Publications by authors named "Robert Davidson"

162 Publications

NO-Stressed Has Decreased Cell Division Rates in the Mouse Spleen.

Infect Immun 2022 Jul 11:e0016722. Epub 2022 Jul 11.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Fluorescence dilution approaches can detect bacterial cell division events and can detect if there are differential rates of cell division across individual cells within a population. This approach typically involves inducing expression of a fluorescent protein and then tracking partitioning of fluorescence into daughter cells. However, fluorescence can be diluted very quickly within a rapidly replicating population, such as pathogenic bacterial populations replicating within host tissues. To overcome this limitation, we have generated two revTetR reporter constructs, where either mCherry or yellow fluorescent protein (YFP) is constitutively expressed and repressed by addition of tetracyclines, resulting in fluorescence dilution within defined time frames. We show that fluorescent signals are diluted in replicating populations and that signal accumulates in growth-inhibited populations, including during nitric oxide (NO) exposure. Furthermore, we show that tetracyclines can be delivered to the mouse spleen during Yersinia pseudotuberculosis infection and defined a drug concentration that results in even exposure of cells to tetracyclines. We then used this system to visualize bacterial cell division within defined time frames postinfection. revTetR-mCherry allowed us to detect slow-growing cells in response to NO in culture; however, this strain had a growth defect within mouse tissues, which complicated results. To address this issue, we constructed revTetR-YFP using the less toxic YFP and showed that heightened NO exposure correlated with heightened YFP signal, indicating decreased cell division rates within this subpopulation . This revTetR reporter will provide a critical tool for future studies to identify and isolate slowly replicating bacterial subpopulations from host tissues.
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http://dx.doi.org/10.1128/iai.00167-22DOI Listing
July 2022

Yersinia pseudotuberculosis doxycycline tolerance strategies include modulating expression of genes involved in cell permeability and tRNA modifications.

PLoS Pathog 2022 05 16;18(5):e1010556. Epub 2022 May 16.

W. Harry Feinstone Department of Molecular Microbiology and Immunology Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.

Antibiotic tolerance is typically associated with a phenotypic change within a bacterial population, resulting in a transient decrease in antibiotic susceptibility that can contribute to treatment failure and recurrent infections. Although tolerant cells may emerge prior to treatment, the stress of prolonged antibiotic exposure can also promote tolerance. Here, we sought to determine how Yersinia pseudotuberculosis responds to doxycycline exposure, to then verify if these gene expression changes could promote doxycycline tolerance in culture and in our mouse model of infection. Only four genes were differentially regulated in response to a physiologically-relevant dose of doxycycline: osmB and ompF were upregulated, tusB and cnfy were downregulated; differential expression also occurred during doxycycline treatment in the mouse. ompF, tusB and cnfy were also differentially regulated in response to chloramphenicol, indicating these could be general responses to ribosomal inhibition. cnfy has previously been associated with persistence and was not a major focus here. We found deletion of the OmpF porin resulted in increased antibiotic accumulation, suggesting expression may promote diffusion of doxycycline out of the cell, while OsmB lipoprotein had a minor impact on antibiotic permeability. Overexpression of tusB significantly impaired bacterial survival in culture and in the mouse, suggesting that tRNA modification by tusB, and the resulting impacts on translational machinery, promotes survival during treatment with an antibiotic classically viewed as bacteriostatic. We believe this may be the first observation of bactericidal activity of doxycycline under physiological conditions, which was revealed by reversing tusB downregulation.
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http://dx.doi.org/10.1371/journal.ppat.1010556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135342PMC
May 2022

Expanded evidence that the 31-gene expression profile test provides clinical utility for melanoma management in a multicenter study.

Curr Med Res Opin 2022 Aug 15;38(8):1267-1274. Epub 2022 Feb 15.

Department of Surgical Oncology, The University of Tennessee Health Science Center, Memphis, TN, USA.

Objective: National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma (CM) recommend physicians consider increased surveillance for patients who typically have lower melanoma survival rates (stages IIB-IV as determined by the American Joint Committee on Cancer (AJCC), 8th edition). However, up to 15% of patients identified as having a low recurrence risk (stages I-IIA) experience disease recurrence, and some patients identified as having a high recurrence risk will not experience any recurrence. The 31-gene expression profile test (31-GEP) stratifies patient recurrence risk into low (Class 1) and high (Class 2) and has demonstrated risk-appropriate impact on disease management and clinical decisions.

Methods: Five-year plans for lab work, frequency of clinical visits, and imaging pre- and post-31-GEP test results were assessed for a cohort of 509 stage I-III patients following an interim subset analysis of 247 patients.

Results: After receiving 31-GEP results, 50.6% of patients had a change in management plans in at least one of the following categories-clinical visits, lab work, or surveillance imaging. The changes aligned with the risk predicted by the 31-GEP for 76.1% of patients with a Class 1 result and 78.7% of patients with a Class 2 result. A Class 1 31-GEP result was associated with changes toward low-intensity management recommendations, while a Class 2 result was associated with changes toward high-intensity management recommendations.

Conclusion: The 31-GEP can stratify patient recurrence risk in patients with CM, and clinicians understand and apply the prognostic ability of the 31-GEP test to alter patient management in risk-appropriate directions.
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http://dx.doi.org/10.1080/03007995.2022.2033560DOI Listing
August 2022

Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A.

Mol Ther Methods Clin Dev 2022 Mar 24;24:20-29. Epub 2021 Nov 24.

