[Management of patent foramen ovale in non-cardiac surgery]. / Gestione della pervietà del forame ovale nella chirurgia non cardiaca.

Patent foramen ovale (PFO) is a remnant of normal fetal anatomy which may persist into adulthood, mostly asymptomatic. In some adults, PFO may result in a potential for shunting venous thromboembolism to the arterial circulation; less frequently it can cause interatrial, right-to-left shunting of deoxygenated blood. The pathogenesis of several medical conditions is related to the presence of PFO. Some randomized clinical trials have shown evidence of benefit for device closure as compared with medical therapy in patients with cryptogenic stroke. The literature reported several cases of carbon dioxide embolism during general laparoscopic surgery and sometimes stroke after laparoscopic or neurosurgery but there are neither prospective studies addressing these issues, nor randomized clinical trials assessing the effectiveness of pharmacotherapy or interventional procedures at decreasing risk. The European position paper suggests routine monitoring in non-cardiac surgery of patients with a PFO and no actual indications for closure. This article aims to further stratify the risk of periprocedural stroke and paradoxical embolism in this category of patients.

Microbiome Profiling in Bladder Cancer Patients Using the First-morning Urine Sample.

Background: Several studies support the interplay between the urinary microbiome (ie, urobiome) and bladder cancer (BCa). Specific urinary bacteria may be responsible for chronic inflammation, which in turn promotes carcinogenesis. Different signatures of urobiome in BCa patients were identified depending on tumor type, geographical area, age, and sex. Objective: We explored the urobiome in BCa patients undergoing transurethral resection of bladder tumor (TURBT), to identify possible predictive biomarkers of cancer. Design setting and participants: The urobiome analysis was conducted in 48 patients (13 females) undergoing TURBT, of whom 30 with BCa (five females) and 18 with benign bladder tumor, analyzing bacterial 16S rRNA by next-generation sequencing in first-morning (FM) urine samples. Forty-three cancer-free individuals and 17 prostate cancer patients were used as controls. Outcome measurements and statistical analysis: First, we identified the better urine collection procedure to perform the urobiome analysis, comparing bacterial composition between catheterized (CAT) and FM urine samples in TURBT patients. Successively, we observed a specific urobiome in BCa patients rather than controls. A combined pipeline including the DESeq2 and linear discriminant analysis effect size tests was used to identify differential urinary taxa, strictly associated with BCa patients. Results and limitations: The bacterial composition of CAT and FM urine samples was comparable, so the latter was used for the following analyses. An increased abundance of Porphyromonas and Porphyromonas somerae was found in BCa patients compared with controls. This signature seems to be more related (p <0.05) to male BCa patients over 50 yr old. Owing to the low biomass of urinary microbiota, several samples were excluded from the study, reducing the number of BCa patients considered. Conclusions: FM urine samples represent a manageable specimen for a urobiome analysis; P. somerae is a specific biomarker of BCa risk. Patient summary: Our study showed an increased abundance of Porphyromonas and Porphyromonas somerae in male bladder cancer (BCa) patients, supporting the use of a first-morning urine sample, a less invasive and low-cost collection method, for the urobiome analysis of patients at risk of BCa.

Development and Validation of an Explainable Radiomics Model to Predict High-Aggressive Prostate Cancer: A Multicenter Radiomics Study Based on Biparametric MRI.

In the last years, several studies demonstrated that low-aggressive (Grade Group (GG) ≤ 2) and high-aggressive (GG ≥ 3) prostate cancers (PCas) have different prognoses and mortality. Therefore, the aim of this study was to develop and externally validate a radiomic model to noninvasively classify low-aggressive and high-aggressive PCas based on biparametric magnetic resonance imaging (bpMRI). To this end, 283 patients were retrospectively enrolled from four centers. Features were extracted from apparent diffusion coefficient (ADC) maps and T2-weighted (T2w) sequences. A cross-validation (CV) strategy was adopted to assess the robustness of several classifiers using two out of the four centers. Then, the best classifier was externally validated using the other two centers. An explanation for the final radiomics signature was provided through Shapley additive explanation (SHAP) values and partial dependence plots (PDP). The best combination was a naïve Bayes classifier trained with ten features that reached promising results, i.e., an area under the receiver operating characteristic (ROC) curve (AUC) of 0.75 and 0.73 in the construction and external validation set, respectively. The findings of our work suggest that our radiomics model could help distinguish between low- and high-aggressive PCa. This noninvasive approach, if further validated and integrated into a clinical decision support system able to automatically detect PCa, could help clinicians managing men with suspicion of PCa.

Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate/High-Risk Pulmonary Embolism: Design of the Multicenter USAT IH-PE Registry and Preliminary Results.

Catheter-based revascularization procedures were developed as an alternative to systemic thrombolysis for patients with intermediate-high- and high-risk pulmonary embolisms. USAT IH-PE is a retrospective and prospective multicenter registry of such patients treated with ultrasound-facilitated, catheter-directed thrombolysis, whose preliminary results are presented in this study. The primary endpoint was the incidence of pulmonary hypertension (PH) at follow-up. Secondary endpoints were short- and mid-term changes in the echocardiographic parameters of right ventricle (RV) function, in-hospital and all-cause mortality, and procedure-related bleeding events. Between March 2018 and July 2023, 102 patients were included. The majority were at intermediate-high-risk PE (86%), were mostly female (57%), and had a mean age of 63.7 ± 14.5 years, and 28.4% had active cancer. Echocardiographic follow-up was available for 70 patients, and in only one, the diagnosis of PH was confirmed by right heart catheterization, resulting in an incidence of 1.43% (CI 95%, 0.036-7.7). RV echocardiographic parameters improved both at 24 h and at follow-up. In-hospital mortality was 3.9% (CI 95%, 1.08-9.74), while all-cause mortality was 11% (CI 95%, 5.4-19.2). Only 12% had bleeding complications, of whom 4.9% were BARC ≥ 3. Preliminary results from the USAT IH-PE registry showed a low incidence of PH, improvement in RV function, and a safe profile.

Reproducibility of an artificial intelligence optical coherence tomography software for tissue characterization: Implications for the design of longitudinal studies.

BACKGROUND: To assess the reproducibility of coronary tissue characterization by an Artificial Intelligence Optical Coherence Tomography software (OctPlus, Shanghai Pulse Medical Imaging Technology Inc.). METHODS: 74 patients presenting with multivessel ST-segment elevation myocardial infarction (STEMI) underwent optical coherence tomography (OCT) of the infarct-related artery at the end of primary percutaneous coronary intervention (PPCI) and during staged PCI (SPCI) within 7 days thereafter in the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and angioX) Treatment-Duration study (ClinicalTrials.gov, NCT01433627). OCT films were run through the OctPlus software. The same region of interest between either side of the stent and the first branch was identified on OCT films for each patient at PPCI and SPCI, thus generating 94 pairs of segments. 42 pairs of segments were re-analyzed for intra-software difference. Five plaque characteristics including cholesterol crystal, fibrous tissue, calcium, lipid, and macrophage content were analyzed for various parameters (span angle, thickness, and area). RESULTS: There was no statistically significant inter-catheter (between PPCI and SPCI) or intra-software difference in the mean values of all the parameters. Inter-catheter correlation for area was best seen for calcification [intraclass correlation coefficient (ICC) 0.86], followed by fibrous tissue (ICC 0.87), lipid (ICC 0.62), and macrophage (ICC 0.43). Some of the inter-catheter relative differences for area measurements were large: calcification 9.75 %; cholesterol crystal 74.10 %; fibrous tissue 5.90 %; lipid 4.66 %; and macrophage 1.23 %. By the intra-software measurements, there was an excellent correlation (ICC > 0.9) for all tissue types. The relative differences for area measurements were: calcification 0.64 %; cholesterol crystal 5.34 %; fibrous tissue 0.19 %; lipid 1.07 %; and macrophage 0.60 %. Features of vulnerable plaque, minimum fibrous cap thickness and lipid area showed acceptable reproducibility. CONCLUSION: The present study demonstrates an overall good reproducibility of tissue characterization by the Artificial Intelligence Optical Coherence Tomography software. In future longitudinal studies, investigators may use discretion in selecting the imaging endpoints and sample size, accounting for the observed relative differences in this study.

