Multivariable Cox proportional hazards regression was used to determine

Multivariable Cox proportional hazards regression was used to determine whether operation type (RN or PN) was associated with postoperative CKD and OS, after adjusting for age, ASA score, hypertension, diabetes mellitus, and preoperative eGFR. Patients were censored at the time of their last GFR estimate. Patients with pre-existing CKD (eGFR that was either ≤60 or ≤45 mL/min/1.73 m2) were not included in this outcome analysis. No patients were excluded from OS analysis based on preoperative eGFR measurements. When multiple eGFR measurements were performed on the same day, only the lowest daily recorded measurement was used to define CKD outcomes. All statistical analyses were conducted with Stata version 12.0 (StataCorp, College Station, TX).

CKD describes a level of renal function ≤60 mL/min/1.73 m2 but above end-stage renal disease of 15 mL/min/1.73 m2 and is classified into stages based on eGFR with each increase in stage associated with higher risk for hospitalization events, cardiovascular disease, and death. To simplify and facilitate earlier identification of CKD and initiate medical interventions to delay CKD progression, equations have been developed to estimate GFR. There have been concerns regarding the general applicability and accuracy of these equations for patient populations for which they gsk3 inhibitor were not originally developed. A newer eGFR equation, the CKD Epidemiology Collaboration (CKD-EPI) equation, was introduced in 2010 and validated in larger and more diverse patient populations. The CKD-EPI equation was reported to be more accurate for patients with eGFR >60 mL/min/1.73 m2 than the Modification of Diet in Renal Disease (MDRD) equation. Another study found the MDRD equation to overestimate by 7% newly developed stage III CKD (eGFR ≤60 mL/min/1.73 m2) in patients who underwent PN when compared with the CKD-EPI equation.
In 2006, using the MDRD equation, we reported that 26% of patients who underwent PN or RN for a small kidney tumor had underlying stage III CKD (eGFR <60 mL/min/1.73 m2), despite serum creatinine levels within normal limits. Using the CKD-EPI equation for the same cohort, we now found that 21% of those with normal baseline serum creatinine levels had pre-existing stage III CKD, which is consistent with comparison reports described above. This finding underlines the importance of now using more accurate estimates of kidney function to avoid overdiagnosis of CKD both at the baseline and as a result of treatment. Furthermore, using the CKD-EPI equation in the entire data set, we demonstrated that 31% of patients presenting with a serum creatinine within normal limits had an eGFR <60 mL/min/1.73 m2. Unlike carefully selected kidney donors, patients with renal tumors have more baseline comorbidities, including hypertension, advanced age, diabetes, and vascular disease that can adversely impact baseline renal function. Retrospective studies have shown that there is an increased risk of developing new onset of CKD after RN when compared with PN. The European Organisation for Research and Treatment of Cancer (EORTC) randomized trial 30904 confirmed the negative renal functional impact of RN compared with PN for small renal masses on postoperative kidney function; however, antibody-mediated immunity reported worse OS for the PN cohort. Although widely cited as the only level-1 evidence for comparing RN with PN, significant limitations exist in the EORTC 30904 trial. The study began in 1992, designed as an intention to treat noninferiority study, at a time when all renal tumors, regardless of size, were resected by RN if the contralateral kidney appeared normal. PN was used sparingly for bilateral renal tumors or tumor in the solitary kidney, and few surgeons worldwide were skilled at PN. Skepticism existed on whether PN was a safe oncological procedure; elements of PN that have evolved since (renoprotection, regional ischemia, careful case selection) were likely not widely employed then. There was little concern that adverse health events would occur following RN because this clinical situation was felt to be similar to that of living kidney donors undergoing surgery for transplantation, despite the fact that even then donors were carefully selected, on average 25 years younger than patients with renal tumors, and by definition, devoid of all serious medical comorbidities. Accrual to the trial was poor; in 1998, the EORTC invited the Eastern Cooperative Oncology Group and Southwest Oncology Group from the United States and the National Cancer Institute of Canada to participate, with the goal of randomizing 1300 patients to detect a 3% difference in survival. The study closed after 11 years with only 541 patients randomized from a total of 45 centers in Europe and North America. For various reasons (including missing pathology, higher stage pathology, tumor multifocality), 81 patients randomized to RN and 73 patients randomized to PN were excluded, leaving 71% of patients for analysis.

