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1.  Attenuation and efficacy of human parainfluenza virus type 1 (HPIV1) vaccine candidates containing stabilized mutations in the P/C and L genes 
Virology Journal  2007;4:67.
Two recombinant, live attenuated human parainfluenza virus type 1 (rHPIV1) mutant viruses have been developed, using a reverse genetics system, for evaluation as potential intranasal vaccine candidates. These rHPIV1 vaccine candidates have two non-temperature sensitive (non-ts) attenuating (att) mutations primarily in the P/C gene, namely CR84GHNT553A (two point mutations used together as a set) and CΔ170 (a short deletion mutation), and two ts att mutations in the L gene, namely LY942A (a point mutation), and LΔ1710–11 (a short deletion), the last of which has not been previously described. The latter three mutations were specifically designed for increased genetic and phenotypic stability. These mutations were evaluated on the HPIV1 backbone, both individually and in combination, for attenuation, immunogenicity, and protective efficacy in African green monkeys (AGMs).
The rHPIV1 mutant bearing the novel LΔ1710–11 mutation was highly ts and attenuated in AGMs and was immunogenic and efficacious against HPIV1 wt challenge. The rHPIV1-CR84G/Δ170HNT553ALY942A and rHPIV1-CR84G/Δ170HNT553ALΔ1710–11 vaccine candidates were highly ts, with shut-off temperatures of 38°C and 35°C, respectively, and were highly attenuated in AGMs. Immunization with rHPIV1-CR84G/Δ170HNT553ALY942A protected against HPIV1 wt challenge in both the upper and lower respiratory tracts. In contrast, rHPIV1-CR84G/Δ170HNT553ALΔ1710–11 was not protective in AGMs due to over-attenuation, but it is expected to replicate more efficiently and be more immunogenic in the natural human host.
The rHPIV1-CR84G/Δ170HNT553ALY942A and rHPIV1-CR84G/Δ170HNT553ALΔ1710–11 vaccine candidates are clearly highly attenuated in AGMs and clinical trials are planned to address safety and immunogenicity in humans.
PMCID: PMC1939843  PMID: 17605811
2.  Make it better but don't change anything 
With massive amounts of data being generated in electronic format, there is a need in basic science laboratories to adopt new methods for tracking and analyzing data. An electronic laboratory notebook (ELN) is not just a replacement for a paper lab notebook, it is a new method of storing and organizing data while maintaining the data entry flexibility and legal recording functions of paper notebooks. Paper notebooks are regarded as highly flexible since the user can configure it to store almost anything that can be written or physically pasted onto the pages. However, data retrieval and data sharing from paper notebooks are labor intensive processes and notebooks can be misplaced, a single point of failure that loses all entries in the volume. Additional features provided by electronic notebooks include searchable indices, data sharing, automatic archiving for security against loss and ease of data duplication. Furthermore, ELNs can be tasked with additional functions not commonly found in paper notebooks such as inventory control. While ELNs have been on the market for some time now, adoption of an ELN in academic basic science laboratories has been lagging. Issues that have restrained development and adoption of ELN in research laboratories are the sheer variety and frequency of changes in protocols with a need for the user to control notebook configuration outside the framework of professional IT staff support. In this commentary, we will look at some of the issues and experiences in academic laboratories that have proved challenging in implementing an electronic lab notebook.
PMCID: PMC2810290  PMID: 20098591
3.  Reduced inclination of cervical spine in a novel notebook screen system - implications for rehabilitation 
Professional working at computer notebooks is associated with high requirements on the body posture in the seated position. By the high continuous static muscle stress resulting from this position at notebooks, professionals frequently working at notebooks for long hours are exposed to an increased risk of musculoskeletal complaints. Especially in subjects with back pain, new notebooks should be evaluated with a focus on rehabilitative issues.
In a field study a new notebook design with adjustable screen was analyzed and compared to standard notebook position.
There are highly significant differences in the visual axis of individuals who are seated in the novel notebook position in comparison to the standard position. Also, differences are present between further alternative notebook positions. Testing of gender and glasses did not reveal influences.
This study demonstrates that notebooks with adjustable screen may be used to improve the posture. Future studies may focus on patients with musculoskeletal diseases.
PMCID: PMC3253038  PMID: 22118159
4.  Molecular Characterization of Putative Virulence Determinants in Burkholderia pseudomallei 
The Scientific World Journal  2014;2014:590803.