Characterisation of coronary microvascular dysfunction in patients with severe aortic stenosis undergoing TAVI.

BACKGROUND: Microvascular resistance reserve (MRR) is a validated measure of coronary microvascular function independent of epicardial resistances. AIMS: We sought to assess whether MRR is associated with adverse cardiac remodelling, a low-flow phenotype and extravalvular cardiac damage (EVCD) in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). METHODS: Invasive thermodilution-based assessment of the coronary microvascular function of the left anterior descending artery was performed in a prospective, multicentre cohort of patients undergoing TAVI. Coronary microvascular dysfunction (CMD) was defined as the lowest MRR tertile of the study cohort. Haemodynamic measurements were performed at baseline and then repeated immediately after TAVI. EVCD and markers of a low-flow phenotype were assessed with echocardiography. RESULTS: A total of 134 patients were included in this study. Patients with low MRR were more frequently females, had a lower estimated glomerular filtration rate and a higher rate of atrial fibrillation. MRR was significantly lower in patients with advanced EVCD (median 1.80 [1.26-3.30] vs 2.50 [1.87-3.41]; p=0.038) and in low-flow, low-gradient AS (LF LG-AS) (median 1.85 [1.20-3.04] vs 2.50 [1.87-3.40]; p=0.008). Overall, coronary microvascular function tended to improve after TAVI and, in particular, MRR increased significantly after TAVI in the subgroup with low MRR at baseline. However, MRR was significantly impaired in 38 (28.4%) patients immediately after TAVI. Advanced EVCD (adjusted odds ratio 3.08 [1.22-7.76]; p=0.017) and a low-flow phenotype (adjusted odds ratio 3.36 [1.08-10.47]; p=0.036) were significant predictors of CMD. CONCLUSIONS: In this observational, hypothesis-generating study, CMD was associated with extravalvular cardiac damage and a low-flow phenotype in patients with severe AS undergoing TAVI.

Valve-in-valve transcatheter aortic valve implantation: The issues behind crossing a bioprosthesis.

Valve-in-valve transcatheter aortic valve implantation (ViV TAVI) is rapidly arising as a safe and effective alternative to redo-surgery in the treatment of bioprostheses deterioration. While scientific community is currently focusing its attention on the most common limitations related to this procedure, such as the risk of coronary obstruction and patient-prosthesis mismatch, data regarding the first step of a ViV TAVI, the crossing of a degenerated bioprosthesis, are still lacking. The aim of this review is to analyze the available information about bioprosthesis crossing, to show the inherent challenges encountered by interventional cardiologists during valve crossing and to describe the current strategies to perform a correct crossing.

Ischemia With No Obstructive Coronary Artery Disease: Are Misdiagnosis and Undertreatment Always Behind the Corner?

Ischemia with no obstructive coronary artery disease (INOCA) is not an uncommon diagnosis in patients presenting with chest pain who undergo clinically indicated coronary angiography. However, the symptoms reported by patients with INOCA may be heterogeneous, leading to misdiagnosis and undertreatment. Herein we report 3 clinical cases of INOCA misdiagnosis and describe how the cases were reinvestigated following the appropriate diagnostic pathway. (Level of Difficulty: Advanced.).

Coronary calcification in patients presenting with acute coronary syndromes: insights from the MATRIX trial.