Only a few studies attempted to compare surgery with chemoradiation

Only a few studies attempted to compare surgery with chemoradiation [7,8,19]. All comparisons were noncontrolled, retrospective, and operated patients were younger (5–7y) and healthier than the irradiated patients. Nevertheless, all 3 studies showed similar overall and cancer-specific survival rates. However, it Cyanine3.5 carboxylic acid must be remembered, that patients with a bulky tumor or obstructed kidney were not candidates for chemoradiation, neither in this study nor in many other Cyanine3.5 carboxylic acid studies [23]. This can potentially increase tumor burden in the operated group and act as a factor decreasing the longevity of those treated with surgery.
When comparing the side effects of treatment (Table 2), it can be noticed that surgery, although associated with a high frequency of blood transfusions (70%), classified as Clavien grade 2, is usually not accompanied with more severe complications. Chemoradiation is also well tolerated by most patients, with grade 3+toxicity occurring in only 12% of the patients, and only 1 patient (given 72Gy) requiring cystectomy for a contracted bladder. This rate is similar to the rate reported by Efstathiou et al. [4] in a combined study of 4 RTOG protocols.
However, there is a fundamental difference between postoperative complications graded by the Clavien system and postchemoradiation grading systems. The Clavien system is based on the magnitude of effort needed to treat the complication. Although this system accurately grades the severity of the early surgical complications, it ignores the expected mutilating sequel of it, namely the loss of the bladder. This can be assessed more adequately by quality-of-life questionnaires. When patients who underwent radical cystectomy were compared with patients treated by chemoradiation, Caffo et al. [24] found that the quality of life after cystectomy was lowered by the presence of stoma, decreased sexual activity, and worsened physical condition. In another study, it was found that patients who had an orthotopic reconstruction had better quality of life than patients who had an ileal conduit did [25]. However, many candidates for cystectomy, especially elderly ones, are not fit for orthotopic diversion and diverted diversion is performed with an ileal conduit after radical cystectomy. In another study, Zietman et al. [26] assessed 32 patients treated by chemoradiation by questionnaires and by urodynamics. Their global health-related quality of life was high, 59% of the men were satisfied with their sex life, and 75% of the patients had a normally functioning bladder.
An additional concern with chemoradiation is the possible need for salvage cystectomy. This surgery was needed in 22% of the patients in the study by Efstathiou et al. [4] and in 2 patients in the current study. Salvage cystectomy is expected to be associated with a higher rate of cardiovascular/hematological complications, reflecting the effect of chemotherapy, and with a higher rate of tissue-healing complications, reflecting radiotherapy. However, in a series of 91 salvage cystectomies, the complication rate was only slightly higher than the reported rate for primary cystectomies, whereas the frequency of major complications and postoperative mortality was not higher [27].


Bladder cancer has the fourth highest incidence of cancer cases in men in the USA and Europe [1,2]. The reported age-adjusted incidence rates in Europe have been highest for Spain (39.0 per 100,000 against 29.1 in European Union-27) [2]. It is 3 to 4 times more frequent in men than in women [3], and 1 in 26 men develop bladder cancer during their lifetime [1]. Burden is high at all phases of treatment and surveillance owing to the frequent tumor recurrence and progression, which leads to long-term clinical monitoring [4].
Health-related quality-of-life (HRQL) evaluation is crucial because patients with bladder cancer continue experiencing treatment-related concern over a long period of cancer monitoring [5,6]. However, systematic reviews [7,8] show that HRQL of patients with bladder cancer is poorly known, with scarce information compared with other cancers. The literature has consistently identified urinary and sexual domains as the patients׳ greatest concern [9]. However, quality of the available information on the effect of bladder cancer on HRQL is mainly affected by retrospective or cross-sectional study designs, nonvalidated HRQL instruments, or failure to adjust for confounder variables [8,10].

Fuhrman grading has long been used to assess prognosis

Fuhrman grading has long been used to assess prognosis of ccRCC [4] and is defined based on increasing nuclear size, irregularity, and nucleolar prominence. Fuhrman grading is closely associated with patient survival [5]. Patients with grades 1 and 2 RCC showed a 94% and 86% 5-year survival rate, respectively, whereas grades 3 and 4 RCC demonstrated survival rates of only 59% and 31% [6]. High Fuhrman grading has been correlated with increased expression of many individual markers, including colony stimulating factor 1 [7], transglutaminase 2 [8], and p21-activated kinase 4 (PAK4) [9], but an exploration has not been made based on global gene expression patterns.
Although the diagnosis of RCC in most cases is established by nephrectomy or partial nephrectomy to obtain tissue for histology, there have been other efforts to investigate molecular biomarkers for diagnosis and prognosis in ccRCC. Genetic changes in the von Hippel-Lindau (VHL) gene have long been associated with RCC [10,11]; however, other individual markers have also been identified. High-expression levels of interleukin-1β and interleukin 18 are predictive of poor prognosis [12]. Elevated expression of hypoxia-inducible protein (HIF) 2, HIF1α, and phosphorylated nuclear factor-kappa β have been shown to be involved in the progression of kidney cysts through tumor development [13]. Others have implicated activation of certain pathways. The mammalian target of rapamycin pathway was shown to be prognostic for recurrence in RCC by examining PTEN, phosphorylated AKT, phosphorylated mammalian target of rapamycin, phosphorylated p70 ribosomal S6 kinase, and phosphorylated 4E-binding protein 1 [14]. Data from the Cancer Genome Atlas have also elucidated potential molecular prognostic signatures using discovery and validation data sets [15]. Aggressive RCC demonstrated a consistent pattern of altered cellular metabolism, which manifested as a metabolic shift towards fatty nimesulide synthesis (i.e., Warburg-like phenotype). The PI(3)K-AKT pathway was found to be repeatedly altered including mutations in genes such as GNB2L1 and SQSTM1 that are involved in activation of signaling. In addition, there is deregulation of the AKT pathway through altered methylation resulting in differential mRNA expression (e.g., hypomethylation of the microRNA 21 promoter and hypermethylation of the PI(3)K inhibitor GRB10).

