IoT-Based Framework for Digital Twins in the Industry 5.0 Era.

Digital twins are considered the next step in IoT-based cyber-physical systems; they allow for the real-time monitoring of assets, and they provide a comprehensive understanding of a system behavior, allowing for data-driven insights and informed choices. However, no comprehensive framework exists for the development of IoT-based digital twins. Moreover, the existing frameworks do not consider the aspects introduced by the Industry 5.0 paradigm, such as sustainability, human-centricity, and resilience. This paper proposes a framework based on the one defined as the outcome of a project funded by the European Union between 2010 and 2013 called the IoT Architectural Reference Model (IoT-A or IoT-ARM), with the aim of the development and implementation of a standard IoT framework that includes digital twins. This framework establishes and implements a standardized collection of architectural instruments for modeling IoT systems in the 5.0 era, serving as a benchmark for the design and implementation of an IoT architecture focused on digital twins and enabling the sustainability, resilience, and human-centricity of the information system. Furthermore, a proof of concept of a monitoring digital twin for a vertical farming system has been developed to test the validity of the framework, and a discussion of applications in the manufacturing and service sectors is presented.

Diagnostic and predictive value of speckle tracking echocardiography in cardiac sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease that may affect the myocardium. This study evaluated the diagnostic and prognostic value of 2-dimensional speckle tracking echocardiography in cardiac sarcoidosis (CS). METHODS: Eighty-three patients with extracardiac, biopsy-proven sarcoidosis and definite/probable diagnosis of cardiac involvement diagnosed from January 2005 through December 2016 were included. Strain parameters in early stages of CS, in a subgroup of 23 CS patients with left ventricular ejection fraction (LVEF) within normal limits (LVEF> 52% for men: > 54% for women, mean value: 57.3% ± 3.8%) and no wall motion abnormalities was compared with 97 controls (1:4) without cardiac disease. LV and right ventricular (RV) global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain and strain rate (SR) analyses were performed with TomTec software and correlated with cardiac outcomes (including heart failure and arrhythmias). This study was approved by the Mayo Clinic Institutional Review Board, and all patients gave informed written consent to participate. RESULTS: Mean age of CS patients was 53.6 ± 10.8 years, and 34.9% were women. Mean LVEF was 43.2% ± 12.4%; LV GLS, - 12.4% ± 3.7%; LV GCS, - 17.1% ± 6.5%; LV GRS, 29.3% ± 12.8%; and RV wall GLS, 14.6% ± 6.3%. In the 23 patients with early stage CS with normal LVEF and RV systolic function, strain parameters were significantly reduced when compared with controls (respectively: LV GLS, - 15.9% ± 2.5% vs - 18.2% ± 2.7% [P = .001]; RV GLS, - 16.9% ± 4.5% vs - 24.1% ± 4.0% [P < .001]). A LV GLS value of - 16.3% provided 82.2% sensitivity and 81.2% specificity for the diagnosis of CS (AUC 0.91), while a RV value of - 19.9% provided 88.1% sensitivity and 86.7% specificity (AUC 0.93). Hospital admission and heart failure significantly correlated to impaired LV GLS (> - 14%). CONCLUSION: Reduced strain values in the LV GLS and RV GLS can be used in the diagnostic algorithm in patients with suspicion of cardiac sarcoidosis. These values also correlate with adverse cardiovascular events.

Cells Adhering to 3D Vertical Nanostructures: Cell Membrane Reshaping without Stable Internalization.

The dynamic interface between the cellular membrane and 3D nanostructures determines biological processes and guides the design of novel biomedical devices. Despite the fact that recent advancements in the fabrication of artificial biointerfaces have yielded an enhanced understanding of this interface, there remain open questions on how the cellular membrane reacts and behaves in the presence of sharp objects on the nanoscale. Here we provide a multifaceted characterization of the cellular membrane's mechanical stability when closely interacting with high-aspect-ratio 3D vertical nanostructures, providing strong evidence that vertical nanostructures spontaneously penetrate the cellular membrane to form a steady intracellular coupling only in rare cases and under specific conditions. The cell membrane is able to conform tightly over the majority of structures with various shapes while maintaining its integrity.

Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management.

OBJECTIVE: An accurate "molecular" diagnosis and classification of similar but distinct diseases is sometime challenging but often crucial for the definition of the appropriate patient medical management and treatment as well as for genetic counseling and risk assessment in families. The advent of next-generation sequencing (NGS), which analysed all known disease-associated genes in parallel in a cost- and time-effective manner, eased this process of disease definition and also for vascular anomalies that are a heterogeneous group of vascular tumors and congenital circulatory malformations and often characterized by overlapping phenotypes. METHODS: We designed a NGS-based screening of the 25 currently most prevalent genes identified in patients with vascular anomalies with Mendelian inheritance and applied this panel to study the DNA of 150 patients affected with vascular anomalies for autosomal recessive and autosomal dominant variants and to analyse the paired blood and DNA from intralesional biopsy specimens in 17 patients for somatic unbalance. Results were confirmed with Sanger sequencing. RESULTS: We identified 14 pathogenic variants in 13 of 150 patients. Eight variants were previously reported as a disease-causing variant, and six were new. In 55 additional probands we detected 75 variants with unknown significance. Moreover, a previously reported somatic variant was detected in five of 17 available tissue biopsy specimens. CONCLUSIONS: Our results show that many genes can cause a wide variety of syndromic and nonsyndromic disorders, confirming that genetic testing by NGS is the approach of choice to diagnose heritable vascular anomalies, especially, but not only, when an intralesional biopsy specimen is available. The identification of the causative genes and the possibility of tracing somatic variants in tissues provide important information about etiology, patient clinical management, and treatment, and it could highlight otherwise unsuspected clinical situations.

Arterial hypertension and cancer.

Arterial hypertension and cancer are two of the most important causes of mortality in the world; correlations between these two clinical entities are complex and various. Cancer therapy using old (e.g., mitotic spindle poisons) as well as new (e.g., monoclonal antibody) drugs may cause arterial hypertension through different mechanisms; sometimes the increase of blood pressure levels may be responsible for chemotherapy withdrawal. Among newer cancer therapies, drugs interacting with the VEGF (vascular endothelial growth factors) pathways are the most frequently involved in hypertension development. However, many retrospective studies have suggested a relationship between antihypertensive treatment and risk of cancer, raising vast public concern. The purposes of this brief review have then been to analyse the role of chemotherapy in the pathogenesis of hypertension, to summarize the general rules of arterial hypertension management in this field and finally to evaluate the effects of antihypertensive therapy on cancer disease.

The role of elasticity on adhesion and clustering of neurons on soft surfaces.

The question of whether material stiffness enhances cell adhesion and clustering is still open to debate. Results from the literature are seemingly contradictory, with some reports illustrating that adhesion increases with surface stiffness and others suggesting that the performance of a system of cells is curbed by high values of elasticity. To address the role of elasticity as a regulator in neuronal cell adhesion and clustering, we investigated the topological characteristics of networks of neurons on polydimethylsiloxane (PDMS) surfaces - with values of elasticity (E) varying in the 0.55-2.65 MPa range. Results illustrate that, as elasticity increases, the number of neurons adhering on the surface decreases. Notably, the small-world coefficient - a topological measure of networks - also decreases. Numerical simulations and functional multi-calcium imaging experiments further indicated that the activity of neuronal cells on soft surfaces improves for decreasing E. Experimental findings are supported by a mathematical model, that explains adhesion and clustering of cells on soft materials as a function of few parameters - including the Young's modulus and roughness of the material. Overall, results indicate that - in the considered elasticity interval - increasing the compliance of a material improves adhesion, improves clustering, and enhances communication of neurons.

Analysis of low-carbon technology innovation efficiency and its influencing factors based on triple helix theory: Evidence from new energy enterprises in China.

