A Low-Cost Hardware Architecture for EV Battery Cell Characterization Using an IoT-Based Platform.

Since 1997, when the first hybrid vehicle was launched on the market, until today, the number of NIMH batteries that have been discarded due to their obsolescence has not stopped increasing, with an even faster rate more recently due to the progressive disappearance of thermal vehicles on the market. The battery technologies used are mostly NIMH for hybrid vehicles and Li ion for pure electric vehicles, making recycling difficult due to the hazardous materials they contain. For this reason, and with the aim of extending the life of the batteries, even including a second life within electric vehicle applications, this paper describes and evaluates a low-cost system to characterize individual cells of commercial electric vehicle batteries by identifying such abnormally performing cells that are out of use, minimizing regeneration costs in a more sustainable manner. A platform based on the IoT technology is developed, allowing the automation of charging and discharging cycles of each independent cell according to some parameters given by the user, and monitoring the real-time data of such battery cells. A case study based on a commercial Toyota Prius battery is also included in the paper. The results show the suitability of the proposed solution as an alternative way to characterize individual cells for subsequent electric vehicle applications, decreasing operating costs and providing an autonomous, flexible, and reliable system.

First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study.

BACKGROUND: Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. METHODS: TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1-5 and 8-12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1-14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. RESULTS: At 1 September 2020, median OS was 22.3 months (95% CI: 18.0-23.7) with TT-B and 17.7 months (95% CI: 12.6-19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55-1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. CONCLUSIONS: TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. CLINICAL TRIAL INFORMATION: NCT02743221 (clinicaltrials.gov).

Democratization of PV Micro-Generation System Monitoring Based on Narrowband-IoT.

Power system configuration and performance are changing very quickly. Under the new paradigm of prosumers and energy communities, grids are increasingly influenced by microgeneration systems connected in both low and medium voltage. In addition, these facilities provide little or no information to distribution and/or transmission system operators, increasing power system management problems. Actually, information is a great asset to manage this new situation. The arrival of affordable and open Internet of Things (IoT) technologies is a remarkable opportunity to overcome these inconveniences allowing for the exchange of information about these plants. In this paper, we propose a monitoring solution applicable to photovoltaic self-consumption or any other microgeneration installation, covering the installations of the so-called 'prosumers' and aiming to provide a tool for local self-consumption monitoring. A detailed description of the proposed system at the hardware level is provided, and extended information on the communication characteristics and data packets is also included. Results of different field test campaigns carried out in real PV self-consumption installations connected to the grid are described and analyzed. It can be affirmed that the proposed solution provides outstanding results in reliability and accuracy, being a popular solution for those who cannot afford professional monitoring platforms.

CIoTVID: Towards an Open IoT-Platform for Infective Pandemic Diseases such as COVID-19.

The factors affecting the penetration of certain diseases such as COVID-19 in society are still unknown. Internet of Things (IoT) technologies can play a crucial role during the time of crisis and they can provide a more holistic view of the reasons that govern the outbreak of a contagious disease. The understanding of COVID-19 will be enriched by the analysis of data related to the phenomena, and this data can be collected using IoT sensors. In this paper, we show an integrated solution based on IoT technologies that can serve as opportunistic health data acquisition agents for combating the pandemic of COVID-19, named CIoTVID. The platform is composed of four layers-data acquisition, data aggregation, machine intelligence and services, within the solution. To demonstrate its validity, the solution has been tested with a use case based on creating a classifier of medical conditions using real data of voice, performing successfully. The layer of data aggregation is particularly relevant in this kind of solution as the data coming from medical devices has a very different nature to that coming from electronic sensors. Due to the adaptability of the platform to heterogeneous data and volumes of data; individuals, policymakers, and clinics could benefit from it to fight the propagation of the pandemic.

Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study.

BACKGROUND: We designed an open-label, noncomparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies. PATIENTS AND METHODS: From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (N = 77) or C-B (N = 76). The primary end point was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary end points included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires), and safety. RESULTS: Median (range) duration of treatment was 7.8 (6.0-9.7) months and 6.2 (4.1-9.1) months in the TT-B and C-B groups, respectively. Median (range) PFS was 9.2 (7.6-11.6) and 7.8 (5.5-10.1) months, respectively. Median (range) OS was 18 (15.2 to NA) and 16.2 (12.5 to NA) months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% versus 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% versus 0% with TT-B) and grade ≥3 diarrhea (8% versus 1% with TT-B), consistent with the known safety profiles of these agents. CONCLUSION: TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL. CLINICAL TRIAL INFORMATION: NCT02743221 (ClinicalTrials.gov).

