Cerebral hemodynamics during atrial fibrillation: Computational fluid dynamics analysis of lenticulostriate arteries using 7 T high-resolution magnetic resonance imaging.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, inducing irregular and faster heart beating. Aside from disabling symptoms-such as palpitations, chest discomfort, and reduced exercise capacity-there is growing evidence that AF increases the risk of dementia and cognitive decline, even in the absence of clinical strokes. Among the possible mechanisms, the alteration of deep cerebral hemodynamics during AF is one of the most fascinating and least investigated hypotheses. Lenticulostriate arteries (LSAs)-small perforating arteries perpendicularly departing from the anterior and middle cerebral arteries and supplying blood flow to basal ganglia-are especially involved in silent strokes and cerebral small vessel diseases, which are considered among the main vascular drivers of dementia. We propose for the first time a computational fluid dynamics analysis to investigate the AF effects on the LSAs hemodynamics by using 7 T high-resolution magnetic resonance imaging (MRI). We explored different heart rates (HRs)-from 50 to 130 bpm-in sinus rhythm and AF, exploiting MRI data from a healthy young male and internal carotid artery data from validated 0D cardiovascular-cerebral modeling as inflow condition. Our results reveal that AF induces a marked reduction of wall shear stress and flow velocity fields. This study suggests that AF at higher HR leads to a more hazardous hemodynamic scenario by increasing the atheromatosis and thrombogenesis risks in the LSAs region.

Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: an Italian Melanoma Intergroup study.

BACKGROUND: Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes. METHODS: To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors. RESULTS: A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients. CONCLUSIONS: Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

Wall-induced anisotropy effects on turbulent mixing in channel flow: A network-based analysis.

Turbulent mixing is studied in the Lagrangian framework with an approach based on the complex network formalism. We consider the motion of passive, noninertial particles inside a turbulent channel simulated at Re_{τ}=950. The time-dependent network is built to evaluate the transfer of tracers between thin wall-parallel layers which partition the channel in the wall-normal direction. By doing so, we are able to assess the spatial and temporal complexities arising from turbulence dynamics and their influence on the mixing process. This approach highlights the effects of small-scale features of turbulent flow structures and also the larger scale effects determined by wall-induced anisotropy. Complex networks, coupled to the Lagrangian description of turbulence, are effective in providing novel insights into inhomogeneous turbulence and mixing.

Water disinfection by orifice-induced hydrodynamic cavitation.

Hydrodynamic Cavitation (HC) is considered as a promising water-disinfection technique. Due to the enormous complexity of the physical and chemical processes at play, research on HC reactors is usually carried out following an empirical approach. Surprisingly, past experimental studies have never been designed on dimensional-analysis principles, which makes it difficult to identify the key processes controlling the problem, isolate their effects and scale up the results from laboratory to full-scale scenarios. The present paper overcomes this issue and applies the principles of dimensional analysis to identify the major non-dimensional parameters controlling disinfection efficacy in classical HC reactors, namely orifice plates. On the basis of this analysis, it presents results from a new set of experiments, which were designed to isolate mainly the effects of the so-called cavitation number (σv). Experimental data confirm that the disinfection efficacy of orifice plates increases with decreasing σv. Finally, in order to discuss the significance of the results presented herein and frame the scope of future research, the present paper provides an overview of the drawbacks associated with dimensional analysis within the context of HC.

Impaired coronary blood flow at higher heart rates during atrial fibrillation: Investigation via multiscale modelling.

BACKGROUND: Different mechanisms have been proposed to relate atrial fibrillation (AF) and coronary flow impairment, even in absence of relevant coronary artery disease (CAD). However, the underlying hemodynamics remains unclear. Aim of the present work is to computationally explore whether and to what extent ventricular rate during AF affects the coronary perfusion. METHODS: AF is simulated at different ventricular rates (50, 70, 90, 110, 130 bpm) through a 0D-1D multiscale validated model, which combines the left heart-arterial tree together with the coronary circulation. Artificially-built RR stochastic extraction mimics the in vivo beating features. All the hemodynamic parameters computed are based on the left anterior descending (LAD) artery and account for the waveform, amplitude and perfusion of the coronary blood flow. RESULTS: Alterations of the coronary hemodynamics are found to be associated either to the heart rate increase, which strongly modifies waveform and amplitude of the LAD flow rate, and to the beat-to-beat variability. The latter is overall amplified in the coronary circulation as HR grows, even though the input RR variability is kept constant at all HRs. CONCLUSIONS: Higher ventricular rate during AF exerts an overall coronary blood flow impairment and imbalance of the myocardial oxygen supply-demand ratio. The combined increase of heart rate and higher AF-induced hemodynamic variability lead to a coronary perfusion impairment exceeding 90-110 bpm in AF. Moreover, it is found that coronary perfusion pressure (CPP) is no longer a good measure of the myocardial perfusion for HR higher than 90 bpm.

