Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Summer

This study analyzes short vlogs posted to YouTube in order to investigate how women and men communicate using vlogs and react as viewers to vlogs. Vlogs are visual texts that are usergenerated. Analyzing online videos presents a new challenge for researchers: traditionally, analysis of visual media and communication focused on either the production or the reception of the material. Our vlog study uses a dual analytical approach to analyze both production and reception, while conducting content, visual and audience analysis, thus making a contribution to the field of new visual media and communication. ______________________________________________________________________________ Heather Molyneaux is an analyst in the People-Centred Technologies group at the National Research Council Institute for Information Technology. Correspondence to: NRC Institute for Information 2 Producing and sharing user-generated video, known as &quot;video blogging,&quot; has recently become popular with millions of people. Video blogs, also known as &quot;vlogs,&quot; are blogs created in video rather than textual form. Vlogs are a form of online publishing, allowing everyone with web access and simple video production tools -such as a computer and a webcam or a cell phone with video capabilities -to create and post content. Most vlogs are authored by individuals and focus on personal themes . Like blogs, vlogs are a user-generated form of online communication that serve as media for social commentary, alternative newscasts, creative outlets or personal online diaries. We chose YouTube as an obvious source of online videos and a potential user community. YouTube is currently the most popular online video website and hosts more videos than rival video sites This study analyzes short vlogs posted to YouTube in order to investigate how and why people communicate using vlogs, and how viewers react to vlogs. In particular we examine potential uses of user-generated video for women, and how women are creating vlogs and using YouTube. Analyzing online videos presents a new challenge for researchers: traditionally, analysis of visual media and communication focused on either the production or the reception by different actors. Our study&apos;s dual analytical approach thus makes a useful contribution to the field of new visual media and communication. Our initial findings reveal gender differences in both vlog creation and YouTube use. Analyzing vlogs Videos are complicated texts requiring careful analysis conducted via various methods. Even though visual analysis is complex and the results usually subjective, videos need to be examined because they are becoming increasingly important in contemporary culture. Videos can aid communication by increasing communication richness, empowering those who develop their own videos and encouraging identity formation among users. Users benefit because video channels allow them to communicate in a more natural way resembling face-to-face communication New technologies could potentially change traditional social and political hierarchies and transform the boundaries between the private and the public Navarro, 1993, Milliken et al, 2008). New technologies also create new spaces for interaction and participation. At the same time, however, such technologies serve to widen gaps to access. Marginalized or minority groups are especially vulnerable to this phenomenon. Communication technology could play a role in turning women&apos;s talk into voice but there are limitations Another concern with the visual representation of women is exploitative images that present women not as subjects but as objects for the male gaze Although intervention is difficult, socially constructed meanings are neither fixed nor unalterable User-generated video on YouTube is just beginning to be examined by scholars. Little is known about who creates these videos, why they post them and who watches them Research methodology The research methods included a content and visual analysis of vlogs on YouTube and a study of YouTube users. Content analysis enables researchers to determine, through careful observation and analysis, the major themes in media content. We conducted our content analysis to explore who is vlogging, how audiences respond to vloggers and the influence of gender on these variables. Interpretations of vlogs change according to place, time and the audience; however visual messages have dominant meanings that provide interpretive boundaries for the decoding of messages 4 We conducted a content analysis on a random sample of YouTube vlogs. At the time of the study there was no obvious category on YouTube for vlogs so we conducted an initial search on YouTube using the term &quot;blog&quot; which returned more than 30,000 entries available for general viewing. For our population we chose vlogs posted over a 15-day period, from October 6 to October 21, 2006. To enable comparison among potentially similar vlogs, vlogs longer than three minutes and non-English vlogs were excluded, leaving us with a population of 1,028 vlogs. Using a listing of random numbers (RAND, 2001) we randomly selected 100 numbers between 1 and 1,028 and selected the vlogs corresponding to these random numbers. The quantitative analysis conducted on this sample is accurate within a 90% confidence level and a 7.8% error level. Since we were counting number of views for each vlog, we waited one month from the time of initial posting to the coding of the video. The vlogs and the profiles of the vloggers were coded for a number of variables, including gender, age, location, audience, message, motivation, technical quality (both audio and visual), and the number of views. Cohen&apos;s Kappa for these variables averaged .85. The final aspect of the research was an audience analysis of vlogs. We collected data on the number of views of each of the vlogs within the random sample and the views and comments from the YouTube site on the four videos analyzed in greater detail. We also conducted a study of 60 participants who were YouTube users. These participants were recruited from a university in Atlantic Canada. The study was designed to include an equal number of males (30) and females (30). Participants viewed the four vlogs described above, in a random order presented in their questionnaire. The study participants completed a paper questionnaire comprised of demographic questions and a section for feedback on the video blogs. Participation took approximately 45 minutes and participants were given a $10 honorarium. Research findings and discussion Our research findings are presented according to the three different methodological and analytical approaches we used, described above. The results of the content analysis conducted on the random sample of our population and the findings from the visual analysis of four vlogs and audience analysis are discussed. Content analysis -the vloggers A content analysis of the characteristics of vloggers in our random sample revealed that the majority of vlogs featured a single participant. Men posted vlogs more than women -58% to 33%; the gender of the vlogger could not be determined for the remaining 9%. When vlogs contained more than one participant, the majority of secondary participants were also male. Most vloggers, 61%, were adults ranging in age from 20 to 50 years, although about one-third, or 36%, were younger. The age of the vlogger could not be determined for 3% of the vlogs. The average age of the main vlog participant was 23 years. There was no great difference in the ages of men and women vloggers: the average age of men was 24, while the average age of women was 21. These findings are not surprising; studies done on internet use in the U.S. show that college students, who have greater access to technology, are frequent internet video users. A 5 2007 PEW internet study indicates that young adults, ages 18-29 are the most avid viewers of online video in the United States Text information posted on the user profiles occasionally differed from that stated in the actual video blog. The most popular misreported information was age. The researchers found four cases of vloggers posting on their profile a different age than they state in the video blog. In all four cases the vloggers were young women, ages 12, 14, 15 and 15, who reported their age in their profile as older than their actual age -86, 22, 20 and 46. Content analysis -the vlogs For our analysis we coded each vlog into one of five categories that we created: personal, public, entertainment, YouTube, and technology. The categorization was based on the message of the video. Personal vlogs offer viewers introductions to the vloggers&apos; personal lives, provide updates on their lives, or act as home movies. Public vlogs report or discuss the news or politics, or offer social commentary. Entertainment vlogs consist of comedy routines, musical numbers, acted skits or dancing or a combination of these elements. YouTube vlogs are videos where people either ask questions for others to answer, respond to questions asked by other vloggers, or discuss other vlogs on YouTube. Technology vlogs either discuss technology or test out equipment. Herring, et al, note in their study of blogs that more bloggers discussed personal matters than any other category Content analysis -image and audio quality The quality of the vlog did not differ by the gender of the vlogger. When coding for quality the researchers took a basic approach, coding for three categories (excellent, acceptable and poor) for the quality of the image and sound. Men and women vloggers scored very similar ratings across the board. The videos created by women vloggers had slightly better image quality, and slightly poorer sound quality than those created by men