Spark Therapeutics, Inc., Philadelphia, PA, USA.

Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent , currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 10 vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic.
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http://dx.doi.org/10.1016/j.omtm.2021.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8666598PMC
March 2022

Stoma-Output Reinfusion Device for Ileostomy Patients: A Feasibility Study.

Dis Colon Rectum 2021 11;64(11):e662-e668

Department of Surgery, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1097/DCR.0000000000002233DOI Listing
November 2021

Integrating 31-Gene Expression Profiling With Clinicopathologic Features to Optimize Cutaneous Melanoma Sentinel Lymph Node Metastasis Prediction.

JCO Precis Oncol 2021 13;5. Epub 2021 Sep 13.

Oregon Health & Science University, Portland, OR.

National guidelines recommend sentinel lymph node biopsy (SLNB) be offered to patients with > 10% likelihood of sentinel lymph node (SLN) positivity. On the other hand, guidelines do not recommend SLNB for patients with T1a tumors without high-risk features who have < 5% likelihood of a positive SLN. However, the decision to perform SLNB is less certain for patients with higher-risk T1 melanomas in which a positive node is expected 5%-10% of the time. We hypothesized that integrating clinicopathologic features with the 31-gene expression profile (31-GEP) score using advanced artificial intelligence techniques would provide more precise SLN risk prediction.

Methods: An integrated 31-GEP (i31-GEP) neural network algorithm incorporating clinicopathologic features with the continuous 31-GEP score was developed using a previously reported patient cohort (n = 1,398) and validated using an independent cohort (n = 1,674).

Results: Compared with other covariates in the i31-GEP, the continuous 31-GEP score had the largest likelihood ratio (G = 91.3, < .001) for predicting SLN positivity. The i31-GEP demonstrated high concordance between predicted and observed SLN positivity rates (linear regression slope = 0.999). The i31-GEP increased the percentage of patients with T1-T4 tumors predicted to have < 5% SLN-positive likelihood from 8.5% to 27.7% with a negative predictive value of 98%. Importantly, for patients with T1 tumors originally classified with a likelihood of SLN positivity of 5%-10%, the i31-GEP reclassified 63% of cases as having < 5% or > 10% likelihood of positive SLN, for a more precise, personalized, and clinically actionable SLN-positive likelihood estimate.

Conclusion: These data suggest the i31-GEP could reduce the number of SLNBs performed by identifying patients with likelihood under the 5% threshold for performance of SLNB and improve the yield of positive SLNBs by identifying patients more likely to have a positive SLNB.
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http://dx.doi.org/10.1200/PO.21.00162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457832PMC
March 2022

How Do Music Activities Affect Health and Well-Being? A Scoping Review of Studies Examining Psychosocial Mechanisms.

Front Psychol 2021 8;12:713818. Epub 2021 Sep 8.

UQ Music, Dance and Health Research Group, The University of Queensland, Brisbane, QLD, Australia.

This scoping review analyzed research about how music activities may affect participants' health and well-being. Primary outcomes were measures of health (including symptoms and health behaviors) and well-being. Secondary measures included a range of psychosocial processes such as arousal, mood, social connection, physical activation or relaxation, cognitive functions, and identity. Diverse music activities were considered: receptive and intentional music listening; sharing music; instrument playing; group singing; lyrics and rapping; movement and dance; and songwriting, composition, and improvisation. Nine databases were searched with terms related to the eight music activities and the psychosocial variables of interest. Sixty-three papers met selection criteria, representing 6,975 participants of all ages, nationalities, and contexts. Receptive and intentional music listening were found to reduce pain through changes in physiological arousal in some studies but not others. Shared music listening (e.g., concerts or radio programs) enhanced social connections and mood in older adults and in hospital patients. Music listening and carer singing decreased agitation and improved posture, movement, and well-being of people with dementia. Group singing supported cognitive health and well-being of older adults and those with mental health problems, lung disease, stroke, and dementia through its effects on cognitive functions, mood, and social connections. Playing a musical instrument was associated with improved cognitive health and well-being in school students, older adults, and people with mild brain injuries effects on motor, cognitive and social processes. Dance and movement with music programs were associated with improved health and well-being in people with dementia, women with postnatal depression, and sedentary women with obesity through various cognitive, physical, and social processes. Rapping, songwriting, and composition helped the well-being of marginalized people through effects on social and cultural inclusion and connection, self-esteem and empowerment. Music activities offer a rich and underutilized resource for health and well-being to participants of diverse ages, backgrounds, and settings. The review provides preliminary evidence that particular music activities may be recommended for specific psychosocial purposes and for specific health conditions.
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http://dx.doi.org/10.3389/fpsyg.2021.713818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455907PMC
September 2021

Printing Methods in the Production of Orodispersible Films.

AAPS PharmSciTech 2021 Apr 9;22(3):129. Epub 2021 Apr 9.

Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSSAHER), Sri Shivarathreeshwara Nagar, Mysore, 570 015, India.

