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Obstacle avoidance is a major challenge during independent mobility for blind or visually impaired (BVI) people. Typically, BVI people can only perceive obstacles at a short distance (about 1 m, in case they are using the white cane), and some obstacles are hard to detect (e.g . , those elevated from the ground), or should not be hit by the white cane (e.g . , a standing person). A solution to these problems can be found in recent computer-vision techniques that can run on mobile and wearable devices to detect obstacles at a distance. However, in addition to detecting obstacles, it is also necessary to convey information about them in real time. This contribution presents WatchOut , a sonification technique for conveying real-time information about the main properties of an obstacle to a BVI person, who can then use this additional feedback to safely navigate in the environment. WatchOut was designed with a user-centered approach, involving four iterations of online listening tests with BVI participants in order to define, improve and evaluate the sonification technique, eventually obtaining an almost perfect recognition accuracy. WatchOut was also implemented and tested as a module of a mobile app that detects obstacles using state-of-the-art computer vision technology. Results show that the system is considered usable and can guide the users to avoid more than 85% of the obstacles.

Navigation assistive technologies are designed to support people with visual impairments during mobility. In particular, turn-by-turn navigation is commonly used to provide walk and turn instructions, without requiring any prior knowledge about the traversed environment. To ensure safe and reliable guidance, many research efforts focus on improving the localization accuracy of such instruments. However, even when the localization is accurate, imprecision in conveying guidance instructions to the user and in following the instructions can still lead to unrecoverable navigation errors. Even slight errors during rotations, amplified by the following frontal movement, can result in the user taking an incorrect and possibly dangerous path. In this article, we analyze trajectories of indoor travels in four different environments, showing that rotation errors are frequent in state-of-art navigation assistance for people with visual impairments. Such errors, caused by the delay between the instruction to stop rotating and when the user actually stops, result in over-rotation . To compensate for over-rotation, we propose a technique to anticipate the stop instruction so that the user stops rotating closer to the target rotation. The technique predicts over-rotation using a deep learning model that takes into account the user’s current rotation speed, duration, and angle; the model is trained with a dataset of rotations performed by blind individuals. By analyzing existing datasets, we show that our approach outperforms a naive baseline that predicts over-rotation with a fixed value. Experiments with 11 blind participants also show that the proposed compensation method results in lower rotation errors (18.8° on average) compared to the non-compensated approach adopted in state-of-the-art solutions (30.1°).

Purpose The administration timing of antiemetic and chemotherapeutic regimens is often determined by regulatory indications, based on registration studies. Oral NEPA, fixed combination of the neurokinin-1 receptor antagonist (NK1RA) netupitant and the 5-hydroxytryptamine-3 RA (5-HT3RA) palonosetron, is recommended to be administered approximately 60 min before chemotherapy. Reducing chair time for chemotherapy administration at oncology day therapy units would improve facility efficiency without compromising patient symptom management. The objective was to determine if oral NEPA can be administered closer to chemotherapy initiation without compromising patient symptom management. Methods NK1 receptor occupancy (NK1RO) time course in the brain was determined using positron emission tomography; netupitant and palonosetron plasma concentration-time profiles were described by pharmacokinetic (PK) models; and the rate, extent, and duration of RO by netupitant and palonosetron were predicted by pharmacodynamic modeling. Clinical efficacy data from a pivotal study in cisplatin and oral NEPA-receiving patients were reviewed in the context of symptom management. Results Striatal 90% NK1RO, assumed to correlate with NK1RA antiemetic efficacy, was predicted at netupitant plasma concentration of 225 ng/mL, reached at 2.23 h following NEPA administration. Palonosetron 90% 5-HT3RO was predicted at a 188-ng/L plasma concentration, reached at 1.05 h postdose. The mean time to first treatment failure for the 1.5% of NEPA-treated patients without complete response receiving highly emetogenic chemotherapy was 8 h. Antiemetic efficacy was sustained over 5 days despite the expected decrease of NK1RO and 5-HT3RO. Conclusions Results suggest that administering oral NEPA closer to initiation of cisplatin administration would provide similar antiemetic efficacy. Prospective clinical validation is required.

This paper describes the design, implementation and outcomes of a teaching activity in high school setting, aimed at supporting a student with visual impairments in learning Mathematics and promoting inclusive learning involving all other students. The teaching activity was defined following an adoption-centered approach. During the initial needs-finding stage, we explored the available instruments for inclusive access and authoring of mathematical formulae, and we identified the LaTeX typesetting language as the instrument of choice. The use of LaTeX was motivated by the fact that it provides a textual representation of mathematical content, thus making it accessible through standard assistive technologies, such as Braille displays and screen readers. LaTeX is also widely used in higher education to author scientific documents, and therefore constitutes a useful skill for future education and employment of all students. We then defined the main steps needed for addressing the topic during a traditional high school mathematical curriculum, and scheduled them in relation to other teaching activities. The students had no difficulties in following the teaching activity, including learning and using LaTeX, and most were eager to apply the acquired skills for authoring lab reports and homework. However, the acceptance of the assistive tool by the student with visual impairments was low. Additionally, most of the other teachers displayed high resistance to change and therefore were not interested in supporting the activity and integrating it with their classes. We highlight the key findings and limitations of the project, and discuss possible improvements over the current approach.