Background and aim: Low-carbon technology innovation(L-CTI) is an essential way to realize the socio-economic transition to a low-carbon model. However, relatively few studies have been conducted on the calculation of low-carbon technology innovation efficiency(L-CTIE) and the identification of factors influencing it. The study intends to assess the L-CTIE of new energy enterprises(L-CTI-NEEs) and to analyze its influencing factors, so as to further improve the L-CTIE capability. Methods: Using the panel data of new energy enterprises(NEEs) in 2010-2020, DEA(BCC)-Malmquist-Tobit method is constructed to static and dynamic evaluate the L-CTIE of new energy enterprises(L-CTIE-NEEs), and analyze its influencing factors with triple helix theory. Results: During the study period, the L-CTIE among NEEs was quite different, and the Malmquist index change trend had phased characteristics. From the perspective of factors influencing innovation efficiency, technology integration capacity of enterprises, support intensity of government and cooperation scale of government-enterprises-universities & research institutions play a crucial part in promoting the EEFCH, PECH and SECH of L-CTIE-NEEs, while resource conversion capacity of universities & research institutions only promotes PECH. Conclusion: According to the research results, a triple helix model of L-CTI-NEEs is constructed to enhance its L-CTIE level.

Between psychopathy and deviant socialization: A close look at the mafia men.

The Italian mafia organizations represent a subculture with values, beliefs and goals that are antithetical to and undermining of the predominant society. The conduct of individual members includes such extreme violence for material gain, it may at least superficially suggest a severe personality disorder. Since the first edition of the DSM and into the 21st century, various terms have been used, sometimes interchangeably, but over time inconsistently, to designate the mentality and practices of mafia members. Only recently has the psychology of mafia members become a focus of serious scientific study. Following broader national multicenter research, the present study aimed at investigating the possible differences in psychopathy between those mafia associates who had been convicted only of mafia association (Group A, bosses), and those who were also convicted of violent crimes (Group B, soldiers). The Psychopathy Checklist-Revised (PCL-R) was administered to n = 48 male inmates convicted of mafia association (Mage 45.0 years, SD 10.9, range 20-80 years); Group A consisted of n = 26 (54%) subjects, Group B n = 22 (46%). Most of the sample (73%) did not manifest psychopathy (PCL-R ≥ 25) nor Mann-Whitney U test disclosed significant differences in the total PCL-R scores between the study groups. We found significantly higher scores of PCR-R factor 1 (interpersonal / affective) in the members of the mafia association also convicted of violent crimes (PCL-R F1, group A: 5.8 ± 3.7; group B: 7.9 ± 3.5; p < 0.05), this difference appeared explainable on the basis of a higher component of affective psychopathy. These initial results add to the limited literature on mafia and psychopathy and seem to suggest the existence of a specific component of psychopathy in the subgroup of mafiosi with overtly violent conduct.

Detection of Early Myocardial Dysfunction by Imaging Biomarkers in Cancer Patients Undergoing Photon Beam vs. Proton Beam Radiotherapy: A Prospective Study.

1. Background: We sought to determine acute and subacute changes in cardiac function after proton beam (PBT) and photon beam (PhT) radiotherapy (RT) using conventional and two-dimensional speckle tracking echocardiography (2D-STE) in patients with malignant breast and thoracic tumors. 2. Methods: Between March 2016 and March 2017, 70 patients with breast or thoracic cancer were prospectively enrolled and underwent transthoracic echocardiography with comprehensive strain analysis at pretreatment, mid-treatment, end of treatment, and 3 months after RT. 3. Results: PBT was used to treat 44 patients; PhT 26 patients. Mean ± SD age was 55 ± 12 years; most patients (93%) were women. The median (interquartile range) of the mean heart dose was lower in the PBT than the PhT group (47 [27-79] vs. 217 [120-596] cGy, respectively; p < 0.001). Ejection fraction did not change in either group. Only the PhT group had reduced systolic tissue Doppler velocities at 3 months. 2D-STE showed changes in endocardial and epicardial longitudinal, radial, and circumferential early diastolic strain rate (SRe) in patients undergoing PhT (global longitudinal SRe, pretreatment vs. end of treatment (p = 0.04); global circumferential SRe, pretreatment vs. at 3-month follow-up (p = 0.003); global radial SRe, pretreatment vs. at 3-month follow-up (p = 0.02) for endocardial values). Epicardial strain values decreased significantly only in patients treated with PhT. Patients in the PhT group had a significant decrease in epicardial global longitudinal systolic strain rate (GLSRs) (epicardial GLSRs, at baseline vs. at end of treatment [p = 0.009]) and in GCSRe and GRSRe (epicardial GCSRe, at baseline vs. at 3-month follow-up (p = 0.02); epicardial GRSRe, at baseline vs. at 3-month follow-up (p = 0.03)) during treatment and follow-up. No changes on 2D-STE were detected in the PBT group. 4. Conclusions: Patients who underwent PhT but not PBT had reduced tissue Doppler velocities and SRe values during follow-up, suggesting early myocardial relaxation abnormalities. PBT shows promise as a cardiac-sparing RT technology.