Orodispersible film (ODF) formulations are promising and progressive drug delivery systems that are widely accepted by subjects across all the age groups. They are traditionally fabricated using the most popular yet conventional method called solvent casting method. The most modern and evolving method is based on printing technologies and such printed products are generally termed as printed orodispersible films (POFs). This modern technology is well suited to fabricate ODFs across different settings (laboratory or industrial) in general and in a pharmacy setting in particular. The present review provides an overview of various printing methods employed in fabricating POFs. Particularly, it provides insight about preparing POFs using inkjet, flexographic, and three-dimensional printing (3DP) or additive manufacturing techniques like filament deposition modeling, hot-melt ram extrusion 3DP, and semisolid extrusion 3DP methods. Additionally, the review is focused on patenting trends in POFs using ESPACENET, a European Patent Office search database. Finally, the review captures future market potential of 3DP in general and ODFs market potential in particular.
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http://dx.doi.org/10.1208/s12249-021-01990-3DOI Listing
April 2021

Activated protein C has a regulatory role in factor VIII function.

Blood 2021 05;137(18):2532-2543

Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.

Mechanisms thought to regulate activated factor VIII (FVIIIa) cofactor function include A2-domain dissociation and activated protein C (APC) cleavage. Unlike A2-domain dissociation, there is no known phenotype associated with altered APC cleavage of FVIII, and biochemical studies have suggested APC plays a marginal role in FVIIIa regulation. However, the in vivo contribution of FVIIIa inactivation by APC is unexplored. Here we compared wild-type B-domainless FVIII (FVIII-WT) recombinant protein with an APC-resistant FVIII variant (FVIII-R336Q/R562Q; FVIII-QQ). FVIII-QQ demonstrated expected APC resistance without other changes in procoagulant function or A2-domain dissociation. In plasma-based studies, FVIII-WT/FVIIIa-WT demonstrated dose-dependent sensitivity to APC with or without protein S, whereas FVIII-QQ/FVIIIa-QQ did not. Importantly, FVIII-QQ demonstrated approximately fivefold increased procoagulant function relative to FVIII-WT in the tail clip and ferric chloride injury models in hemophilia A (HA) mice. To minimize the contribution of FV inactivation by APC in vivo, a tail clip assay was performed in homozygous HA/FV Leiden (FVL) mice infused with FVIII-QQ or FVIII-WT in the presence or absence of monoclonal antibody 1609, an antibody that blocks murine PC/APC hemostatic function. FVIII-QQ again demonstrated enhanced hemostatic function in HA/FVL mice; however, FVIII-QQ and FVIII-WT performed analogously in the presence of the PC/APC inhibitory antibody, indicating the increased hemostatic effect of FVIII-QQ was APC specific. Our data demonstrate APC contributes to the in vivo regulation of FVIIIa, which has the potential to be exploited to develop novel HA therapeutics.
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http://dx.doi.org/10.1182/blood.2020007562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109017PMC
May 2021

Yersinia pseudotuberculosis: Cultivation, Storage, and Methods for Introducing DNA.

Curr Protoc Microbiol 2020 12;59(1):e122

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Yersinia pseudotuberculosis has been studied for many decades, and research on this microbe has taught us a great deal about host-pathogen interactions, bacterial manipulation of host cells, virulence factors, and the evolution of pathogens. This microbe should not be cultivated at 37°C because this is a trigger that the bacterium uses to sense its presence within a mammalian host and results in expression of genes necessary to colonize a mammalian host. Prolonged growth at this temperature can result in accumulation of mutations that reduce the virulence of the strain, so all protocols need to be modified for growth at room temperature, or 26°C. This article describes protocols for cultivating this microbe and for its long-term storage and its genetic manipulation by transformation and conjugation. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Growth of Y. pseudotuberculosis from a stock Basic Protocol 2: Growth of Y. pseudotuberculosis in liquid medium from a single colony Basic Protocol 3: Freezing Y. pseudotuberculosis in glycerol for long-term storage Basic Protocol 4: Transformation of Y. pseudotuberculosis by electroporation Basic Protocol 5: Tri-parental mating/conjugation.
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http://dx.doi.org/10.1002/cpmc.122DOI Listing
December 2020

An engineered human albumin enhances half-life and transmucosal delivery when fused to protein-based biologics.

Sci Transl Med 2020 10;12(565)

Centre for Immune Regulation (CIR) and Department of Immunology, University of Oslo and Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway.

Needle-free uptake across mucosal barriers is a preferred route for delivery of biologics, but the efficiency of unassisted transmucosal transport is poor. To make administration and therapy efficient and convenient, strategies for the delivery of biologics must enhance both transcellular delivery and plasma half-life. We found that human albumin was transcytosed efficiently across polarized human epithelial cells by a mechanism that depends on the neonatal Fc receptor (FcRn). FcRn also transported immunoglobulin G, but twofold less than albumin. We therefore designed a human albumin variant, E505Q/T527M/K573P (QMP), with improved FcRn binding, resulting in enhanced transcellular transport upon intranasal delivery and extended plasma half-life of albumin in transgenic mice expressing human FcRn. When QMP was fused to recombinant activated coagulation factor VII, the half-life of the fusion molecule increased 3.6-fold compared with the wild-type human albumin fusion, without compromising the therapeutic properties of activated factor VII. Our findings highlight QMP as a suitable carrier of protein-based biologics that may enhance plasma half-life and delivery across mucosal barriers.
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http://dx.doi.org/10.1126/scitranslmed.abb0580DOI Listing
October 2020

Rural development and shifts in household dietary practices from 1999 to 2010 in the Tapajós River region, Brazilian Amazon: empirical evidence from dietary surveys.

Global Health 2020 04 22;16(1):36. Epub 2020 Apr 22.