The Gram-negative saprophyte Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease which is endemic in Southeast Asia and northern Australia. This bacterium possesses many virulence factors which are thought to contribute to its survival and pathogenicity. Using a virulent clinical isolate of B. pseudomallei and an attenuated strain of the same B. pseudomallei isolate, 6 genes BPSL2033, BP1026B_I2784, BP1026B_I2780, BURPS1106A_A0094, BURPS1106A_1131, and BURPS1710A_1419 were identified earlier by PCR-based subtractive hybridization. These genes were extensively characterized at the molecular level, together with an additional gene BPSL3147 that had been identified by other investigators. Through a reverse genetic approach, single-gene knockout mutants were successfully constructed by using site-specific insertion mutagenesis and were confirmed by PCR. BPSL2033::Km and BURPS1710A_1419::Km mutants showed reduced rates of survival inside macrophage RAW 264.7 cells and also low levels of virulence in the nematode infection model. BPSL2033::Km demonstrated weak statistical significance (P = 0.049) at 8 hours after infection in macrophage infection study but this was not seen in BURPS1710A_1419::Km. Nevertheless, complemented strains of both genes were able to partially restore the gene defects in both in vitro and in vivo studies, thus suggesting that they individually play a minor role in the virulence of B. pseudomallei.
PMCID: PMC4158159  PMID: 25215325
5.  An Innovative Smartphone-Based Otorhinoendoscope and Its Application in Mobile Health and Teleotolaryngology 
The traditional otorhinoendoscope is widely used in the diagnosis of a variety of ear and nose diseases, but only one doctor can use it at a time. It is also very difficult to share observations from one doctor with another doctor. With advances in electronic health technology, the extended potential application of smartphones to support medical practice or mobile health has grown steadily.
The first phase of the study discussed how smartphones may be used for otorhinoscopic imaging and image management via an innovative adaptor. The second phase of the study was to evaluate the diagnostic capability of the smartphone-based otorhinoendoscope, as compared to the traditional otorhinoendoscope, and its application in mobile health and teleotolaryngology.
We designed a unique adaptor to connect the otorhinoendoscope and smartphone in order to perform smartphone-based otorhinoendoscopy. The main aim was to transform the smartphone into an otorhinoendoscope. We devised a method that would allow us to use the smartphone’s camera to capture otorhinoscopic images. Using a freely available Web-based real-time communication application platform and the 3G (or WIFI) network, the smartphone-based otorhinoendoscope could synchronize the smartphone-based otorhinoscopic image with smartphones, tablet PCs, computer notebooks, or personal computers.
We investigated the feasibility of telemedicine using a smartphone, tablet PC, and computer notebook. Six types of clinical otorhinoscopic images were acquired via the smartphone-based otorhinoendoscope from six patients, which were examined in this study. Three teleconsultants (doctors A, B, and C) reviewed the six types of clinical otorhinoscopic images and made a telediagnosis. When compared to the face-to-face diagnosis, which was made in-person via a traditional otorhinoendoscope, the three teleconsultants obtained scores of a correct primary telediagnosis 83% (5/6), 100% (6/6), and 100% (6/6) of the time, respectively. When the clinical data were provided, the three teleconsultants obtained a correct secondary telediagnosis score of 100% (6/6), 100% (6/6), and 100% (6/6) of the time, respectively.
The use of previously available technologies in the absence of any additional expensive devices could significantly increase the quality of diagnostics while lowering extraneous costs. Furthermore, this could also increase the connectivity between most isolated family doctors and remote referral centers.
PMCID: PMC3961810  PMID: 24590187
otorhinoendoscope; smartphone; mobile health; teleotolaryngology; telediagnosis
6.  Using tablets to support self-regulated learning in a longitudinal integrated clerkship 
Medical Education Online  2014;19:10.3402/meo.v19.23638.
The need to train physicians committed to learning throughout their careers has prompted medical schools to encourage the development and practice of self-regulated learning by students. Longitudinal integrated clerkships (LICs) require students to exercise self-regulated learning skills. As mobile tools, tablets can potentially support self-regulation among LIC students.
We provided 15 LIC students with tablet computers with access to the electronic health record (EHR), to track their patient cohort, and a multiplatform online notebook, to support documentation and retrieval of self-identified clinical learning issues. Students received a 1-hour workshop on the relevant features of the tablet and online notebook. Two focus groups with the students were used to evaluate the program, one early and one late in the year and were coded by two raters.
Students used the tablet to support their self-regulated learning in ways that were unique to their learning styles and increased access to resources and utilization of down-time. Students who used the tablet to self-monitor and target learning demonstrated the utility of tablets as learning tools.
LICs are environments rich in opportunity for self-regulated learning. Tablets can enhance students’ ability to develop and employ self-regulatory skills in a clinical context.
PMCID: PMC3955768  PMID: 24646438
mobile learning; self-regulated learning; clinical learning; longitudinal integrated clerkship; workplace learning
7.  Mobile education in autopsy conferences of pathology: presentation of complex cases 
Diagnostic Pathology  2006;1:42.
MeduMobile was a project to develop and evaluate learning scenarios for medical students and teachers by use of video communication and notebooks. Its core part was assigned to various medical routines, conferences or meetings such as doctor-patient bedside conversation. These were filmed by video teams and broadcasted live via the WLAN of the Charité campus to course participating students. One type of the learning arrangements was the autopsy conference as an on-call scenario.