Estudio de caso. Sector de la sanidad animal frente al huracán «Irma¼ en Cuba.

This case study outlines the actions of Cuba's Veterinary Service, as part of the country's disaster risk reduction and management system, in response to Hurricane Irma. The phenomenon affected ten of Cuba's 15 provinces and caused significant damage in 53 of its municipalities (29.6%). During the response effort, the pre-established measures for the various phases (warning, alert and emergency) were deployed according to the disaster reduction plans for each level. In all provinces, animals were protected by moving them to safer locations, allowing for pre-established sanitary measures and technical assistance. Nonetheless, damage was incurred, mainly to the roofs of some animal housing. The following deaths were recorded: 210,150 poultry, 2,752 cattle (of which 73.8% were calves) and 866 pigs (of which 68% were young animals). In addition, 7% of the inventory of hives was damaged and 3.3% of hives were lost. Damage to infrastructure included: 466 poultry houses, 1,422 cattle houses, 431 pig houses, 1,200 wind pumps and 13 of the country's 17 feed concentrate plants. As no major damage was reported to the Veterinary Service's facilities (laboratories and offices), its viability was guaranteed at all times. Rapid damage assessment enabled priorities for rehabilitation and recovery actions to be set, with the result that, just three months after the hurricane had struck, 67% of the poultry houses and 33% of the pig houses had been restored. This article focuses on preparedness, response and lessons learned.

Dans cette étude de cas, les auteurs retracent les activités menées lors du passage de l'ouragan Irma par les Services vétérinaires cubains, en tant que composante du système d'atténuation et de gestion du risque de catastrophe. Le phénomène a touché dix des quinze provinces du pays, entraînant des destructions importantes dans 56 communes (29,6 %). Lors de la réponse, les moyens prévus dans les plans de réduction des catastrophes pour les différentes phases (information, alerte et intervention d'urgence) ont été déployés à chaque niveau. Dans chaque province, la protection des animaux a été assurée en les évacuant vers des lieux plus sûrs, en appliquant les mesures sanitaires prévues et en mettant en place une assistance technique. L'ouragan a néanmoins occasionné des dégâts, en particulier la destruction de la couverture de nombreuses installations d'élevage. Les pertes enregistrées dans les cheptels se sont réparties comme suit : 210 150 volailles, 2 752 bovins (dont 73,8 % de veaux) et 866 porcs (dont 68 % de porcelets). En ce qui concerne les ruches, 7 % d'entre elles ont subi des dommages et 3,3 % ont été détruites. En termes d'infrastructures, des dégâts ont été enregistrés sur 466 bâtiments avicoles, 1 422 bâtiments d'élevage bovin, 431 bâtiments d'élevage porcin, 1 200 pompes éoliennes et 13 des 17 usines de production de concentrés pour l'alimentation animale. Les installations des Services vétérinaires (laboratoires et bureaux) n'ont subi aucun dommage grave, de sorte que ces Services sont restés opérationnels en permanence. L'évaluation rapide des dégâts a permis d'établir les priorités concernant les mesures de reconstruction et de redressement. Trois mois seulement après le passage de l'ouragan, 67 % des bâtiments avicoles et 33 % des bâtiments d'élevage porcin étaient réparés. Les auteurs soulignent les mesures de préparation et de réponse ainsi que les leçons apprises.