Centro de Desenvolvimento Sustentável, Universidade de Brasília, Campus Universitário Darcy Ribeiro, Gleba A, Asa Norte, Brasília, DF, 70910-900, Brazil.

Background: Research on changing dietary practices is rare in lower and middle income countries, and understanding the impact of global economic processes on population health and nutrition is important, especially of rural communities. We analyzed the diet of 22 families in Brasília Legal, a riverside community in the Tapajós River region of the Brazilian Amazon, using nonparametric tests to compare dietary surveys taken in 1999 and 2010.

Results: Data from the two surveys show that food obtained through commercial supply chains became more frequent in household diets, corresponding to significant increases in daily consumption of food items rich in energy, protein, and sugar. At the same time, there was a decline in traditional Amazonian food intake.

Conclusions: Comparing these results with household socio-economic characteristics and drawing on open-ended interviews, we consider the multiple influences that economic development processes may have had on local diets. The introduction of new income sources and employment opportunities, infrastructural and transportation expansion, as well as environmental change appear to have influenced the observed dietary shifts. Such shifts are likely to have important implications for the nutritional status of communities in the Amazon, highlighting concerning trade-offs between current development trajectories and human health. Public policies and health education programs must urgently consider the interactions between sustainable development priorities in order to address emerging health risks in this rapidly changing region.
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http://dx.doi.org/10.1186/s12992-020-00564-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178734PMC
April 2020

Time to diagnosis of tuberculosis is greater in older patients: a retrospective cohort review.

ERJ Open Res 2019 Oct 4;5(4). Epub 2019 Nov 4.

London North West University Healthcare NHS Trust, London, UK.

Introduction: Age-related immunosenescence influences the presentation of tuberculosis (TB) in older patients. Here, we explore the clinical and radiological presentation of TB in the elderly and the factors associated with time to treatment for TB.

Methods: This is a retrospective cohort study comparing the clinical, radiological and demographic characteristics of TB patients aged ≥65 years with TB patients aged 18-64 years in a large cohort of TB patients in the UK. Factors associated with the time to presentation and time to treatment were identified using a multivariable analysis model.

Results: 1023 patients were included in the analyses: 679 patients aged 18-64 years and 344 patients aged ≥65 years. "Classical" symptoms of TB (cough, haemoptysis, fever, nights sweats and weight loss) were less common among older patients with pulmonary TB (PTB) (p<0.05), but dyspnoea was more common among older patients (p=0.001). Time from presenting in secondary care to starting treatment was shorter in younger compared with older patients: 3 15 days (p=0.001). When adjusted for age, factors associated with shorter time to treatment from symptom onset include sex (male female) (hazard ratio (HR) 1.23 (95% CI 1.05-1.46)), UK born (HR 1.23 (95% CI 1.05-1.46)) and HIV (HR 2.07 (95% CI 1.30-3.29)). Only age remained an independent predictor of time to treatment in a multivariable model (HR 0.98 (95% CI 0.98-0.99)). For those with PTB, chest radiography findings showed that cavitation and lymphadenopathy were more common among younger patients (p=0.001).

Conclusions: Older patients aged ≥65 years with TB had fewer "classical" clinical and radiological presentations of TB, which may explain longer times to starting treatment from symptom onset compared with younger patients aged <65 years.
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http://dx.doi.org/10.1183/23120541.00228-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826249PMC
October 2019

Enantioselective Synthesis of -Benzylic Heterocycles: A Nickel and Photoredox Dual Catalysis Approach.

Org Lett 2019 11 24;21(22):8957-8961. Epub 2019 Oct 24.

Dr. Reddy's Laboratories (EU) , 410 Science Park, Milton Road , Cambridge CB4 0PE , United Kingdom.

Reported herein is a dual nickel- and photoredox-catalyzed modular approach for the preparation of enantioenriched -benzylic heterocycles. α-Heterocyclic carboxylic acids, easily obtainable from common commercial material, are reported as suitable substrates for a decarboxylative strategy in conjunction with a chiral pyridine-oxazoline (PyOx) ligand, providing quick access to enantioenriched drug-like products. The presence of a directing group on the heterocyclic moiety is shown to be beneficial, affording improved stereoselectivity in a number of cases.
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http://dx.doi.org/10.1021/acs.orglett.9b03338DOI Listing
November 2019

Advocacy Beyond Identity: A Dutch Gay/Lesbian Organization's Embrace of a Public Policy Strategy.

J Homosex 2020 18;67(1):35-57. Epub 2018 Oct 18.

University of Amsterdam, AISSR, Amsterdam, Netherlands.

The gay/lesbian social movement has primarily been understood as an identity movement. This article contributes to expanding understandings of the gay/lesbian movement by following the advocacy of the Dutch Association for the Integration of Homosexuality COC (COC) as a case of a gay/lesbian movement organization's expansion of its action repertoire to include public policy goals. On the basis of archival and interview data, this article identifies several factors that enabled the COC to see the Dutch government as a potential public policy partner. Previous legal successes and facilitation by the institutionalized wing of the women's movement, coupled with a constitutional change, resulted in the COC's development of a policy strategy. By tracing the history of the COC's strategic interactions, this article demonstrates that, while an identity strategy was constant throughout the COC's advocacy, the organization could combine an identity strategy with strategies of legal change, cultural change, and public policy.
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http://dx.doi.org/10.1080/00918369.2018.1525944DOI Listing
January 2020

Building a profile of subjective well-being for social media users.