Materials and methods
The MeduMobile project consisted of two main compartments: the regular seminar event which took place every week or month, and the on-call event. For an on-call event the students were informed two hours before the lesson's start. A mobile video team organised the video conference via a specific MeduMobile seminar system. This software offered the students to log. The MeduMobile seminar system is based on the Windows operating system and realises an extended video communication via WLAN. Thirteen access points were implemented at the Charité Campus Virchow Klinikum and Campus Mitte. A questionnaire was developed to investigate in the response and learning effect of the mobile seminar system.
During the MeduMobile project 42 video conferences with (cumulative) 145 participating students took place. Four autopsy conferences could be organised as on-call scenarios within this project. A prospective, not randomised follow-up study was included 25 students of the 1st – 6th clinical semester. According to the answers, professional reasoning, professional performance, sustainability, and the complexity were broadly accepted by the students.
In principle, the MeduMobile realised an interdisciplinary case presentation using video conference and web page. The evaluation indicates a high acception of such complex case presentation with multidisciplinary settings. The use of the notebooks in mobile learning enables an interconnective training and promotes a complex learning.
PMCID: PMC1654189  PMID: 17094805
8.  A Virtual Notebook for biomedical work groups. 
During the past several years, Baylor College of Medicine has made a substantial commitment to the use of information technology in support of its corporate and academic programs. The concept of an Integrated Academic Information Management System (IAIMS) has proved central in our planning, and the IAIMS activities that we have undertaken with funding from the National Library of Medicine have proved to be important extensions of our technology development. Here we describe our Virtual Notebook system, a conceptual and technologic framework for task coordination and information management in biomedical work groups. When fully developed and deployed, the Virtual Notebook will improve the functioning of basic and clinical research groups in the college, and it currently serves as a model for the longer-term development of our entire information management environment.
PMCID: PMC227118  PMID: 3046694
9.  Pharmacological characterization of AM1710, a putative cannabinoid CB2 agonist from the cannabilactone class: Antinociception without central nervous system side-effects 
Cannabinoid CB2 agonists produce antinociception without central nervous system (CNS) side-effects. This study was designed to characterize the pharmacological and antinociceptive profile of AM1710, a CB2 agonist from the cannabilactone class of cannabinoids. AM1710 did not exhibit off-target activity at 63 sites evaluated. AM1710 also exhibited limited blood brain barrier penetration. AM1710 was evaluated in tests of antinociception and CNS activity. CNS side-effects were evaluated in a modified tetrad (tail flick, rectal temperature, locomotor activity and rota-rod). Pharmacological specificity was established using CB1 (SR141716) and CB2 (SR144528) antagonists. AM1710 (0.1–10 mg/kg i.p.) produced antinociception to thermal but not mechanical stimulation of the hindpaw. AM1710 (5 mg/kg i.p.) produced a longer duration of antinociceptive action than the aminoalkylindole CB2 agonist (R,S)-AM1241 (1 mg/kg i.p.) at maximally antinociceptive doses. Antinociception produced by the low (0.1 mg/kg i.p.) dose of AM1710 was blocked selectively by the CB2 antagonist SR144528 (6 mg/kg i.p.), whereas antinociception produced by the high dose of AM1710 (5 mg/kg i.p.) was blocked by either SR144528 (6 mg/kg i.p.) or SR141716 (6 mg/kg i.p.). AM1710 did not produce hypoactivity, hypothermia, tail flick antinociception, or motor ataxia when evaluated in the tetrad at any dose. In conclusion, AM1710, a CB2-preferring cannabilactone, produced antinociception in the absence of CNS side-effects. Thus, any CB1-mediated antinociceptive effects of this compound may be attributable to peripheral CB1 activity. The observed pattern of pharmacological specificity produced by AM1710 is consistent with limited blood brain barrier penetration of this compound and absence of CNS side-effects.
PMCID: PMC3089437  PMID: 21382397
cannabinoid; CB2; antinociception; tetrad; pain
10.  From documents to datasets: A MediaWiki-based method of annotating and extracting species observations in century-old field notebooks 
ZooKeys  2012;235-253.
Part diary, part scientific record, biological field notebooks often contain details necessary to understanding the location and environmental conditions existent during collecting events. Despite their clear value for (and recent use in) global change studies, the text-mining outputs from field notebooks have been idiosyncratic to specific research projects, and impossible to discover or re-use. Best practices and workflows for digitization, transcription, extraction, and integration with other sources are nascent or non-existent. In this paper, we demonstrate a workflow to generate structured outputs while also maintaining links to the original texts. The first step in this workflow was to place already digitized and transcribed field notebooks from the University of Colorado Museum of Natural History founder, Junius Henderson, on Wikisource, an open text transcription platform. Next, we created Wikisource templates to document places, dates, and taxa to facilitate annotation and wiki-linking. We then requested help from the public, through social media tools, to take advantage of volunteer efforts and energy. After three notebooks were fully annotated, content was converted into XML and annotations were extracted and cross-walked into Darwin Core compliant record sets. Finally, these recordsets were vetted, to provide valid taxon names, via a process we call “taxonomic referencing.” The result is identification and mobilization of 1,068 observations from three of Henderson’s thirteen notebooks and a publishable Darwin Core record set for use in other analyses. Although challenges remain, this work demonstrates a feasible approach to unlock observations from field notebooks that enhances their discovery and interoperability without losing the narrative context from which those observations are drawn.