Maternal psychological distress in primary care and association with child behavioural outcomes at age three

Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers’ mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00787-015-0777-2) contains supplementary material, which is available to authorized users

Using Simulation Models to Evaluate Ape Nest Survey Techniques

BACKGROUND: Conservationists frequently use nest count surveys to estimate great ape population densities, yet the accuracy and precision of the resulting estimates are difficult to assess. METHODOLOGY/PRINCIPAL FINDINGS: We used mathematical simulations to model nest building behavior in an orangutan population to compare the quality of the population size estimates produced by two of the commonly used nest count methods, the 'marked recount method' and the 'matrix method.' We found that when observers missed even small proportions of nests in the first survey, the marked recount method produced large overestimates of the population size. Regardless of observer reliability, the matrix method produced substantial overestimates of the population size when surveying effort was low. With high observer reliability, both methods required surveying approximately 0.26% of the study area (0.26 km(2) out of 100 km(2) in this simulation) to achieve an accurate estimate of population size; at or above this sampling effort both methods produced estimates within 33% of the true population size 50% of the time. Both methods showed diminishing returns at survey efforts above 0.26% of the study area. The use of published nest decay estimates derived from other sites resulted in widely varying population size estimates that spanned nearly an entire order of magnitude. The marked recount method proved much better at detecting population declines, detecting 5% declines nearly 80% of the time even in the first year of decline. CONCLUSIONS/SIGNIFICANCE: These results highlight the fact that neither nest surveying method produces highly reliable population size estimates with any reasonable surveying effort, though either method could be used to obtain a gross population size estimate in an area. Conservation managers should determine if the quality of these estimates are worth the money and effort required to produce them, and should generally limit surveying effort to 0.26% of the study area, unless specific management goals require more intensive sampling. Using site- and time- specific nest decay rates (or the marked recount method) are essential for accurate population size estimation. Marked recount survey methods with sufficient sampling effort hold promise for detecting population declines

Distress and satisfaction with research participation: Impact on retention in longitudinal disaster research

© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).Previous studies of the impact of post-trauma research participation indicate that while the research experience may be emotional, it can still be valued by participants. This paper describes participant experiences of the Australian post-bushfire research study–Beyond Bushfires. It examines the relationships between distress during research participation, probable mental health conditions, and satisfaction with the research experience over time. A range of strategies was incorporated into the study, including a distress and risk assessment and referral protocol, to minimise any risk of harm for people who had experienced the 2009 bushfires and their aftermath. Participants included 1056 respondents (Wave 1) interviewed via telephone and web-based survey between December 2011 through January 2013, and 736 (76.1%) of the participants were re-surveyed between July and November 2014 (Wave 2). Research impact was monitored through two questions about survey experience on each occasion. Reported distress at completing the survey was generally low, while overall satisfaction was relatively high. Participants’ reported satisfaction was not associated with their reported level of distress as a result of the survey; and reported participation distress at Wave 1 did not predict whether a respondent would return to complete the survey at Wave 2. Fire-related Posttraumatic stress symptoms were associated with increased satisfaction and likelihood to return at Wave 2. These findings suggest that for Beyond Bushfires survey respondents the perceived benefits outweighed the costs of participation over time

A privacy-preserving solution for compressed storage and selective retrieval of genomic data

In clinical genomics, the continuous evolution of bioinformatic algorithms and sequencing platforms makes it beneficial to store patients' complete aligned genomic data in addition to variant calls relative to a reference sequence. Due to the large size of human genome sequence data files (varying from 30 GB to 200 GB depending on coverage), two major challenges facing genomics laboratories are the costs of storage and the efficiency of the initial data processing. In addition, privacy of genomic data is becoming an increasingly serious concern, yet no standard data storage solutions exist that enable compression, encryption, and selective retrieval. Here we present a privacy-preserving solution named SECRAM (Selective retrieval on Encrypted and Compressed Reference-oriented Alignment Map) for the secure storage of compressed aligned genomic data. Our solution enables selective retrieval of encrypted data and improves the efficiency of downstream analysis (e.g., variant calling). Compared withBAM, thede factostandard for storing aligned genomic data, SECRAM uses 18%less storage. Compared with CRAM, one of the most compressed nonencrypted formats (using 34% less storage than BAM), SECRAM maintains efficient compression and downstream data processing, while allowing for unprecedented levels of security in genomic data storage. Compared with previous work, the distinguishing features of SECRAM are that (1) it is position-based insteadofread-based,and(2)itallowsrandomqueryingofasubregionfromaBAM-likefileinanencryptedform.Ourmethod thus offers a space-saving, privacy-preserving, and effective solution for the storage of clinical genomic data. © 2016 Szalaj et al

Efficacy of novel SPAK inhibitor ZT-1a derivatives (1c, 1d, 1g & 1h) on improving post-stroke neurological outcome and brain lesion in mice

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData availability: Data will be made available on request.SPAK inhibitor ZT-1a was previously shown to be neuroprotective in murine ischemic stroke models. In this study, we further examined the efficacy of four ZT-1a derivatives (ZT-1c, -1d, -1g and -1h) on reducing stroke-induced sensorimotor function impairment and brain lesions. Vehicle control (Veh) or ZT-1 derivatives were administered via osmotic pump to adult C57BL/6J mice during 3–21 h post-stroke. Neurological behavior of these mice was assessed at days 1, 3, 5, and 7 post-stroke and MRI T2WI and DTI analysis was subsequently conducted in ex vivo brains. Veh-treated stroke mice displayed sensorimotor function deficits compared to Sham mice. In contrast, mice receiving ZT-1a derivatives displayed significantly lower neurological deficits at days 3–7 post-stroke (p -1c > -1g > -1h. The Veh-treated stroke mice displayed white matter tissue injury, reflected by reduced fractional anisotropy (FA) or axial diffusivity (AD) values in external capsule, internal capsule and hippocampus. In contrast, only ZT-1a-as well as ZT-1c-treated stroke mice exhibited significantly higher FA and AD values. These findings demonstrate that post-stroke administration of SPAK inhibitor ZT-1a and its derivatives (ZT-1c and ZT-1d) is effective in protecting gray and white matter tissues in ischemic brains, showing a potential for ischemic stroke therapy development.Veteran AffairsNational Institutes of Health (NIH)Royal Societ

Long-lived photoexcited states in polydiacetylenes with different molecular and supramolecular organization

With the aim of determining the importance of the molecular and supramolecular organization on the excited states of polydiacetylenes, we have studied the photoinduced absorption spectra of the red form of poly[1,6-bis(3,6-didodecyl-N-carbazolyl)-2,4-hexadiyne] (polyDCHD-S) and the results compared with those of the blue form of the same polymer. An interpretation of the data is given in terms of both the conjugation length and the interbackbone separation also in relation to the photoinduced absorption spectra of both blue and red forms of poly[1,6-bis(N-carbazolyl)-2,4-hexadiyne] (polyDCHD), which does not carry the alkyl substituents on the carbazolyl side groups. Information on the above properties is derived from the analysis of the absorption and Raman spectra of this class of polydiacetylenes

Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis

BACKGROUND: A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population. METHODS: Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis. RESULTS: A significant association of the MUC5B promoter single nucleotide polymorphism with IPF (p=2.04 x 10(-17); OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF. CONCLUSIONS: We confirm the MUC5B variant association with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association

The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects