Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program

Background: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval. Methods: Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model. Results: A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis. Conclusions: The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab

Exploring the land-use urban heat island nexus under climate change conditions using machine learning approach: A spatio-temporal analysis of remotely sensed data

Urbanization strongly correlates with land use land cover (LULC) dynamics, which further links to changes in land surface temperature (LST) & urban heat island (UHI) intensity. Each LULC type influences UHI differently with changing climate, therefore knowing this impact & connection is critical. To understand such relations, long temporal studies using remote sensing data play promising role by analysing the trend with continuity over vast area. Therefore, this study is aimed at machine learning centred spatio-temporal analysis of LST and land use indices to identify their intra-urban interaction during 1991–2021 (summer) in Imola city (specifically representing small urban environment) using Landsat-5/8 imageries. It was found that LST in 2021 increased by 38.36% from 1991, whereas average Normalised Difference Built-up Index (NDBI) increased by 43.75%, associating with increased thermal stress area evaluated using ecological evaluation index. Major LULC transformations included green area into agricultural arable-land and built-up. Finally, the modelled output shows that built-up & vegetation index have strongly impacted LST. This study, help to understand the relative impact of land-use dynamics on LST at intra-urban level specifically with respect to the small urban settings. Further assisting in designing and regenerating urban contexts with stable configuration, considering sustainability and liveable climate, for benefit of health of public and fragile population in particular

Side effects of analgesia may significantly reduce quality of life in symptomatic multiple myeloma: a cross-sectional prevalence study

Background Pain is a common symptom in patients with multiple myeloma (MM). Many patients are dependent on analgesics and in particular opioids, but there is limited information on the impact of these drugs and their side effects on health-related quality of life (HRQoL). Method In a cross-sectional study, semi-structured interviews were performed in 21 patients attending the hospital with symptomatic MM on pain medications. HRQoL was measured using items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Results Patients were able to recall a median of two (range 0–4) analgesics. They spontaneously identified a median of two (range 1–5) side effects attributable to their analgesic medications. Patients’ assessment of HRQoL based on the EORTC QLQ-C30 questions 29/30 was mean 48.3 (95 % CI; 38.7–57.9) out of 100. Patients’ assessment of their HRQoL in the hypothetical situation, in which they would not experience any side effects from analgesics, was significantly higher: 62.6 (53.5–71.7) (t test, p=0.001). Conclusion This study provides, for the first time, evidence that side effects of analgesics are common in symptomatic MM and may result in a statistically and clinically significant reduction of self-reported HRQoL

Relation between Morphology and Chiroptical Properties in Chiral Conducting Polymer Films: A Case Study in Chiral PEDOT

The electronic properties of conducting polymers are influenced by their micro- and macrostructural orders, which can be tailored by substituent modification. However, while the effect of substituents on conducting polymers is extensively investigated, chiral substituents are far less studied. Furthermore, many chiral conducting polymers have regioirregular structures, which result in polymer films with inferior properties. In this work, we apply electronic circular dichroism (ECD) spectroscopy to study the morphological changes to the chiral polymers under different polymerization conditions. For this purpose, we investigated 3,4-ethylenedioxythiophene (EDOT) derivatives having two stereogenic centers on each monomer and bearing methyl or phenyl side groups (dimethyl-EDOT and diphenyl-EDOT, respectively). Polymerizing the enantiomerically pure monomers produces regioregular and stereoregular dimethyl-PEDOT and diphenyl-PEDOT, respectively. The effect of the electrolyte and solvent on polymer film morphology was studied using scanning electron microscopy (SEM) and ECD, showing a correlation between the polymer's morphology and the chiroptical properties of its films. We found that, for diphenyl-PEDOT, the combination of perchlorate anion electrolyte and acetonitrile solvent resulted in a unique morphology characterized by significant intermolecular interactions. These interactions were clearly observable in the ECD spectra in the form of exciton couplings, whose presence was supported by TD-DFT calculations. A small enantiomeric excess was sufficient to induce very intense ECD signals, demonstrating chiral amplification in electropolymerized films

Development of a Pilot Borehole Storage System of Solar Thermal Energy: Modeling, Design, and Installation