“Compose your notes as if you were writing a letter to someone a century in the future.”
Perrine and Patton (2011)
PMCID: PMC3406479  PMID: 22859891
Field notes; notebooks; crowd sourcing; digitization; biodiversity; transcription; text-mining; Darwin Core; Junius Henderson; annotation; taxonomic referencing; natural history; Wikisource; Colorado; species occurrence records
11.  LabTrove: A Lightweight, Web Based, Laboratory “Blog” as a Route towards a Marked Up Record of Work in a Bioscience Research Laboratory 
PLoS ONE  2013;8(7):e67460.
The electronic laboratory notebook (ELN) has the potential to replace the paper notebook with a marked-up digital record that can be searched and shared. However, it is a challenge to achieve these benefits without losing the usability and flexibility of traditional paper notebooks. We investigate a blog-based platform that addresses the issues associated with the development of a flexible system for recording scientific research.
Methodology/Principal Findings
We chose a blog-based approach with the journal characteristics of traditional notebooks in mind, recognizing the potential for linking together procedures, materials, samples, observations, data, and analysis reports. We implemented the LabTrove blog system as a server process written in PHP, using a MySQL database to persist posts and other research objects. We incorporated a metadata framework that is both extensible and flexible while promoting consistency and structure where appropriate. Our experience thus far is that LabTrove is capable of providing a successful electronic laboratory recording system.
LabTrove implements a one-item one-post system, which enables us to uniquely identify each element of the research record, such as data, samples, and protocols. This unique association between a post and a research element affords advantages for monitoring the use of materials and samples and for inspecting research processes. The combination of the one-item one-post system, consistent metadata, and full-text search provides us with a much more effective record than a paper notebook. The LabTrove approach provides a route towards reconciling the tensions and challenges that lie ahead in working towards the long-term goals for ELNs. LabTrove, an electronic laboratory notebook (ELN) system from the Smart Research Framework, based on a blog-type framework with full access control, facilitates the scientific experimental recording requirements for reproducibility, reuse, repurposing, and redeployment.
PMCID: PMC3720848  PMID: 23935832
12.  Chronic cannabinoid CB2 activation reverses paclitaxel neuropathy without tolerance or CB1-dependent withdrawal 
Biological psychiatry  2014;77(5):475-487.
Mixed cannabinoid CB1/CB2 agonists such as Δ9-tetrahydrocannabinol (Δ9-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown.
We evaluated anti-allodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1KO, CB2KO, and WT mice. Comparisons were made with the prototypic classical cannabinoid Δ9-THC. We also explored the site and possible mechanism of action of AM1710.
Paclitaxel-induced mechanical and cold allodynia developed equivalently in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ9-THC suppressed established paclitaxel-induced allodynia in WT mice. Unlike Δ9-THC, chronic AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Anti-allodynic efficacy of systemic AM1710 was absent in CB2KO mice or WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal AM1710 also attenuated paclitaxel-induced allodynia in WT but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 anti-allodynic efficacy. Finally, both acute and chronic treatment with AM1710 decreased mRNA levels of tumor necrosis factor alpha and monocyte chemoattractant protein-1 in lumbar spinal cord of paclitaxel-treated WT mice.
Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.
PMCID: PMC4209205  PMID: 24853387
Cannabinoid CB2; chemotherapy-induced neuropathic pain; knockout mouse; tolerance; precipitated withdrawal; side effect
13.  A pocket guide to electronic laboratory notebooks in the academic life sciences 
F1000Research  2016;5:2.
Every professional doing active research in the life sciences is required to keep a laboratory notebook. However, while science has changed dramatically over the last centuries, laboratory notebooks have remained essentially unchanged since pre-modern science. We argue that the implementation of electronic laboratory notebooks (eLN) in academic research is overdue, and we provide researchers and their institutions with the background and practical knowledge to select and initiate the implementation of an eLN in their laboratories. In addition, we present data from surveying biomedical researchers and technicians regarding which hypothetical features and functionalities they hope to see implemented in an eLN, and which ones they regard as less important. We also present data on acceptance and satisfaction of those who have recently switched from paper laboratory notebook to an eLN.  We thus provide answers to the following questions: What does an electronic laboratory notebook afford a biomedical researcher, what does it require, and how should one go about implementing it?
PMCID: PMC4722687  PMID: 26835004
Code of Federal Regulations Title 21; Documentation; Data storage; Good Scientific Practice; Good Laboratory Practice; Laboratory information management systems; Software
14.  Mediators between Theoretical and Practical Medieval Knowledge: Medical Notebooks from the Cairo Genizah and their Significance 
Medical History  2013;57(4):487-515.