Materials and methods


In earlier work by our group [18] and others [19], increased expression of the individual marker KIM1 (kidney injury molecule 1) was shown to differentiate RCC from nonmalignant kidney. Although that result was confirmed in the current dataset (data not shown), here we expanded on that aim by using global gene expression analysis to characterize differences between high-grade and low-grade ccRCC. In order to achieve this objective, gene expression microarrays were performed on high-grade and low-grade ccRCC as well as non-tumorigenic conditions (normal kidney adjacent to tumor and benign kidney disease). We identified potential markers that demonstrate a progression from normal or benign through low-grade ccRCC to an extreme level of expression in the high-grade ccRCC. This included entities that have been previously shown to have a quantitative change in association with either RCC or ccRCC (Fig. 3). In the current study, CP is up-regulated more than 2-fold in low-grade ccRCC compared with either normal kidney or benign, but is up-regulated more than 10-fold in high-grade ccRCC compared with either nonmalignant sample type. In the direct comparison, CP is up-regulated 4.5-fold (P = 0.002) in high-grade vs. low-grade ccRCC. CP encodes a secreted metalloprotein that binds copper in plasma and has been shown in other studies to be up-regulated in RCC [20–22]. Other genes are down-regulated in ccRCC. Cadherin 1 (CDH1, also known as E-cadherin) is down-regulated in both high-grade and low-grade ccRCC compared with normal and benign and is down-regulated 2.2-fold (P = 0.041) in high-grade vs. low-grade ccRCC. The encoded protein is a cell-cell adhesion glycoprotein whose loss contributes to progression by increasing proliferation, invasion, or metastasis. In addition to confirming the current results of higher expression in ccRCC compared with normal and benign, CDH1 protein expression correlated to invasion and metastasis [23].

br Conclusions br Introduction Urban green spaces including


Urban green spaces, including parks, gardens, treed avenues, cemeteries, sports fields and undeveloped lots, are well researched as vital for human quality of life and avian ecology (Konijnendijk, 2003; Traut and Hostetler, 2004Konijnendijk, 2003; Gill and Brumm, 2014). Studies of avian urban presence are bolstered by increased urbanization, green space development, variable and increased urban avian presence and conservation politics (Lim and Sodhi, 2004; White et al., 2005; Lepczyk and Warren, 2012). Bird species size, vegetation configuration, human behaviour and cultural features such as roads may contribute to avian presence or absence (Hostetler and Knowles-Yanez, 2003; Erickson, 2004; Campbell, 2008, 2009). Bird behaviour and reactions to these variables may also be conditioned by predator avoidance and feeding cediranib (Marzluff et al. 2001; Campbell, 2010; Diaz et al., 2013).
Avian reactive distances in human presence may be measured by three parameters: (1) the alert distance, or the distance between the subject bird and the approaching human at the first noticeable attention from the bird; (2) the flight distance, or the distance between the subject bird and the approaching human when the bird takes flight, always equal to or less than the alert distance; and (3) the alert period, or the time between first alert and flight, as the bird observes the intruding person and ceases foraging activity. Alternatively, during the alert period the bird may resume foraging, especially if human-offered food is available (Campbell, 2007, 2010; Clucas and Marzluff, 2012; Gill and Brumm, 2014).
Larger bird size, more open and lower vegetation, increased human movements, lack of human feeding behaviour and increased distance of roads and footpaths are identified as factors for longer alert distances (Skagen et al., 1991; Holmes et al., 1993; Campbell, 2006). Larger birds have a larger awareness radius, hence their earlier awareness of human presence influences longer reactive distances (Lima and Zollner, 1996; Gutzwiller et al., 1998; Kiltie, 2000). Birds in open fields may be more sensitive to predation risk, due to the lack of cover, hence they have longer alert and flight distances and shorter alert periods (Ydenberg and Dill, 1986; Kramer and Bonenfant, 1997; Diaz et al., 2013).
Taller vegetation may influence longer alert distances, as birds may fly earlier due to the longer journey to the higher branches of trees (Fernández-Juricic et al., 2001; Campbell, 2010). The lack of the refuge of dense shrubbery and undergrowth, may also encourage earlier flight (Martín and López, 1995; Kramer and Bonenfant, 1997). When in same-species or multiple-species flocks, some studies indicate that the most sensitive individual may initiate the flight response, the so-called sentinent hypothesis (Metcalfe, 1984; Paton et al., 2000; Weston et al., 2012). However, this situation would be difficult to observe with solitary feeding birds, as many species only rarely feed both individually and in flocks, and distances among the different individuals would have to be controlled in a study (Campbell, 2010).
Birds near roads and footpaths may have shorter alert and flight distances, due to increased habituation to human presence or human feeding behaviour (Campbell, 2007). Human behaviour is probably the most important factor for alert and flight distances (Campbell, 2008; Clucas et al., 2011; Clucas and Marzluff, 2012). Human disturbances are measurable in degrees of impact, hence while some studies measure avian reactions to uniform human behaviour, others assess the impacts of different human behaviors on the subject bird (Fernández-Juricic et al., 2001; Campbell, 2010).
This article examines the alert and flight distances and alert periods of seven passerine and non-passerine species in the green spaces of Nanaimo, Canada (Fig. 1, Table 1). These species were selected for their common status, combined size range, and presence in a wide range of vegetation structures and types. Bird size, standardized methods of observer approach, dominant vegetation cover (trees, shrubs, undergrowth and/or grass), vegetation height, and road, pavement and footpath proximity are examined as predictors of alert and flight distances and alert periods. The aim of the study was to determine bird species tolerance to variable styles of human approaches.