This paper investigates how touchscreen exploration and verbal feedback can be used to support blind people to access visual artwork. We present two artwork exploration modalities. The first one, attribute-based exploration, extends prior work on touchscreen image accessibility, and provides fine-grained segmentation of artwork visual elements; when the user touches an element, the associated attributes are read. The second one, hierarchical exploration, is designed with domain experts and provides multi-level segmentation of the artwork; the user initially accesses a general description of the entire artwork and then explores a coarse segmentation of the visual elements with the corresponding high-level descriptions; once selected, coarse segments are subdivided into fine-grained ones, which the user can access for more detailed descriptions. The two exploration modalities, implemented as a mobile web app, were evaluated through a user study with 10 blind participants. Both modalities were appreciated by the participants. Attribute-based exploration is perceived to be easier to access. Instead, the hierarchical exploration was considered more understandable, useful, interesting and captivating, and the participants remembered more details about the artwork with this modality. Participants commented that the two modalities work well together and therefore both should be made available.

Purpose No prior studies investigated the role of ultrasound in the assessment of response of patients undergoing treatment of metatarsalgia with custom-made orthoses. Our aim was to describe ultrasound findings of patients with plantar forefoot pain treated with custom-made foot orthoses. Methods Twenty patients (15 females; mean age: 62.6 ± 11 years) affected by metatarsalgia in 27/40 feet underwent clinical evaluation before, three months and six months after treatment with custom-made full foot insole with a support proximal and an excavation below the painful metatarsals. Ultrasound was performed before and three months after the use of orthoses to examine the presence of intermetatarsal/submetatarsal bursitis, metatarsophalangeal joints effusion, anterior plantar fat pad oedema, flexor tendinitis/tenosynovitis, and Morton’s neuroma. Outcome measures were clinical response with Foot Function Index (FFI)/Visual Analogue Scale (VAS) and ultrasound features changes. Results Median VAS and FFI before treatment were 8[5–8.5] and 45.85[32.4–59.4], respectively. After 3 and 6 months of insoles use, both median VAS (2.5 [0–5] and 0 [0–2.75], respectively) and median FFI (7.9 [3.95–20] and 0 [0–3.95], respectively) showed a significant reduction in pain and disability (p p Conclusion Ultrasound might be able to detect some imaging features associated with the response of forefoot pain to custom-made foot orthoses, especially intermetatarsal bursitis.

Purpose Palonosetron hydrochloride is a specific 5-HT3 receptor antagonist, used to prevent chemotherapy-induced nausea and vomiting (CINV), and is a known chemical entity currently registered in the oral and IV forms in several countries worldwide. Methods Single-center, single-dose, 3-treatment, open-label, randomized, 3-period, phase-I cross-over study, conducted in 18 individuals (16 males and 2 females). The primary objective was to assess the pharmacokinetic profile of Palonosetron 0.25, 0.5 and 0.75mg, after a single, oral administration in Chinese male and female healthy volunteers. Results After administration of a single oral dose of 0.25mg, 0.5mg, or 0.75mg palonosetron in Chinese male and female healthy subjects, plasma palonosetron concentrations reached maximum values (Cmax) of 673 ± 151 pg/mL, 1330 ± 258 pg/mL, and 1990 ± 490 pg/mL, respectively, at 3-5 h (tmax). The plasma elimination half-life for 0.25, 0.5 and 0.75 mg of palonosetron was 41.8±9.72 hours, 44.6±8.59 hours and 42.3±8.51 hours, respectively. Single oral doses of 0.25mg, 0.5mg, or 0.75mg palonosetron were safe and well tolerated among all the 18 subjects involved. Conclusions The PK of palonosetron was found to be linear in the dose range of 0.25 to 0.75 mg. Oral palonosetron in doses up to 0.75 mg was well tolerated in healthy Chinese subjects. The PK and safety data obtained from this study were similar to previous phase I studies with IV palonosetron.

Oral NEPA, the only fixed-combination antiemetic, is composed of the neurokinin-1 receptor antagonist netupitant (300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (0.50 mg). This study was conducted to evaluate the pharmacokinetic profile of netupitant and its main metabolites M1 and M3, and palonosetron in Chinese subjects. Oral NEPA tolerability and safety were also analyzed. This was a single-center, single-dose phase 1 study in healthy, adult Chinese volunteers. Eligible subjects received oral NEPA, and blood samples were collected on day 1 predose and at various time points up until day 10 postdose. Pharmacokinetic parameters were analyzed using noncompartmental methods. For safety assessments, adverse events (AEs) were monitored during the study. In total 18 Chinese healthy volunteers received oral NEPA. Netupitant mean maximum plasma concentration (Cmax) [± standard deviation] of 698 ± 217 ng/mL was reached at 3–6 h, with a mean total exposure (AUC0–inf) of 22,000 ± 4410 h·ng/mL. For palonosetron, a mean Cmax of 1.8 ± 0.252 ng/mL was reached at 2–6 h postadministration, with a mean AUC0–inf of 81.0 ± 14.0 h·ng/mL. The most common treatment-related AEs in > 2 subjects were constipation (n = 9) and tiredness (n = 3). No severe AEs were observed, and no subject withdrew due to AEs. Following single-dose administration of oral NEPA in Chinese subjects, the pharmacokinetic profiles of the NEPA components were mostly similar to those reported previously in Caucasians. NEPA was well tolerated with a safety profile in line with that observed in pivotal trials in Caucasians.

