Search

Nowadays, the majority of Internet traffic is multimedia content. Video streaming services are in high demand by end users and use HTTP Adaptive Streaming (HAS) as transmission protocol. HAS splits the video into non-overlapping chunks and each video chunk can be encoded independently using different representations. Therefore, these encode tasks can be parallelized and Cloud computing can be used for this. However, in the most extended solutions, the infrastructure must be configured and provisioned in advance. Recently, serverless platforms have made posible to deploy functions that can scale from zero to a configurable maximum. This work presents and analyses the behavior of event-driven serverless functions to encode video chunks and to compute, optionally, the quality of the encoded videos. These functions have been implemented using an adapted version of embedded Tomcat to deal with CloudEvents. We have deployed these event-driven serverless pipelines for video coding and quality metrics on an on-premises serverless platform based on Knative on one master node and eight worker nodes. We have tested the scalability and resource consumption of the proposed solution using two video codecs: x264 and AV1, varying the maximum number of replicas and the resources allocated to them (fat and slim function replicas). We have encoded different 4K videos to generate multiple representations per function call and we show how it is possible to create pipelines of serverless media functions. The results of the different tests carried out show the good performance of the serverless functions proposed. The system scales the replicas and distributes the jobs evenly across all the replicas. The overall encoding time is reduced by 18% using slim replicas but fat replicas are more adequate in live video streaming as the encoding time per chunk is reduced. Finally, the results of the pipeline test show an appropriate distribution and chaining among the available replicas of each function type.

Criminal behaviour has previously been associated with an increased risk for several mental health problems, but little is known about the association between criminal behaviour and dementia. We aimed to examine how the criminal background (type of crime, number of convictions, length of the sentence) is associated with dementia and mild cognitive impairment (MCI), and how mental and physical health disorders and educational attainment influenced these associations. A nationwide cohort of 3,617,028 individuals born between 1932 and 1962 were linked with criminal and medical records using Swedish national registers. We used Cox regression models to examine the associations. Increased risks for dementia (Hazard ratios (HRs) 1.54, 95% confidence interval (CI) 1.50–1.57) and MCI (1.55, 1.50–1.61) were found in individuals with criminal background, particularly among those who committed violent or several crimes, or with long sentences. After full adjustment of covariates, the associations attenuated but remained statistically significant for dementia (1.25, 1.22–1.28) and MCI (1.27, 1.22–1.32). The attenuation was mostly explained by mental health problems -depression, anxiety, schizophrenia spectrum disorders, substance use disorder (SUD), and bipolar disorder- (dementia: 1.34, 1.31–1.37; MCI: 1.35, 1.30–1.40). SUD contributed the most to attenuate the associations. Our results may provide important insights to health and penal systems by showing the importance of considering the severity of the criminal background and life-course mental health when assessing the risk of neurodegenerative disorders.

CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.

Food system analysis in arid and semi-arid countries inevitably meets water availability as a major constraining food system driver. Many such countries are net food importers using food subsidy systems, as water resources do not allow national food self-sufficiency. As this leaves countries in a position of dependency on international markets, prices and export bans, it is imperative that every domestic drop of water is used efficiently. In addition, policies can be geared towards ‘water footprints’, where water use efficiency is not just evaluated at the field level but also at the level of trade and import/export. In this paper, Egyptian food systems are described based on production, distribution and consumption statistics, key drivers and food system outcomes, i.e., health, sustainable land and water use, and inclusiveness. This is done for three coarsely defined Egyptian food systems: traditional, transitional and modern. A water footprint analysis then shows that for four MENA countries, differences occur between national green and blue water volumes, and the volumes imported through imported foods. Egypt has by far the largest blue water volume, but on a per capita basis, other countries are even more water limited. Then for Egypt, the approach is applied to the wheat and poultry sectors. They show opportunities but also limitations when it comes to projected increased water and food needs in the future. An intervention strategy is proposed that looks into strategies to get more out of the food system components production, distribution and consumption. On top of that food subsidy policies as well as smart water footprint application may lead to a set of combined policies that may lead to synergies between the three food system outcomes, paving the way to desirable food system transformation pathways.