PLoS One 2017 14;12(11):e0187278. Epub 2017 Nov 14.

Two Cloaks Ltd., Glasgow, United Kingdom.

Subjective well-being includes 'affect' and 'satisfaction with life' (SWL). This study proposes a unified approach to construct a profile of subjective well-being based on social media language in Facebook status updates. We apply sentiment analysis to generate users' affect scores, and train a random forest model to predict SWL using affect scores and other language features of the status updates. Results show that: the computer-selected features resemble the key predictors of SWL as identified in early studies; the machine-predicted SWL is moderately correlated with the self-reported SWL (r = 0.36, p < 0.01), indicating that language-based assessment can constitute valid SWL measures; the machine-assessed affect scores resemble those reported in a previous experimental study; and the machine-predicted subjective well-being profile can also reflect other psychological traits like depression (r = 0.24, p < 0.01). This study provides important insights for psychological prediction using multiple, machine-assessed components and longitudinal or dense psychological assessment using social media language.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187278PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685571PMC
December 2017

Reduction of soil erosion and mercury losses in agroforestry systems compared to forests and cultivated fields in the Brazilian Amazon.

J Environ Manage 2017 Dec 30;203(Pt 1):522-532. Epub 2017 Aug 30.

Université Paris Descartes/USPC, 19 rue de Dantzig, Paris, 75015, France.

In addition to causing physical degradation and nutrient depletion, erosion of cultivated soils in the Amazon affects aquatic ecosystems through the release of natural soil mercury (Hg) towards lakes and rivers. While traditional agriculture is generally cited as being among the main causes of soil erosion, agroforestry practices are increasingly appreciated for soil conservation. This study was carried out in family farms of the rural Tapajós region (Brazil) and aimed at evaluating soil erosion and associated Hg release for three land uses. Soils, runoff water and eroded sediments were collected at three sites representing a land cover gradient: a recently burnt short-cycle cropping system (SCC), a 2-year-old agroforestry system (AFS) and a mature forest (F). At each site, two PVC soil erosion plots (each composed of three 2 × 5 m isolated subplots) were implemented on steep and moderate slopes respectively. Sampling was done after each of the 20 rain events that occurred during a 1-month study period, in the peak of the 2011 rain season. Runoff volume and rate, as well as eroded soil particles with their Hg and cation concentrations were determined. Total Hg and cation losses were then calculated for each subplot. Erosion processes were dominated by land use type over rainfall or soil slope. Eroded soil particles, as well as the amount of Hg and cations (CaMgK) mobilized at the AFS site were similar to those at the F site, but significantly lower than those at the SCC site (p < 0.0001). Erosion reduction at the AFS site was mainly attributed to the ground cover plants characterizing the recently established system. Moreover, edaphic change throughout AFS and F soil profiles differed from the SCC site. At the latter site, losses of fine particles and Hg were enhanced towards soil surface, while they were less pronounced at the other sites. This study shows that agroforestry systems, even in their early stages of implementation, are characterized by low erosion levels resembling those of local forest environments, thus contributing to the maintenance of soil integrity and to the reduction of Hg and nutrient mobility.
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http://dx.doi.org/10.1016/j.jenvman.2017.07.037DOI Listing
December 2017

Screening contacts of patients with extrapulmonary TB for latent TB infection.

Thorax 2018 03 11;73(3):277-278. Epub 2017 May 11.

Department of Infectious Diseases, Northwick Park Hospital, London, UK.

2016 TB National Institute for Health and Care Excellence (NICE) guidelines imply that contacts of extrapulmonary TB do not require screening for latent TB infection. At our high TB prevalence site, we identified 189 active cases of TB for whom there were 698 close contacts. 29.1% of the contacts of pulmonary TB and 10.7% of the contacts of extrapulmonary TB had active or latent TB infection. This supports screening contacts of extrapulmonary TB at our site and presents a way to access high-risk individuals. We propose to continue to screen the contacts of our patients with extrapulmonary TB and recommend other TB units audit their local results.
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http://dx.doi.org/10.1136/thoraxjnl-2016-209639DOI Listing
March 2018

Complications of miliary tuberculosis: low mortality and predictive biomarkers from a UK cohort.

BMC Infect Dis 2017 04 20;17(1):295. Epub 2017 Apr 20.

Department of Infectious Diseases, Northwick Park Hospital, Northwest London Teaching Hospitals NHS Trust, London, UK.

Background: Untreated, miliary tuberculosis (TB) has a mortality approaching 100%. As it is uncommon there is little specific data to guide its management. We report detailed data from a UK cohort of patients with miliary tuberculosis and the associations and predictive ability of admission blood tests with clinical outcomes.

Methods: Routinely collected demographic, clinical, blood, imaging, histopathological and microbiological data were assessed for all patients with miliary TB identified from the London TB register from 2008 to 2012 from Northwest London Hospitals NHS Trust. Multivariable logistic regression was used to assess factors independently associated with the need for critical care intervention. Receiver operator characteristics (ROC) were calculated to assess the discriminatory ability of admission blood tests to predict clinical outcomes.

Results: Fifty-two patients were identified with miliary tuberculosis, of whom 29% had confirmed central nervous system (CNS) involvement. Magnetic resonance imaging (MRI) was more sensitive than computed tomography (CT) or lumbar puncture for detecting CNS disease. Severe complications were frequent, with 15% requiring critical care intervention with mechanical ventilation. This was independently associated with admission hyponatraemia and elevated alanine aminotransferase (ALT). Having an admission sodium ≥125 mmol/L and an ALT <180 IU/L had 82% sensitivity and 100% specificity for predicting a favourable outcome with an area under the ROC curve (AUC) of 0.91. Despite the frequency of severe complications, one-year mortality was low at 2%.

