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An expanded role for cardiac implantable electronic devices (CIEDs) in recent decades reflects an aging population and broader indications for devices, including both primary prevention and management of dysrhythmias. CIED infection is one of the most important device-related complications and has a major impact on mortality, quality of life, healthcare utilization, and cost. Unfortunately, the investigation and management of CIED infection remain complex, often necessitating complete and timely removal of the device and leads in order to eradicate the infection. In addition, the translation of knowledge from an extensive literature to a disparate group of medical practitioners has often been inadequate. This review of CIED infection management highlights the significant advances made during the past decade, including diagnostic criteria, advanced imaging, and next-generation sequencing for culture-negative cases or those in which uncertainty remains. We also outline the role and indication for powered lead extraction, the process of antibiotic choice and treatment duration, considerations related to the timing and location for reimplantation, and preimplantation risk stratification and associated interventions to reduce the risk of CIED infection. Résumé: L’élargissement du rôle des dispositifs électroniques cardiaques implantables (DECI) au cours des dernières décennies reflète le vieillissement de la population et les indications plus vastes des dispositifs, notamment dans la prévention primaire et la prise en charge des dysrythmies. Les infections liées aux DECI sont l’une des plus importantes complications liées aux dispositifs et ont des conséquences majeures sur la mortalité, la qualité de vie, l’utilisation et les coûts des soins de santé. Malheureusement, le dépistage et la prise en charge des infections liées aux DECI demeurent complexes et nécessitent souvent le retrait complet et rapide du dispositif et des sondes en vue d’éradiquer l’infection. De plus, l’application des connaissances issues d’une vaste littérature à un groupe disparate de médecins praticiens a souvent été inadéquate. La présente revue sur la prise en charge des infections liées aux DECI illustre les avancées importantes réalisées au cours de la dernière décennie, notamment les critères diagnostiques, l’imagerie avancée et le séquençage de prochaine génération des cas à culture négative ou de ceux pour lesquels des incertitudes demeurent. Nous avons aussi décrit le rôle et les indications d’extraction des sondes fonctionnelles, le processus du choix des antibiotiques et de la durée du traitement, les considérations relatives au moment et au lieu de la réimplantation, et la stratification du risque en préimplantation et les interventions associées afin de réduire le risque d’infections liées aux DECI.

Background Real-world data (RWD) from the Society for Vascular Surgery Vascular Quality Initiative (VQI) registry has been used to support US Food and Drug Administration (FDA) regulatory decisions regarding vascular devices. The variables of cost and time needed for these registry-based studies have not been previously compared to traditional, independent, industry studies that would otherwise have been conducted to support regulatory decisions.Objectives To determine the potential value (cost and time saving and return on investment) created by device evaluation studies using the VQI registry infrastructure.Methods We compared studies that used data from the VQI registry with estimated costs of independent industry studies (counterfactual studies) using an established model using design specifications determined by FDA reviewers.Results We analyzed the initial six studies evaluating vascular devices for regulatory decisions using data from the VQI registry that generated evidence for four device manufacturers. Return on investment for these studies was estimated to be 143% and cost saving as 59% based on an actual per patient (with 5-year follow-up) cost of US$11K using VQI data versus US$26K from the counterfactual when averaged across all studies. Significant enrollment time savings (45%–71%) were also realized compared with industry-based estimates.Conclusions The use of RWD from the VQI registry in this study and the transcatheter valve treatment coordinated registry network in a prior study indicates that substantial value was added to device evaluation projects by the reuse of registry data, with additional potential savings if linked claims data can be used instead of costly long-term in-person follow-up.