Quantum chromodynamics, the theory of the strong force, describes interactions of coloured quarks and gluons and the formation of hadronic matter. Conventional hadronic matter consists of baryons and mesons made of three quarks and quark-antiquark pairs, respectively. Particles with an alternative quark content are known as exotic states. Here a study is reported of an exotic narrow state in the D0D0π+ mass spectrum just below the D*+D0 mass threshold produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The state is consistent with the ground isoscalar $${{{{{{\rm{T}}}}}}}_{{{{{{\rm{c}}}}}}{{{{{\rm{c}}}}}}}^{+}$$ T c c + tetraquark with a quark content of $${{{{{\rm{c}}}}}}{{{{{\rm{c}}}}}}\overline{{{{{{\rm{u}}}}}}}\overline{{{{{{\rm{d}}}}}}}$$ c c u ¯ d ¯ and spin-parity quantum numbers JP = 1+. Study of the DD mass spectra disfavours interpretation of the resonance as the isovector state. The decay structure via intermediate off-shell D*+ mesons is consistent with the observed D0π+ mass distribution. To analyse the mass of the resonance and its coupling to the D*D system, a dedicated model is developed under the assumption of an isoscalar axial-vector $${{{{{{\rm{T}}}}}}}_{{{{{{\rm{c}}}}}}{{{{{\rm{c}}}}}}}^{+}$$ T c c + state decaying to the D*D channel. Using this model, resonance parameters including the pole position, scattering length, effective range and compositeness are determined to reveal important information about the nature of the $${{{{{{\rm{T}}}}}}}_{{{{{{\rm{c}}}}}}{{{{{\rm{c}}}}}}}^{+}$$ T c c + state. In addition, an unexpected dependence of the production rate on track multiplicity is observed.

Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy and overall prognosis remains poor, with a median survival of less than 24 months. Sequencing studies have revealed a high prevalence of genomic alterations in CCA, with multiple potential therapeutic targets. Next-generation sequencing (NGS) can identify actionable mutations such as FGFR, IDH, BRAF, ERBB2, ROS1, or microsatellite instability (MSI-H), among others.We conducted a retrospective multicenter study in Spain in 2019. Thirty consecutive patients from 15 centers were included. All patients were diagnosed with advanced CCA and underwent NGS (FoundationOne®) in 2019. Twenty-four patients underwent tissue-based NGS (FoundationOne® CDx), and 6 patients underwent blood-based NGS (FoundationOne®Liquid) with sequencing panels of 324 and 70 genes, respectively RESULTS: We identified 12 patients (40%) with an actionable genetic alteration in tissue: 2 FGFR2 fusions, 6 IDH1 mutations, 1 ERBB2 mutation, 1 ROS1 fusion, 1 PIK3CA mutation, and 1 MSI-H.Comprehensive genomic profiling (CGP) in cholangiocarcinoma can identify, in a high proportion of patients, clinically relevant genomic alterations that can lead to targeted therapies, expanding treatment options.

Maintenance of the natural flow regime is essential for continued wetland integrity; however, the flow regime is greatly influenced by both natural and anthropogenic forces. Wetlands may be particularly susceptible to altered flow regimes as they are directly impacted by water flows at a variety of time scales. In Puerto Rico, contemporary water management is decreasing freshwater recharge to wetlands and contributes to the salinization of important coastal wetlands as sea levels rise. Further, downscaled climate models predict an increase in drought frequency, intensity, and duration by mid-century. Conflicts over water allocation seem imminent between human and ecological needs. Current minimum flow policies are insufficient given the complexities of ecosystem processes and the changes in precipitation patterns and sea level rise that are expected in the future. Improved flow policies need to be established that reflect the functional relationships between specific representative ecological resources and components of the natural flow regime across all relevant time scales. Similarly, flow policies need to be developed within a landscape scale to implicitly address the socio-ecological trade-offs as well as the complexities of water management. Multi-disciplinary collaborations will be essential for increasing our resiliency to anticipated future changes.

Nowadays, more than 75% of Internet traffic is multimedia traffic, moreover mobile traffic is growing at a rate of 50% each year. All these data together with the evolution of the cloud infrastructures lead us to develop Cloud Mobile Media (CMM) architectures to support the needs demanded by end users. Nevertheless, due to an inherit higher and variable end to end delay mainly as a result of the virtualization process, new challenges appear in particular for live video streaming applications in order to keep a good Quality of Experience (QoE) of the delivered video. Thus, to keep client’s satisfaction within good levels in terms of Mean Opinion Score (MOS), we propose an adaptive QoE-based architecture running on CMM infrastructures for live streaming services. In order to carry out this goal, we propose an estimation of MOS values using an statistical method based on factor analysis. This estimation is based on different measured variables throughout the CMM infrastructure. In addition, we compare the accuracy of the estimated MOS against well-known publicly available video quality algorithms. With these estimations, our proposal is based on two added controllers to the CMM infrastructure: (a) the Software Defined Network controller that acts as a master and (b) the Media Streamer controller. Each one does different actions on the CMM infrastructure in order to maintain and improve the QoE at each end user. Finally, this architecture has been implemented over a fat tree topology in order to show their functionality. The results show that our proposal works properly and it adapts quickly to the network changes in order to deliver a good MOS.