NEPA is the first fixed‐combination antiemetic composed of the neurokinin‐1 receptor antagonist netupitant (netupitant; 300 mg) and the 5‐hydroxytryptamine‐3 receptor antagonist palonosetron (palonosetron; 0.50 mg). This study evaluated the pharmacokinetic profiles of netupitant and palonosetron. The pharmacokinetic profiles of both drugs were summarized using data from phase 1‐3 clinical trials. netupitant and palonosetron have high absolute bioavailability (63%‐87% and 97%, respectively). Their overall systemic exposures and maximum plasma concentrations are similar under fed and fasting conditions. netupitant binds to plasma proteins in a high degree (>99%), whereas palonosetron binds to a low extent (62%). Both drugs have large volumes of distribution (cancer patients: 1656‐2257 L and 483‐679 L, respectively). netupitant is metabolized by cytochrome P450 3A4 to 3 major pharmacologically active metabolites (M1, M2, and M3). palonosetron is metabolized by cytochrome P450 2D6 to 2 major substantially inactive metabolites (M4 and M9). Both drugs have similar intermediate‐to‐low systemic clearances and long half‐lives (cancer patients: netupitant, 19.5‐20.8 L/h and 56.0‐93.8 hours; palonosetron: 7.0‐11.3 L/h and 43.8‐65.7 hours, respectively). netupitant and its metabolites are eliminated via the hepatic/biliary route (87% of the administered dose), whereas palonosetron and its metabolites are mainly eliminated via the kidneys (85%‐93%). Altogether, these data explain the lack of pharmacokinetic interactions between netupitant and palonosetron at absorption, binding, metabolic, or excretory level, thus highlighting their compatibility as the oral fixed combination NEPA, with administration convenience that may reduce dosing mistakes and increase treatment compliance.

Independent mobility is one of the main challenges for blind or visually impaired (BVI) people. In particular, BVI people often need to identify and avoid nearby obstacles, for example a bicycle parked on the sidewalk. This is generally achieved with a combination of residual vision, hearing and haptic sensing using the white cane. However, in many cases, BVI people can only perceive obstacles at short distance (typically about 1m, i.e., the white cane detection range), in other situations obstacles are hard to detect (e.g., those elevated from the ground), while others should not be hit by the white cane (e.g., a standing person). Thus, some time and effort are required to identify the object in order to understand how to avoid it. A solution to these problems can be found in recent computer vision techniques that can run on mobile and wearable devices to detect obstacles at a distance. However, in addition to detecting obstacles, it is also necessary to convey information about them to a BVI user. This contribution presents WatchOut, a sonification technique for conveying real-time information about the main characteristics of an obstacle to a BVI person, who can then use this additional feedback to safely navigate in the environment. WatchOut was designed with a user-centric approach, involving two iterations of online questionnaires with BVI participants in order to define, improve and evaluate the sonification technique. WatchOut was implemented and tested as a module of a mobile app that detects obstacles using state-of-the-art computer vision technology. Results show that the system is considered usable, and can guide the users to avoid more than 85% of the obstacles.

We present AudioFunctions.web, a web app that uses sonification, earcons and speech synthesis to enable blind people to explore mathematical function graphs. The system is designed for personalized access through different interfaces (touchscreen, keyboard, touchpad and mouse) on both mobile and traditional devices, in order to better adapt to different user abilities and preferences. It is also publicly available as a web service and can be directly accessed from the teaching material through a hypertext link. An experimental evaluation with 13 visually impaired participants highlights that, while the usability of all the presented interaction modalities is high, users with different abilities prefer different interfaces to interact with the system. It is also shown that users with higher level of mathematical education are capable of better adapting to interaction modalities considered more difficult by others.

People with sight impairments can access to a mathematical expression by using its LaTeX source. However, this mechanisms have several drawbacks: (1) it assumes the knowledge of the LaTeX, (2) it is slow, since LaTeX is verbose and (3) it is error-prone since LATEX is a typographical language. In this paper we study the design of a natural language generation system for producing a mathematical sentence, i.e. a natural language sentence expressing the semantics of a mathematical expression. Moreover, we describe the main results of a first human based evaluation experiment of the system for Italian language.

Independent mobility is a challenge for people with visual impairment or blindness. Groundbreaking innovation comes from mobile devices (e.g., smartphones) that are convenient platforms to provide assistive technologies in the form of mobile applications. This paper presents ZebraRecognizer, a software module that recognizes zebra crossings and that advances state-of-the-art along two directions. First, it removes projection distortion from the acquired image, hence improving the accuracy of the recognition and making it possible to compute the quantified relative position of the crossing with respect to the user, which is crucial to effectively guide the user. Second, ZebraRecognizer is efficient, as it adopts a customized version of the EDLines algorithm that is also implemented to run in parallel on the GPU. Experimental results show that ZebraRecognizer is accurate, efficient and it computes the crossings position precisely.

TL-recognizer detects traffic lights from a mobile device camera.Robust method for unsupervised image acquisition and segmentation.Robust solution: traffic lights are clearly visible in different light conditions.Solution is reliable: precision 1 and recall 0.8 in different light conditions.Solution is efficient: computation time ~100źms on a Nexus 5. Independent mobility involves a number of challenges for people with visual impairment or blindness. In particular, in many countries the majority of traffic lights are still not equipped with acoustic signals. Recognizing traffic lights through the analysis of images acquired by a mobile device camera is a viable solution already experimented in scientific literature. However, there is a major issue: the recognition techniques should be robust under different illumination conditions.This contribution addresses the above problem with an effective solution: besides image processing and recognition, it proposes a robust setup for image capture that makes it possible to acquire clearly visible traffic light images regardless of daylight variability due to time and weather. The proposed recognition technique that adopts this approach is reliable (full precision and high recall), robust (works in different illumination conditions) and efficient (it can run several times a second on commercial smartphones). The experimental evaluation conducted with visual impaired subjects shows that the technique is also practical in supporting road crossing.

Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome.

Summary Objectives To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods Fourteen patients with advanced solid tumors not responsive to previous antitumor treatments received BBR 3464 on a daily × 5 schedule every twenty-eighth day. The drug was given as a one-hour infusion with pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. A modified accelerated titration escalation design was used. Total and free platinum (Pt) concentrations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle. Results Dose was escalated four times up to 0.17 mg/m2/ day. Short-lasting neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m2 Nausea and vomiting were rare, neither neuro- nor renal toxic effects were observed. BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-life of several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 were higher than on day 1, indicating drug accumulation. Approximately 10% of the equivalent dose of BBR3464 (2.2%–13.4%) was recovered in a 24-hour urine collection. Conclusions The higher than expected incidence of neutropenia and GI toxicity might be related to the prolonged half-life and accumulation of total and free Pt after daily administrations. Lack of nephrotoxicity and the low urinary excretion support the use of the drug without hydration. The single intermittent schedule has been selected for clinical development.

For children with visual impairments, learning mathematics entails significant difficulties. This is partially due to the fact that both traditional and digital didactic tools for teaching mathematics to children often integrate visual elements into explanations and exercises in order to improve children's engagement and comprehension. These visual elements, however, are not accessible to students with visual impairments. Approaches that substitute visual information with audio or haptic stimulation exist, but they incur in several problems, including the need of a supervisor or expensive specialized hardware. To address this issue, we propose Math Melodies, a didactic software for the teaching of mathematics to primary school children. The application is freely available for iPad devices, and it presents 19 different exercise types, each with multiple levels of difficulty. The exercises are immersed within an adventurous story organized into 10 chapters. Math Melodies enables exploration of audio-visual elements on a touchscreen and provides multi-modal feedback that entertains and engages both visually impaired and sighted children simultaneously.

NEPA is the fixed combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron. The intravenous (i.v.) formulation of NEPA (fosnetupitant 235 mg/palonosetron 0.25 mg) was developed to enhance the convenience of NEPA administration. In a phase 3 study, i.v. NEPA showed acceptable safety with low risk for injection-site reactions. This study evaluated the pharmacokinetics and safety of i.v. NEPA in cancer patients. This was a single-center, single-dose phase 1 study in patients receiving highly emetogenic chemotherapy. Patients received a 30-min infusion of i.v. NEPA plus oral dexamethasone (12 mg) prior to chemotherapy, and oral dexamethasone (8 mg/daily) on days 2–4. Twenty-four patients received the complete i.v. NEPA infusion volume. Fosnetupitant maximum plasma concentration (Cmax) was reached at the end of infusion and decreased to Fosnetupitant conversion to netupitant occurred rapidly in cancer patients. Netupitant and palonosetron pharmacokinetic profiles in i.v. NEPA were similar to those reported for oral NEPA. i.v. NEPA was well tolerated with a similar safety profile to oral NEPA. i.v. NEPA provides additional administration convenience. Clinical trial registration number: EudraCT 2015-004750-18.

Patients on treatment with levothyroxine (T4) are informed to take this drug in the morning, at least 30 min before having breakfast. A significant decrease of T4 absorption was reported, in fact, when T4 solid formulations are taken with food or coffee. According to preliminary clinical study reports, administration of T4 oral solution appears to be less sensitive to the effect of breakfast beverages on oral bioavailability. In the present study, stability of T4 oral solution added to breakfast beverages was investigated. A 1 mL ampoule of single-dose Tirosint® oral solution (IBSA Farmaceutici Italia, Lodi, Italy) was poured into defined volumes of milk, tea, coffee, and coffee with milk warmed at 50 °C, as well as in orange juice at room temperature. Samples were sequentially collected up to 20 min and analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The results of the study demonstrated that T4 is stable in all beverages after 20 min incubation. Demonstration of T4 stability is a prerequisite for a thorough evaluation of the effect of breakfast beverages on the bioavailability of T4 given as oral solution and for a better understanding of the reasons underlying a decreased T4 bioavailability administered as solid formulations.

Rich Internet applications have removed most of the constraints of Web 1.0 while giving users more responsiveness and advanced browsing and interaction experiences. These new horizons, however, raise many challenges for people with disabilities or using limited hardware and software technologies, whose risk to be excluded from the benefits deriving from advanced web applications. To address this problem, WCAG 2.0 guidelines have been released as the newest World Wide Web Consortium recommendation for accessible web content, and WAI-ARIA is a candidate recommendation which provides reference specifications for accessible rich Internet applications. However, both specifications contain a huge amount of information that often discourages most web designers from dealing with accessibility issues. Moreover, guidelines are suitable and usually adopted to judge a design solution a posteriori, but they do not suggest how to face a design problem constructively. This paper proposes a design pattern language for accessibility. The language can be regarded as a universal design resource for helping web designers create accessible rich Internet applications compliant with the most recent standards. Knowledge representation through design patterns reflects the problem-solving approach usually followed by software and web designers, while pattern organization in a structured language aims to guide web designers throughout the design process. The language has been implemented as an accessible rich Internet application itself, thus allowing designers with disabilities to participate in web design. In order to evaluate the design pattern language, a three-step process was carried out including: (1) a heuristic analysis with a group of human---computer interaction experts, (2) a survey study with a group of web designers, and (3) a validation on the field with two designers who have been requested to apply the language in real design cases.

