Health Technology

Am J Nephrol. 2019 Mar 27;49(4):317-327. doi: 10.1159/000499532. [Epub ahead of print]

Comparison of 24-hour and Office Pulse Wave Velocity for Prediction of Mortality in Hemodialysis Patients.

Matschkal J1, Mayer CC2,3, Sarafidis PA4, Lorenz G5, Braunisch MC5, Guenthner R5, Angermann S5, Steubl D5, Kemmner S5, Bachmann Q5, Hauser C5, Nerl L5, Baumann M6, Mann JF7, Moog P5, Kuechle C5, Renders L5, Heemann U5, Wassertheurer S2,3, Schmaderer C5.

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Abstract

BACKGROUND:

Mortality in hemodialysis patients still remains unacceptably high. Enhanced arterial stiffness is a known cardiovascular risk factor, and pulse wave velocity (PWV) has proven to be a valid parameter to quantify risk. Recent studies showed controversial results regarding the prognostic significance of PWV for mortality in hemodialysis patients, which may be due to methodological issues, such as assessment of PWV in the office setting (Office-PWV).

METHOD:

This study cohort contains patients from the "Risk stratification in end-stage renal disease - the ISAR study," a multicenter prospective longitudinal observatory cohort study. We examined and compared the predictive value of ambulatory 24-hour PWV (24 h-PWV) and Office-PWV on mortality in a total of 344 hemodialysis patients. The endpoints of the study were all-cause and cardiovascular mortality. Survival analysis included Kaplan-Meier estimates and Cox regression analysis.

RESULTS:

During a follow-up of 36 months, a total of 89 patients died, 35 patients due to cardiovascular cause. Kaplan-Meier estimates for tertiles of 24 h-PWV and Office-PWV were similarly associated with mortality. In univariate Cox regression analysis, 24 h-PWV and Office-PWV were equivalent predictors for all-cause and cardiovascular mortality. After adjustment for common risk factors, only 24 h-PWV remained solely predictive for all-cause mortality (hazard ratio 2.51 [95% CI 1.31-4.81]; p = 0.004).

CONCLUSIONS:

Comparing both measurements, 24 h-PWV is an independent predictor for all-cause-mortality in hemodialysis patients beyond Office-PWV.

© 2019 S. Karger AG, Basel.

KEYWORDS:

Ambulatory blood pressure monitoring; Arterial stiffness; Chronic hemodialysis; Mortality; Pulse wave velocity

PMID: 30917369 DOI: 10.1159/000499532

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2.

Cell Rep. 2019 Mar 26;26(13):3772-3783.e6. doi: 10.1016/j.celrep.2019.02.090.

Simplified Intestinal Microbiota to Study Microbe-Diet-Host Interactions in a Mouse Model.

Kovatcheva-Datchary P1, Shoaie S2, Lee S2, Wahlström A1, Nookaew I3, Hallen A1, Perkins R1, Nielsen J4, Bäckhed F5.

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Abstract

The gut microbiota can modulate human metabolism through interactions with macronutrients. However, microbiota-diet-host interactions are difficult to study because bacteria interact in complex food webs in concert with the host, and many of the bacteria are not yet characterized. To reduce the complexity, we colonize mice with a simplified intestinal microbiota (SIM) composed of ten sequenced strains isolated from the human gut with complementing pathways to metabolize dietary fibers. We feed the SIM mice one of three diets (chow [fiber rich], high-fat/high-sucrose, or zero-fat/high-sucrose diets [both low in fiber]) and investigate (1) how dietary fiber, saturated fat, and sucrose affect the abundance and transcriptome of the SIM community, (2) the effect of microbe-diet interactions on circulating metabolites, and (3) how microbiota-diet interactions affect host metabolism. Our SIM model can be used in future studies to help clarify how microbiota-diet interactions contribute to metabolic diseases.

Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

diet; metabolome; microbiota; transcriptome

PMID: 30917328 DOI: 10.1016/j.celrep.2019.02.090

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3.

Cell Rep. 2019 Mar 26;26(13):3741-3751.e5. doi: 10.1016/j.celrep.2019.02.094.

High-Resolution Structure of Cas13b and Biochemical Characterization of RNA Targeting and Cleavage.

Slaymaker IM1, Mesa P2, Kellner MJ3, Kannan S4, Brignole E5, Koob J6, Feliciano PR5, Stella S2, Abudayyeh OO4, Gootenberg JS7, Strecker J8, Montoya G2, Zhang F9.