The CKM angleγis measured for the first time from mixing-inducedCPviolation between$$ {B}_s^0\to {D}_s^{\mp }{K}^{\pm }{\pi}^{\pm }{\pi}^{\mp } $$Bs0→Ds∓K±π±π∓and$$ {\overline{B}}_s^0\to {D}_s^{\pm }{K}^{\mp }{\pi}^{\mp }{\pi}^{\pm } $$B¯s0→Ds±K∓π∓π±decays reconstructed in proton-proton collision data corresponding to an integrated luminosity of 9 fb−1recorded with the LHCb detector. A time-dependent amplitude analysis is performed to extract theCP-violating weak phaseγ− 2βsand, subsequently,γby taking the$$ {B}_s^0\hbox{-} {\overline{B}}_s^0 $$Bs0‐B¯s0mixing phaseβsas an external input. The measurement yieldsγ= (44 ± 12)° modulo 180°, where statistical and systematic uncertainties are combined. An alternative model-independent measurement, integrating over the five-dimensional phase space of the decay, yields$$ \gamma =\left({44}_{-13}^{+20}\right){}^{\circ} $$γ=44−13+20°modulo 180°. Moreover, the$$ {B}_s^0\hbox{-} {\overline{B}}_s^0 $$Bs0‐B¯s0oscillation frequency is measured from the flavour-specific control channel$$ {B}_s^0\to {D}_s^{-}{\pi}^{+}{\pi}^{+}{\pi}^{-} $$Bs0→Ds−π+π+π−to be ∆ms= (17.757 ± 0.007(stat) ± 0.008(syst)) ps−1, consistent with and more precise than the current world-average value.

The presentation of two pure tones to each ear separately with a slight difference in their frequency results in the perception of a single tone that fluctuates in amplitude at a frequency that equals the difference of interaural frequencies. This perceptual phenomenon is known as binaural auditory beats, and it is thought to entrain electrocortical activity and enhance cognition functions such as attention and memory. The aim of this study was to determine the effect of binaural auditory beats on long-term memory. Participants (n = 32) were kept blind to the goal of the study and performed both the free recall and recognition tasks after being exposed to binaural auditory beats, either in the beta (20 Hz) or theta (5 Hz) frequency bands and white noise as a control condition. Exposure to beta-frequency binaural beats yielded a greater proportion of correctly recalled words and a higher sensitivity index d' in recognition tasks, while theta-frequency binaural-beat presentation lessened the number of correctly remembered words and the sensitivity index. On the other hand, we could not find differences in the conditional probability for recall given recognition between beta and theta frequencies and white noise, suggesting that the observed changes in recognition were due to the recollection component. These findings indicate that the presentation of binaural auditory beats can affect long-term memory both positively and negatively, depending on the frequency used.

Purpose of ReviewCurrent traditional treatments for ADHD present serious limitations in terms of long-term maintenance of symptom remission and side effects. Here, we provide an overview of the rationale and scientific evidence of the efficacy of neurofeedback in regulating the brain functions in ADHD. We also review the institutional and professional regulation of clinical neurofeedback implementations.Recent FindingsBased on meta-analyses and (large multicenter) randomized controlled trials, three standard neurofeedback training protocols, namely theta/beta (TBR), sensori-motor rhythm (SMR), and slow cortical potential (SCP), turn out to be efficacious and specific. However, the practical implementation of neurofeedback as a clinical treatment is currently not regulated.SummaryWe conclude that neurofeedback based on standard protocols in ADHD should be considered as a viable treatment alternative and suggest that further research is needed to understand how specific neurofeedback protocols work. Eventually, we emphasize the need for standard neurofeedback training for practitioners and binding standards for use in clinical practice

The necessity of energy-efficient systems in order to protect our environment, cope with global warming, and facilitate sustainable development is paramount for the researching world because the survival of the planet is at stake. Thus, optimizing the energy efficiency of wireless communications not only reduces environmental impact, but also cuts overall network costs and helps make communication more practical and affordable in a pervasive setting. This paper is focused on a solution to enhance the energy efficiency in outdoor wireless local area networks using the standard IEEE 802.11b/g. So, from a previous study about the weather s impact on the number of control frame errors and retransmissions, we propose a green cognitive algorithm that adapts wireless transmissions to the channel conditions caused by the weather. The goal is to reduce retransmissions and control errors in order to save energy and to enhance network performance. Our proposal is based on a mathematical analysis in which we see how the frame error rate is related to the power consumption according to the modulation scheme and data rate used by transmitters. Finally, several simulations show that the green cognitive algorithm presented in this paper involves significant energy savings for outdoors WLANs., This work has been supported by the Vice-Rectorate for Research, Innovation and Transfer of the Universitat Politecnica de Valencia through the programme of International Campus of Excellence funded by Ministry of Education of Spain, and through the programme of Predoctoral Research Grants (FPI-UPV). The authors would like to thank the Information and Communications Systems Office (ASIC), Borja Opticos Enterprise and Azimut Electronics Company for their collaboration and support.