Many traffic lights are still not equipped with acoustic signals. It is possible to recognize the traffic light color from a mobile device, but this requires a technique that is stable under different illumination conditions. This contribution presents TL-recognizer, an application that recognizes traffic lights from a mobile device camera. The proposed solution includes a robust setup for image capture as well as an image processing technique. Experimental results give evidence that the proposed solution is practical.

A mobile application that detects an item’s color is potentially very useful for visually impaired people. However, users could run into difficulties when centering the target item in the mobile device camera field of view. To address this problem, in this contribution we propose a mobile application that detects the color of the item pointed by the user with one finger. In its current version, the application requires the user to wear a marker on the finger used for pointing. A preliminary evaluation conducted with blind users confirms the usefulness of the application, and encourages further development.

e22180Background: Anamorelin is an oral selective ghrelin receptor agonist in development that showed benefits for patients with advanced non-small cell lung cancer and anorexia/cachexia (ROMANA st...

Notation is a tool of thought, recording and communicating concepts and activities related to a domain of knowledge. In the history of mathematical notation, written notation is usually considered. However, to be an effective thinking tool, notation must be properly perceived. Blind and partially sighted people run into difficulty in making, exploring and understanding mathematical concepts conceived for being represented in multi-dimensional space. In this paper, we capitalize on the multifaceted nature of digital symbols to define multimodal digital notation for graph structures that allows blind and partially sighted people to represent graph structures, reason about them and communicate their reasoning with sighted people as well as each other. As support tool for notation proposed we have designed a multimodal interactive system, in which haptic signals play a crucial role. An evolutionary prototype of the system has been developed and evaluated according to the star life cycle model.

Paclitaxel poliglumex (CT-2103; XYOTAX) is an innovative macromolecular taxane designed to increase the therapeutic index of paclitaxel. This large macromolecule conjugate of paclitaxel and poly-L-glutamic acid accumulates in tumor tissues by taking advantage of the enhanced permeability of tumor vasculature and lack of lymphatic drainage. Paclitaxel poliglumex prolongs exposure to active drug and minimizes systemic exposure. Preclinical studies in animal tumor models demonstrate enhanced safety and efficacy relative to paclitaxel when administered as a single agent or in conjunction with radiation. Clinical pilot studies with paclitaxel poliglumex showed improved outcomes compared to standard taxanes and allowed a more convenient administration schedule. Human pharmacokinetic data are consistent with prolonged tumor exposure to active drug and a limited systemic exposure. Based on these results, three ongoing randomized phase III trials were initiated to test the efficacy of paclitaxel poliglumex in patients with advanced non-small cell lung carcinoma.

Patients with headache commonly seek care at an emergency department (ED). Patients with headache in fact account for between 1 and 2% of admissions to an ED. Therefore the ED physician must recognize symptoms and characteristics of headache that signal a potential significant organic problem in order to select appropriate tests and treatment. Key to the correct management of headache in ED is a careful, thorough history of the patient. This article summarizes what the ED physician should take into consideration in order to distinguish who simply needs reassurance and analgesia and who needs further investigation.

BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.

Autonomous mobility is a challenge for visually impaired people. In the last years, a number of solutions have been proposed in the scientific literature to support visually impaired people during road crossing. In our previous work we presented Zebra Localizer a mobile application that detects zebra crossings and guides the user to safely cross. In this paper we present the Zebra Recognizer algorithm that improves the detection module of our solution and that applies innovative solutions in the field of zebra crossings recognition. The major contribution resides in the fact that Zebra Recognizer rectifies the ground plane hence removing the projection distortion of the extracted features. This leads to two major advantages: first, it possible to compute the relative distance between the user and the zebra crossing in meters. Second, the grouping and validation criteria specifically designed for the rectified line segments are much more effective, hence improving the accuracy of the recognition. An additional contribution consists in a significantly improved computation time. Indeed, Zebra Recognizer is 3 time faster than our previous solution, thanks to the adoption of a personalized version of the EDLines algorithm to detect the line segments.

Tablet computers are becoming a common tool to support learning since primary school. Indeed, many didactic applications are already available on online stores. Most of these applications engage the child by immersing the educational purpose of the software within an entertaining environment, often in the form of a game with sophisticated graphic and interaction. Unfortunately, this makes most of these applications inaccessible to visually impaired children. In this contribution we present MathMelodies, an iPad application that supports math learning in primary school and that is designed to be accessible also to visually impaired children. We describe the main challenges we faced during the development of this didactic application that is both engaging and accessible. The application, currently publicly available, is collecting enthusiastic reviews from teachers, who often contribute with precious insight for improving the solution.

It is well known that mathematics presents a number of hindrances to visually impaired students. In case of function graphs, for example, several assistive solutions have been proposed to enhance their accessibility. Unfortunately, both hardware tools (e.g., tactile paper) and existing software applications cannot guarantee, at the same time, a clear understanding of the graph and a full autonomous study. In this paper we present AudioFunctions, an iPad app that adopts three sonification techniques to convey information about the function graph. Our experimental evaluation, conducted with 7 blind people, clearly highlights that, by using AudioFunctions, students have a better understanding of the graph than with tactile paper and existing software solutions.