direct renin inhibitors The positive influence of the LW observed on the hospital

The positive influence of the LW observed on the hospital personnel is particularly important as they are present in the hospital on a daily basis and it may affect their performance at work. Some authors have detected an improvement of workplace attitude when there is visual access to greenery (Lottrup et al., 2013). Leather et al. (1998) found that having a view of a green outdoor environment from the workplace window resulted in the employees feeling less uptight. Pati et al. (2008) established that nurses exposed to a nature view showed improved alertness level and reduced stress. This supports the fact that more than 75% of the hospital workers interviewed agreed with the investment made on the LW. However, it is interesting to note that, among the participants thinking that the hospital should not spend more than 100 € per year on vegetation, 24.5% are workers. In the case of patients or visitors, the percentage was only around 15%. This could be explained because hospital workers believe that investments should be made in other, more important items. Also, there was a significance difference in the interest in gardening and plants between workers and the rest of the sample (F=4.907; p=0.002).
Taking all of this into account, the main question that remains is: can an LW actually be considered a cost-effective investment? Even according to the results shown in this study, the answer to this question is still inconclusive. It will depend on the factors considered, as many indirect intangible benefits are in play. For example, Perini and Rosasco (2013) concluded that an LW of the same type as the one installed in the hospital was not economically sustainable. In their study, they quantified the direct renin inhibitors use reduction, the expenses reduction in the façade management, the air quality improvement and the increase in property value. Nonetheless, other soft benefits, such as the ones considered in this study, were not included. The main reason for the unsustainability was found to be the high maintenance costs incurred due to the size of the LW used in the model (over 200m2) which also led to an elevated installation cost. This is an important point as maintenance costs are often computed per area unit, though they depend on other variables such as the type and complexity of the LW or its height. This means that bigger LWs usually have higher maintenance costs but do not necessarily entail a higher media repercussion or more psychological benefits. Perini and Rosasco (2016) point again to the installation and maintenance costs as the key factors for the economic sustainability of greening systems, which might be improved by means of incentives such as tax reductions. Notwithstanding, actually improving the economic sustainability of these systems relies on being capable of quantifying the wide range of benefits procured by them.



In the United States, urban lands have been projected to increase from 3.1% to 8.1% (392,400km2) between 2000 and 2050 (Nowak and Walton, 2005) with a concomitant predicted increase of urban dwellers globally from 3.6 billion to 6.3 billion in the same time frame (United Nations, 2012). Soils found in urbanized landscapes often exhibit biogeochemical processes that are distinctly altered when compared to natural landscapes. As a result of urban development, soil quality is typically diminished resulting in reduced ecosystem services and less successful landscape plant establishment.
In the urbanized environment, it has been shown that soils make up 64% of the terrestrial carbon sink followed by vegetation making up an additional 20% (Churkina et al., 2010). In these environments, soil damage is often highly pronounced because of multiple stresses such as compaction, contamination, frequent land use and burying of anthropogenic waste materials. Characteristics of urban soil include: high soil bulk density, low organic matter, poor structure, high pH, low water holding capacity, decreased aggregate stability, inadequate soil volume for root proliferation and decreased microbial biomass and activity (Jim, 1998; Scharenbroch et al., 2005). These diminished properties compromise soil health and create an inhospitable environment to support plant growth. It has been shown that within the first two years of new street tree plantings mortality can be as high as 34% in the city environment (Nowak et al., 1990). Urban soil limitations have been shown to account for 80% of issues relating to maintenance of urban vegetation (Layman et al., 2016; Patterson et al., 1980). As a result, strategies are needed to address specific soil limitations in order to support the development and longevity of urban forests.