All-Optical and Label-Free Stimulation of Action Potentials in Neurons and Cardiomyocytes by Plasmonic Porous Metamaterials.

Optical stimulation technologies are gaining great consideration in cardiology, neuroscience studies, and drug discovery pathways by providing control over cell activity with high spatio-temporal resolution. However, this high precision requires manipulation of biological processes at genetic level concealing its development from broad scale application. Therefore, translating these technologies into tools for medical or pharmacological applications remains a challenge. Here, an all-optical nongenetic method for the modulation of electrogenic cells is introduced. It is demonstrated that plasmonic metamaterials can be used to elicit action potentials by converting near infrared laser pulses into stimulatory currents. The suggested approach allows for the stimulation of cardiomyocytes and neurons directly on commercial complementary metal-oxide semiconductor microelectrode arrays coupled with ultrafast pulsed laser, providing both stimulation and network-level recordings on the same device.

Cardiovascular Organ Damage in Clinical Subtypes of Systemic Sclerosis: Arterial Stiffness and Echocardiography Might Not Be the Ideal Tools for Patient Risk Stratification.

BACKGROUND: Vascular damage is recognized as a diagnostic landmark in systemic sclerosis (SSc), both in its limited and diffuse subtypes. Early detection at a subclinical stage with transthoracic echocardiography (TTE) and carotid femoral pulse wave velocity (cfPWV) may be helpful in therapeutic planning and management. Aim of the Study. The aim of the study was to evaluate presence of subclinical cardiovascular damage in patients with limited and diffuse SSc in comparison with a cohort of healthy individuals. METHODS: Consecutive patients with limited and diffuse SSc underwent complete TTE and cfPWV and a complete review of clinical data. As controls, 23 healthy subjects with similar hemodynamic profiles were selected. RESULTS: 41 patients (35 female, aged 56.9 years), 21 with diffuse and 20 with limited SSc, were recruited. Past medical history, cardiovascular risk factors, gender distribution, and disease duration were similar in the two groups as well as TTE parameters and hemodynamic indexes-cfPWV (6.5 [6-6.8] vs. 7.0 [6.2-8.5], p=0.24) and augmentation index (145.6 ± 14.2 vs. 149 ± 20.6, p=0.52). Patients with limited SSc were 10 years older than patients with diffuse SSc. In the multiple regression analysis, only age (p=0.0154) and disease duration (p=0.0467) resulted as the significant determinant of cfPWV. When compared to healthy controls, no significant difference emerged in TTE or hemodynamic indexes. CONCLUSION: In SSc, cfPWV increases with age, with no additional impact of pathology or subtype. Vascular damage in the SSc population is not accurately reflected in increased arterial stiffness, as evaluated with cfPWV, or classically defined echocardiographic findings of organ damage (i.e., left ventricular concentric remodelling and increased filling pressures).

Multiple Myeloma Patients Undergoing Carfilzomib: Development and Validation of a Risk Score for Cardiovascular Adverse Events Prediction.