AIMS: The role of coronary calcification on clinical outcomes among different revascularization strategies in patients presenting with acute coronary syndromes (ACSs) has been rarely investigated. The aim of this investigation is to evaluate the role of coronary calcification, detected by coronary angiography, in the whole spectrum of patients presenting with acute ACS. METHODS AND RESULTS: The present study was a post hoc analysis of the MATRIX programme. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction (MI), or stroke up to 365 days. Among the 8404 patients randomized in the MATRIX trial, data about coronary calcification were available in 7446 (88.6%) and therefore were included in this post hoc analysis. Overall, 875 patients (11.7%) presented with severe coronary calcification, while 6571 patients (88.3%) did not present severe coronary calcification on coronary angiography. Fewer patients with severe coronary calcification underwent percutaneous coronary intervention whereas coronary artery bypass grafting or medical therapy-only was more frequent compared with patients without severe calcification. At 1-year follow-up, MACE occurred in 237 (27.1%) patients with severe calcified coronary lesions and 985 (15%) patients without severe coronary calcified lesions [hazard ratio (HR) 1.91; 95% confidence interval (CI) 1.66-2.20, P < 0.001]. All-cause mortality was 8.6% in patients presenting with and 3.7% in those without severe coronary calcification (HR 2.38, 1.84-3.09, P < 0.001). Patients with severe coronary calcification incurred higher rate of MI (20.1% vs. 11.5%, HR 1.81; 95% CI 1.53-2.1, P < 0.001) and similar rate of stroke (0.8% vs. 0.6%, HR 1.35; 95% CI 0.61-3.02, P = 0.46). CONCLUSION: Patients with ACS and severe coronary calcification, as compared to those without, are associated with worse clinical outcomes irrespective of the management strategy.

Hemodynamic failure and graft dysfunction after lung transplant: A possible clinical continuum with immediate and long-term consequences.

INTRODUCTION: The postoperative hemodynamic management after lung transplant (LUTX) is guided by limited evidence. We aimed to describe and evaluate risk factors and outcomes of postoperative vasoactive support of LUTX recipients. METHODS: In a single-center retrospective analysis of consecutive adult LUTX, two cohorts were identified: (1) patients needing prolonged vasoactive support (>12 h from ICU admission) (VASO+); (2) or not (VASO-). Postoperative hemodynamic characteristics were thoroughly analyzed. Risk factors and outcomes of VASO+ versus VASO- cohorts were assessed by multivariate logistic regression and propensity score matching. RESULTS: One hundred and thirty-eight patients were included (86 (62%) VASO+ versus 52 (38%) VASO-). Vasopressors (epinephrine, norepinephrine, dopamine) were used in the first postoperative days (vasoactive inotropic score at 12 h: 6 [4-12]), while inodilators (dobutamine, levosimendan) later. Length of vasoactive support was 3 [2-4] days. Independent predictors of vasoactive use were: LUTX indication different from cystic fibrosis (p = .003), higher Oto score (p = .020), longer cold ischemia time (p = .031), but not preoperative cardiac catheterization. VASO+ patients showed concomitant hemodynamic and graft impairment, with longer mechanical ventilation (p = .010), higher primary graft dysfunction (PGD) grade at 72 h (PGD grade > 0 65% vs. 31%, p = .004, OR 4.2 [1.54-11.2]), longer ICU (p < .001) and hospital stay (p = .013). Levosimendan as a second-line inodilator appeared safe. CONCLUSIONS: Vasoactive support is frequently necessary after LUTX, especially in recipients of grafts of lesser quality. Postoperative hemodynamic dysfunction requiring vasopressor support and graft dysfunction may represent a clinical continuum with immediate and long-term consequences. Further studies may elucidate if this represents a possible treatable condition.

Mortality across treatment strategies in intermediate-to-high risk pulmonary embolism in the modern era: A meta-analysis of observational studies and RCTs.