Background: Interleukin-13 (IL-13) is a key mediator of T-helper-cell-type-2 (Th-2)-driven asthma, the inhibition of which may improve treatment outcomes. We examined the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of VR942, a dry-powder formulation containing CDP7766, a high-affinity anti-human-IL-13 antigen-binding antibody fragment being developed for the treatment of asthma. Methods: We conducted a phase 1, randomized, double-blind, placebo-controlled, ascending-dose study at Hammersmith Medicines Research, London, UK, which is now complete. Healthy adults aged 18–50 years (n = 40) were randomized 3:1 to a single inhaled dose of VR942 0.5, 1.0, 5.0, 10, or 20 mg, or placebo. Adults aged 18–50 years who were diagnosed with asthma for ≥6 months before screening, and had forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values ≥70% of the predicted values at screening (n = 45), were randomized to once-daily inhaled VR942 0.5 or 10 mg, or placebo (2:2:1), or VR942 20 mg or placebo (3:2), for 10 days. All participants were randomized to receive VR942 or placebo based on a randomization list prepared by an independent HMR statistician using SAS® software (SAS Institute, Cary, NC). The primary outcome was safety and tolerability of VR942 (safety population, defined as all who received at least one dose of VR942 or placebo). This study is listed on ClinicalTrials.gov (NCT02473939). Findings: In the VR942 and placebo groups, treatment-emergent adverse events (TEAEs) were reported in 10/30 (33%) and 0/10 (0%) healthy participants, and in 16/29 (55%) and 9/16 (56%) participants with asthma, respectively. Mild intermittent wheezing occurred in 7 participants (VR942 20 mg, n = 4; corresponding placebo, n = 3), resolving spontaneously within 1 h. All TEAEs were mild or moderate; there were no deaths, serious adverse events, or clinically significant changes in vital signs, electrocardiograms, or laboratory parameters. There was no clinically significant immunogenicity, with only one participant with asthma considered positive for treatment-related immunogenicity for CDP7766. Interpretation: This study, considered to be the only example of a dry powder anti-IL-13 fragment antibody being administered via inhalation, demonstrated that single and repeat doses were well tolerated over a period of up to 10 days in duration. Rapid and durable inhibition of fractional exhaled nitric oxide (FeNO) (secondary outcome) provided evidence of pharmacological engagement with the IL-13 target in the airways of participants diagnosed with mild asthma. These data, together with the numerical improvements observed for predose FEV1, justify further clinical evaluation of VR942 in a broader population of patients with asthma, and continue to support the development of an inhaled anti-IL-13 antibody fragment as a potential future treatment that is alternative to monoclonal antibodies delivered via the parenteral route. Funding: Study funding and funding for the medical writing and editorial support for preparation of the manuscript were split equally between the two study co-funders (Vectura Ltd and UCB Pharma). Keywords: Asthma, Immunotherapy, Interleukin-13, Pharmacodynamics, Safety, Tolerability

The environmental fungus Cryptococcus gattii emerged on Vancouver Island, British Columbia (BC), in 1999. By the end of 2006, it led to 176 cases and eight deaths – one of the highest burdens of C gattii disease worldwide. The present paper describes three cases, and the BC experience in the diagnosis and management of this infection. All three cases presented with pulmonary findings, including cryptococcomas and infiltrates. One also presented with brain cryptococcomas. Cases were diagnosed by chest and brain imaging, and laboratory evidence including serum or cerebrospinal fluid cryptococcal antigen detection and culture of respiratory or cerebrospinal fluid specimens. Genotyping of fungal isolates confirmed infection with C gattii VGIIa. Pulmonary cases were treated with fluconazole. One patient with central nervous system disease was treated with amphotericin B followed by fluconazole. Although this infection remains rare, clinicians should be aware of it in patients with a compatible clinical presentation who are either living in or returning from a trip to BC.

BACKGROUND: The management of HIV-infected patients with cytomegalovirus (CMV) disease has changed significantly with the availability of highly active antiretroviral therapy (HAART).