Spatial characterization of turbulent channel flow via complex networks.

A network-based analysis of a turbulent channel flow numerically solved at Re_{τ}=180 is proposed as an innovative perspective for the spatial characterization of the flow field. Two spatial networks corresponding to the streamwise and wall-normal velocity components are built, where nodes represent portions of volume of the physical domain. For each network, links are active if the correlation coefficient of the corresponding velocity component between pairs of nodes is sufficiently high, thus unveiling the strongest kinematic relations. Several network measures are studied in order to explore the interrelations between nodes and their neighbors. Specifically, long-range links are localized between near-wall regions and associated with the temporal persistence of coherent patterns, namely high and low speed streaks. Furthermore, long-range links play a crucial role as intermediary for the kinematic information flow, as emerges from the analysis of indirect connections between nodes. The proposed approach provides a framework to investigate spatial structures of the turbulent dynamics, showing the full potential of complex networks. Although the network analysis is based on the two-point correlation, it is able to advance the level of information, by exploiting the texture created by active links in all directions. Based on the observed findings, the current approach can pave the way for an enhanced spatial interpretation of the turbulence dynamics.

National water, food, and trade modeling framework: The case of Egypt.

This paper introduces a modeling framework for the analysis of real and virtual water flows at national scale. The framework has two components: (1) a national water model that simulates agricultural, industrial and municipal water uses, and available water and land resources; and (2) an international virtual water trade model that captures national virtual water exports and imports related to trade in crops and animal products. This National Water, Food & Trade (NWFT) modeling framework is applied to Egypt, a water-poor country and the world's largest importer of wheat. Egypt's food and water gaps and the country's food (virtual water) imports are estimated over a baseline period (1986-2013) and projected up to 2050 based on four scenarios. Egypt's food and water gaps are growing rapidly as a result of steep population growth and limited water resources. The NWFT modeling framework shows the nexus of the population dynamics, water uses for different sectors, and their compounding effects on Egypt's food gap and water self-sufficiency. The sensitivity analysis reveals that for solving Egypt's water and food problem non-water-based solutions like educational, health, and awareness programs aimed at lowering population growth will be an essential addition to the traditional water resources development solution. Both the national and the global models project similar trends of Egypt's food gap. The NWFT modeling framework can be easily adapted to other nations and regions.

Changes in bacteria composition and efficiency of constructed wetlands under sustained overloads: A modeling experiment.

The average organic and hydraulic loads that Constructed Wetlands (CWs) receive are key parameters for their adequate long-term functioning. However, over their lifespan they will inevitably be subject to either episodic or sustained overloadings. Despite that the consequences of sustained overloading are well known (e.g., clogging), the threshold of overloads that these systems can tolerate is difficult to determine. Moreover, the mechanisms that might sustain the buffering capacity (i.e., the reduction of peaks in nutrient load) during overloads are not well understood. The aim of this work is to evaluate the effect of sudden but sustained organic and hydraulic overloads on the general functioning of CWs. To that end, the mathematical model BIO_PORE was used to simulate five different scenarios, based on the features and operation conditions of a pilot CW system: a control simulation representing the average loads; 2 simulations representing +10% and +30% sustained organic overloads; one simulation representing a sustained +30% hydraulic overload; and one simulation with sustained organic and hydraulic overloads of +15% each. Different model outputs (e.g., total bacterial biomass and its spatial distribution, effluent concentrations) were compared among different simulations to evaluate the effects of such operation changes. Results reveal that overloads determine a temporary decrease in removal efficiency before microbial biomass adapts to the new conditions and COD removal efficiency is recovered. Increasing organic overloads cause stronger temporary decreases in COD removal efficiency compared to increasing hydraulic loads. The pace at which clogging develops increases by 10% for each 10% increase on the organic load.