Ethical gap With highly urbanized countries of the world emitting

Ethical gap: With highly urbanized countries of the world emitting carbon dioxide at 8.54 t/capita and the emergence of cities in climate change arena (both as local units of governance and as trans-national members), it could now be reasonably argued to strengthen their role in carbon management and to relocate the responsibility of ‘access and allocation’ to the local governance level, alike political, legal/functional mandate. With ample empirical evidence on growing association of urbanization and global emissions in the rich countries and middle income urbanized countries at the cost of rural poor constituencies, it is high time to push the envelope a little further to suggest plentitude of opportunities for the rural subjects in poorer countries to demand their fair share of carbon access and allocation, globally, and also at the country level when it is the case. Considering their grave technical and financial incapacities, specially against the cities and in fact lack of awareness about their ‘carbon right’, it may be virtually impossible for them to manage their entitlement separately to begin with, but through national rural forums, coalitions or transnational networks representing rural and poorest world constituencies. There is also a possibility whereby their entitlement amalgamates with the adjoining city/cities, based on their carbon flows and cities become custodians of their hinterlands (city-regions) while managing and negotiating carbon. This would actually help bring the issue of carbon space to ground and relate it with other material and energy flows inherent in its bio-geochemical pituitary adenylate cyclase-activating peptide across local governing units. But is there sufficient consensus toward fair CAA at the sub-national level? This requires to bridge empirical and governance gaps at the local level.
Governance gap: International environmental governance has already been understood as a regime complex (Keohane and Victor, 2010), multiplicity of organizations and polycentricity (Ostrom, 2010), “matching principal” in international law (Adler, 2005). This is in line with ‘multilevel’ understanding of governance, pressing the need to move away from viewing the state as the primary target of transnational networks (Lipschutz, 1996; Vogler, 2003; Betsill and Bulkeley, 2004). While any treaty would be signed internationally, each country would require internal policies involving participation of government units, business, scientific institutions and citizen group to take mitigation actions. Local-level efforts significantly influence user behavior and choices as shown by Dietz et al. (2009). Using metadata from countries of the developing world (Puppim de Oliveira et al., 2013), it has been further emphasized that it is technically possible to reduce GHG and also achieve urban development goals. Involvement of multiple agencies in carbon governance at different scales facilitates systematic and transformative governance enabling inclusion, participation in pursuance of climate and development agenda (irrespective of the numerical entitlement), fostering deontological norms of ethics and giving reasonable opportunities to assert politically. But how would this be governed on ground? Cities are now aptly being perceived as sustainability ‘hot-spots’ (GEA, 2012) and urban governance of climate change is where international and national carbon control regimes are seen ‘coming to ground’ (While et al., 2010) for ‘governance experiments’ (Hoffman, 2011) and reconfiguration of state-based political authority (Bulkeley, 2010), although there is no further detail of what would be the role mechanism and rules of the game.

Conclusions and way forward

Disclosure statement


With the depletion of the traditional resources such as coal, petroleum, gas and other non-renewable fossil fuels, the problem of global warming continues to worsen. Words such as low-carbon, energy conservation, and environmental protection have gradually becoming the focus points across the world (Alshehry and Belloumi, 2015; Heidari et al., 2015; Lin and Moubarak, 2014; Mahdi Ziaei, 2015). With the continuous high-speed development of the Chinese economy, the demand for thermal comfort in the housing environments has become higher and higher, and district heating has gradually moved to southern areas, for example, central heating systems are emerging in many cities in the Yangtze River Basin, and air conditioning areas is common in the northern area, where lots of air-conditioners have been installed in residential buildings in cold northeast China. The applications of air-conditioning and heating system are expanding, and the demand for peak load of the power supply system in both summer and winter is increasing sharply, with the phenomenon of switching off power or limiting electricity supply occurring frequently in many cities (Chen et al., 2015; Lin and Liu, 2015; Yu et al., 2015). To reduce the building energy consumption and the amount of carbon dioxide emissions, the Chinese Government has established various policies and regulations, including encouraging the use of renewable and clean sources of energy, and has enacted a series of design standards for the energy efficiency of residential buildings. Various demonstration projects for the energy efficiency of residential buildings and application of renewable energy are being carried out in many cities (Li et al., 2015; Cai et al., 2014). Particularly, in hot-summer and cold-winter or hot-summer and warm-winter zones in Southern China, ground source or water source heat pumps not only can provide cooling in summer, but also can provide heating in winter and a domestic hot water supply system for many residential buildings. Once these projects have been finished, management and maintenance of the central air-conditioning system will be unavoidable. The management of heating in the northern region for centralized heating is relatively simple because of the cold climate and the clear start and end date, which is stipulated by the government (Feng, 2004; Lang, 2004; Zhang and Fu, 2009). However, in Southern China, residents who are used to using the air conditioning intermittently in accordance with their individual needs have an obvious tendency of heating diversification. As there is lack of policies and regulations on air-conditioning and heating periods at present in Southern China, the operation and management of buildings using central air-conditioning systems directly face blind spots in regard the policies and regulations and the contradictions in the diversification which are demanded by people. Thus, it is a difficult issue as to who is to decide the APHP start and end date for a building using central air-conditioning and heating systems. The issue involves many factors, and has a significant impact on the operation and management of air-conditioning equipment, and affects people’s consciousness of energy saving. It is a new aspect which is often encountered in the course of promoting energy conservation in existing buildings. Therefore, further research and discussion are necessary. A new method based on the existing seasonal division is presented in this paper, and the APHP of fourteen representative cities in Southern China were studied, and the method was validated according to the test data from a building in Chengdu.