Educational robotics is one of the most prosperous fields of study currently. Although expensive educational robotic kits are used in high schools to teach robotics. University students do not have the knowledge base on the matter yet. More often, low-cost printed modular robots are used. 3d printers are the emergent tool to do faster prototypes in a cheaper way. Also, Open Source technologies are the way to share information. In this paper, we have done a low-cost printed modular robotic platform to teach robotics. Furthermore, we have done several experiments on how to teach educational robotics. Lastly, we have proposed a statistical model to get results from the experiments.

One of the main problems in marine fish farms sustainability is the amount of uneaten feed and fecal waste dispersed and deposited on the seabed under the cages. It damages the fauna and flora, and decreases the economic benefits because the wastage of the uneaten food. Several country governments and international associations have published laws and rules about the maximum permitted pollution on the seabed in order to avoid having high impact on the environment. In this paper, we propose an underwater wireless group-based sensor network in order to quantify and monitor the accurate amount of pollution that is deposited on the seabed. First, we present an analytical model and study the best location to place the sensor nodes. The mobility of the nodes and the group-based protocol operation is described. Our wireless group-based sensor network proposal is able to determine the amount of food that is wasted while it measures the amount of deposits generated. This data can be used to compute and estimate more accurately the amount of food that should be thrown into the cage. Finally, several simulations are presented in order to show the network traffic and to verify the correct operation of the wireless sensor system., This work has been partially supported by the "Ministerio de Ciencia e Innovacion", through the "Plan Nacional de I+D+i 2008-2011" in the "Subprograma de Proyectos de Investigacion Fundamental", project TEC2011-27516, and by the Polytechnic University of Valencia, though the PAID-15-11 multidisciplinary projects.

In this study, a novel colloidal shell formation phenomenon was observed when sulfuric acid droplets underwent neutralization in marine cylinder lubricant at 115 ± 5 °C using heating microcapillary videomicroscopy. Immediately upon injection, shells formed, wrapping the acidic droplets and detached slowly afterward. Shells were optically transparent, about 2 μm thick, and strongly cohesive and rigid since they could deform the contained acid droplet into a non-spherical shape. Shell surface is most likely hydrophobic since the acid droplets did not wet it. It is thought that these shells were made of hydrated calcium sulfate nanoparticles embedded within an organic matrix. This material was presumably formed when oil additives reacted with sulfuric acid right upon exposure. The discovery of this shell formation, which has not been previously reported in the literature, could be important since these shells could be precursors in the formation of well-known deposits found in diesel engine cylinder liners such as “liner lacquer” or “bore glaze,” which impact negatively the performance of marine diesel engines.

To evaluate the efficacy of transpyloric feeding (TPF) compared with gastric feeding (GF) with regard to the incidence of ventilator-associated pneumonia in severe traumatic brain injury patients (TBI).Prospective, open-label, randomized study in an intensive care unit of a university hospital.One hundred and four CHI adult patients admitted for TBI between April 2007 and December 2008. Patients were included within the first 24 h after ICU admission and were followed until discharge or 30 days after admission.Patients were randomized to TPF or GF groups. They received the same diet, with 25 kcal kg(-1) day(-1) of calculated energy requirements and a nitrogen intake of 0.2 g N kg(-1) day(-1). Primary outcome was the incidence of early and ventilatory-associated pneumonia. Secondary outcomes were enteral nutrition-related gastrointestinal complications (GIC), days on mechanical ventilation, length of ICU stay and hospital stay, and sequential organ failure assessment score (SOFA).The TPF group had a lower incidence of pneumonia, OR 0.3 (95% CI 0.1-0.7, P = 0.01). There were no significant differences in other nosocomial infections. The TPF group received higher amounts of diet compared to the GF group (92 vs. 84%, P0.01) and had lesser incidence of increased gastric residuals, OR 0.2 (95% CI 0.04-0.6, P = 0.003).Enteral nutrition delivered through the transpyloric route reduces the incidence of overall and late pneumonia and improves nutritional efficacy in severe TBI patients.