The concept of “magic bullet” was first proposed by Paul Ehrlich at the beginning of the 20th century, when he conceived the possibility to have a selective compound, linked to a toxin, that would be able to discriminate and kill a disease-causing organism. Research on the immune system and antibodies (Abs) continued, and during the 1960s and 1970s the concept of “cell surface differentiation antigens” and the development of hybridoma technology, for the generation of monoclonal antibodies (mAbs), led to the possibility of distinguishing normal cells from malignant cells. This boosted research on Abs and the development of Ab-based biologic drugs. At present, more than 30 Abs have been approved by the US Food and Drug Administration (FDA) for human therapy in cancer, autoimmunity, and inflammation, and hundreds of new antibody-derived reagents are now in clinical trials.

Nimesulide is a selective COX-2 inhibitor used in a variety of inflammatory, pain and fever states. After oral administration the drug is rapidly and extensively absorbed. Nimesulide is rapidly distributed, extensively bound to albumin and eliminated with a terminal half-life of about 4 h. Excretion of the unchanged drug in urine and faeces is negligible. Nimesulide is mainly cleared from the body by metabolic transformation and the principal active metabolite is the 4′-hydroxyl derivative (M1). After oral administration, nimesulide shows linear pharmacokinetics in the dose range from 25 to 100 mg. The usual therapeutic regimen is 100 mg p.o. twice daily. The pharmacokinetic profiles of nimesulide and M1 in children and elderly do not differ from those of healthy young subjects. The pharmacokinetics of nimesulide and M1 are not altered in moderate renal impairment. Pharmacokinetic interactions between nimesulide and other drugs given in combination were absent or of no clinical significance.

The anthracenedione analogue, BBR 2778 is an active antitumour agent preclinically and has reduced potential for cardiotoxicity compared with other similar drugs in preclinical models. BBR 2778 was administered 3 weekly by a 1 h intravenous (i.v.) infusion to 24 patients and the dose escalated rapidly from 20 to 240 mg/m2. The dose-limiting toxicity (DLT) was neutropenia, common toxicity criteria (CTC) grade 4 in 3/5 patients at 240 mg/m2. Other toxicities > or = CTC grade 3 were: vomiting, lymphopenia, thrombocytopenia and lethargy. Blue discoloration of veins and urine was also noted. In 1 patient (120 mg/m2, four cycles) left ventricular ejection reaction (LVEF) fell (CTC grade 2) but with no clinical sequelae. BBR 2778 plasma pharmacokinetics were biphasic (mean t(1/2) at 180 mg/m2 = 14.1 h) and the urinary elimination of the unchanged drug was < 10%. In a patient with previously treated small cell lung carcinoma (SCLC), a 49% reduction in measurable disease was noted with resolution of pericardial and pleural effusions (120 mg/m2 x eight cycles). From the results of this phase I study a dose of 180 mg/m2 as a 1 h infusion every 3 weeks would be recommended for phase II trials.

We previously reported that induction of selective GH deficiency in the rat exacerbates cardiac dysfunction induced by experimental ischemia and reperfusion performed on the explanted heart. In the same model, short-term treatment with hexarelin, a GH-releasing peptide, reverted this effect, as did GH. To ascertain whether hexarelin had non-GH-mediated protective effects on the heart, we compared hexarelin and GH treatment in hypophysectomized rats. Hexarelin (80 μg/kg sc), given for 7 days, prevented exacerbation of the ischemia-reperfusion damage induced by hypophysectomy. We also demonstrate that hexarelin prevents increases in left ventricular end diastolic pressure, coronary perfusion pressure, reactivity of the coronary vasculature to angiotensin II, and release of creatine kinase in the heart perfusate. Moreover, hexarelin prevents the fall in prostacyclin release and enhances recovery of contractility. Treatment with GH (400 μg/kg sc) produced similar results, whereas administration of EP 51389 (8...

The ability of hexarelin, a recently synthesized hexapeptide with a strong growth hormone (GH)-releasing activity, or of GH itself to display a protectant activity against postischemic ventricular dysfunction in senescent hearts was studied in 24-month-old male rats. Heart preparations from control (saline-treated) senescent rats, subjected to moderate ischemia, showed at reperfusion: (a) a low recovery of postischemic left ventricular developed pressure (LVDP; 37% of the preischemic values; from 90 +/- 5.7 to 33.5 +/- 3.8 mm Hg; p0.01; n = 10) coupled to a substantial increase in coronary perfusion pressure (CPP; 71% over baseline; from 68.3 +/- 5.2 to 116.8 +/- 4.6 mm Hg; p0.01; n = 10); (b) a marked increase of creatine kinase (CK) released in the perfusates (6.6-fold increase over preischemic values; from 45 +/- 4 to 298 +/- 25 mU/min/g wet tissue; p0.001; n = 10). In vivo administration of hexarelin (80 microg/kg, b.i.d., s.c.) for 21 days resulted in a striking heart protection against reperfusion stunning. In fact, the recovery of LVDP at reperfusion was almost complete (90% of the preischemic values; from 93 +/- 5.8 to 83.7 +/- 5.9 mm Hg; p0.05; n = 9), and the increase in coronary resistance was minimal (from 67 +/- 5.8 to 79.7 +/- 6.9 mm Hg; p0.05; n = 9). Furthermore, the concentration of CK in the perfusates was increased only twofold (from 45.8 +/- 5.5 to 90 +/- 7.2 mU/min/g wet tissue; p0.05; n = 9), with a gradual return toward basal values at the end of reperfusion. The protectant activity of hexarelin was divorced from any detectable alteration of the somatotropic function, as assessed by pituitary GH messenger RNA (mRNA) and plasma insulin-like growth factor I levels. In vivo administration of GH (400 microg/kg b.i.d., s.c.) for the same time lapse resulted in only a partial protectant activity: 55% of LVDP recovery (from 91.5 +/- 6.2 to 50 +/- 3.5 mm Hg; p0.01; n = 6); 65% increase of coronary resistance (from 68 +/- 4.3 to 112.2 +/- 5.2 mm Hg; p0.01; n = 6); 5.3-fold increase of CK concentrations in heart perfusates on reperfusion (from 43.8 +/- 3.8 to 232 +/- 16 mU/min/g wet tissue; p0.001; n = 6). Evaluation of the rate of release of 6-keto-prostaglandin F1alpha (PGF1alpha), the stable metabolite of prostacyclin, in heart perfusates, and assessment of the vasopressor activity of angiotensin II on the coronary vasculature, did not show any change in these parameters among the three experimental groups. Collectively these data indicate that hexarelin displays a strong heart-protectant activity against myocardial stunning in senescent rats. The protection afforded by the peptide is likely due to a direct cardiotropic action and is far greater than that of GH. Neither compound appears able to interfere with the endothelium-dependent relaxant mechanism.