Greater Kuala Lumpur GKL is

Greater Kuala Lumpur (GKL) is the most urbanized conurbation of Malaysia (DOS Malaysia, 2011). The 2785km2 area covers two administrative center, namely Kuala Lumpur WP Putrajaya with their peripheral local districts, including Gombak, Hulu Langat, Klang, Petaling Jaya and northern part of Sepang as shown later in Fig. 3. Past studies reported that the urban core of GKL experienced higher temperature up to 5.5°C than its rural park and this city is on average 3.9°C hotter than other cities in Malaysia (Elsayed, 2012; Ng et al., 2005; Sani, 1986). Recent numerical effort has also found that higher mean daily temperature modelled for the Putrajaya compared to its pre-urbanized form by around 0.79°C (Morris et al., 2015). GKL lies in a flat valley to the east of the Straits of Malacca and bounded by the elevated barriers of Sumatra island and Titiwangsa highlands as shown in Fig. 1. The region is identified as the land-side coastal tropical salvinorin regime that features great influence of land-sea breezes (Kikuchi and Wang, 2008). However, such valley-like topography with narrow water body between the highlands is prone to develop internally circulating air throughout the day during calm wind season, i.e. air that exited the land at night is trapped and re-circulates back to the land during the day (Fujita et al., 2010; Lo et al., 2006; Tso, 1996). The vulnerability of region to the heat and pollutants accumulation therefore depends heavily on its mutual interaction with the local circulation as observed in other coastal cities such as São Paulo, Pearl River Delta, New York, London, salvinorin etcetera (Chemel and Sokhi, 2012; Freitas et al., 2006; Lo et al., 2006; Thompson et al., 2007). Such a unique topography of GKL therefore intrigues the effect of urban heating on the local climatic conditions especially the topographic land/sea flow.
To this end, the paper attempts to scrutinize the effect of urban heating phenomenon as a result of urbanization on the diurnal sea/land breeze circulation in GKL by using a numerical modelling tool, the Advanced Research core of the Weather Research and Forecast (WRF-ARW) system version (3.6.1) (Skamarock et al., 2008; Wang et al., 2015b). The model is verified with near surface meteorological condition from ground weather station to ensure the land surface condition is well simulated. At the same time, the paper compares the default WRF setting to the locally calibrated setting on the land surface characteristics pertinent to urban-scale heat modelling study. Since development of these local information from scratch is an intricate process, this paper attempts to examine the significance of updated land use map and calibrated urban canopy treatment approaches to improve the model performance to simulate the urban heating phenomenon in GKL. Therefore, the paper also aims to shed light on the sensitivity of WRF model performance in representing the near surface meteorological condition and urban heating effect with different selection of land use and urban surface parameterization schemes, especially when local information is scarce and inadequate.

Model configuration and experiment design

Result and analysis
We first examine the sensitivity of modelled near surface parameters for the original WRF MODIS LU map and our newly developed LU map for Selangor in Section 3.1.1. With the updated LU map, we then explore the effect of urban canopy treatment approach on the near surface condition and their respective influence on the urban heating phenomenon in Section 3.1.2. After gaining more confidence with the model settings, the best performing model setting tested with lowest statistical error is used as a benchmark to study the effect of urbanization on the local climatic condition in GKL in Section 3.2.

The effect of urbanization is determined through the difference between the urbanization case and a control case with no urban surfaces (noURB). At night, greater heat is detected at urbanized land compared to noURB case and thus confirming the formation of UHI at night (up to 1.89°C). Urbanization has altered the local circulation of sea breeze and mountain flow. As a result of pressure difference induced by urbanization, the coastal region has experienced an accelerated sea-breeze and more moisture during the day. Although the sea-breeze circulation effect is strengthened and prolonged as a result of urbanization, it does not propagate through the urban region during the day. Such a circulation pattern might have impeded the dispersion of heat and atmospheric pollutants depending on the synoptic condition. Suppressed daytime circulation of urban region near the mountainous region can potentially hinder the dispersion of air pollution produced. From which, it gives a brief explanation to the high local pollution episode experienced by the GKL region especially during the inter-monsoonal period (Latif et al., 2012). Urbanization on the flat valley between the coast and hills significantly alters the topographic circulation, making the GKL a complex yet interesting case study on interaction of urban and rural pollutants.

The paper provides results of D plane

The paper provides results of 2D plane strain dynamic numerical analyses, conducted in FLAC 7.0 (Itasca, 2011a), for deep circular underground structures subjected to vertically traveling shear waves, produced by a sinusoidal input velocity. In the analyses, the liner is assumed elastic with a tied interface, i.e. no relative displacement between the structure and the ground. To evaluate the effect of the flexibility ratio on the seismic response without additional variables, the same interface is used in all the analyses. A tied interface is selected, as it purchase Pepstatin A includes a combined normal-shear stress transmission at the interface. The ground is considered dry (drained) i.e., no excess pore pressures are generated, with either linear-elastic or nonlinear elastoplastic response. In both cases, the effect of the input frequency on the distortions of the tunnel cross section is evaluated, as well as the effect of relative stiffness on the distortions of the liner. For the nonlinear ground, the loadings in the structure (thrusts and bending moments) are also obtained. Comparisons in terms of distortions of the liner, for the linear-elastic and the nonlinear elastoplastic ground, are provided.