Alteration of cerebrovascular haemodynamic patterns due to atrial fibrillation: an in silico investigation.

There has recently been growing evidence that atrial fibrillation (AF), the most common cardiac arrhythmia, is independently associated with the risk of dementia. This represents a very recent frontier with high social impact for the number of individuals involved and for the expected increase in AF incidence in the next 40 years. Although a number of potential haemodynamic processes, such as microembolisms, altered cerebral blood flow, hypoperfusion and microbleeds, arise as connecting links between the two pathologies, the causal mechanisms are far from clear. An in silico approach is proposed that combines in sequence two lumped-parameter schemes, for the cardiovascular system and the cerebral circulation. The systemic arterial pressure is obtained from the cardiovascular system and used as the input for the cerebral circulation, with the aim of studying the role of AF on the cerebral haemodynamics with respect to normal sinus rhythm (NSR), over a 5000 beat recording. In particular, the alteration of the haemodynamic (pressure and flow rate) patterns in the microcirculation during AF is analysed by means of different statistical tools, from correlation coefficients to autocorrelation functions, crossing times, extreme values analysis and multivariate linear regression models. A remarkable signal alteration, such as a reduction in signal correlation (NSR, about 3 s; AF, less than 1 s) and increased probability (up to three to four times higher in AF than in NSR) of extreme value events, emerges for the peripheral brain circulation. The described scenario offers a number of plausible cause-effect mechanisms that might explain the occurrence of critical events and the haemodynamic links relating to AF and dementia.

In silico analysis of the anti-hypertensive drugs impact on myocardial oxygen balance.

Hypertension is a very common pathology, and its clinical treatment largely relies on different drugs. Some of these drugs exhibit specific protective functions in addition to those resulting from blood pressure reduction. In this work, we study the impact of commonly used anti-hypertensive drugs (RAAS, [Formula: see text] and calcium channel blockers) on myocardial oxygen supply-consumption balance, which plays a crucial role in type 2 myocardial infarction. To this aim, 42 wash-out hypertensive patients were selected, a number of measured data were used to set a validated multi-scale cardiovascular model to subject-specific conditions, and the administration of different drugs was suitably simulated. Our results ascribe the well-known major cardioprotective efficiency of [Formula: see text] blockers compared to other drugs to a positive change of myocardial oxygen balance due to the concomitant: (1) reduction in aortic systolic, diastolic and pulse pressures, (2) decrease in left ventricular work, diastolic cavity pressure and oxygen consumption, (3) increase in coronary flow and (4) ejection efficiency improvement. RAAS blockers share several positive outcomes with [Formula: see text] blockers, although to a reduced extent. In contrast, calcium channel blockers seem to induce some potentially negative effects on the myocardial oxygen balance.

Fluid dynamics of heart valves during atrial fibrillation: a lumped parameter-based approach.

Atrial fibrillation (AF) consequences on the heart valve dynamics are usually studied along with a valvular disfunction or disease, since in medical monitoring, the two pathologies are often concomitant. Aim of the present work is to study, through a stochastic lumped-parameter approach, the basic fluid dynamics variations of heart valves, when only paroxysmal AF is present with respect to the normal sinus rhythm in absence of any valvular pathology. Among the most common parameters interpreting the valvular function, the most useful turns out to be the regurgitant volume. During AF, both atrial valves do not seem to worsen their performance, while the ventricular efficiency is remarkably reduced.

Thin-film-induced morphological instabilities over calcite surfaces.

Precipitation of calcium carbonate from water films generates fascinating calcite morphologies that have attracted scientific interest over past centuries. Nowadays, speleothems are no longer known only for their beauty but they are also recognized to be precious records of past climatic conditions, and research aims to unveil and understand the mechanisms responsible for their morphological evolution. In this paper, we focus on crenulations, a widely observed ripple-like instability of the the calcite-water interface that develops orthogonally to the film flow. We expand a previous work providing new insights about the chemical and physical mechanisms that drive the formation of crenulations. In particular, we demonstrate the marginal role played by carbon dioxide transport in generating crenulation patterns, which are indeed induced by the hydrodynamic response of the free surface of the water film. Furthermore, we investigate the role of different environmental parameters, such as temperature, concentration of dissolved ions and wall slope. We also assess the convective/absolute nature of the crenulation instability. Finally, the possibility of using crenulation wavelength as a proxy of past flows is briefly discussed from a theoretical point of view.

