in 3 (3 %) and residual mitral regurgitation in 1 (1 %) patient. During a median follow-up of 5.4 years (interquartile range 3.4-9.5), 25 patients died, 6 due to end-stage heart failure. Ten patients were hospitalized for heart failure. The estimated event-free survival rate at 10 years was 48.2 % (95 % CI 33.5 %-62.9 %). Recurrent mitral regurgitation was observed in 14 patients and most often caused by leaflet tethering. When analyzed as a time-dependent variable, recurrent regurgitation was related to the occurrence of the primary endpoint (hazard ratio 3.192, 95 % CI 1.219-8.359, p = 0.018). On exploratory sub-analyses, no recurrent regurgitation was observed after restrictive annuloplasty or in patients with paroxysmal atrial fibrillation. Moreover, recurrent regurgitation was observed more often when signs of left ventricular impairment were present preoperatively. CONCLUSIONS: Despite good initial results, recurrent regurgitation was a frequent observation after valve repair for mitral regurgitation in atrial fibrillation and had an effect on heart failure related morbidity and mortality. Refinements in the timing of surgery and surgical technique might help improve outcomes.

The impact of annuloplasty ring or band implantation on post-repair mitral valve haemodynamic performance.

OBJECTIVES: The clinical importance of optimal post-repair mitral valve diastolic performance is increasingly being recognized. The haemodynamic effect of a partial annuloplasty band implantation, in comparison to a full ring, remains insufficiently explored. METHODS: Patients undergoing mitral valve repair for pure degenerative disease between 2011 and 2019 at 2 experienced heart valve centres were eligible for inclusion. Exclusion criteria were concomitant procedures other than tricuspid valve repair and ablation procedures for atrial fibrillation. Pre-discharge and follow-up echocardiograms (1-4 years after surgery) were analysed to assess haemodynamic mitral valve performance. RESULTS: Of 535 patients meeting the inclusion criteria, 364 (68.0%) patients underwent full annuloplasty ring and 171 (31.0%) partial band implantation. On predischarge echocardiogram, post-repair mitral valve gradient and area did not differ between groups [2.89 mmHg (IQR 2.26-3.72) vs 2.60 mmHg (IQR 1.91-3.55), P = 0.19 and 1.98 cm2 (IQR 1.66-2.46) vs 2.03 cm2 (IQR 1.55-3.06), P = 0.15]. However, multivariable linear regression analysis demonstrated band annuloplasty as a determinant of larger valve area (coefficient 0.467 cm2, standard error 0.105, P < 0.001). On multivariable analysis, no significant impact on post-repair gradient was observed (-0.370 mmHg, standard error 0.167, P = 0.36). At follow-up, the differences between groups disappeared and multivariable regression analysis failed to demonstrate a significant impact of annuloplasty device type on mitral valve gradient (coefficient -0.095 mmHg, standard error 0.171, P = 1.00) or area (coefficient -0.085 cm2, standard error 0.120, P = 1.00). These results were confirmed with a linear mixed model analysis. CONCLUSIONS: Partial band annuloplasty was related to an improved haemodynamic profile directly after valve repair for degenerative disease but the effect was short-lived. Our results suggest that the type of annuloplasty device has no durable impact on diastolic valve performance.

Aortic valve visualization and pressurization device: a novel device for intraoperative evaluation of aortic valve repair procedures.

OBJECTIVES: Aortic valve repair procedures are technically challenging, and current intraoperative evaluation methods often fail to predict the final echocardiographic result. We have developed a novel intraoperative aortic valve visualization and pressurization (AVP) device, enabling valve inspection under physiological conditions, and measuring aortic valve insufficiency (AI) during cardioplegic arrest. METHODS: The AVP device is attached to the (neo)aorta, after any type of aortic valve repair, while the heart is arrested. The root is pressurized (60-80 mmHg) using a saline solution and an endoscope is introduced. The valve is inspected, and the amount of valvular leakage is measured. Postoperative 'gold standard' transesophageal echocardiogram measurements of AI are performed and compared against regurgitation volume measured. RESULTS: In 24 patients undergoing valve-sparing root replacement, the AVP device was used. In 22 patients, postoperative echocardiographic AI was ≤ grade 1. The median leakage was 90 ml/min, IQR 60-120 ml/min. In 3 patients, additional adjustments after visual inspection was performed. In 2 patients, with complex anatomy, the valve was replaced. In one, after evaluation with the device, there was undesirable result visually and residual AI of 330 ml/min, and in another, 260 ml/min residual AI was measured and valve restriction on visual inspection. CONCLUSIONS: The novel AVP device enables intraoperative evaluation of the valve under physiological conditions, while still on arrested heart, and allows for targeted adjustments. The AVP device can be an important aid for intraoperative evaluation of the aortic valve, during valve repair and valve-sparing procedures, thereby making the operative result more predictable and the operation more efficient.

Closed-Loop ventilation using sidestream versus mainstream capnography for automated adjustments of minute ventilation-A randomized clinical trial in cardiac surgery patients.

