Legionella pneumophila strain 130b possesses a unique combination of type IV secretion systems and novel Dot/Icm secretion system effector proteins

Legionella pneumophila is a ubiquitous inhabitant of environmental water reservoirs. The bacteria infect a wide variety of protozoa and, after accidental inhalation, human alveolar macrophages, which can lead to severe pneumonia. The capability to thrive in phagocytic hosts is dependent on the Dot/Icm type IV secretion system (T4SS), which translocates multiple effector proteins into the host cell. In this study, we determined the draft genome sequence of L. pneumophila strain 130b (Wadsworth). We found that the 130b genome encodes a unique set of T4SSs, namely, the Dot/Icm T4SS, a Trb-1-like T4SS, and two Lvh T4SS gene clusters. Sequence analysis substantiated that a core set of 107 Dot/Icm T4SS effectors was conserved among the sequenced L. pneumophila strains Philadelphia-1, Lens, Paris, Corby, Alcoy, and 130b. We also identified new effector candidates and validated the translocation of 10 novel Dot/Icm T4SS effectors that are not present in L. pneumophila strain Philadelphia-1. We examined the prevalence of the new effector genes among 87 environmental and clinical L. pneumophila isolates. Five of the new effectors were identified in 34 to 62% of the isolates, while less than 15% of the strains tested positive for the other five genes. Collectively, our data show that the core set of conserved Dot/Icm T4SS effector proteins is supplemented by a variable repertoire of accessory effectors that may partly account for differences in the virulences and prevalences of particular L. pneumophila strains. Copyright © 2010, American Society for Microbiology. All Rights Reserved

Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study

Background: Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues. // Methods: We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion. // Results: Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product. // Conclusions: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Designing self-service technologies for e-wellness

In the context of an international economic shift from manufacturing to services and the constant expansion of industries towards online services (Sheth and Sharma, 2008), this study is concerned with the design of self-service technologies (SSTs) for online environments. An industry heavily adopting SSTs across a variety of different services is Health and Wellness, where figures show an ever growing number of health and wellness apps being developed, downloaded and abandoned (Kelley, 2014). Little is known about how to enhance people’s engagement with online wellness SSTs to support self-health management and self-efficacy. This literature review argues that service design of wellness SSTs in online contexts can be improved by developing an enhanced understanding from a people perspective and customer experience point of view. Customer value, quality of service, usability, and self-efficacy all play an important role in understanding how to design SSTs for wellness and keep users engaged. There is a need for further study on how people interact and engage with online services in the context of wellness in order to design engaging wellness services

Identifying Mobile Health Engagement Stages: Interviews and Observations for Developing Brief Message Content (Preprint)

BACKGROUND Interest in mobile health (mHealth) has increased recently, and research suggests that mHealth devices can enhance end-user engagement, especially when used in conjunction with brief message content. OBJECTIVE This research aims to explore the &lt;i&gt;stages of engagement&lt;/i&gt; framework for mHealth devices and develop a method to generate brief message content to promote sustained user engagement. This study uses the framework by O’Brien and Toms as a point of departure, where engagement is defined as the uptake or the use of an mHealth device. The framework is a linear repeatable process, including &lt;i&gt;point of engagement&lt;/i&gt;, &lt;i&gt;period of engagement&lt;/i&gt;, &lt;i&gt;disengagement&lt;/i&gt;, and &lt;i&gt;re-engagement&lt;/i&gt;. Each stage is characterized by attributes related to a person’s technology experience. Although the literature has identified stages of engagement for health-related technology, few studies explore mHealth engagement. Furthermore, little research has determined a method for creating brief message content at each stage in this engagement journey. METHODS Interviews and observations from 19 participants who used mHealth technologies (apps, devices, or wellness websites) in a solo capacity were recruited for sample group 1. In sample group 2, interviews, and observations from 25 participants using mHealth technologies in a group capacity through the Global Corporate Challenge were used. These samples were investigated at 3 time points in both research contexts. The results underwent deductive-inductive thematic analysis for the engagement stages’ framework and attributes. RESULTS In addition to the 4 stages identified by O’Brien and Toms, 2 additional stages, self-management and limited engagement, were identified. &lt;i&gt;Self-management&lt;/i&gt; captures where users had disengaged from their technology but were still engaged with their health activity. &lt;i&gt;Limited engagement&lt;/i&gt; captures where group mHealth users had minimal interaction with their mHealth technology but continued to engage in a group fitness activity. The results revealed that mHealth engagement stages were nonlinear and embedded in a wider engagement context and that each stage was characterized by a combination of 49 attributes that could be organized into 8 themes. Themes documented the total user experience and included technology usability, technology features, technology aesthetics, use motivations, health awareness, goal setting, social support, and interruptions. Different themes were found to have more relevance at different engagement stages. Knowing themes and attributes at all engagement stages allows technology developers and health care professionals to generate relevant brief message content informed by a person-centered approach. CONCLUSIONS This research extends an existing engagement stages framework and identifies attributes and themes relevant to mHealth technology users’ total user experience and incorporates concepts derived from health, business studies, and information systems literature. In addition, we offer a practical 5-step process based on a person-centered approach to develop mHealth technology brief message content for sustained engagement. </sec

Identifying Mobile Health Engagement Stages: Interviews and Observations for Developing Brief Message Content