Cardiovascular adverse events (CVAEs) are linked to Carfilzomib (CFZ) therapy in multiple myeloma (MM); however, no validated protocols on cardiovascular risk assessment are available. In this prospective study, the effectiveness of the European Myeloma Network protocol (EMN) in cardiovascular risk assessment was investigated, identifying major predictors of CVAEs. From January 2015 to March 2020, 116 MM patients who had indication for CFZ therapy underwent a baseline evaluation (including blood pressure measurements, echocardiography and arterial stiffness estimation) and were prospectively followed. The median age was 64.53 ± 8.42 years old, 56% male. Five baseline independent predictors of CVAEs were identified: office systolic blood pressure, 24-h blood pressure variability, left ventricular hypertrophy, pulse wave velocity value and global longitudinal strain. The resulting 'CVAEs risk score' distinguished a low- and a high-risk group, obtaining a negative predicting value for the high-risk group of 90%. 52 patients (44.9%) experienced one or more CVAEs: 17 (14.7%) had major and 45 (38.7%) had hypertension-related events. In conclusion, CVAEs are frequent and a specific management protocol is crucial. The EMN protocol and the risk score proved to be useful to estimate the baseline risk for CVAEs during CFZ therapy, allowing the identification of higher-risk patients.

Effects of Carfilzomib Therapy on Left Ventricular Function in Multiple Myeloma Patients.

Background: Carfilzomib improves the prognosis of multiple myeloma (MM) patients but significantly increases cardiovascular toxicity. The timing and effect of Carfilzomib therapy on the left ventricular function is still under investigation. We sought to assess the echocardiographic systo-diastolic changes, including global longitudinal strain (GLS), in patients treated with Carfilzomib and to identify predictors of increased risk of cardiovascular adverse events (CVAEs) during therapy. Methods: Eighty-eight patients with MM performed a baseline cardiovascular evaluation comprehensive of transthoracic echocardiogram (TTE) before the start of Carfilzomib therapy and after 6 months. All patients were clinically followed up to early identify the occurrence of CVAEs during the whole therapy duration. Results: After Carfilzomib treatment, mean GLS slightly decreased (-22.2% ± 2.6 vs. -21.3% ± 2.5; p < 0.001). Fifty-eight percent of patients experienced CVAEs during therapy: 71% of them had uncontrolled hypertension, and 29% had major CVAEs or CV events not related to arterial hypertension. GLS variation during therapy was not related to an increased risk of CVAEs; however, patients with baseline GLS ≥ -21% and/or left ventricular ejection fraction (LVEF) ≤ 60% had a greater risk of major CVAEs (OR = 6.2, p = 0.004; OR = 3.7, p = 0.04, respectively). Carfilzomib led to a higher risk of diastolic dysfunction (5.6 vs. 13.4%, p = 0.04) and to a rise in E/e' ratio (8.9 ± 2.7 vs. 9.7 ± 3.7; p = 0.006). Conclusion: Carfilzomib leads to early LV function impairment early demonstrated by GLS changes and diastolic dysfunction. Baseline echocardiographic parameters, especially GLS and LVEF, might improve cardiovascular risk stratification before treatment.

Central pulse pressure is inversely associated with proximal aortic remodelling.

OBJECTIVES: Hypertension leads to aortic stiffening and dilatation but unexpected data from the Framingham Heart Study showed an inverse relationship between brachial pulse pressure and aortic diameter. Aortic dilatation would not only lead to lower pulse pressure but also to a worse prognosis (cardiac events, heart failure). Invasive pressure may be more informative but data are lacking. AIM: This study evaluated the relationship between invasively measured central blood pressure and proximal aortic diameter. METHODS: In 71 consecutive patients referred to invasive haemodynamic study, proximal aortic remodelling was evaluated in terms of Z-score, comparing diameters measured at the sinus of Valsalva to the diameter expected according to patients' age, sex and body height. Pressures were recorded directly in the proximal aorta by means of a catheter before coronary assessment. RESULTS: The mean invasive aortic SBPs and DBPs were 146 ±â€Š23 and 78 ±â€Š13 mmHg, respectively, giving a central pulse pressure (cPP inv) of 68 ±â€Š21 mmHg. Proximal aortic diameter was 34.9 ±â€Š19.4 mm, whereas Z-score was -0.3 ±â€Š1.7. Patients with higher cPPinv showed a significantly lower Z-score (-0.789 vs. 0.155, P = 0.001). cPPinv was inversely related to Z-score (R = -0.271, P = 0.022) independently from age, mean blood pressure and heart rate (ß = -0.241, P = 0.011). CONCLUSION: Aortic root Z-score is inversely associated with invasively measured central pulse pressure in a cohort of patients undergoing invasive coronary assessment. Remodelling at the sinuses of Valsalva may be a compensatory mechanism to limit pulse pressure.