The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: distribution and association with graft outcomes.

Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score<4 [median KDPI: 87; interquartile range (IQR): 78-94] and 62 with a score=4 [median KDPI: 87; IQR: 76-93]; 102 dual transplants [median KDPI: 93; IQR: 86-96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18-51). PTDB-based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80-90 and of 37% for kidneys with a KDPI of 91-100. Although 1-year estimated GFRs were significantly lower in recipients of marginal kidneys (-9.3, -17.9 and -18.8 mL/min, for dual transplants, single kidneys with PTDB score<4 and =4, respectively; p<0.001), graft survival (median follow-up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80-1.79; p=0.38]). In conclusion, PTDB-based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.

Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): final results of the ROSORC trial.

BACKGROUND: The ROSORC trial, a randomised, phase II trial comparing sorafenib plus interleukin (IL-2) versus sorafenib alone as first-line treatment of metastatic renal cell carcinoma (mRCC) failed to demonstrate differences in progression-free survival (PFS). Updated overall survival (OS) results are reported. PATIENTS AND METHODS: In this study, 128 patients were randomised to receive sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 million international units (MIU) five times per week for 6 weeks every 8 weeks (arm A) or sorafenib alone (arm B). OS was estimated with the Kaplan-Meier method and compared with the two-sided log-rank test. RESULTS: After a median follow-up of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in arms A and B, respectively (P = 0.667). The 5-year OS was 26.3% [95% confidence interval (CI) 15.9-43.5) and 23.1% (95% CI 13.2-40.5) for the combination- and single-agent arm, respectively. Most of the patients who were refractory to first-line treatment were subsequently treated with different targeted agents; they had a median survival greater than expected. CONCLUSIONS: This outcome suggests a synergistic effect of the subsequent therapies following sorafenib failure. CLINICALTRIALSGOV IDENTIFIER: NCT00609401.

Liver metastases from melanoma: hepatic intra-arterial chemotherapy. A retrospective study.

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (IAC) as treatment for patients with hepatic melanoma metastases.Twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic IAC delivery. The catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable.IAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. Median time to progression was 6.2 months (95% CI 3.7-10.5) and median overall survival was 21 months (95% CI 8-39).IAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported.

Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine- based regimens.

BACKGROUND: This study compared the central nervous system (CNS) metastasis incidence between a temozolomide- and a dacarbazine-based regimen in untreated stage IV melanoma patients. METHODS: A total of 150 patients were randomly assigned to receive either oral temozolomide (200 mg m(-2) per day; days 1-5) or intravenous dacarbazine (800 mg m(-2); day 1), in combination with intravenous cisplatin (75 mg m(-2); day 1) and subcutaneous interleukin-2 (3 MU twice daily; days 9-18), every 28 days (CTI and CDI). RESULTS: A total of 149 patients were eligible for an intention-to-treat analysis (CTI: n=74, CDI: n=75). The 1-year cumulative CNS incidence failure was 20.6% for CTI and 31.1% for CDI (P=0.22). In all 24 patients in CTI (32%) and 34 (45%) in CDI developed CNS metastases; 31 patients died of early systemic progression, before CNS evaluation. Median survival time was 8.4 months in the CTI and 8.7 in the CDI arm; in patients with CNS metastases the median survival time was 13.5 months in the CTI and 11.5 in the CDI arm. No difference in toxicity was observed between the two arms. CONCLUSION: The incidence of CNS failures in metastatic melanoma was not significantly reduced and the clinical course was not modified substituting a dacarbazine-based regimen with a temozolomide-based regimen. Patients who developed CNS metastases did not have a worse prognosis than patients progressing in other sites and should not be excluded from new investigational studies.

Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial.