This article presents a plethora of fragments from the medical notebooks found in the Cairo Genizah that comprise a unique source of historical data for scholarly study and for a better understanding of the ways in which medieval medical knowledge in Egypt was transferred from theory to practice and vice versa. These documents provide the most direct evidence we have for preferred practical medical recipes because they record the choices of medical practitioners in medieval Cairo. Since the language most commonly used in them was Judaeo-Arabic, they were evidently written by Jews. The medical genre in the notebooks was primarily pharmacopoeic, consisting of apparently original recipes for the treatment of various diseases. There are also a few notebooks on materia medica. The subject matter of the Genizah medical notebooks shows that they were mostly of an eclectic nature, i.e. the writers had probably learnt about these treatments and recipes from their teachers, applied them at the hospitals where they worked or copied them from the books they read. Foremost among the subjects dealt with were eye diseases, followed by skin diseases, coughs and colds, dentistry and oral hygiene, and gynaecological conditions. The writers of the Genizah notebooks apparently recorded the practical medical knowledge they wished to preserve for their future use as amateur physicians, students, traditional healers or professional practitioners.
PMCID: PMC3865955  PMID: 24069914
Cairo Genizah; History of Medicine; Jewish; Medieval Middle East; Middle Ages; Notebook
15.  The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB2 receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy 
Molecular Pain  2012;8:71.
Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB2 agonist, produces antinociception without producing central nervous system (CNS)-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel). A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4) signaling to both chemotherapy-induced neuropathy and CB2 agonist efficacy.
AM1710 (0.1, 1 or 5 mg/kg i.p.) suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB2 antagonist AM630 (3 mg/kg i.p.), but not the CB1 antagonist AM251 (3 mg/kg i.p.), consistent with a CB2-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p.) failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action.
Our results indicate that activation of cannabinoid CB2 receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB2 receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents.
PMCID: PMC3502129  PMID: 22998838
Endocannabinoid; Cannabilactone; AM1710; Chemotherapy; Neuropathic pain; Chemokine; CXCR4; Mechanical allodynia; Cold allodynia; Hyperalgesia
16.  Guidelines for information about therapy experiments: a proposal on best practice for recording experimental data on cancer therapy 
BMC Research Notes  2012;5:10.
Biology, biomedicine and healthcare have become data-driven enterprises, where scientists and clinicians need to generate, access, validate, interpret and integrate different kinds of experimental and patient-related data. Thus, recording and reporting of data in a systematic and unambiguous fashion is crucial to allow aggregation and re-use of data. This paper reviews the benefits of existing biomedical data standards and focuses on key elements to record experiments for therapy development. Specifically, we describe the experiments performed in molecular, cellular, animal and clinical models. We also provide an example set of elements for a therapy tested in a phase I clinical trial.
We introduce the Guidelines for Information About Therapy Experiments (GIATE), a minimum information checklist creating a consistent framework to transparently report the purpose, methods and results of the therapeutic experiments. A discussion on the scope, design and structure of the guidelines is presented, together with a description of the intended audience. We also present complementary resources such as a classification scheme, and two alternative ways of creating GIATE information: an electronic lab notebook and a simple spreadsheet-based format. Finally, we use GIATE to record the details of the phase I clinical trial of CHT-25 for patients with refractory lymphomas. The benefits of using GIATE for this experiment are discussed.
While data standards are being developed to facilitate data sharing and integration in various aspects of experimental medicine, such as genomics and clinical data, no previous work focused on therapy development. We propose a checklist for therapy experiments and demonstrate its use in the 131Iodine labeled CHT-25 chimeric antibody cancer therapy. As future work, we will expand the set of GIATE tools to continue to encourage its use by cancer researchers, and we will engineer an ontology to annotate GIATE elements and facilitate unambiguous interpretation and data integration.
PMCID: PMC3285520  PMID: 22226027
17.  RS/1 in the Clinical Environment 
This paper describes the design of RS/1,™ the Research System, and its use in clinical patient studies. RS/1 is an interactive computer software system developed by the Medical Systems Group at BBN.
Investigators and technicians who have never before used computers can learn RS/1 with a few hours of training. It uses familiar and intuitive concepts for data handling and data analysis, such as the “automated notebook” format of data storage, the direct use of graphs in curve-fitting, and a simple command language.
Its versatility has made RS/1 useful in clinical research contexts, especially for studies involving patient care data.
PMCID: PMC2203896
18.  A patient-centered analysis of enrollment and retention in a randomized behavioral trial of two cognitive rehabilitation interventions for Mild Cognitive Impairment 
A major potential barrier for studying behavioral interventions for patients with Mild Cognitive Impairment (MCI) is the willingness and ability of people to enroll in and adhere to behavioral interventions, especially when the intervention involves dyads of patients with MCI and support partners. Details regarding recruitment strategies and processes (such as number of dyads screened) are often missing from reports of behavioral trials. In addition, reports do not detail the reasons a potentially eligible candidate opts out of participation in a research study.