INTRODUCTION: Pulmonary embolism (PE) represents one of the leading causes of death worldwide and mainly treated with medical management, although the utility of more invasive approaches has emerged more recently. This meta-analysis aims to evaluate the 30-day mortality of intermediate-to-high risk PE across different treatment strategies. METHODS: A systematic literature review and meta-analysis was conducted using PubMed and Cochrane databases. All studies reporting 30-day mortality rates in intermediate-to-high-risk PE were included. Meta-regression analysis and sensitivity analysis were performed on the primary endpoint, 30-day mortality, and secondary endpoints (RV/LV ratio, mPAP, and long-term mortality, any bleeding events). RESULTS: Of the 2390 studies published between 2000 and 2022, 76 studies (74 observational and 2 RCTs for a total of 1,194,285 patients in the medical cohort and 3007 in the interventional cohort) were included. The median age was 71.4 (IQR 62.8-77.3) years, 53.6% were women. 30-day mortality in the patients treated with medical management was 9.1% (6.6-12.6). In the interventional cohort, 30-day mortality was 2.1% (1.5-3.1) while the pre- vs post-procedure change in mean difference was -6.1 mmHg (-11.2 to -1.1) for mPAP and - 0.41 (-0.51 to - 0.31) for RV/LV ratio. The overall bleeding rate in the interventional cohort was 4.9% (CI 2.6-8.9), without differences between the two strategies (RR 1.26 CI 0.89-1.78). CONCLUSION: Intermediate-high-risk mortality in pulmonary embolisms treated with medical management remains high in the modern era. Despite the absence of comparative studies, an interventional approach may have a lower 30-day mortality rate and a good safety profile.

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with ß-Thalassemia-like Phenotypes.

The erythroid transcriptional factor Krüppel-like factor 1 (KLF1) is a master regulator of erythropoiesis. Mutations that cause KLF1 haploinsufficiency have been linked to increased fetal hemoglobin (HbF) and hemoglobin A2 (HbA2) levels with ameliorative effects on the severity of ß-thalassemia. With the aim of determining if KLF1 gene variations might play a role in the modulation of ß-thalassemia, in this study we screened 17 subjects showing a ß-thalassemia-like phenotype with a slight or marked increase in HbA2 and HbF levels. Overall, seven KLF1 gene variants were identified, of which two were novel. Functional studies were performed in K562 cells to clarify the pathogenic significance of these mutations. Our study confirmed the ameliorative effect on the thalassemia phenotype for some of these variants but also raised the notion that certain mutations may have deteriorating effects by increasing KLF1 expression levels or enhancing its transcriptional activity. Our results indicate that functional studies are required to evaluate the possible effects of KLF1 mutations, particularly in the case of the co-existence of two or more mutations that could differently contribute to KLF1 expression or transcriptional activity and consequently to the thalassemia phenotype.

MRI/real-time ultrasound image fusion guided high-intensity focused ultrasound: a prospective comparative and functional analysis of different ablative techniques.

BACKGROUND: The aim of this paper was to compare safety and functional outcomes of total, hemi and focal ablation by the latest focal high-intensity focused ultrasound (HIFU) device. METHODS: This is a prospective study including patients with low to intermediate-risk PCa treated with HIFU by Focal One® device from 11/2018 to 3/2020. Before the treatment all patients underwent mp-magnetic resonance imaging (MRI) and subsequent MRI/transrectal ultrasound (TRUS) fusion and standard biopsy. Patients were stratified according to the type of ablation: total, hemi- or focal ablation. Functional data (IPSS, Quality of Life [QoL], IIEF-5, maximum flow [Qmax] and post void residual [PVR] at flowmetry) were assessed preoperatively and at 1, 3, 6 and 12 months after treatment. Moreover, the urinary symptoms reported by patients at IPSS questionnaire were divided in "irritative" and "obstructive" and compared. RESULTS: One hundred patients were enrolled. Median prostate volume and lesion diameter were 46 (IQR 25-75) mL and 10 (IQR 6-13) mm. 15, 50 and 35 patients underwent total, hemi- and focal ablation, respectively. No differences were found between them except for operative time (lower in the focal group, P<0.01). Significant lower incidence of irritative symptoms was identified in the focal group compared to the others (P<0.05 at 1 and 3 months of follow-up). No differences were found among the baseline status and the postoperative assessment in terms of obstructive IPSS items, IIEF-5, QoL, Qmax and PVR (all P value>0.05). CONCLUSIONS: Our study suggests that patients' specific HIFU tailoring with the MRI/real-time TRUS Guidance by Focal One® device is able to minimize the side effects of treatment.

Nasal Microbiome in COVID-19: A Potential Role of Corynebacterium in Anosmia.

The evolution and the development of the symptoms of Coronavirus disease 19 (COVID-19) are due to different factors, where the microbiome plays a relevant role. The possible relationships between the gut, lung, nasopharyngeal, and oral microbiome with COVID-19 have been investigated. We analyzed the nasal microbiome of both positive and negative SARS-CoV-2 individuals, showing differences in terms of bacterial composition in this niche of respiratory tract. The microbiota solution A (Arrow Diagnostics) was used to cover the hypervariable V1-V3 regions of the bacterial 16S rRNA gene. MicrobAT Suite and MicrobiomeAnalyst program were used to identify the operational taxonomic units (OTUs) and to perform the statistical analysis, respectively. The main taxa identified in nasal microbiome of COVID-19 patients and in Healthy Control subjects belonged to three distinct phyla: Proteobacteria (HC = 14%, Cov19 = 35.8%), Firmicutes (HC = 28.8%, Cov19 = 30.6%), and Actinobacteria (HC = 56.7%, Cov19 = 14.4%) with a relative abundance > 1% in all groups. A significant reduction of Actinobacteria in Cov19 group compared to controls (P < 0.001, FDR = 0.01) was found. The significant reduction of Actinobacteria was identified in all taxonomic levels down to the genus (P < 0.01) using the ANOVA test. Indeed, a significantly reduced relative abundance of Corynebacterium was found in the patients compared to healthy controls (P = 0.001). Reduced abundance of Corynebacterium has been widely associated with anosmia, a common symptom of COVID-19 as suffered from our patients. Contrastingly, the Corynebacterium genus was highly represented in the nasal mucosa of healthy subjects. Further investigations on larger cohorts are necessary to establish functional relationships between nasal microbiota content and clinical features of COVID-19.

Characterization of compliance phenotypes in COVID-19 acute respiratory distress syndrome.

BACKGROUND: Coronavirus disease 2019-associated acute respiratory distress syndrome (COVID-19 ARDS) seems to differ from the "classic ARDS", showing initial significant hypoxemia in the face of relatively preserved compliance and evolving later in a scenario of poorly compliant lungs. We tested the hypothesis that in patients with COVID-19 ARDS, the initial value of static compliance of respiratory system (Crs) (1) depends on the previous duration of the disease (i.e., the fewer days of illness, the higher the Crs and vice versa) and (2) identifies different lung patterns of time evolution and response to prone positioning. METHODS: This was a single-center prospective observational study. We enrolled consecutive mechanically ventilated patients with a diagnosis of COVID-19 who met ARDS criteria, admitted to intensive care unit (ICU). Patients were divided in four groups based on quartiles of initial Crs. Relationship between Crs and the previous duration of the disease was evaluated. Respiratory parameters collected once a day and during prone positioning were compared between groups. RESULTS: We evaluated 110 mechanically ventilated patients with a diagnosis of COVID-19 who met ARDS criteria admitted to our ICUs. Patients were divided in groups based on quartiles of initial Crs. The median initial Crs was 41 (32-47) ml/cmH2O. No association was found between the previous duration of the disease and the initial Crs. The Crs did not change significantly over time within each quartile. Positive end-expiratory pressure (PEEP) and driving pressure were respectively lower and greater in patients with lower Crs. Prone positioning significantly improved PaO2/FiO2 in the 4 groups, however it increased the Crs significantly only in patients in lower quartile of Crs. CONCLUSIONS: In our cohort, the initial Crs is not dependent on the previous duration of COVID-19 disease. Prone positioning improves oxygenation irrespective to initial Crs, but it ameliorates respiratory mechanics only in patients with lower Crs.