Prognostic role of the ascending aorta dilatation in patients with arterial hypertension.

BACKGROUND: Ascending aorta (ASC) dilatation (AAD) is a common finding in arterial hypertension, affecting about 15% of hypertensive patients. AAD is associated with an increase in cardiac and vascular hypertension-related organ damage, but its prognostic role is unknown. The aim of the study was to evaluate the prognostic value of AAD as predictor of cardiovascular events in essential hypertensive patients. METHODS: Recruited patients underwent two-dimensional transthoracic echocardiography from 2007 to 2013 and followed-up for cardiovascular events until November 2018 by phone call and hospital information system check. ASC diameter and AAD were defined using both absolute and scaled definitions. Four hundred and twenty-three hypertensive patients were included in our study. RESULTS: During a median follow-up of 7.4 years (interquartile range 5.6-9.1 years), 52 events were observed. After adjusting for age, sex and BSA, both ASC diameter and AAD definition, according to ARGO-SIIA project, resulted associated with a greater risk of cardiovascular event (both P < 0.010), even after adjusting for major confounders (both P < 0.010). Moreover, we observed that the assessment of ASC improves risk stratification compared with pulse wave velocity alone, and that in absence of AAD, sinus of valsalva dilatation lost any prognostic value (P = 0.262). CONCLUSIONS: ASC diameter and AAD are both associated with a greater risk of cardiovascular events. ASC should be assessed to optimize risk stratification in hypertensive patients and its dilatation may be considered as a surrogate for vascular organ damage.

Microfluidic Multielectrode Arrays for Spatially Localized Drug Delivery and Electrical Recordings of Primary Neuronal Cultures.

Neuropathological models and neurological disease progression and treatments have always been of great interest in biomedical research because of their impact on society. The application of in vitro microfluidic devices to neuroscience-related disciplines provided several advancements in therapeutics or neuronal modeling thanks to the ability to control the cellular microenvironment at spatiotemporal level. Recently, the introduction of three-dimensional nanostructures has allowed high performance in both in vitro recording of electrogenic cells and drug delivery using minimally invasive devices. Independently, both delivery and recording have let to pioneering solutions in neurobiology. However, their combination on a single chip would provide further fundamental improvements in drug screening systems and would offer comprehensive insights into pathologies and diseases progression. Therefore, it is crucial to develop platforms able to monitor progressive changes in electrophysiological behavior in the electrogenic cellular network, induced by spatially localized injection of biochemical agents. In this work, we show the application of a microfluidic multielectrode array (MEA) platform to record spontaneous and chemically stimulated activity in primary neuronal networks. By means of spatially localized caffeine injection via microfluidic nanochannels, the device demonstrated its capability of combined localized drug delivery and cell signaling recording. The platform could detect activity of the neural network at multiple sites while delivering molecules into just a few selected cells, thereby examining the effect of biochemical agents on the desired portion of cell culture.

Intracellular Recording of Human Cardiac Action Potentials on Market-Available Multielectrode Array Platforms.

High quality attenuated intracellular action potentials from large cell networks can be recorded on multi-electrode arrays by means of 3D vertical nanopillars using electrical pulses. However, most of the techniques require complex 3D nanostructures that prevent the straightforward translation into marketable products and the wide adoption in the scientific community. Moreover, 3D nanostructures are often delicate objects that cannot sustain several harsh use/cleaning cycles. On the contrary, laser optoacoustic poration allows the recording of action potentials on planar nanoporous electrodes made of noble metals. However, these constraints of the electrode material and morphology may also hinder the full exploitation of this methodology. Here, we show that optoacoustic poration is also very effective for porating cells on a large family of MEA electrode configurations, including robust electrodes made of nanoporous titanium nitride or disordered fractal-like gold nanostructures. This enables the recording of high quality cardiac action potentials in combination with optoacoustic poration, providing thus attenuated intracellular recordings on various already commercial devices used by a significant part of the research and industrial communities.