A group-based network architecture provides many benefits for the whole network increasing the content availability, providing fault tolerance and giving more scalability. Many grid architectures have been developed since the first proto-grid systems in the early 70's, but no one of them is based on groups. This paper proposes a group-based grid architecture using an efficient neighbor node selection. The architecture organizes logical connections between nodes from different groups of nodes allowing sharing resources, data or computing time between groups. Connections are used to find and share available resources from other groups and they are established based on node's available capacity. Suitable nodes have higher roles in the architecture and their function is to organize connections based on a node selection process. Nodes' logical connections topology changes depending on some dynamic parameters. The architecture is scalable and fault-tolerant. The designed protocol, its management and real measurements are shown. It could be used as an intergrid protocol.

Grouping nodes gives better performance to the whole network by diminishing the average network delay and avoiding unnecessary message forwarding and additional overhead. Many routing protocols for ad-hoc and sensor networks have been designed but none of them are based on groups. In this paper, we will start defining group-based topologies, and then we will show how some wireless ad hoc sensor networks (WAHSN) routing protocols perform when the nodes are arranged in groups. In our proposal connections between groups are established as a function of the proximity of the nodes and the neighbor's available capacity (based on the node's energy). We describe the architecture proposal, the messages that are needed for the proper operation and its mathematical description. We have also simulated how much time is needed to propagate information between groups. Finally, we will show a comparison with other architectures.

The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and thus calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Here we present a de novo branching cascades approach wherein simple primary substrates follow different cascade reactions to create various distinct molecular frameworks in a scaffold diversity phase. Later, the scaffold elaboration phase introduces further complexity to the scaffolds by creating a number of chiral centres and incorporating new hetero- or carbocyclic rings. Thus, employing N-phenyl hydroxylamine, dimethyl acetylenedicarboxylate and allene ester as primary substrates, a compound collection of sixty one molecules representing seventeen different scaffolds is built up that delivers a potent tubulin inhibitor, as well as inhibitors of the Hedgehog signalling pathway. This work highlights the immense potential of cascade reactions to deliver compound libraries enriched in structural and functional diversity.

DNA polymerase mu (Pol mu) is a family X enzyme with unique substrate specificity that contributes to its specialized role in nonhomologous DNA end joining (NHEJ). To investigate Pol mu's unusual substrate specificity, we describe the 2.4 A crystal structure of the polymerase domain of murine Pol mu bound to gapped DNA with a correct dNTP at the active site. This structure reveals substrate interactions with side chains in Pol mu that differ from other family X members. For example, a single amino acid substitution, H329A, has little effect on template-dependent synthesis by Pol mu from a paired primer terminus, but it reduces both template-independent and template-dependent synthesis during NHEJ of intermediates whose 3' ends lack complementary template strand nucleotides. These results provide insight into the substrate specificity and differing functions of four closely related mammalian family X DNA polymerases.

Transdominant genetic selections can yield protein fragment and peptide modulators of specific biochemical pathways. In yeast, such screens have been highly successful in targeting the MAP (mitogen-activated protein) kinase growth-control pathway. We performed a similar type of selection aimed at recovery of modulators of the mammalian MAP kinase cascade. Two pathway activators were identified, fragments of the TrkB and Raf-1 kinases. In a second selection directed at the β-catenin growth-control pathway, three different clones encoding cadherin fragments were recovered. In neither selection were peptide inhibitors observed. We conclude that some transdominant selections in mammalian cells can readily yield high-penetrance protein fragments, but may be less amenable to isolation of peptide inhibitors.

Background: Although a variety of antireflux procedures and medications are used to treat gastroesophageal reflux disease (GERD), reliable large-animal models of GERD that can be used to objectively compare the efficacy of these treatments are lacking. Methods: Esophageal manometry and 24-h gastroesophageal pH monitoring with event data were performed in 18 mongrel dogs with a cervical esophagopexy. We then calculated a modified DeMeester score: The Duke Canine reflux score (DCR). Thereafter, the animals underwent a 4-cm anterior distal esophageal myotomy, incision of the left diaphragmatic crus, and intrathoracic gastric cardiopexy. Postoperative 24-h pH and manometry were obtained 2 weeks later. Results: The postoperative 24-h pH results showed a significant increase in the mean DCR score (5.9 ± 4.5 vs 84.9 ± 56.1, p < 0.0002), and manometry indicated a significant decrease in mean lower esophageal sphincter (LES) pressure (7.1 ± 2.9 vs 3.2 ± 2.5 mmHg, p < 0.0001). Conclusion: This technique reliably creates a canine model of GERD.