The ability of hexarelin, an effective growth hormone (GH)-releasing hexapeptide, to reverse the worsening of cardiac dysfunction in GH-deficient animals was studied in young male rats passively immunized by administration of an anti-GH-releasing hormone (GHRH) serum. Heart preparations from anti-GHRH serum-treated rats, undergoing low-flow ischemia and reperfusion, showed: (1) a progressive increase of left ventricular end-diastolic pressure during the ischemic period and a poor recovery of contractility at reperfusion with a consistent decrease of the left ventricular-developed pressure; (2) a decreased rate of formation of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), a stable metabolite of prostacyclin, in perfusates from preischemic and reperfusion periods; (3) an increased vasopressor activity of angiotensin II. Hexarelin (80 microg/kg, bid, s.c.), administered for 15 days to anti-GHRH serum-treated rats, restored to normal the impaired somatotropic function and counteracted the ischemic damage, improving postischemic left ventricular developed pressure to values higher than those of controls. Furthermore, both the generation of 6-keto-PGF1alpha and the vasopressor activity of angiotensin II reverted to those of control preparations. Administration of hexarelin to control rats induced a considerable improvement of postischemic ventricular function of the perfused hearts which was similar to that present in preparations from anti-GHRH serum-treated rats given hexarelin. This protective activity was divorced from any further stimulation of somatotropic function. Collectively, these data indicate that, in GH-deficient rats, hexarelin is capable of restoring somatotropic function and has a beneficial effect in myocardial ischemia and reperfusion damage. In addition, the increased responsiveness of the coronary vasculature to angiotensin II and the decreased generation of prostacyclin in hearts from GH-deficient rats would indicate that for prevention of injury and dysfunction of the vascular endothelium a normal somatotropic function is mandatory.

Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.

Acute myocardial infarction was induced in New Zealand male albino rabbits. 3 days after surgery, the mortality rate and plasma CPK activity were reduced by 64% and 66% respectively by intravenous infusion of Oligotide (32 mg/kg/h for 6h), a single-stranded oligodeoxyribonucleotide of mammalian origin. Perfused hearts, obtained from Oligotide-treated rabbits 3 days after surgery, showed a strength of contraction in the range of that of hearts of sham-operated animals and an ameliorated postsynaptic β-adrenergic and cholinergic receptor function. In addition, in these hearts, “ex vivo” treatment with Oligotide resulted in almost complete preservation of both adrenergic and cholinergic responses to their specific agonists. These data suggest that Oligotide by protecting the hearts from the ischemic damage and possibly by restricting left ventricular tissue necrosis may have normalized the biological responses of this organ to isoproterenol and preserved the integrity of coronary endothelial-dependent relaxant function.

Paolo Scarpazza1, Cristoforo Incorvaia2, Paolo Amboni3, Giuseppe di Franco1, Stefania Raschi1, Pierfranco Usai1, Monica Bernareggi1, Cristiano Bonacina1, Chiara Melacini1, Roberta Cattaneo1, Serena Bencini1, Chiara Pravettoni2, Gian Galeazzo Riario-Sforza2, Gianni Passalacqua4, Walter Casali11Divisione di Broncopneumotisiologia, Ospedale Civile, Vimercate, Italy; 2Pulmonary Rehabilitation, Istituti Clinici di Perfezionamento, Milan, Italy; 3Clinical Chemistry Laboratory, Ospedali Riuniti, Bergamo, Italy; 4Allergy and Respiratory Diseases, University Of Genoa, Genoa, ItalyBackground: Noninvasive mechanical ventilation (NIMV) is an effective tool in treating patients with acute respiratory failure (ARF), since it reduces both the need for endotracheal intubation and the mortality in comparison with nonventilated patients. A particular issue is represented by the outcome of NIMV in patients referred to the emergency department for ARF and with a do-not-intubate (DNI) status because of advanced age or excessively critical conditions. This study evaluated long-term survival in a group of elderly patients with acute hypercapnic ARF who had a DNI order and who were successfully treated by NIMV.Methods: The population consisted of 54 patients with a favorable outcome after NIMV for ARF. They were followed up for 3 years by regular control visits, with at least one visit every 4 months, or as needed according to the patient’s condition. Of these, 31 continued NIMV at home and 23 were on long-term oxygen therapy (LTOT) alone.Results: A total of 16 of the 52 patients had not survived at the 1-year follow-up, and another eight patients died during the 3-year observation, with an overall mortality rate of 30.8% after 1 year and 46.2% after 3 years. Comparing patients who continued NIMV at home with those who were on LTOT alone, 9 of the 29 patients on home NIMV died (6 after 1 year and 3 after 3 years) and 15 of the 23 patients on LTOT alone died (10 after 1 year and 5 after 3 years).Conclusion: These results show that elderly patients with ARF successfully treated by NIMV following a DNI order have a satisfactory long-term survival.Keywords: COPD, acute respiratory failure, mortality rate, respiratory failure