Arterial Hypertension and Multiple Myeloma: Physiopathology and Cardiovascular Risk and 'Practical' Indications in Patients Receiving Carfilzomib.

The introduction of carfilzomib in the treatment of relapsing and refractory multiple myeloma has allowed a significant increase in survival. The most frequent adverse effect of Carfilzomib treatment is arterial hypertension, even though the exact physiopathological mechanism are still unclear. MM patients, on the other hand, often present significant cardiovascular risk factors and comorbidities. Uncontrolled hypertension is frequently the cause of cardiovascular complications. It has been estimated that up to 50% of subjects in the general population are unaware of their hypertensive condition and only half of those who are aware of this risk factor present good control of blood pressure. Although the management of arterial hypertension is clearly important in reducing the risk of cardiovascular events, and is well described by the current guidelines, no clear indications are provided on how to approach and treat specifically MM patients undergoing treatment with proteasome inhibitors. The aim of our work is to summarize a practical approach to the stratification of cardiovascular risk of hypertensive in patients who are candidates for or actively treated with carfilzomib for refractory multiple myeloma (MMR). MM patients eligible for carfilzomib treatment should preliminary undergo a careful cardiovascular risk stratification. Perspective studies will help to better identify the specific risk factors that should be considered and treated in these patients.

Cardiovascular Organ Damage and Blood Pressure Levels Predict Adverse Events in Multiple Myeloma Patients Undergoing Carfilzomib Therapy.

Carfilzomib is a second-generation proteasome inhibitor approved for the treatment of multiple myeloma (MM). It seems to determine cardiovascular toxicity, primarily arterial hypertension. No predictive factors for cardiovascular adverse events (CVAEs) are known in patients affected by multiple myeloma treated with carfilzomib. We evaluated the role of cardiovascular organ damage parameters to predict CVAEs in MM patients taking carfilzomib. Seventy patients affected by MM were prospectively enrolled. A comprehensive cardiovascular evaluation was performed before carfilzomib therapy; they underwent a transthoracic echocardiogram and the assessment of carotid-femoral pulse wave velocity. All the patients were followed up (FU) to determine the incidence of CVAEs. The mean age was 60.3 ± 8.2, and 51% were male. The median FU was 9.3 (4.3; 20.4) months. A proportion of 33% experienced CVAEs, 91% of them had uncontrolled hypertension, 4.5% acute coronary syndrome, and 4.5% cardiac arrhythmias. Subjects with CVAEs after carfilzomib treatment had significantly higher blood pressure values, left ventricular mass (98 ± 23 vs. 85 ± 17 g/m2, p = 0.01), and pulse wave velocity (8.5 ± 1.7 vs. 7.5 ± 1.6 m/s, p = 0.02) at baseline evaluation compared to the others. Furthermore, baseline uncontrolled blood pressure, left ventricular hypertrophy, and pulse wave velocity ≥ 9 m/s were able to identify patients at higher risk of developing CVAEs during FU. These preliminary findings indicate that blood pressure control, left ventricular mass, and pulse wave velocity may predict CVAEs in MM patients treated with carfilzomib.

Membrane Poration Mechanisms at the Cell-Nanostructure Interface.

3D vertical nanostructures have become one of the most significant methods for interfacing cells and the nanoscale and for accessing significant intracellular functionalities such as membrane potential. As this intracellular access can be induced by means of diverse cellular membrane poration mechanisms, it is important to investigate in detail the cell condition after membrane rupture for assessing the real effects of the poration techniques on the biological environment. Indeed, differences of the membrane dynamics and reshaping have not been observed yet when the membrane-nanostructure system is locally perturbed by, for instance, diverse membrane breakage events. In this work, new insights are provided into the membrane dynamics in case of two different poration approaches, optoacoustic- and electro-poration, both mediated by the same 3D nanostructures. The experimental results offer a detailed overview on the different poration processes in terms of electrical recordings and membrane conformation.