Background: The purpose of this study was to determine if maternal pneumoperitoneum with carbon dioxide (CO2) produces evidence of central nervous system (CNS) injury in preterm fetal guinea pigs. Methods: Thirty pregnant guinea pigs at gestational day (GD) 45 were assigned at random to one of three treatment groups: anesthesia only, CO2 pneumoperitoneum (5 mmHg), or laparotomy. Dams were killed 3 or 5 days postprocedure and fetal brains (83 total) harvested and fixed for subsequent histopathologic evaluation. For comparative purposes, histologic features of fetal guinea pig brain injury were defined from examination of fetal brains harvested from an additional dam that underwent laparotomy with 20 min of uterine arterial occlusion. Results: Carbon dioxide pneumoperitoneum did not increase maternal/fetal morbidity. No evidence of brain injury was found in fetuses from any of the treatment groups. Conclusion: Carbon dioxide pneumoperitoneum at 5 mmHg for 40 min in the pregnant guinea pig does not produce evidence of fetal brain injury.

The Internet has become an important new tool for the delivery and acquisition of medical information. A 13-item questionnaire designed to collect information on the attitudes and practices of surgeons regarding the use of the Internet as a medical resource was posted on the World Wide Web and also sent via e-mail. Over a 2-month period, 459 surgeons were enrolled in this study. Most of the respondents were identified as male surgeons (96%) between the ages of 31 and 50 years (79.25%). They accessed the Internet mainly from their homes (67.10%) and offices (17%) using 56 Kbps (34.86%) and 33.6 Kbps (21.79%) modems. These participants indicated that they use the Internet to expand their knowledge of general surgery (78.87%), learn more about technologies related to the practice of surgery (74.51%), access the Medline medical database (73.20%), and locate other resources for academic purposes (68%). Approximately half of them said that they favored the use of robotic assist devices in the operating room (53%), and most supported the use of technology for telementoring purposes (78%). Almost 80% professed an interest in video streaming technology applied to surgical education. This study showed that the Internet is a useful and powerful real-time survey tool that can help us to assess the impact of the World Wide Web and related technologies on surgical education and practice. However, the respondents in this study belong to a biased group that is already familiar with the Internet and computer technology and thus may not be representative of the surgical community as a whole.

Miami-Dade County is a major HIV epicenter and a port of entry for immigrants from nations with high endemic rates of tuberculosis (TB). We analyzed data from an unlinked (blinded) serosurvey of clients attending four Miami TB clinics to elucidate the dynamic HIV seroprevalence patterns in relation to demographics and risk behaviors. Data were analyzed from 3,107 consecutive TB patients at four TB treatment clinics over eight years. Overall HIV seroprevalence was 23.6% with a significantly higher infection rate for men (26.6%) compared to women (17.3%) (p < 0.0001). In rank order, the HIV infection rates were 30.3% for black non-Hispanics, 24.7% for white non-Hispanics and 14.2% for Hispanics. U.S.-born clients had significantly higher HIV rates compared with foreign-born clients (32.4% vs. 18.5%, p < 0.0001). HIV rates declined over six years from (32.5% to 15.9%, p < 0.0001) with significant trends observed for men and women; and for blacks, whites and Hispanics. Seroprevalence was 15.7% for clients identifying heterosexual contact as their only risk. Highly significant increases in seroprevalence above this heterosexual-contact-only `baseline', were found for clients disclosing the following high-risk behaviors: male-to-male sex, drug injection, smoking crack cocaine, receiving or giving money/drugs for sex, and sexual contact with a drug injector or HIV-infected partner. While highly significant elevations in HIV seroprevalence were associated with each of these definitive risk behaviors, even the baseline HIV infection rate of 15.7% in heterosexual-contact-only clients was markedly higher than that of the general population. These findings underscore the need to obtain routine HIV serology on all TB patients.

Hepatocyte growth factor triggers a complex biological program leading to invasive cell growth by activating the c-Met receptor tyrosine kinase. Following activation, Met signaling is elicited via its interactions with SH2-containing proteins, or via the phosphorylation of the docking protein Gab1, and the subsequent interaction of Gab1 with additional SH2-containing effector molecules. We have previously shown that the interaction between phosphorylated Gab1 and the adaptor protein Crk mediates activation of the JNK pathway downstream of Met. We report here that c-Cbl, which is a Gab1-like docking protein, also becomes tyrosine-phosphorylated in response to Met activation and serves as a docking molecule for various SH2-containing molecules, including Crk. We further show that Cbl is similarly capable of enhancing Met-induced JNK activation, and several lines of experimentation suggests that it does so by interacting with Crk. We also show that both Cbl and Gab1 enhance Met-induced activation of another MAP kinase cascade, the ERK pathway, in a Crk-independent manner. Taken together, our studies demonstrate a previously unidentified functional role for Cbl in Met signaling and suggest that Met utilizes at least two docking proteins, Gab1 and Cbl, to activate downstream signaling pathways. Oncogene (2000) 19, 4058 - 4065.