BACKGROUND: INTELLiVENT-Adaptive Support Ventilation (ASV) is a closed-loop ventilation mode that uses capnography to adjust tidal volume (VT) and respiratory rate according to a user-set end-tidal CO2 (etCO2) target range. We compared sidestream versus mainstream capnography with this ventilation mode with respect to the quality of breathing in patients after cardiac surgery. METHODS: Single-center, single-blinded, non-inferiority, randomized clinical trial in adult patients scheduled for elective cardiac surgery that were expected to receive at least two hours of postoperative ventilation in the ICU. Patients were randomized 1:1 to closed-loop ventilation with sidestream or mainstream capnography. Each breath was classified into a zone based on the measured VT, maximum airway pressure, etCO2 and pulse oximetry. The primary outcome was the proportion of breaths spent in a predefined 'optimal' zone of ventilation during the first three hours of postoperative ventilation, with a non-inferiority margin for the difference in the proportions set at -20%. Secondary endpoints included the proportion of breaths in predefined 'acceptable' and 'critical' zones of ventilation, and the proportion of breaths with hypoxemia. RESULTS: Of 80 randomized subjects, 78 were included in the intention-to-treat analysis. We could not confirm the non-inferiority of closed-loop ventilation using sidestream with respect to the proportion of breaths in the 'optimal' zone (mean ratio 0.87 [0.77 to ∞]; P = 0.116 for non-inferiority). The proportion of breaths with hypoxemia was higher in the sidestream capnography group versus the mainstream capnography group. CONCLUSIONS: We could not confirm that INTELLiVENT-ASV using sidestream capnography is non-inferior to INTELLiVENT-ASV using mainstream capnography with respect to the quality of breathing in subjects receiving postoperative ventilation after cardiac surgery. TRIAL REGISTRATION: NCT04599491 (clinicaltrials.gov).

Intrinsic histological and morphological abnormalities of the pediatric thoracic aorta in bicuspid aortic valve patients are predictive for future aortopathy.

BACKGROUND: Patients with a bicuspid aortic valve (BAV) have an increased risk to develop aortic complications. Many studies are pointing towards a possible embryonic explanation for the development of both a bicuspid aortic valve as well as a defective ascending aortic wall in these patients. The fetal and newborn ascending aortic wall has however scarcely been studied in bicuspid aortic valve patients. We hypothesize that early histopathological defects might already be visible in the fetal and pediatric ascending aortic wall of bicuspid aortic valve patients, indicating at an early embryonic defect. METHODS: Non-dilated BAV ascending aortic wall samples were collected (n = 40), categorized in five age groups: premature (age range 17.5 weeks + days GA till 37.6 weeks + days GA) 2. neonate (age range 1 - 21 days) 3. infant (age range 1 month - 4 years) 4. adolescent (age range 12 years - 15 years) and 5. adult (age range 41 - 72 years). Specimen were studied for intimal and medial histopathological features. RESULTS: The premature ascending aortic wall has a significantly thicker intimal and significantly thinner medial layer as compared to all other age categories (p < 0.05). After birth the intimal thickness decreases significantly. The medial layer increases in thickness before adulthood (p < 0.05) with an increasing number of elastic lamellae (p < 0.01) and interlamellar mucoid extracellular matrix accumulation (p < 0.0001). Intimal atherosclerosis was scarce and medial histopathological features such as overall medial degeneration, smooth muscle cell nuclei loss and elastic fiber fragmentation were not appreciated in the BAV ascending aortic wall of any age. CONCLUSIONS: The main characteristics of a bicuspid ascending aortic wall are already present before adulthood, albeit not before birth. Considering the early manifestations of ascending aortic wall pathology in bicuspid aortic valve patients, the pediatric population should be considered while searching for markers predictive for future aortopathy.

Confounding adjustment in observational studies on cardiothoracic interventions: a systematic review of methodological practice.

OBJECTIVES: It is unknown which confounding adjustment methods are currently used in the field of cardiothoracic surgery and whether these are appropriately applied. The aim of this study was to systematically evaluate the quality of conduct and reporting of confounding adjustment methods in observational studies on cardiothoracic interventions. METHODS: A systematic review was performed, which included all observational studies that compared different interventions and were published between 1 January and 1 July 2022, in 3 European and American cardiothoracic surgery journals. Detailed information on confounding adjustment methods was extracted and subsequently described. RESULTS: Ninety-two articles were included in the analysis. Outcome regression (n = 49, 53%) and propensity score (PS) matching (n = 44, 48%) were most popular (sometimes used in combination), whereas 11 (12%) studies applied no method at all. The way of selecting confounders was not reported in 42 (46%) of the studies, solely based on previous literature or clinical knowledge in 14 (16%), and (partly) data-driven in 25 (27%). For the studies that applied PS matching, the matched cohorts comprised on average 46% of the entire study population (range 9-82%). CONCLUSIONS: Current reporting of confounding adjustment methods is insufficient in a large part of observational studies on cardiothoracic interventions, which makes quality judgement difficult. Appropriate application of confounding adjustment methods is crucial for causal inference on optimal treatment strategies for clinical practice. Reporting on these methods is an important aspect of this, which can be improved.