Dynamic web sites and rich internet applications have recently got widespread. An important challenge is guaranteeing their accessibility to all potential users regardless of physical and cognitive disabilities as well as hardware and software limitations. To this aim, WCAG 2.0 guidelines have been released as the newest W3C recommendation for accessible web content, and WAI-ARIA are reference specifications for accessible rich internet applications. However, both design resources contain a huge amount of information, and, like all standards and guidelines, do not provide designers with a clear design method. This paper proposes a design pattern language for accessibility to help web designers create accessible rich internet applications compliant with the most recent standards. The language has been implemented as an accessible rich internet application itself, allowing designers with disabilities to participate in web design. The results of a preliminary evaluation are finally discussed.

In this double-blind, randomized study, five healthy subjects per group received doses of 15, 20, or 25 mg of teicoplanin per kg of body weight, and one subject per group received a 0.9% NaCl placebo as single intravenous infusion over 30 min. Serial blood samples and urine were collected for 13 days postadministration, and concentrations of teicoplanin were determined by microbiological assay. The pharmacokinetic data were analyzed by noncompartmental and compartmental analyses. Laboratory safety tests, audiometry, and serum creatinine clearance measurements were done prior to day 1 and on days 2 and 14. In the three groups, peak levels at the end of the infusion averaged 194, 197, and 253 mg/liter, respectively. Mean concentrations in plasma 24 h after the administration were 10.5, 13.6, and 19.8 mg/liter, respectively. Mean values of volume of distribution at steady state were 0.80, 0.87, and 0.87 liters/kg, respectively. Terminal half-lives averaged 88, 83, and 92 h. Mean total clearance values were 10.9, 11.0, and 11.3 mg/h/kg, respectively, with renal clearance accounting for 75, 81, and 78%, respectively, of the total. The 13-day cumulative mean urinary recovery ranged from 71 to 78% of the dose within the groups. The pharmacokinetics of teicoplanin appears to be linear in the range of administered doses. Teicoplanin was generally well tolerated. Side effects, appearing in five subjects, were represented by fevers, chills, and skin reactions; these adverse reactions were mild, but one episode of rash necessitated the interruption of infusion, and one episode of chills necessitated treatment with corticosteroids. There was no indication of drug-related modifications of laboratory test results.

Blind and visually impaired students seldom choose to attend university technical or scientific courses. The major problems concern access to scientific documentation, to scientific software and getting advantage of attending lessons. Many solutions exist, but they are often available or known at national level. This paper introduces the @science thematic network, which aims at collecting and documenting pratices and experiences at transnational level to facilitate blind and visually impaired students to go through scientific studies at university.

Understanding a mathematical concept, expressed in a written form, requires the exploration of the whole symbolic expression to recognize its component significant patterns as well as its overall structure. This exploration is difficult for visually impaired people whether the symbolic expression is materialized as an oral description or a Braille expression. The paper introduces the notion of Haptic Mathematics as a digital medium of thought and communication of mathematical concepts that adopts the nomenclature and language of Mathematics and makes its expressions perceptible as sets of haptic signals. As a first step toward Haptic Mathematics, the paper presents a system adopting an audio-haptic interaction whose goal is to enable visual impaired or blind people to reason on graph structures and communicate their reasoning with sighted people. The paper describes a first system prototype and some preliminary usability results aimed at evaluating the effectiveness of the proposal.

The purpose of the study was to evaluate the safety, efficacy, and pharmacokinetics of pixantrone (BBR2778) when substituted for etoposide in the ESHAP regimen in patients with aggressive relapsed or refractory non-Hodgkin's lymphoma. Nineteen patients received protocol therapy, consisting of pixantrone 80 mg/m2 over 1 h on day 1, methylprednisolone 500 mg on days 1 - 5, cisplatin 25 mg/m2 on days 1 - 4, and cytarabine 2000 mg/m2 on day 5. Cycles were repeated every 21 days, in the outpatient setting. Dose limiting toxicity, consisting of bone marrow suppression, occurred at the first dose level (80 mg/m2), which was defined as the recommended dose. Grade 3 and 4 toxicities were mainly hematologic. Only one patient had grade 4 febrile neutropenia. No significant decreases in ejection fraction greater than 20% occurred. Overall response rate was 58%, with 37% complete and 21% partial responses. Six of the 11 responders (55%) underwent stem cell transplant. Median time to progression and overall median survival were 5.7 months and 14.5 months, respectively. There is no significant interaction between pixantrone and the combined drugs. The recommended dose of pixantrone in combination with methylprednisolone, cytarabine, and cisplatin (PSHAP) is 80 mg/m2. PSHAP is an active salvage regimen and should be further evaluated as a pretransplant cytoreductive regimen.