Borehole thermal energy storage systems represent a potential solution to increase the energy efficiency of renewable energy plants, but they generally have to comply with strict regulatory frameworks, mainly due to the deliberate modification of the subsoil’s natural state. This paper presents the design, testing, and monitoring phases carried out to set up a borehole thermal energy storage (BTES) system able to exploit the excess solar heat from photovoltaic thermal (PVT) collectors. The case study is the refurbishment of a pig nursery barn, hosting up to 2500 weaners, in Northern Italy. This study aims to define a BTES suitable to develop a heating system based on renewable energy, ensuring environmental protection and long-term sustainability. The retrofitting intervention includes the installation of a dual-source heat pump (DSHP), in order to recover the solar heat stored in summer during winter. Specific constraints by the Environmental Authority were as follows: maximum storage temperature of 35 °C, authorization to intercept the shallowest aquifer at a maximum depth of 30 m, obligation of BHE grouting, and the definition of a strategy for continuous measuring and monitoring of the groundwater’s thermophysical properties. The results were used as inputs to optimize the design and installation of the integrated system with PVT, BTES, and DSHP

Policy and political challenges for a better world: The United States and China pathways towards the 2030 Agenda

The Agenda 2030 poses critical elements regarding the transition towards a more sustainable development. This paper aims at exploring and comparing the path of sustainable development within the United States and China at the subnational level. An index of Integrated Sustainable Development is introduced to measure local sustainable development on an internationally-comparable scale. This Index is computed both at the national and subnational level and the resulting scores are compared within and across the two countries, also through the adoption of convergence and cluster analysis, allowing to answer four questions: Are the US and China moving towards a sustainable development agenda? Are the current achievements uniformly distributed within the two countries? Are states/provinces converging towards a more uniform level of sustainable development? Do the existing differences and analogies between states and provinces give rise to common clusters across the two countries? The results lead to one robust conclusion: while the US can claim a better result in the national and subnational rankings of sustainable development, China exhibits a more balanced achievement in terms of synergies across Goals and spatial distribution. Nonetheless, both countries are characterized by subnational disparities and scarce achievements of Planet-related Goals. Policy recommendations are discussed accordingly

Assessment of construction and demolition waste materials for sublayers of low traffic rural roads

The need for exploiting massive amounts of natural raw materials for constructing pavements of roads as a key element for development of infrastructures in modern age, together with enormous production amounts of wastes related to civil engineering activities as biggest portion of solid waste generated all over the world, have highlighted the importance of utilizing recycled aggregates of these materials in road pavement layers. The key factor in this quest, is to evaluate load-bearing abilities of various kinds of waste aggregates. Aggregates of reclaimed asphalt, pre-stressed or normal concrete, masonry and demolition waste (CDW) exhibit different behavior under loading after compaction. The ideal situation would be to achieve the densest compacted and durable layer in order to get the highest durability, comparing to traditional road materials. In this study, aggregates from four types of recycled materials are being subjected to study for unbound and cemented pavement layers. Initial laboratory evaluations of size and composition are followed by constructing a field on a subgrade with high non-homogenous surface. Vibrating elastic modulus (Evib) for these materials were determined by Continuous Compaction Control (CCC) Oscillating Rollers. It is observed that, despite the weaknesses arisen from weak components such as masonry and elongated tiles, the stabilized distribution of the particle size can accelerate reaching to final compaction of unbound aggregates with roller passing. This process could be repeated with more or less same pattern in cemented layer, which exhibited an enhanced stiffness and uniformity in order to minimize the weak parts of non-uniform subgrade layer, and provide a high rigid pavement

Research model for farm building design: General structure and physiognomic characterization phase

The design of contemporary farm buildings often subordinates architectural quality and aesthetic features to economic aspects, thus leading to poor landscape consistency and compatibility.  The research presented in this paper is based on the theoretical principle that historic rural buildings, being expression of an accumulation of empirical knowledge broadly associated with high architectural quality, have remarkable potentials to contribute with useful elements to the design of contemporary buildings, and on the awareness that the design process is also necessarily and substantially determined by technological, economic and functional variables.  The paper presents the FarmBuiLD model (Farm Building Landscape Design), a research model proposed by the authors as a tool for the analysis of the architectural characteristics of both historical and contemporary rural buildings, as well as the meta-design of new construction and transformation of contemporary rural buildings.  In particular, the work focuses on the general structure of this model and a synthesis of the main results of the critical analysis of the scientific literature aimed at identifying a set of synthetic architectural parameters suitable for its implementation, through the interpretation of the main physiognomical characteristics of rural buildings.  These parameters are not meant as a tool to obtain quantitative data to be translated into design constraints automatically; on the contrary, they are mainly considered as an interpretive-analytical tool, part of a broader knowledge framework aimed at supporting, stimulating and suggesting the design choices.Keywords: Rural building design, historical-typological consistency, landscape compatibility, architectural quality, analytical and meta-design criteria, Italian rural building heritage Citation: Tassinari P, D. Torreggiani, S. Benni, and E. Dall’Ara.  Research model for farm building design: General structure and physiognomic characterization phase.  Agric Eng Int: CIGR Journal, 2010; 12(1): 47-54