Linear elastic analysis
The ground-structure system is discretized in FLAC with meshes with dimensions 600m wide and 100m or 50m high, to evaluate the effect of input frequency and the effect of flexibility ratio, respectively. The reasons to select these two different heights are explained later. For both meshes, square elements (1m×1m) are used away from the tunnel, and square elements with a smaller size (0.5m×0.5m), close to the tunnel, within a rectangular section of 60m×40m. The center of the tunnel is located 25m above the bottom of the model. Fig. 1 shows the meshes used for the dynamic numerical analyses.
A sinusoidal input velocity is imposed at the bottom of the discretization. Free-field boundaries on the sides and quiet boundaries at the bottom of the model are used. These are absorbing boundaries that use independent dashpots in the normal and shear directions, to prevent reflection of waves back into the model and avoid energy radiation (these boundaries are a built-in option in FLAC). By using absorbing boundaries, plane waves propagating upward do not distort at the lateral boundaries and do no reflect at the bottom boundary. (Itasca, 2011b; Lysmer and Kuhlemeyer, 1969).
The appropriate width of the model and good performance of the absorbing boundaries are verified by comparing shear strains at different points through the width of the mesh, for specific depths. Although not included here, the results show negligible differences at points located up to 80m on each side of the center of the model. So the proposed discretization is considered adequate.
The tunnel support is modeled with elastic beam elements. Beam elements are frequently used in this type of simulations because, similar to beams, liners must support axial forces and bending moments (e.g., Bobet, 2010; Wang, 1993).

Nonlinear elastoplastic analysis
It must be noted that due to the stiffness degradation of the ground, the flexibility ratio changes during the dynamic loading. More precisely, if the liner remains in its elastic regime F decreases, as the ground becomes more flexible with deformation, i.e., the tunnel becomes stiffer with respect to the ground as the ground deforms. The flexibility ratios reported here are those computed using the degraded stiffness of the medium at peak distortions of the tunnel. The free field shear strains used for the normalization correspond to those of the degraded ground.

Summary and conclusions
The results show that for both linear-elastic and nonlinear elastoplastic ground, there is no effect of the input frequency on the seismic response of the tunnel, when the input frequency is smaller than 5Hz ( ratios larger than ten for linear-elastic and nine for nonlinear ground). Pseudo-static analyses can therefore be conducted for tunnels located far from the seismic source (for distances between 10 and 100km from the epicenter, after Dowding, 1985), irrespective of the soil model used in the simulations.

Bainbridge suggested that D TEE both real time and electrocardiography

Bainbridge (2005) suggested that 3-D TEE, both real time and electrocardiography-gated full volume, could allow a comprehensive evaluation of atheromas in the descending igf1r inhibitor by assessing their thickness, volume and shape. Later, Aggeli et al. (2011) studied the feasibility of using 3-D TEE to depict and quantify the atheromatous burden, and Hammoudi et al. (2014) supported these early findings by comparing 3-D and 2-D technique.
Furthermore, Piazzese et al. (2014) illustrated the feasibility and accuracy of this approach, proposing a semi-automated segmentation of aortic plaques. However, because of the limited field of view, a single 3-D data set can visualize only limited portions of the aorta, and several volumes need to be acquired and analyzed separately to quantify the total amount of plaques and their location at different aortic levels. In this framework, we hypothesized that a compounding strategy could be efficiently designed and implemented to reconstruct wider segments of the descending thoracic aorta, by combining 3-D data sets acquired at different aortic levels.
Accordingly, the aim of the work described here was to propose a robust and efficient framework to reconstruct the descending thoracic aorta by multiview compounding of 3-D TEE aortic data sets to improve visualization and quantification of total atheroma burden. To this end, an ad hoc image acquisition protocol to obtain ordered and partially overlapped 3-D TEE aortic data sets was implemented, followed by dedicated image processing to align and fuse all acquired data sets.
Compounding of 3-D echo images has been used previously to improve information content and image quality, with applications mainly in TTE (Gooding et al. 2010; Piella et al. 2013; Rajpoot et al. 2011; Soler et al. 2005; Yao et al. 2011) and in TEE cardiac images (Housden et al. 2013). We present for the first time a compounding approach in which 3-D TEE aortic data sets are combined to allow reconstruction of the descending aorta. In this work, we extend our previous conference paper (Carminati et al. 2014), in which the first step of the proposed approach featuring image registration was presented and applied to a smaller pathologic population.