BACKGROUND: Preclinical investigations support combining sorafenib with IL-2 in the treatment of metastatic renal cell carcinoma (mRCC). METHODS: In this open-label, phase II study, 128 patients with mRCC were randomised to receive oral sorafenib, 400 mg twice daily, plus subcutaneous IL-2, 4.5 million international units (MIU) five times per week for 6 in every 8 weeks, or sorafenib alone. After enrolment of the first 40 patients, IL-2 dose was reduced to improve the tolerability. RESULTS: After a median follow-up of 27 months, median progression-free survival (PFS) was 33 weeks with sorafenib plus IL-2, and 30 weeks with sorafenib alone (P=0.109). For patients receiving the initial higher dose of IL-2, median PFS was 43 weeks vs 31 weeks for those receiving the lower dose. The most common adverse events were asthenia, hand-foot syndrome, hypertension, and diarrhoea. Grade 3-4 adverse events were reported for 38 and 25% of patients receiving combination and single-agent treatment, respectively. CONCLUSION: The combination of sorafenib and IL-2 did not demonstrate improved efficacy vs sorafenib alone. Improvements in PFS appeared greater in patients receiving higher-dose IL-2.

Expanding the criteria of organ procurement from donors with prostate cancer: the application of the new Italian guidelines.

Prostate cancer (CaP) represents the most prevalent malignancy in men more than 60-year-old, posing a problem in organ procurement from elderly subjects. However, most of the currently diagnosed CaP are low-grade and intraprostatic, with low metastatic risk, and there is recent evidence that most patients are overdiagnosed. The Italian National guidelines about organ acceptance from neoplastic donors changed in March 2005, extending the pool of potential candidates with CaP and introducing the function of a second opinion expert. Between 2001 and February 2005, 40 candidate donors with total PSA>/=10 and/or positive digital rectal examination underwent histopathological analysis of the prostate: 15 (37.5%) donors harboured CaP, and 25 (62%) were judged at 'standard risk'. After the introduction of the new guidelines in 2005, the second opinion expert judged at 'standard risk' 48 of 65 donors, while 17 of 65 needed histopathological analysis. Four (6.2%) donors harboured CaP, and 61 (94%) where judged at 'standard risk', with a significant increase of donated and actually transplanted organs. The application of the new guidelines and the introduction of a second opinion expert allowed a significant extension of the 'standard risk' category also to CaP patients, decreasing the histopathological examinations and expanding the donor pool.

The Donor Action Project: a valuable tool to measure quality and efficacy of the donation process in Emilia-Romagna.

INTRODUCTION: The international project Donor Action (DA) started in Emilia-Romagna (ER) in July 1998, involving 24 main regional intensive care units (ICUs) of which 6 have neurosurgery units. Using a data-analysis computer system, we sought to measure the efficiency and quality of the donation process. METHODS: Our study analyzed all data collected by the DA system from July 1998 to December 2008. In particular, we evaluated the following markers: patients with brain damage (BD)/total ICU deaths (Index I); brain death assessments/potential donors (PD, patients in the ICU for more than 6 hours; Index II); refusals/consent requests (Index III); effective donors/total encephalic deaths (PROC 1); and brain death assessments/total encephalic deaths (PROC 2). After collection, data were analyzed by the Regional Transplant Reference Center (CRT)-ER and sent to the National Transplant Centre (CNT) using Q-pido software for comparison with other Italian regions. RESULTS: During the study period, despite a significant decrease in Index I, we observed a considerable increase in Index II, and, consequently, in donation efficacy. Additionally, we reported a slight increase in Index III. Finally, both PROC 1 and PROC 2 increased through the years, suggesting an improved efficacy of the donation/transplantation system. CONCLUSIONS: Based on our experience, the DA project to increase the level of attention of ICU medical staff about organ donation and to increase interactions between transplantation coordinators and CRT-ER seemed to ameliorate both procurement and transplantation activities.

Flow non-normality-induced transient growth in superposed Newtonian and non-Newtonian fluid layers.

In recent years non-normality and transient growths have attracted much interest in fluid mechanics. Here, we investigate these topics with reference to the problem of interfacial instability in superposed Newtonian and non-Newtonian fluid layers. Under the hypothesis of the lubrication theory, we demonstrate the existence of significant transient growths in the parameter space region where the dynamical system is asymptotically stable, and show how they depend on the main physical parameters. In particular, the key role of the density ratio is highlighted.