Este artículo esboza las acciones del Servicio Veterinario como parte del sistema cubano de reducción y gestión del riesgo de desastres ante el huracán «Irma¼, en forma de estudio de caso. El fenómeno afectó a 10 de las 15 provincias del país y ocasionó daños importantes en 53 de sus municipios (29,6%). Durante la respuesta, se desplegaron las medidas preestablecidas para las diferentes fases (informativa, de alerta y de emergencia) en los planes de reducción de desastres correspondientes a cada nivel. En todas las provincias se protegieron animales trasladándolos a lugares más seguros, garantizando las medidas sanitarias preestablecidas y la asistencia técnica. No obstante, se produjeron daños, fundamentalmente en techos de algunas instalaciones de crianza. Se registró la muerte de: 210 150 aves de corral, 2 752 bovinos (un 73,8% eran terneros) y 866 porcinos (un 68% eran crías). También sufrió daño el 7% del inventario de colmenas, y se perdió un 3,3% de las colmenas. Los daños en infraestructuras comprendieron: 466 naves de producción avícola; 1 422 naves de producción bovina, 431 naves de producción porcina; 1 200 molinos a viento y 13 de 17 fábricas de alimento concentrado. No se reportaron daños de importancia en las instalaciones del Servicio Veterinario (laboratorios y oficinas), por lo que su viabilidad estuvo garantizada en todo momento. La rápida evaluación de los daños posibilitó establecer prioridades respecto a las acciones de rehabilitación y recuperación, y tan solo tres meses después del impacto del huracán, el 67% de las naves de producción avícola y el 33% de las de producción porcina estaban recuperadas. Se destacan los preparativos, la respuesta y las lecciones aprendidas.

A Comprehensive Survey about Thermal Comfort under the IoT Paradigm: Is Crowdsensing the New Horizon?

This paper presents a review of technologies under the paradigm 4.0 applied to the study of the thermal comfort and, implicitly, energy efficiency. The research is based on the analysis of the Internet of Things (IoT) literature, presenting a comparison among several approaches adopted. The central objective of the research is to outline the path that has been taken throughout the last decade towards a people-centric approach, discussing how users switched from being passive receivers of IoT services to being an active part of it. Basing on existing studies, authors performed what was a necessary and unprecedented grouping of the IoT applications to the thermal comfort into three categories: the thermal comfort studies with IoT hardware, in which the approach focuses on physical devices, the mimicking of IoT sensors and comfort using Building Simulation Models, based on the dynamic modelling of the thermal comfort through IoT systems, and Crowdsensing, a new concept in which people can express their sensation proactively using IoT devices. Analysing the trends of the three categories, the results showed that Crowdsensing has a promising future in the investigation through the IoT, although some technical steps forward are needed to achieve a satisfactory application to the thermal comfort matter.

An Artificial Intelligence-Based Collaboration Approach in Industrial IoT Manufacturing: Key Concepts, Architectural Extensions and Potential Applications.

The digitization of manufacturing industry has led to leaner and more efficient production, under the Industry 4.0 concept. Nowadays, datasets collected from shop floor assets and information technology (IT) systems are used in data-driven analytics efforts to support more informed business intelligence decisions. However, these results are currently only used in isolated and dispersed parts of the production process. At the same time, full integration of artificial intelligence (AI) in all parts of manufacturing systems is currently lacking. In this context, the goal of this manuscript is to present a more holistic integration of AI by promoting collaboration. To this end, collaboration is understood as a multi-dimensional conceptual term that covers all important enablers for AI adoption in manufacturing contexts and is promoted in terms of business intelligence optimization, human-in-the-loop and secure federation across manufacturing sites. To address these challenges, the proposed architectural approach builds on three technical pillars: (1) components that extend the functionality of the existing layers in the Reference Architectural Model for Industry 4.0; (2) definition of new layers for collaboration by means of human-in-the-loop and federation; (3) security concerns with AI-powered mechanisms. In addition, system implementation aspects are discussed and potential applications in industrial environments, as well as business impacts, are presented.

Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial.

BACKGROUND: Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI. PATIENTS AND METHODS: This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed. RESULTS: Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR. CONCLUSIONS: High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations. CLINICALTRIALS.GOV NUMBER: NCT01704703. EUDRACT NUMBER: 2012-001955-38.

Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study.

Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number: NCT01183780.

Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy.