To describe the challenges and successes of enrollment and retention in a behavioral trial for persons with MCI and their care partners, and to better understand barriers to participation from the patient’s point of view.
Multi-site, randomized trial
Major medical centers
Our accrual target for the study was 60 participants. Potential candidates were patients presenting to memory evaluation clinics whose resulting clinical diagnosis was MCI. A total of 200 consecutive potential candidates were approached about participating in the study across the three sites.
Detailed recruitment and retention data of a randomized trial comparing two behavioral interventions (memory notebook training versus computer training) provided in two separate training time frames (10 days versus 6 weeks).
Structured interview with those declining to participate in the trial.
Overall recruitment 37% with a range of 13%–72% across sites. Overall retention 86% with a range of 74%–94% across sites.
The primary barriers to enrollment from the patient’s perspective were distance to the treatment center and competing comprehensive behavioral programming. However, retention data suggest that those dyads who enroll in behavioral programs are highly committed.
PMCID: PMC4936534  PMID: 27398353
MCI; behavioral intervention; recruitment; retention
19.  Animal Study Registries: Results from a Stakeholder Analysis on Potential Strengths, Weaknesses, Facilitators, and Barriers 
PLoS Biology  2016;14(11):e2000391.
Publication bias in animal research, its extent, its predictors, and its potential countermeasures are increasingly discussed. Recent reports and conferences highlight the potential strengths of animal study registries (ASRs) in this regard. Others have warned that prospective registration of animal studies could diminish creativity, add administrative burdens, and complicate intellectual property issues in translational research. A literature review and 21 international key-informant interviews were conducted and thematically analyzed to develop a comprehensive matrix of main- and subcategories for potential ASR-related strengths, weaknesses, facilitators, and barriers (SWFBs). We identified 130 potential SWFBs. All stakeholder groups agreed that ASRs could in various ways improve the quality and refinement of animal studies while allowing their number to be reduced, as well as supporting meta-research on animal studies. However, all stakeholder groups also highlighted the potential for theft of ideas, higher administrative burdens, and reduced creativity and serendipity in animal studies. Much more detailed reasoning was captured in the interviews than is currently found in the literature, providing a comprehensive account of the issues and arguments around ASRs. All stakeholder groups highlighted compelling potential strengths of ASRs. Although substantial weaknesses and implementation barriers were highlighted as well, different governance measures might help to minimize or even eliminate their impact. Such measures might include confidentiality time frames for accessing prospectively registered protocols, harmonized reporting requirements across ASRs, ethics reviews, lab notebooks, and journal submissions. The comprehensive information gathered in this study could help to guide a more evidence-based debate and to design pilot tests for ASRs.
Author Summary
The manifold contributions over the last years on “publication bias” and “reproducibility crisis” in animal research initiated a debate on whether and how prospective animal study registries (ASRs) should be established in analogy to clinical trial registries. All recent debate, however, followed rather broad lines of argumentation and concluded that future decision-making on the issue of ASRs depends strongly on better knowledge about relevant characteristics of ASRs and about conflicting stakeholder interests. More qualitative but systematically developed evidence in this regard is needed. The primary objective of this study, therefore, was to present a systematically derived spectrum of all relevant strengths, weaknesses, facilitators and barriers (SWFBs) for ASRs. A systematic literature review and 21 key-informant interviews with experts from preclinical and clinical research, industry, and regulatory bodies were conducted to fulfill this objective. Our investigations resulted in a comprehensive and structured account of 130 issues and arguments around ASRs. Future debate and decision-making on ASRs might be heavily influenced by arguments and reasoning from individual experts and thus result in “eminence-based” policy making that relies on expert opinion. This study’s comprehensive spectrum of arguments and issues around ASR, developed through systematic and transparent methods, helps to balance the ongoing debate and thus facilitate a more evidence-based policy making.
PMCID: PMC5104355  PMID: 27832101
There are now hundreds of thousands of pathogenicity assertions that relate genetic variation to disease, but most of this clinically utilized variation has no accepted quantitative disease risk estimate. Recent disease-specific studies have used control sequence data to reclassify large amounts of prior pathogenic variation, but there is a critical need to scale up both the pace and feasibility of such pathogenicity reassessments across human disease. In this manuscript we develop a shareable computational framework to quantify pathogenicity assertions. We release a reproducible “digital notebook” that integrates executable code, text annotations, and mathematical expressions in a freely accessible statistical environment. We extend previous disease-specific pathogenicity assessments to over 6,000 diseases and 160,000 assertions in the ClinVar database. Investigators can use this platform to prioritize variants for reassessment and tailor genetic model parameters (such as prevalence and heterogeneity) to expose the uncertainty underlying pathogenicity-based risk assessments. Finally, we release a website that links users to pathogenic variation for a queried disease, supporting literature, and implied disease risk calculations subject to user-defined and disease-specific genetic risk models in order to facilitate variant reassessments.