Developing a 3D City Digital Twin: Enhancing Walkability through a Green Pedestrian Network (GPN) in the City of Imola, Italy

Predominantly, dense historical cities face insufficient pedestrian-level greenery in the urban spaces. The lack of greenery impacts the human thermal comfort on the walking paths, which contributes to a considerable reduction in pedestrian flow rate. This study aims at developing a model to assess pedestrian-level thermal comfort in city environments and then evaluate the feasibility of creating a green pedestrian network (GPN). Imola, as a historical city in Italy with a compact urban pattern, is selected as the case study of this paper. To accomplish this, a three-dimensional digital twin at city scale is developed for the recognition of real-time shade patterns and for designing a GPN in this city. The 3D model of the proposed digital twin is developed in the Rhinoceros platform, and the physiological equivalence temperature (PET) is simulated through EnergyPlus, Honeybee, and Ladybug components in grasshopper. This study provides the city with a digital twin that is capable of examining pedestrian-level thermal comfort for designing a GPN based on real-time PET in the compact urban morphology of Imola. The PET model indicates that during the hottest hour of the 25th of June, pedestrians in open spaces can experience 3  C more than on narrow shaded streets. The results are validated based on in situ datasets that prove the reliability of the developed digital twin for the GPN. It provides urban planners and policy makers with a precise and useful methodology for simulating the effects of pedestrian-level urban greenery on human thermal comfort and also guarantees the functionality of policies in different urban settings

Teratology Primer-2nd Edition (7/9/2010)