Constitutive activation of the Met tyrosine kinase results in transformation of cells of diverse origin. Recent studies have demonstrated a role for the c-Jun N-terminal kinase (JNK) in Met-induced transformation, but little is known about the molecular mechanisms that connect Met to JNK activation. Our studies show that activated Met associates with, and phosphorylates, the docking protein Gab1, which in turn binds to the src homology 2 (SH2)-domain of the adapter protein Crk and recruits Crk to the Met signaling complex. Formation of the Gab1 - Crk complex correlates with Met-induced JNK activation, and mutant forms of Met that fail to induce the complex formation also fail to activate JNK. Importantly, expression of a loss-of-function mutant of Crk severely impairs activation of the JNK pathway by Met. We also show here that Met controls the transcription of the matrix metalloproteinase-1 (MMP-1) gene in carcinoma cells and that this transcriptional regulation occurs in a Crk - JNK-dependent manner through an AP-1 element in the MMP-1 promoter. Taken together, our data implicate the Gab1 - Crk signaling complex in Met-induced JNK activation and suggest that the Gab1 - Crk complex formation may be an important event in regulating the tumorigenic phenotype of Met-transformed cells.

In the early 1990s, HIV seroprevalence was highest at the Miami homeless clinic among 16 homeless sites participating in a nationwide sentinel survey. To examine dynamic seroprevalence patterns in Miami's homeless clients in relation to demographics and risk behaviors over six years, we analyzed data from an unlinked (blinded) serosurvey of clients attending the principal primary care clinic serving Miami's homeless. Data were from 3,797 medical encounters with homeless persons who, on their initial clinic visit within an annual survey period, received routine serologic testing and a risk behavior survey. Overall HIV seroprevalence was 15.9% and infection rates for men (16.4%) and women (14.5%) did not differ. Seroprevalence for blacks (19.9%) was significantly higher than for Hispanics (9.1%) or whites (8.3%) (p < 0.0001). Seroprevalence was 12.6% (35 times the national rate) for clients reporting heterosexual contact as their only risk. Significant increases in seroprevalence, above this heterosexual-contact-only 'baseline', were found for clients disclosing high-risk behaviors: male-to-male sex, drug injection, receiving or giving money/drugs for sex, and sexual contact with a drug injector or HIV-infected partner (p < 0.0001). Seroprevalence declined over six years from 23.2 to 7.2% (p < 0.0001). Significant downward trends were observed for men and women, blacks and Hispanics, men who have sex with men, and clients reporting heterosexual contact. The proportion of clients reporting high-risk behaviors decreased sharply (p < 0.0001). Elevated HIV seroprevalence in Miami's homeless clients was strongly associated with high-risk behaviors. Expansion of HIV prevention and HIV/drug treatment services for homeless persons is strongly recommended.

Cardiovascular variables of both mother and fetus and total bile acid levels were monitored in amniotic fluid and in maternal and fetal plasma after the administration of a single intravenous high dose (29 mg) of cholic acid to a pregnant ewe. We observed the diffusion of significant quantities of cholic acids from the mother to the fetus and amniotic fluid. Nevertheless, cardiovascular parameters (heart rate, blood pressure, PO2, PCO2 and pH) were not affected, neither did intra-amniotic pressure show significant changes compared with the initial experimental conditions. It is concluded that an acute increase in maternal plasma levels of bile acids does not produce important adverse effects in either the mother animal or the fetus and consequently, if bile acids should be deemed responsible for any deleterious effect observed in a preterm fetus in intrahepatic cholestasis, this should be considered as the consequence of a chronic process.

We describe the clinical and laboratory features of an unusual case with Sezary cell-like leukemia. Clinical manifestations were: anemia (Hb 9.4 g/dl), severe thrombocytopenia (5 x 10(9)/l), lymphocytosis (43 x 10(9)/l) and splenomegaly. There was no lymphadenopathy, hepatomegaly or skin lesions. Bone marrow trephine showed diffuse infiltration by atypical lymphoid cells. By ultrastructural analysis the cells were small to medium-size lymphocytes with nuclear features identical to Sezary cells. Immunophenotyping showed that most peripheral blood mononuclear cells were negative with B lymphoid, myeloid, and stem cell-associated markers and were also negative with most T lymphoid markers (CD2, CD4, membrane/cytoplasmic CD3, CD5 and CD8). However, they were positive with CD38 (70%), CD7 (25%) and TIA-2 (25%). Molecular analysis showed a clonal rearrangement of the TCR beta and gamma chain genes. The patient was initially treated with vincristine, doxorubicin and asparaginase and then with six cycles of CHOP, achieving a complete remission and remaining free of disease 22 months from diagnosis. Aberrant immunophenotypes are not frequent in primary T cell leukemias. This is the first case of a rare type of T cell neoplasm, Sezary cell-like leukemia, in which cells lacked most of the T cell-associated antigens.