Conclusions: Although severe complications of miliary tuberculosis were frequent, mortality was low with timely access to critical care intervention, anti-tuberculous therapy and possibly corticosteroid use. Clinical outcomes could accurately be predicted using routinely collected biochemistry data.
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http://dx.doi.org/10.1186/s12879-017-2397-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399311PMC
April 2017

Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK.

BMC Infect Dis 2017 03 24;17(1):231. Epub 2017 Mar 24.

Department of Infection, Northwick Park Hospital, London North West Healthcare NHS Trust, London, UK.

Background: We describe drug-induced liver injury (DILI) secondary to antituberculous treatment (ATT) in a large tuberculosis (TB) centre in London; we identify the proportion who had risk factors for DILI and the timing and outcome of DILI.

Methods: We identified consecutive patients who developed DILI whilst on treatment for active TB; patients with active TB without DILI were selected as controls. Comprehensive demographic and clinical data, management and outcome were recorded.

Results: There were 105 (6.9%) cases of ATT-associated DILI amongst 1529 patients diagnosed with active TB between April 2010 and May 2014. Risk factors for DILI were: low patient weight, HIV-1 co-infection, higher baseline ALP, and alcohol intake. Only 25.7% of patients had British or American Thoracic Society defined criteria for liver test (LT) monitoring. Half (53%) of the cases occurred within 2 weeks of starting ATT and 87.6% occurred within 8 weeks. Five (4.8%) of seven deaths were attributable to DILI.

Conclusions: Only a quarter of patients who developed DILI had British or American Thoracic Society defined criteria for pre-emptive LT monitoring, suggesting that all patients on ATT should be considered for universal liver monitoring particularly during the first 8 weeks of treatment.
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http://dx.doi.org/10.1186/s12879-017-2330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366108PMC
March 2017

Regional adaptation defines sensitivity to future ocean acidification.

Nat Commun 2017 01 9;8:13994. Epub 2017 Jan 9.

Marine Biology &Ecology Research Centre, School of Marine Science and Engineering, Plymouth University, Drake Circus, Plymouth, Devon PL4 8AA, UK.

Physiological responses to temperature are known to be a major determinant of species distributions and can dictate the sensitivity of populations to global warming. In contrast, little is known about how other major global change drivers, such as ocean acidification (OA), will shape species distributions in the future. Here, by integrating population genetics with experimental data for growth and mineralization, physiology and metabolomics, we demonstrate that the sensitivity of populations of the gastropod Littorina littorea to future OA is shaped by regional adaptation. Individuals from populations towards the edges of the natural latitudinal range in the Northeast Atlantic exhibit greater shell dissolution and the inability to upregulate their metabolism when exposed to low pH, thus appearing most sensitive to low seawater pH. Our results suggest that future levels of OA could mediate temperature-driven shifts in species distributions, thereby influencing future biogeography and the functioning of marine ecosystems.
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http://dx.doi.org/10.1038/ncomms13994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227702PMC
January 2017

Environmental and Anthropogenic Factors Influencing Mercury Dynamics During the Past Century in Floodplain Lakes of the Tapajós River, Brazilian Amazon.

Arch Environ Contam Toxicol 2017 Jan 17;72(1):11-30. Epub 2016 Nov 17.

Centro de Desenvolvimento Sustentável (CDS), Universidade de Brasília, Brasília, Brazil.

In the Tapajós River region of the Brazilian Amazon, mercury (Hg) is a prevalent contaminant in the aquatic ecosystem. Few studies have used comprehensive chronological analyses to examine the combined effects of environmental and anthropogenic factors on Hg accumulation in sediments. Total mercury (THg) content was measured in sediments from eight floodplain lakes and 210 isotope analysis was used to develop a timeline of THg accumulation. Secondary data representing environmental and anthropogenic factors were analyzed using geo-spatial analyses. These include land-cover change, hydrometeorological time-series data, lake morphology, and watershed biophysical characteristics. The results indicate that THg accumulation and sedimentation rates have increased significantly at the surface of most sediment cores, sometimes doubling since the 1970s. Human-driven land-cover changes in the watershed correspond closely to these shifts. Tropical deforestation enhances erosion, thereby mobilizing the heavy metal that naturally occurs in soils. Environmental factors also contribute to increased THg content in lacustrine sediments. Climate shifts since the 1980s are further compounding erosion and THg accumulation in surface sediments. Furthermore, variations in topography, soil types, and the level of hydrological connectivity between lakes and the river explain observed variations in THg fluxes and sedimentation. Although connectivity naturally varies among sampled lakes, deforestation of sensitive floodplain vegetation has changed lake-river hydrology in several sites. In conclusion, the results point to a combination of anthropogenic and environmental factors as determinants of increased THg accumulation in tropical floodplain sediments in the Tapajós region.
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http://dx.doi.org/10.1007/s00244-016-0325-1DOI Listing
January 2017

Factors which influence treatment initiation for pulmonary non-tuberculous mycobacterium infection in HIV negative patients; a multicentre observational study.

Respir Med 2016 11 6;120:101-108. Epub 2016 Oct 6.