BACKGROUND: Extended RAS analysis is mandatory in metastatic colorectal cancer (mCRC) patients. The optimal threshold of RAS mutated subclones to identify patients most likely to benefit from antiepidermal growth factor receptor (EGFR) therapy is controversial. Our aim was to assess the clinical impact of detecting mutations in RAS, BRAF, PIK3CA and EGFRS492R in basal tissue tumour samples by using a highly sensitive next-generation sequencing (NGS) technology in mCRC patients treated with chemotherapy plus anti-EGFR or anti-vascular endothelial growth factor. PATIENTS AND METHODS: Five hundred and eighty-one tumour samples from untreated mCRC patients from 7 clinical studies were collected. Mutational analysis was carried out by standard-of-care (therascreen pyro) with a sensitivity detection of 5% mutant allele fraction (MAF), and compared with NGS technology using 454GS Junior platform (Roche Applied Science, Germany) with a sensitivity of 1%. Molecular results were correlated with clinical outcomes. RESULTS: After quality assessment, 380 samples were evaluable for molecular analysis. Standard-of-care mutational analysis detected RAS, BRAFV600E or PIK3CA mutations in 56.05% of samples compared with 69.21% by NGS (P = 0.00018). NGS identified coexistence of multiple low-frequency mutant alleles in 96 of the 263 mutated cases (36.5%; range 2-7). Response rate (RR), progression-free survival (PFS) and overall survival (OS) were increasingly improved in patients with RAS wild-type, RAS/BRAF wild-type or quadruple (KRAS/NRAS/BRAF/PIK3CA) wild-type tumours treated with anti-EGFR, assessed by standard-of-care. No additional benefit in RR, PFS or OS was observed by increasing the detection threshold to 1% by NGS. An inverse correlation between the MAF of the most prevalent mutation detected by NGS and anti-EGFR response was observed (P = 0.039). EGFRS492Rmutation was not detected in untreated samples. CONCLUSIONS: No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours.

First-line single-agent regorafenib in frail patients with metastatic colorectal cancer: a pilot phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

BACKGROUND: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC. METHODS: Frail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. MAIN OBJECTIVE: to assess progression-free survival (PFS) rate at 6 months. Treatment consisted of 28-day cycles of orally administered regorafenib 160 mg/day (3 weeks followed by 1 week rest). RESULTS: Forty-seven patients were included in the study. Median age was 81 years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6 months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6 months (95%CI 2.7-8.4). Median overall survival (OS) was 16 months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirty-nine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%). CONCLUSIONS: The study did not meet the pre-specified boundary of 55% PFS rate at 6 months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach. TRIAL REGISTRATION: This trial was prospectively registered at EudraCT ( 2013-000236-94 ). Date of trial registration: April 9th, 2013.

Genotype-based selection of treatment of patients with advanced colorectal cancer (SETICC): a pharmacogenetic-based randomized phase II trial.

Background: There has been little progress toward personalized therapy for patients with metastatic colorectal cancer (mCRC). TYMS-3' untranslated region (UTR) 6 bp ins/del and ERCC1-118C/T polymorphisms were previously reported to facilitate selecting patients for fluoropyrimidine-based treatment in combination with oxaliplatin as first-line therapy. We assessed the utility of these markers in selecting therapy for patients with mCRC. Patients and methods: This randomized, open-label phase II trial compared bevacizumab plus XELOX (control) versus treatment tailored according to TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Patients randomized to the experimental treatment received bevacizumab plus FUOX, FUIRI, XELIRI, or XELOX depending on their combination of favorable polymorphisms for FUOX treatment (TYMS-3'UTR ins/del or del/del; ERCC1-118T/T). Progression-free survival (PFS) was the primary end point. Results: Overall, 195 patients were randomized (control n = 65; experimental n = 130). The primary objective was not met: median PFS was 9.4 months in the control group and 10.1 months in the experimental group (P = 0.745). Median overall survival was similar in both groups (16.5 versus 19.1 months, respectively; P = 0.797). Patients in the experimental group had a significantly higher overall response rate (ORR; 65% versus 47% in the control group; P = 0.042) and R0 resection rate (86% versus 44%, respectively; P = 0.018). Neuropathy, hand-foot syndrome, thrombocytopenia, and dysesthesia were significantly less common in the experimental group. Conclusions: This study did not show survival benefits after treatment personalization based on polymorphisms in mCRC. However, the improved ORR and R0 resection rate and fewer disabling toxicities suggest that tailoring therapy by TYMS-3'UTR and ERCC1-118 polymorphisms warrants further investigation in patients with mCRC. ClinicalTrials.gov: NCT01071655.

Commissioning of the Controlled and Automatized Testing Facility for Human Behavior and Control (CASITA).