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Abstract

Type VI CRISPR-Cas systems contain programmable single-effector RNA-guided RNases, including Cas13b, one of the four known family members. Cas13b, which has been used for both RNA editing and nucleic acid detection, is unique among type VI CRISPR effectors in its linear domain architecture and CRISPR RNA (crRNA) structure. Here, we report the crystal structure of Prevotella buccae Cas13b (PbuCas13b) bound to crRNA at 1.65 Å resolution. This structure, combined with biochemical experiments assaying the stability, kinetics, and function of Cas13b, provides a mechanistic model for Cas13b target RNA recognition and identifies features responsible for target and cleavage specificity. Based on these observations, we generated Cas13b variants with altered cleavage preferences, which may expand the utility of nuclease-based RNA detection assays and other applications of Cas13b in mammalian cells.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

KEYWORDS:

CRISPR-Cas9 system; Cas13b; RNA-targeting; crystal structure; type VI CRISPR

PMID: 30917325 DOI: 10.1016/j.celrep.2019.02.094

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4.

J Nurs Manag. 2018 Jul;26(5):495-497. doi: 10.1111/jonm.12676.

Simulation: Smoothing the transition from undergraduate to new graduate.

Hayes C1.

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PMID: 30917209 DOI: 10.1111/jonm.12676

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5.

PLoS One. 2019 Mar 27;14(3):e0213377. doi: 10.1371/journal.pone.0213377. eCollection 2019.

Efficient removal of Pb(II) from aqueous solution by a novel ion imprinted magnetic biosorbent: Adsorption kinetics and mechanisms.

He Y1, Wu P1, Xiao W2, Li G3, Yi J1, He Y1, Chen C4, Ding P1, Duan Y1.

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Abstract

It is vital to understand the adsorption mechanisms and identify the adsorption kinetics when applying an adsorbent to remove heavy metals from aqueous solution. A Pb(II) imprinted magnetic biosorbent (Pb(II)-IMB) was developed for the removal of Pb2+ via lead ion imprinting technology and crosslinking reactions among chitosan (CTS), Serratia marcescens and Fe3O4. The effect of different parameters such as solution pH, adsorbent dosage, selectivity sorption and desorption were investigated on the absorption of lead ion by Pb(II)-IMB. The adsorbent was characterized by a Brunauer-Emmett Teller (BET) analysis, X-ray diffraction (XRD), vibrating sample magnetometry (VSM), scanning electron microscopy (SEM) and energy dispersive spectrometry (EDS). The adsorption kinetics, equilibrium and thermodynamics of Pb(II)-IMB for Pb(II) were studied. The results of the abovementioned analyses showed that the adsorption kinetic process fit well with the second-order equation. The adsorption isotherm process of Pb(II) on the Pb(II)-IMB was closely related to the Langmuir model. Thermodynamic studies suggested the spontaneous and endothermic nature of adsorption of Pb(II) by Pb(II)-IMB. The adsorption mechanism of Pb(II)-IMB was studied by Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The results indicated that the nitrogen in the amino group and the oxygen in the hydroxyl group of Pb(II)-IMB were coordination atoms.

PMID: 30917141 DOI: 10.1371/journal.pone.0213377

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6.

PLoS Comput Biol. 2019 Mar 27;15(3):e1006865. doi: 10.1371/journal.pcbi.1006865. [Epub ahead of print]

LMTRDA: Using logistic model tree to predict MiRNA-disease associations by fusing multi-source information of sequences and similarities.

Wang L1, You ZH1, Chen X2, Li YM3, Dong YN4, Li LP1, Zheng K1.

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Abstract

Emerging evidence has shown microRNAs (miRNAs) play an important role in human disease research. Identifying potential association among them is significant for the development of pathology, diagnose and therapy. However, only a tiny portion of all miRNA-disease pairs in the current datasets are experimentally validated. This prompts the development of high-precision computational methods to predict real interaction pairs. In this paper, we propose a new model of Logistic Model Tree for predicting miRNA-Disease Association (LMTRDA) by fusing multi-source information including miRNA sequences, miRNA functional similarity, disease semantic similarity, and known miRNA-disease associations. In particular, we introduce miRNA sequence information and extract its features using natural language processing technique for the first time in the miRNA-disease prediction model. In the cross-validation experiment, LMTRDA obtained 90.51% prediction accuracy with 92.55% sensitivity at the AUC of 90.54% on the HMDD V3.0 dataset. To further evaluate the performance of LMTRDA, we compared it with different classifier and feature descriptor models. In addition, we also validate the predictive ability of LMTRDA in human diseases including Breast Neoplasms, Breast Neoplasms and Lymphoma. As a result, 28, 27 and 26 out of the top 30 miRNAs associated with these diseases were verified by experiments in different kinds of case studies. These experimental results demonstrate that LMTRDA is a reliable model for predicting the association among miRNAs and diseases.

PMID: 30917115 DOI: 10.1371/journal.pcbi.1006865

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7.

Health Technol Assess. 2019 Mar;23(13):1-226. doi: 10.3310/hta23130.

Three biomarker tests to help diagnose preterm labour: a systematic review and economic evaluation.