Foreword: What is Teratology? “What a piece of work is an embryo!” as Hamlet might have said. “In form and moving how express and admirable! In complexity how infinite!” It starts as a single cell, which by repeated divisions gives rise to many genetically identical cells. These cells receive signals from their surroundings and from one another as to where they are in this ball of cells —front or back, right or left, headwards or tailwards, and what they are destined to become. Each cell commits itself to being one of many types; the cells migrate, combine into tissues, or get out of the way by dying at predetermined times and places. The tissues signal one another to take their own pathways; they bend, twist, and form organs. An organism emerges. This wondrous transformation from single celled simplicity to myriad-celled complexity is programmed by genes that, in the greatest mystery of all, are turned on and off at specified times and places to coordinate the process. It is a wonder that this marvelously emergent operation, where there are so many opportunities for mistakes, ever produces a well-formed and functional organism. And sometimes it doesn’t. Mistakes occur. Defective genes may disturb development in ways that lead to death or to malformations. Extrinsic factors may do the same. “Teratogenic” refers to factors that cause malformations, whether they be genes or environmental agents. The word comes from the Greek “teras,” for “monster,” a term applied in ancient times to babies with severe malformations, which were considered portents or, in the Latin, “monstra.” Malformations can happen in many ways. For example, when the neural plate rolls up to form the neural tube, it may not close completely, resulting in a neural tube defect—anencephaly if the opening is in the head region, or spina bifida if it is lower down. The embryonic processes that form the face may fail to fuse, resulting in a cleft lip. Later, the shelves that will form the palate may fail to move from the vertical to the horizontal, where they should meet in the midline and fuse, resulting in a cleft palate. Or they may meet, but fail to fuse, with the same result. The forebrain may fail to induce the overlying tissue to form the eye, so there is no eye (anophthalmia). The tissues between the toes may fail to break down as they should, and the toes remain webbed. Experimental teratology flourished in the 19th century, and embryologists knew well that the development of bird and frog embryos could be deranged by environmental “insults,” such as lack of oxygen (hypoxia). But the mammalian uterus was thought to be an impregnable barrier that would protect the embryo from such threats. By exclusion, mammalian malformations must be genetic, it was thought. In the early 1940s, several events changed this view. In Australia an astute ophthalmologist, Norman Gregg, established a connection between maternal rubella (German measles) and the triad of cataracts, heart malformations, and deafness. In Cincinnati Josef Warkany, an Austrian pediatrician showed that depriving female rats of vitamin B (riboflavin) could cause malformations in their offspring— one of the early experimental demonstrations of a teratogen. Warkany was trying to produce congenital cretinism by putting the rats on an iodine deficient diet. The diet did indeed cause malformations, but not because of the iodine deficiency; depleting the diet of iodine had also depleted it of riboflavin! Several other teratogens were found in experimental animals, including nitrogen mustard (an anti cancer drug), trypan blue (a dye), and hypoxia (lack of oxygen). The pendulum was swinging back; it seemed that malformations were not genetically, but environmentally caused. In Montreal, in the early 1950s, Clarke Fraser’s group wanted to bring genetics back into the picture. They had found that treating pregnant mice with cortisone caused cleft palate in the offspring, and showed that the frequency was high in some strains and low in others. The only difference was in the genes. So began “teratogenetics,” the study of how genes influence the embryo’s susceptibility to teratogens. The McGill group went on to develop the idea that an embryo’s genetically determined, normal, pattern of development could influence its susceptibility to a teratogen— the multifactorial threshold concept. For instance, an embryo must move its palate shelves from vertical to horizontal before a certain critical point or they will not meet and fuse. A teratogen that causes cleft palate by delaying shelf movement beyond this point is more likely to do so in an embryo whose genes normally move its shelves late. As studies of the basis for abnormal development progressed, patterns began to appear, and the principles of teratology were developed. These stated, in summary, that the probability of a malformation being produced by a teratogen depends on the dose of the agent, the stage at which the embryo is exposed, and the genotype of the embryo and mother. The number of mammalian teratogens grew, and those who worked with them began to meet from time to time, to talk about what they were finding, leading, in 1960, to the formation of the Teratology Society. There were, of course, concerns about whether these experimental teratogens would be a threat to human embryos, but it was thought, by me at least, that they were all “sledgehammer blows,” that would be teratogenic in people only at doses far above those to which human embryos would be exposed. So not to worry, or so we thought. Then came thalidomide, a totally unexpected catastrophe. The discovery that ordinary doses of this supposedly “harmless” sleeping pill and anti-nauseant could cause severe malformations in human babies galvanized this new field of teratology. Scientists who had been quietly working in their laboratories suddenly found themselves spending much of their time in conferences and workshops, sitting on advisory committees, acting as consultants for pharmaceutical companies, regulatory agencies, and lawyers, as well as redesigning their research plans. The field of teratology and developmental toxicology expanded rapidly. The following pages will show how far we have come, and how many important questions still remain to be answered. A lot of effort has gone into developing ways to predict how much of a hazard a particular experimental teratogen would be to the human embryo (chapters 9–19). It was recognized that animal studies might not prove a drug was “safe” for the human embryo (in spite of great pressure from legislators and the public to do so), since species can vary in their responses to teratogenic exposures. A number of human teratogens have been identified, and some, suspected of teratogenicity, have been exonerated—at least of a detectable risk (chapters 21–32). Regulations for testing drugs before market release have greatly improved (chapter 14). Other chapters deal with how much such things as population studies (chapter 11), post-marketing surveillance (chapter 13), and systems biology (chapter 16) add to our understanding. And, in a major advance, the maternal role of folate in preventing neural tube defects and other birth defects is being exploited (chapter 32). Encouraging women to take folic acid supplements and adding folate to flour have produced dramatic falls in the frequency of neural tube defects in many parts of the world. Progress has been made not only in the use of animal studies to predict human risks, but also to illumine how, and under what circumstances, teratogens act to produce malformations (chapters 2–8). These studies have contributed greatly to our knowledge of abnormal and also normal development. Now we are beginning to see exactly when and where the genes turn on and off in the embryo, to appreciate how they guide development and to gain exciting new insights into how genes and teratogens interact. The prospects for progress in the war on birth defects were never brighter. F. Clarke Fraser McGill University (Emeritus) Montreal, Quebec, Canad