Human behavior is one of the most challenging aspects in the understanding of building physics. The need to evaluate it requires controlled environments and facilities in which researchers can test their methods. In this paper, we present the commissioning of the Controlled and Automatized Testing Facility for Human Behavior (CASITA). This is a controlled space emulation of an office or flat, with more than 20 environmental sensors, 5 electrical meters, and 10 actuators. Our contribution shown in this paper is the development of an infrastructure-Artificial Intelligence (AI) model pair that is perfectly integrated for the study of a variety of human energy use aspects. This facility will help to perform studies about human behavior in a controlled space. To verify this, we have tested this emulation for 60 days, in which equipment was turned on and off, the settings of the conditioning system were modified remotely, and lighting operation was similar to that in real behaviors. This period of commissioning generated 74.4 GB of raw data including high-frequency measurements. This work has shown that CASITA performs beyond expectations and that sensors and actuators could enable research on a variety of disciplines related to building physics and human behavior. Also, we have tested the PROPHET software, which was previously used in other disciplines and found that it could be an excellent complement to CASITA for experiments that require the prediction of several pertinent variables in a given study. Our contribution has also been to proof that this package is an ideal "soft" addition to the infrastructure. A case study forecasting energy consumption has been performed, concluding that the facility and the software PROPHET have a great potential for research and an outstanding accuracy.

Precise Correction of Disease Mutations in Induced Pluripotent Stem Cells Derived From Patients With Limb Girdle Muscular Dystrophy.

Limb girdle muscular dystrophies types 2B (LGMD2B) and 2D (LGMD2D) are degenerative muscle diseases caused by mutations in the dysferlin and alpha-sarcoglycan genes, respectively. Using patient-derived induced pluripotent stem cells (iPSC), we corrected the dysferlin nonsense mutation c.5713C>T; p.R1905X and the most common alpha-sarcoglycan mutation, missense c.229C>T; p.R77C, by single-stranded oligonucleotide-mediated gene editing, using the CRISPR/Cas9 gene-editing system to enhance the frequency of homology-directed repair. We demonstrated seamless, allele-specific correction at efficiencies of 0.7-1.5%. As an alternative, we also carried out precise gene addition strategies for correction of the LGMD2B iPSC by integration of wild-type dysferlin cDNA into the H11 safe harbor locus on chromosome 22, using dual integrase cassette exchange (DICE) or TALEN-assisted homologous recombination for insertion precise (THRIP). These methods employed TALENs and homologous recombination, and DICE also utilized site-specific recombinases. With DICE and THRIP, we obtained targeting efficiencies after selection of ~20%. We purified iPSC corrected by all methods and verified rescue of appropriate levels of dysferlin and alpha-sarcoglycan protein expression and correct localization, as shown by immunoblot and immunocytochemistry. In summary, we demonstrate for the first time precise correction of LGMD iPSC and validation of expression, opening the possibility of cell therapy utilizing these corrected iPSC.

Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression.

BACKGROUND: The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months). PATIENTS AND METHODS: OS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs. RESULTS: Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups. CONCLUSIONS: These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01183780.

DICE, an efficient system for iterative genomic editing in human pluripotent stem cells.

To reveal the full potential of human pluripotent stem cells, new methods for rapid, site-specific genomic engineering are needed. Here, we describe a system for precise genetic modification of human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). We identified a novel human locus, H11, located in a safe, intergenic, transcriptionally active region of chromosome 22, as the recipient site, to provide robust, ubiquitous expression of inserted genes. Recipient cell lines were established by site-specific placement of a 'landing pad' cassette carrying attP sites for phiC31 and Bxb1 integrases at the H11 locus by spontaneous or TALEN-assisted homologous recombination. Dual integrase cassette exchange (DICE) mediated by phiC31 and Bxb1 integrases was used to insert genes of interest flanked by phiC31 and Bxb1 attB sites at the H11 locus, replacing the landing pad. This system provided complete control over content, direction and copy number of inserted genes, with a specificity of 100%. A series of genes, including mCherry and various combinations of the neural transcription factors LMX1a, FOXA2 and OTX2, were inserted in recipient cell lines derived from H9 ESC, as well as iPSC lines derived from a Parkinson's disease patient and a normal sibling control. The DICE system offers rapid, efficient and precise gene insertion in ESC and iPSC and is particularly well suited for repeated modifications of the same locus.

Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial.

BACKGROUND: For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting. PATIENTS AND METHODS: OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis. RESULTS: In patients assigned to bevacizumab-FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9-22.3) months and 11·5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively). CONCLUSIONS: Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab-FOLFOXIRI. CLINICALTRIALSGOV: NCT00778102.