PMCID: PMC4720982  PMID: 26776189
21.  Utilisation of internet resources for continuing professional development: a cross-sectional survey of general practitioners in Scotland 
BMC Medical Education  2016;16:24.
Participation in continuing professional development (CPD) is a professional and regulatory expectation of general practitioners (GPs). Traditionally, CPD activity was undertaken face-to-face in educational settings, but internet based formats have found increasing favour. The need for doctors to use the internet for service and educational purposes is growing, particularly in support of specialty training and appraisal. We aimed to determine how GPs in Scotland utilise online resources in support of their CPD. This involved identifying which resources are used and how frequently, along with their preferences as to how and why they access these resources.
A cross sectional study was undertaken using an online questionnaire to survey general practitioners across Scotland. Data were subjected to descriptive analysis and differences in attitudinal responses between groups and Fischer's exact tests were calculated.
Three hundred and eighty-three GP responses were received, with the majority being female (n = 232, 60.6 %) and GP partners (n = 236, 61.6 %). The majority used the internet on three or more working days per week or more frequently (n = 361, 94.3 %) with the three most common reasons being to obtain information for a patient (n = 358, 93.5 %), answering a clinical question (n = 357, 93.2 %) and CPD purposes (n = 308, 80.4 %). Of 37 online resources used by respondents, the top five were SIGN Guidelines (n = 303, 79.3 %), BMJ Learning (n = 279, 73.0 %), NICE Guidelines (n = 255, 66.8 %), GP Notebook (n = 243, 63.6 %) and Google (n = 234, 61.3 %). Low use of social media such as Facebook (n = 11, 2.9 %) and Twitter (n = 11, 2.9 %) was reported for CPD. A majority agreed that 'reading information online' (95.0 %) and 'completing online learning modules' (87.4 %) were the most valued online activities. Slow internet connections (n = 240, 62.7 %), website access restrictions (n = 177, 46.2 %) and difficulties logging into online CPD resources (n = 163, 42.6 %) were reported barriers. Significant response differences (P < 0.05) were found between groups based on high volume online usage, gender and age.
The majority of respondents had positive attitudes to using online resources for continuing professional development, and a preference for evidence-based and peer reviewed online resources. Information technology (IT) difficulties remain a barrier to effective utilisation. The findings have implications for future planning and design of online resources and IT infrastructure.
Electronic supplementary material
The online version of this article (doi:10.1186/s12909-016-0540-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4721189  PMID: 26791566
Online resources; Internet; e-learning; Continuing professional development; General practice
22.  Effect of reduced visual acuity on precision of two-dimensional tracing movements 
Journal of Optometry  2015;9(2):93-101.
We intended to assess consequences of reduced visual acuity for performance in a natural simple motor task (tracing) using objective kinematic performance measures. Specifically, we intended to elucidate the kind of relationship between the task performance and best corrected binocular visual acuity and to determine the threshold of visual acuity when task performance starts to deteriorate.
Ninety-five individuals with different best corrected visual acuity participated in the study (age 49 ± 12 years, mean ± SD, 27 men and 68 women). The participants manually traced maze-like visual patterns of different spatial complexity presented on the screen of a portable notebook computer using Clinical Kinematic Assessment Tool software. Tracing error was computed as performance measure in each trial with a spatial pattern matching technique – rigid point set registration method.
The segmented linear regression analysis showed that the relation between visual acuity and tracing errors was best described with a regression function having a break point between two data segments. Tracing performance was unaffected by values of visual acuity below 0.2 on logMAR scale, but when logMAR values increased above this critical limit (i.e. when visual acuity is further reduced), tracing errors linearly increased. The rate of the increase of the tracing error correlated with the complexity of visual stimulus shape.
Testing of fine motor functions with objective kinematic measures during visuomotor tasks may help differentiating between actual effects of reduced visual acuity on eye–hand coordination in individuals with similar levels of impairment of visual acuity.
PMCID: PMC4812010  PMID: 26002409
Eye–hand coordination; Tracing; Visual acuity; Low vision; Coordinación ojo-mano; Trazado; Agudeza visual; Baja visión
23.  Engaging diverse underserved communities to bridge the mammography divide 
BMC Public Health  2011;11:47.
Breast cancer screening continues to be underutilized by the population in general, but is particularly underutilized by traditionally underserved minority populations. Two of the most at risk female minority groups are American Indians/Alaska Natives (AI/AN) and Latinas. American Indian women have the poorest recorded 5-year cancer survival rates of any ethnic group while breast cancer is the number one cause of cancer mortality among Latina women. Breast cancer screening rates for both minority groups are near or at the lowest among all racial/ethnic groups. As with other health screening behaviors, women may intend to get a mammogram but their intentions may not result in initiation or follow through of the examination process. An accumulating body of research, however, demonstrates the efficacy of developing 'implementation intentions' that define when, where, and how a specific behavior will be performed. The formulation of intended steps in addition to addressing potential barriers to test completion can increase a person's self-efficacy, operationalize and strengthen their intention to act, and close gaps between behavioral intention and completion. To date, an evaluation of the formulation of implementation intentions for breast cancer screening has not been conducted with minority populations.