London North West Healthcare NHS Trusts, London, UK.

Background: Clinical, radiological and microbiological criteria inform diagnosis of pulmonary Non-Tuberculous Mycobacteria (NTM) disease and treatment decisions. This multicentre, review aims to characterise NTM disease meeting ATS/IDSA criteria and define factors associated with initiation of treatment.

Methods: Sputum samples growing NTM from 5 London hospitals between 2010 and 2014 were identified. Data for HIV-negative individuals meeting ATS/IDSA guidelines for pulmonary NTM disease were extracted. Associations between clinical variables and treatment decision were investigated using Chi-squared, Fishers-exact or Mann Whitney tests. Factors associated with treatment in univariate analysis (p < 0.150) were included in a multivariate logistic regression model.

Results: NTM were identified from 817 individuals' sputum samples. 108 met ATS/IDSA criteria. 42/108 (39%) were initiated on treatment. Median age was 68 (56-78) in the cohort. On multivariate analysis, factors significantly associated with treatment of pulmonary NTM infection were: Cavitation on HRCT (OR: 6.49; 95% CI: 2.36-17.81), presenting with night sweats (OR 4.18; 95% CI: 1.08-16.13), and presenting with weight loss (OR 3.02; 95% CI: 1.15-7.93). Of those treated, 18(43%) have completed treatment, 9(21%) remain on treatment, 10(24%) stopped due to side effects, 5(12%) died during treatment. Mortality was 31% (n = 13) in treated versus 21% (n = 14) in the non-treated cohort. Subgroup analysis of individual NTM species did not observe any differences in treatment initiation or outcomes between groups.

Discussion: Decision to treat pulmonary NTM infection requires clinical judgement when interpreting clinical guidelines. Factors independently associated with decision to treat in this HIV-negative cohort include cavitation on HRCT and presenting with night sweats or weight loss.
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http://dx.doi.org/10.1016/j.rmed.2016.10.001DOI Listing
November 2016

Direct NHC-catalysed redox amidation using CO2 for traceless masking of amine nucleophiles.

Chem Commun (Camb) 2016 Oct 3;52(78):11638-41. Epub 2016 Aug 3.

Department of Chemistry, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK. m.fuchter.imperial.ac.uk.

The N-heterocyclic carbene (NHC)-catalysed redox amidation reaction is poorly developed and usually requires catalytic co-additives for electron-rich amine nucleophiles. We report a masking strategy (using CO2) that couples release of the free amine nucleophile to catalytic turnover, and in doing so, enables direct catalytic redox amidation of electron-rich amines.
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http://dx.doi.org/10.1039/c6cc04639hDOI Listing
October 2016

A rapid pro-hemostatic approach to overcome direct oral anticoagulants.

Nat Med 2016 08 25;22(8):924-32. Epub 2016 Jul 25.

Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.

Direct inhibitors of coagulation factor Xa (FXa) or thrombin are promising oral anticoagulants that are becoming widely adopted. The ability to reverse their anticoagulant effects is important when serious bleeding occurs or urgent medical procedures are needed. Here, using experimental mouse models of hemostasis, we show that a variant coagulation factor, FXa(I16L), rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors. The ability of FXa(I16L) to reverse the anticoagulant effects of FXa inhibitor depends, at least in part, on the ability of the active site inhibitor to hinder antithrombin-dependent FXa inactivation, paradoxically allowing uninhibited FXa to persist in plasma. Because of its inherent catalytic activity, FXa(I16L) is more potent (by >50-fold) in the hemostasis models tested than a noncatalytic antidote that is currently in clinical development. FXa(I16L) also reduces the anticoagulant-associated bleeding in vivo that is induced by the thrombin inhibitor dabigatran. FXa(I16L) may be able to fill an important unmet clinical need for a rapid, pro-hemostatic agent to reverse the effects of several new anticoagulants.
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http://dx.doi.org/10.1038/nm.4149DOI Listing
August 2016

Clinical impact of a 31-gene expression profile test for cutaneous melanoma in 156 prospectively and consecutively tested patients.

Curr Med Res Opin 2016 09 3;32(9):1599-604. Epub 2016 Jun 3.

g Miller Start Center for Cancer Care , San Antonio , TX , USA.

Objective: DecisionDx-Melanoma * is a 31-gene expression profile test that predicts the risk of metastasis in patients with primary cutaneous melanoma (CM). This study was designed to ascertain clinical management changes determined by the test outcome, which classifies CM patients being at low (Class 1) or high (Class 2) risk for recurrence.

Research Design And Methods: Medical charts were reviewed from 156 CM patients from six institutions (three dermatology and three surgical oncology practices) who were consecutively tested between May 2013 and December 2015. Clinical management data that were compiled and compared before and after receipt of the 31-gene expression test result included frequency of physical exams, frequency and modality of imaging, and referrals to surgical and medical oncologists.

Results: Forty-two percent of patients were Stage I, 47% were Stage II and 8% were Stage III. Overall, 95 patients (61%) were Class 1 and 61 (39%) were Class 2. Documented changes in management were observed in 82 (53%) patients, with the majority of Class 2 patients (77%) undergoing management changes compared to 37% of Class 1 patients (p < 0.0001 by Fisher's exact test). The majority (77/82, 94%) of these changes were concordant with the risk indicated by the test result (p < 0.0001 by Fisher's exact test), with increased management intensity for Class 2 patients and reduced management intensity for Class 1 patients.

Conclusions: Molecular risk classification by gene expression profiling has clinical impact and influences physicians to direct clinical management of CM patients. The vast majority of the changes implemented after the receipt of test results were reflective of the low or high recurrence risk associated with the patient's molecular classification. Because follow-up data was not collected for this patient cohort, the study is limited for the assessment of the impact of gene expression profile based management changes on healthcare resource utilization and patient outcome.
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http://dx.doi.org/10.1080/03007995.2016.1192997DOI Listing
September 2016

Early MRI versus conventional management in the detection of occult scaphoid fractures: what does it really cost? A rural pilot study.

J Med Radiat Sci 2016 03 18;63(1):9-16. Epub 2016 Jan 18.

South West Healthcare Warrnambool Victoria Australia; Centre for Rural Emergency Medicine Deakin University Warrnambool Victoria Australia.

Introduction: To compare the cost-effectiveness and patient impact between acute magnetic resonance imaging (MRI) management and conventional management in the diagnosis of occult scaphoid fractures in a rural setting.

Methods: Consecutive patients presenting to a rural emergency department (ED) with a suspected scaphoid fracture were randomly assigned to either conventional management (6) or acute MRI management (10) (3 patients were excluded from the study analysis). All healthcare costs were compared between the two management groups and potential impacts on the patients' pain, mobility and lifestyle were also measured.

Results: There were no significant differences between the two groups at baseline. There was one (10%) scaphoid fracture in the MRI group and none in the conventional group (P = 0.42). A larger proportion of other fractures were diagnosed in the MRI group (20% (2) vs. 16.7% (1), P = 0.87), as well as less clinic attendances (1 (0-2.25) vs. 4 (2.25-5)) and diagnostic services (1 (1-1.25) vs. 2 (1-3)). Median management costs were $485.05 (AUD) (MRI) and $486.90 (AUD) (conventional). The MRI group had better pain and satisfaction scores as well as less time of immobilisation, treatment and time off work.

Conclusion: MRI dramatically reduces the amount of unnecessary immobilisation, time of treatment and healthcare usage in a rural setting. The two protocols are suggested to be equivalent financially. When potential societal costs, the amount of unnecessary immobilisation, low prevalence of true fractures and patient satisfaction are considered, acute MRI should be the management technique of choice. Further studies are still required to assess the best method for managing bone bruise within the scaphoid.
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http://dx.doi.org/10.1002/jmrs.153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775832PMC
March 2016

Optimizing the Exposure Indicator as a Dose Management Strategy in Computed Radiography.

Radiol Technol 2016 Mar-Apr;87(4):380-91

Purpose: To investigate a technique for optimizing radiation dose and image quality for a computed radiography system.

Methods: Entrance skin doses were measured for phantom models of the pelvis and lumbar spine imaged using the vendor's recommended exposure settings (ie, the reference doses) as well as doses above and below the vendor's recommended settings for both body parts. Images were assessed using visual grading analysis (VGA).

Results: The phantom dosimetry results revealed strong positive linear relationships between dose and milliampere seconds (mAs), mAs and inverse exposure indicator (EI), and dose and inverse EI for both body parts. The VGA showed that optimized values of 16 mAs/EI = 136 for the anteroposterior (AP) pelvis and 32 mAs/EI = 139 for the AP lumbar spine did not compromise image quality.

Discussion: Selecting optimized mAs reduced dose by 36% compared with the vendor's recommended mAs (dose) values.

Conclusion: Optimizing the mAs and associated EIs can be an effective dose management strategy.
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December 2016

Galaxy-M: a Galaxy workflow for processing and analyzing direct infusion and liquid chromatography mass spectrometry-based metabolomics data.

Gigascience 2016 23;5:10. Epub 2016 Feb 23.

School of Biosciences, University of Birmingham, Birmingham, B15 2TT UK.

Background: Metabolomics is increasingly recognized as an invaluable tool in the biological, medical and environmental sciences yet lags behind the methodological maturity of other omics fields. To achieve its full potential, including the integration of multiple omics modalities, the accessibility, standardization and reproducibility of computational metabolomics tools must be improved significantly.

Results: Here we present our end-to-end mass spectrometry metabolomics workflow in the widely used platform, Galaxy. Named Galaxy-M, our workflow has been developed for both direct infusion mass spectrometry (DIMS) and liquid chromatography mass spectrometry (LC-MS) metabolomics. The range of tools presented spans from processing of raw data, e.g. peak picking and alignment, through data cleansing, e.g. missing value imputation, to preparation for statistical analysis, e.g. normalization and scaling, and principal components analysis (PCA) with associated statistical evaluation. We demonstrate the ease of using these Galaxy workflows via the analysis of DIMS and LC-MS datasets, and provide PCA scores and associated statistics to help other users to ensure that they can accurately repeat the processing and analysis of these two datasets. Galaxy and data are all provided pre-installed in a virtual machine (VM) that can be downloaded from the GigaDB repository. Additionally, source code, executables and installation instructions are available from GitHub.

Conclusions: The Galaxy platform has enabled us to produce an easily accessible and reproducible computational metabolomics workflow. More tools could be added by the community to expand its functionality. We recommend that Galaxy-M workflow files are included within the supplementary information of publications, enabling metabolomics studies to achieve greater reproducibility.
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http://dx.doi.org/10.1186/s13742-016-0115-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765054PMC
October 2016
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