Background Interest in mobile health (mHealth) has increased recently, and research suggests that mHealth devices can enhance end-user engagement, especially when used in conjunction with brief message content. Objective This research aims to explore the stages of engagement framework for mHealth devices and develop a method to generate brief message content to promote sustained user engagement. This study uses the framework by O’Brien and Toms as a point of departure, where engagement is defined as the uptake or the use of an mHealth device. The framework is a linear repeatable process, including point of engagement, period of engagement, disengagement, and re-engagement. Each stage is characterized by attributes related to a person’s technology experience. Although the literature has identified stages of engagement for health-related technology, few studies explore mHealth engagement. Furthermore, little research has determined a method for creating brief message content at each stage in this engagement journey. Methods Interviews and observations from 19 participants who used mHealth technologies (apps, devices, or wellness websites) in a solo capacity were recruited for sample group 1. In sample group 2, interviews, and observations from 25 participants using mHealth technologies in a group capacity through the Global Corporate Challenge were used. These samples were investigated at 3 time points in both research contexts. The results underwent deductive-inductive thematic analysis for the engagement stages’ framework and attributes. Results In addition to the 4 stages identified by O’Brien and Toms, 2 additional stages, self-management and limited engagement, were identified. Self-management captures where users had disengaged from their technology but were still engaged with their health activity. Limited engagement captures where group mHealth users had minimal interaction with their mHealth technology but continued to engage in a group fitness activity. The results revealed that mHealth engagement stages were nonlinear and embedded in a wider engagement context and that each stage was characterized by a combination of 49 attributes that could be organized into 8 themes. Themes documented the total user experience and included technology usability, technology features, technology aesthetics, use motivations, health awareness, goal setting, social support, and interruptions. Different themes were found to have more relevance at different engagement stages. Knowing themes and attributes at all engagement stages allows technology developers and health care professionals to generate relevant brief message content informed by a person-centered approach. Conclusions This research extends an existing engagement stages framework and identifies attributes and themes relevant to mHealth technology users’ total user experience and incorporates concepts derived from health, business studies, and information systems literature. In addition, we offer a practical 5-step process based on a person-centered approach to develop mHealth technology brief message content for sustained engagement. </jats:sec

Identifying Mobile Health Engagement Stages:Interviews and Observations for Developing Brief Message Content

BACKGROUND: Interest in mobile health (mHealth) has increased recently, and research suggests that mHealth devices can enhance end-user engagement, especially when used in conjunction with brief message content. OBJECTIVE: This research aims to explore the stages of engagement framework for mHealth devices and develop a method to generate brief message content to promote sustained user engagement. This study uses the framework by O'Brien and Toms as a point of departure, where engagement is defined as the uptake or the use of an mHealth device. The framework is a linear repeatable process, including point of engagement, period of engagement, disengagement, and re-engagement. Each stage is characterized by attributes related to a person's technology experience. Although the literature has identified stages of engagement for health-related technology, few studies explore mHealth engagement. Furthermore, little research has determined a method for creating brief message content at each stage in this engagement journey. METHODS: Interviews and observations from 19 participants who used mHealth technologies (apps, devices, or wellness websites) in a solo capacity were recruited for sample group 1. In sample group 2, interviews, and observations from 25 participants using mHealth technologies in a group capacity through the Global Corporate Challenge were used. These samples were investigated at 3 time points in both research contexts. The results underwent deductive-inductive thematic analysis for the engagement stages' framework and attributes. RESULTS: In addition to the 4 stages identified by O'Brien and Toms, 2 additional stages, self-management and limited engagement, were identified. Self-management captures where users had disengaged from their technology but were still engaged with their health activity. Limited engagement captures where group mHealth users had minimal interaction with their mHealth technology but continued to engage in a group fitness activity. The results revealed that mHealth engagement stages were nonlinear and embedded in a wider engagement context and that each stage was characterized by a combination of 49 attributes that could be organized into 8 themes. Themes documented the total user experience and included technology usability, technology features, technology aesthetics, use motivations, health awareness, goal setting, social support, and interruptions. Different themes were found to have more relevance at different engagement stages. Knowing themes and attributes at all engagement stages allows technology developers and health care professionals to generate relevant brief message content informed by a person-centered approach. CONCLUSIONS: This research extends an existing engagement stages framework and identifies attributes and themes relevant to mHealth technology users' total user experience and incorporates concepts derived from health, business studies, and information systems literature. In addition, we offer a practical 5-step process based on a person-centered approach to develop mHealth technology brief message content for sustained engagement.</p

SRA down under: cache and analysis platform for infectious disease

SRA, NCBI's Sequence Read Archive, is a valuable resource holding a near definitive collection of the world's collective sequenced reads for academic purposes. Increasingly, these reads are being used for both basic research and clinical investigations. When time is a critical factor in analysis, such as during bacterial outbreaks, the geographical separation between Australia and the offshore NCBI SRA servers can result in significant delays that may have adverse clinical outcomes. To address this, Queensland Genomics commissioned a pilot program for the establishment of a local Australian SRA Cache. Utilizing the hosting capabilities of the NeCTAR Research Cloud, QRIScloud's HTC infrastructure and the MeDiCI data fabric as a storage solution, and the software stack of Cromwell for workflow management, PostgreSQL database for sample and job metadata, and a coordinator Python Flask application, a local cache of seventeen bacterial species was established. Furthermore, the workflow capabilities of Cromwell were leveraged to provide analysis solutions for cached sample data, including quality control and taxonomic profiling, and individual and multiple sample analysis. Moving forward to a broader rollout of increased bacterial species, it was found that the initial storage estimation did not keep up with the exponential increase sequencing reads uploaded to NCBI SRA, which while highlighting the increasing availability and importance in modern research, will need to be addressed