In the proposed program, community health workers will meet with rural-dwelling Latina and American Indian women one-on-one to educate them about breast cancer and screening and guide them through a computerized and culturally tailored "implementation intentions" program, called Healthy Living Kansas - Breast Health, to promote breast cancer screening utilization. We will target Latina and AI/AN women from two distinct rural Kansas communities. Women attending community events will be invited by CHWs to participate and be randomized to either a mammography "implementation intentions" (MI2) intervention or a comparison general breast cancer prevention informational intervention (C). CHWs will be armed with notebook computers loaded with our Healthy Living Kansas - Breast Health program and guide their peers through the program. Women in the MI2 condition will receive assistance with operationalizing their screening intentions and identifying and addressing their stated screening barriers with the goal of guiding them toward accessing screening services near their community. Outcomes will be evaluated at 120-days post randomization via self-report and will include mammography utilization status, barriers, and movement along a behavioral stages of readiness to screen model.
This highly innovative project will be guided and initiated by AI/AN and Latina community members and will test the practical application of emerging behavioral theory among minority persons living in rural communities.
Trial Registration
ClinicalTrials (NCT): NCT01267110
PMCID: PMC3036625  PMID: 21255424
24.  ST1710–DNA complex crystal structure reveals the DNA binding mechanism of the MarR family of regulators 
Nucleic Acids Research  2009;37(14):4723-4735.
ST1710, a member of the multiple antibiotic resistance regulator (MarR) family of regulatory proteins in bacteria and archaea, plays important roles in development of antibiotic resistance, a global health problem. Here, we present the crystal structure of ST1710 from Sulfolobus tokodaii strain 7 complexed with salicylate, a well-known inhibitor of MarR proteins and the ST1710 complex with its promoter DNA, refined to 1.8 and 2.10 Å resolutions, respectively. The ST1710–DNA complex shares the topology of apo-ST1710 and MarR proteins, with each subunit containing a winged helix-turn-helix (wHtH) DNA binding motif. Significantly large conformational changes occurred upon DNA binding and in each of the dimeric monomers in the asymmetric unit of the ST1710–DNA complex. Conserved wHtH loop residues interacting with the bound DNA and mutagenic analysis indicated that R89, R90 and K91 were important for DNA recognition. Significantly, the bound DNA exhibited a new binding mechanism.
PMCID: PMC2724296  PMID: 19509310
25.  Intrathecal cannabilactone CB2R agonist, AM1710, controls pathological pain and restores basal cytokine levels 
Pain  2012;153(5):1091-1106.
Spinal glial and proinflammatory cytokine actions are strongly implicated in pathological pain. Spinal administration of the anti-inflammatory cytokine, interleukin-10 (IL-10) abolishes pathological pain and suppresses proinflammatory interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α). Drugs that bind the cannabinoid type 2 receptor (CB2R) expressed on spinal glia reduce mechanical hypersensitivity. To better understand the CB2R-related anti-inflammatory profile of key anatomical nociceptive regions, we assessed mechanical hypersensitivity and protein profiles following intrathecal application of the cannabilactone CB2R agonist, AM1710, in two animal models; unilateral sciatic nerve chronic constriction injury(CCI), and spinal application of HIV-1 glycoprotein 120 (gp120), a model of peri-spinal immune activation. In CCI animals, lumbar dorsal spinal cord and corresponding dorsal root ganglia (DRG) were evaluated by immunohistochemistry for expression of IL-10, IL-1β, phosphorylated p38-mitogen-activated-kinase (p-p38MAPK), a pathway associated with proinflammatory cytokine production, glial cell markers, and degradative endocannabinoid enzymes including monoacyl glycerol lipase (MAGL). AM1710 reversed bilateral mechanical hypersensitivity. CCI revealed decreased IL-10 expression in dorsal spinal cord and DRG while AM1710 resulted in increased IL-10, comparable to controls. Adjacent DRG and spinal sections revealed increased IL-1β, p-p38MAPK, glial markers and/or MAGL expression, while AM1710 suppressed all but spinal p-p38MAPK and microglial activation. In spinal gp120 animals, AM1710 prevented bilateral mechanical hypersensitivity. For comparison to immunohistochemistry, IL-1β and TNF-α protein quantification from lumbar spinal and DRG homogenates was determined, and revealed increased DRG IL-1β protein levels from gp120, that was robustly prevented by AM1710 pretreatment. Cannabilactone CB2R agonists are emerging as anti-inflammatory agents with pain therapeutic implications.
PMCID: PMC3603341  PMID: 22425445
cannabinoid; CCI; paraffin immunohistochemistry; rat; spectral analysis; gp120

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