A 29-year-old female patient presented with a giant melanoma on the external side of the left arm and concomitant multiple visceral metastases. The patient also had major depression and had avoided a consultation despite the large size of the lesion, delaying the diagnosis and treatment of her melanoma, which as far as we know is the largest, primary cutaneous melanoma ever reported. Excision of the tumor was performed as a palliative treatment and she died 1 month later. Depression has been identified as a factor that can worsen the course of a disease, although in this case it could have been the direct consequence of the dermatologic process.

Nat. Struct. Mol. Biol. 14, 45–53 (2007); published online 10 December 2006; corrected after print 15 June 2007 In the version of this article initially published, the crystallization conditions were incorrectly reported. The correct conditions are as follows: 95 mM sodium citrate (pH 5.6), 19% (v/v) isopropanol, 19% (w/v) PEG 4,000 and 5% (v/v) glycerol.

Cytokine flow cytometry (CFC) or intracellular cytokine staining (ICS) can quantitate antigen-specific T cell responses in settings such as experimental vaccination. Standardization of ICS among laboratories performing vaccine studies would provide a common platform by which to compare the immunogenicity of different vaccine candidates across multiple international organizations conducting clinical trials. As such, a study was carried out among several laboratories involved in HIV clinical trials, to define the inter-lab precision of ICS using various sample types, and using a common protocol for each experiment (see additional files online). Three sample types (activated, fixed, and frozen whole blood; fresh whole blood; and cryopreserved PBMC) were shipped to various sites, where ICS assays using cytomegalovirus (CMV) pp65 peptide mix or control antigens were performed in parallel in 96-well plates. For one experiment, antigens and antibody cocktails were lyophilised into 96-well plates to simplify and standardize the assay setup. Results (CD4+cytokine+ cells and CD8+cytokine+ cells) were determined by each site. Raw data were also sent to a central site for batch analysis with a dynamic gating template. Mean inter-laboratory coefficient of variation (C.V.) ranged from 17–44% depending upon the sample type and analysis method. Cryopreserved peripheral blood mononuclear cells (PBMC) yielded lower inter-lab C.V.'s than whole blood. Centralized analysis (using a dynamic gating template) reduced the inter-lab C.V. by 5–20%, depending upon the experiment. The inter-lab C.V. was lowest (18–24%) for samples with a mean of >0.5% IFNγ + T cells, and highest (57–82%) for samples with a mean of

Dear Sir: The differentiation of monoclonal gammopathy of undetermined significance (MGUS) from multiple myeloma (MM) is fraught with difficulty when the monoclonal protein is recognized. A number of parameters have been evaluated in patients with MGUS as compared to MM. However, no studies have been carried out to evaluate the usefulness of monoclonal antibodies in distinguishing between MGUS and MM. The immunological phenotype of MM has been studied in the last few years. Most of the plasma cells from patients with MM react with monoclonal antibodies (McAb) CD38 (OKT10) and CD9 (FMC 8), but usually lack Sm Ig and the I a. CD 19 (B 4), CD 20 (B 1), CD 21 (B 2), and CD 10 (CALLA) antigens [1, 2, 4, 5]. However, expression of plasma cells in monoclonal gammopathy of undetermined significance (MGUS) has so far not been reported. We analyzed the plasma cells of bone-marrow smears from 13 patients with MM and from 9 patients with MGUS. We used the alkaline-phosphatase/anti-alkaline phosphatase (APAAP) technique [3], with a panel of monoclonal antibodies against CD 38 (OKT 10), CD 10 (J 5), CD 21 (B 2), and I a. Our results are shown in Table 1. Most of the plasma cells in both groups were CALLA, B 2, and I a negative, as described in the literature on myeloma cells. Like plasma cells in MM, most of the plasma cells from patients with MGUS reacted with the McAb OKT 10, showing no difference between the groups when Student's t-test was used. Based on the results from our study, plasma cells in MGUS express the same surface markers as myeloma cells. Consequently, the use of specific McAb (at least not the McAb used in this study) is