Extrapulmonary infection with Pneumocystis carinii, although uncommon, is increasingly recognized. Use of aerosolized pentamidine versus a systemic medication is thought to be a contributing factor due to the low concentrations of drug that are incapable of suppressing systemic infection. Infection with P carinii has been reported in every organ system including the gastrointestinal system. A 28-year-old acquired immunodeficiency syndrome patient receiving prophylaxis with aerosolized pentamidine who presented with a solitary rectal ulcer is reported. Initial biopsy was characteristic of extrapulmonary P carinii infection, with numerous organisms present. Occasional cytomegalovirus inclusion bodies were noted which may have been a copathogen but which were not treated. Treatment with intravenous pentamidine resulted in documented eradication of P carinii and complete resolution of the ulcer. Although lower gastrointestinal pneumocystosis has been described without ulceration, this is the first description of rectal ulceration presenting as the initial manifestation of extrapulmonary pneumocystosis.

Objective: To describe patients with fungal infections in whom drug interactions and bioavailability problems were associated with itraconazole treatment failure.

Candidemia and invasive candidiasis (C/IC) are life-threatening opportunistic infections that add excess morbidity, mortality and cost to the management of patients with a range of potentially curable underlying conditions. The Association of Medical Microbiology and Infectious Disease Canada developed evidence-based guidelines for the approach to the diagnosis and management of these infections in the ever-increasing population of at-risk adult patients in the health care system. Over the past few years, a new and broader understanding of the epidemiology and pathogenesis of C/IC has emerged and has been coupled with the availability of new antifungal agents and defined strategies for targeting groups at risk including, but not limited to, acute leukemia patients, hematopoietic stem cell transplants and solid organ transplants, and critical care unit patients. Accordingly, these guidelines have focused on patients at risk for C/IC, and on approaches of prevention, early therapy for suspected but unproven infection, and targeted therapy for probable and proven infection.

This paper offers an insight into the development, use and governance of e-repositories for learning and teaching, illustrated by Eric Raymond's bazaar and cathedral analogies and by a comparison of collection strategies that focus on content coverage or on the needs of users. It addresses in particular the processes that encourage and achieve community engagement. This insight is illustrated by one particular e-repository, the Education Media On-Line (EMOL) service. This paper draws analogies between the bazaar approach for open source software development and its possibilities for developing e-repositories for learning and teaching. It suggests in particular that the development, use and evaluation of online moving pictures and sound objects for learning and teaching can benefit greatly from the community engagement lessons provided by the development, use and evaluation of open source software. Such lessons can be underpinned by experience in the area of learning resource collections, where repositories have been classified as ‘collections-based' or ‘user-based'. Lessons from the open source movement may inform the development of e-repositories such as EMOL in the future.

This paper draws upon our experience of converting an existing educational videocassette into a video stream and presents a case study of the important issues that arose. The process was undertaken to apply some potential benefits of a new technology to support learners in higher education (HE). It was, however, by no means unproblematic and the issues that arose need to receive serious consideration if the potential of streaming technology is to be harnessed for more effective learning opportunities for students. 'Streaming' is a way of transmitting video (or other media files) across the Internet (or by similar means). It is an alternative to downloaded delivery of these media and viewers do not have lengthy 'download waits'. A more comprehensive definition is provided elsewhere (Brown, 2002). The term used here to describe the processes involved in enabling a video recording, made for delivery via videocassette recorder (VCR), to be transmitted across the Internet is 're-purposing'. One process within this broad remit is that of making specific changes to the content of the video recording. This is referred to as 're-engineering'. The authors all have a strong commitment to the use of video in HE and have actively participated in the re-purposing reported here. They feel that since the Joint Information

Gastrointestinal manifeslations may be encountered throughout, the course of HIV disease. The problems range from asymptomatic hairy leukoplakia lo overwhelming diarrhea due to opportunistic infections such as cryptosporidiosis. Diarrheal disease is an important contributing factor to wasting in advanced HIV disease. Considerable progress has been made in recents years regarding our understanding or HIV-related diarrhea, including etiological agents, diagnostic methods and treatment.