In this section we describe the methodologic framework for reconstruction of the descending thoracic aorta from single-view 3-D TEE aortic data sets. As illustrated schematically in Figure 1, the proposed approach can be summarized in the following stages:


Identification and characterization of aortic lesions are recognized as clinically relevant, as the presence of aortic plaques is an independent risk factor for stroke and peripheral embolization (Cohen et al. 1997) and is also associated with carotid, coronary and renal artery disease (Fazio et al. 1993; Kronzon and Tunick 2006). TEE technology is a suitable tool for assessing aortic atherosclerosis (Vaduganathan et al. 1997; Vegas and Meineri 2010), as it is routinely performed to identify cardiac sources of emboli and, during cardiac surgery, to guide the introduction of the cannula into the aorta to prevent peri-procedural plaque embolization.
We propose a robust and efficient approach to the 3-D reconstruction of the descending thoracic aorta by fusion of single-view 3-D TEE aortic data sets. Recent developments in medical image fusion research have been leading to promising results, with potential useful impact on clinical applications such as diagnosis, monitoring and analysis (James and Dasarathy 2014). In particular, compounding of multiple echo images was previously proposed, with a reported valuable improvement in image quality (Behar et al. 2003; Gooding et al. 2010; Krücker et al. 2000; Leotta and Martin 1999; Piella et al. 2013; Rajpoot et al. 2011; Soler et al. 2005, 2006; Yao et al. 2011). Among these, compounding strategies have been proposed and tested in phantoms (Behar et al. 2003), using 3D TTE (Piella et al. 2013; Rajpoot et al. 2011; Soler et al. 2005; Yao et al. 2011) and 3-D fetal cardiac images (Gooding et al. 2010), 3-D breast images (Krücker et al. 2000; Soler et al. 2006) and shoulder rotator cuff 3-D images (Leotta and Martin 1999).

br Introduction High amplitude ultrasound waves have

High-amplitude ultrasound waves have been reported to be capable of cavitation-induced soft tissue destruction (Barnard et al. 1955; Cathignol et al. 1998; Dunn and Fry 1971; Fry and Dunn 1956; Fry et al. 1970; Tavakkoli et al. 1997). Histotripsy uses short (<20 cycles), high-pressure (>10 MPa) ultrasound pulses to generate contained dense bubble clouds and produce well-demarcated tissue fractionation (Lake et al. 2008; Parsons et al. 2006a; Roberts 2005; Vlaisavljevich et al. 2013). When these energetic bubble clouds are targeted at a fluid–tissue interface, controlled tissue erosion can also be created (Miller et al. 2013; Owens et al. 2011; Xu et al. 2004, 2010). Additionally, histotripsy can induce controlled comminution of model renal calculi at a fluid–calculus interface (Duryea et al. 2011a, 2011b).
Maxwell et al. (2013) found that when histotripsy is applied with pulses shorter than 2 cycles, the formation of a dense bubble cloud depends only on the applied peak negative pressure (p−) exceeding the “intrinsic threshold” of the medium (absolute value of 26–30 MPa in most soft MK-2206 with high water content). With an applied p− not significantly higher than this threshold, a very precise, sub-wavelength lesion could consistently be generated (“microtripsy”) (Lin et al. 2014b).
Our recent study (Lin et al. 2014a) reported that a sub-threshold high-frequency probe pulse (3 MHz, <2 cycles) can be enabled by a sub-threshold low-frequency pump pulse (500 kHz, <2 cycles) to exceed the intrinsic threshold. This pump–probe method of controlling a supra-threshold volume is called dual-beam histotripsy. Because the low-frequency pulse experiences less attenuation/aberration, and the high-frequency pulse can provide precision in lesion formation, this dual-beam histotripsy approach can be very useful in situations where precise lesion formation is required through a highly attenuative/aberrative medium, especially if a small acoustic window is available for the high-frequency pulse (Lin et al. 2014a). Conventionally, the transmission pulse amplitude of a diagnostic ultrasound transducer does not exceed defined limits to avoid inducing possible harmful bio-effects. Thermal index (TI) and mechanical index (MI) are the two primary metrics that the U.S. Food and Drug Administration (FDA) used to regulate the acoustic output of a diagnostic ultrasound system. However, for therapeutic ultrasound systems, these restrictions no longer apply, and some studies have investigated using diagnostic ultrasound transducers to perform therapeutic procedures. Specifically, Bailey et al. used acoustic radiation forces generated by a diagnostic transducer and a Verasonics system to displace kidney stones, to expel small stones or relocate an obstructing stone to a non-obstructing location (Bailey et al. 2013; Harper et al. 2013; Sorensen et al. 2013).

In this study, a 20-element 345-kHz array transducer was used to provide the low-frequency pump pulses, whereas an ATL L7-4 imaging transducer (Philips Healthcare, Andover, MA, USA) pulsed by a Verasonics ultrasound system was used to generate the high-frequency probe pulses. The feasibility of this dual-beam histotripsy approach using an imaging transducer was tested with red blood cell (RBC) tissue-mimicking phantoms and validated in ex vivo porcine liver tissue. The capability of steering bubble clouds and lesions by steering the imaging transducer was also investigated. In the ex vivo porcine liver experiments, the L7-4 imaging transducer was used together with the Verasonics system to provide image feedback for treatment monitoring as well as to form lesion-producing bubble clouds.


We have illustrated that a sub-threshold high-frequency probe pulse provided by an imaging transducer can create lesion-producing bubble clouds when this probe pulse is “enabled” by a sub-threshold low-frequency pump pulse to exceed the intrinsic threshold (dual-beam histotripsy [Lin et al. 2014a] using an “imaging transducer”).