Varley-Campbell J1, Mújica-Mota R1, Coelho H1, Ocean N1, Barnish M1, Packman D1, Dodman S1, Cooper C1, Snowsill T1,2, Kay T3, Liversedge N3, Parr M4, Knight L3, Hyde C1, Shennan A5,6, Hoyle M1.

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Abstract

BACKGROUND:

Preterm birth may result in short- and long-term health problems for the child. Accurate diagnoses of preterm births could prevent unnecessary (or ensure appropriate) admissions into hospitals or transfers to specialist units.

OBJECTIVES:

The purpose of this report is to assess the test accuracy, clinical effectiveness and cost-effectiveness of the diagnostic tests PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim® Partus (Medix Biochemica, Espoo, Finland) and the Rapid Fetal Fibronectin (fFN)® 10Q Cassette Kit (Hologic, Inc., Marlborough, MA, USA) at thresholds ≠50 ng/ml [quantitative fFN (qfFN)] for women presenting with signs and symptoms of preterm labour relative to fFN at 50 ng/ml.

METHODS:

Systematic reviews of the published literature were conducted for diagnostic test accuracy (DTA) studies of PartoSure, Actim Partus and qfFN for predicting preterm birth, the clinical effectiveness following treatment decisions informed by test results and economic evaluations of the tests. A model-based economic evaluation was also conducted to extrapolate long-term outcomes from the results of the diagnostic tests. The model followed the structure of the model that informed the 2015 National Institute for Health and Care Excellence guidelines on preterm labour diagnosis and treatment, but with antenatal steroids use, as opposed to tocolysis, driving health outcomes.

RESULTS:

Twenty studies were identified evaluating DTA against the reference standard of delivery within 7 days and seven studies were identified evaluating DTA against the reference standard of delivery within 48 hours. Two studies assessed two of the index tests within the same population. One study demonstrated that depending on the threshold used, qfFN was more or less accurate than Actim Partus, whereas the other indicated little difference between PartoSure and Actim Partus. No study assessing qfFN and PartoSure in the same population was identified. The test accuracy results from the other included studies revealed a high level of uncertainty, primarily attributable to substantial methodological, clinical and statistical heterogeneity between studies. No study compared all three tests simultaneously. No clinical effectiveness studies evaluating any of the three biomarker tests were identified. One partial economic evaluation was identified for predicting preterm birth. It assessed the number needed to treat to prevent a respiratory distress syndrome case with a 'treat-all' strategy, relative to testing with qualitative fFN. Because of the lack of data, our de novo model involved the assumption that management of pregnant women fully adhered to the results of the tests. In the base-case analysis for a woman at 30 weeks' gestation, Actim Partus had lower health-care costs and fewer quality-adjusted life-years (QALYs) than qfFN at 50 ng/ml, reducing costs at a rate of £56,030 per QALY lost compared with qfFN at 50 ng/ml. PartoSure is less costly than Actim Partus while being equally effective, but this is based on diagnostic accuracy data from a small study. Treatment with qfFN at 200 ng/ml and 500 ng/ml resulted in lower cost savings per QALY lost relative to fFN at 50 ng/ml than treatment with Actim Partus. In contrast, qfFN at 10 ng/ml increased QALYs, by 0.002, and had a cost per QALY gained of £140,267 relative to fFN at 50 ng/ml. Similar qualitative results were obtained for women presenting at different gestational ages.

CONCLUSION:

There is a high degree of uncertainty surrounding the test accuracy and cost-effectiveness results. We are aware of four ongoing UK trials, two of which plan to enrol > 1000 participants. The results of these trials may significantly alter the findings presented here.

STUDY REGISTRATION:

The study is registered as PROSPERO CRD42017072696.

FUNDING:

The National Institute for Health Research Health Technology Assessment programme.

PLAIN-LANGUAGE-SUMMARY:

Infants may suffer from health problems if they are born early. If a mother has symptoms of labour before her baby is due, a test could be used to predict if the symptoms are real or a false alarm. A test could help the doctor to decide whether the mother needs treatment or to move to a specialist hospital or if she could be sent home (if it is a false alarm). Our report compares three tests [PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim® Partus (Medix Biochemica, Espoo, Finland) and the Fetal Fibronectin (fFN) Test (Hologic, Inc., Marlborough, MA, USA)] on how well they predict an early birth and how the costs and the long-term health outcomes of the child compare between and among tests. All the published literature reporting the accuracy of the three tests and their costs was reviewed. We developed a new cost-effectiveness model, which estimated the long-term health outcomes of the child based on the test results. Twenty of the studies reviewed looked at how good the tests were at predicting an early birth within the next 7 days, and six looked at predicting birth within 48 hours. The designs of the studies and the women taking part in the studies varied greatly. This meant that comparing the accuracy of the tests was very difficult and it would be unfair to decide which test was the best. Our model suggested no firm conclusions for the cost-effectiveness of fFN compared with Actim Partus. PartoSure appears to be less costly than Actim Partus and equally good at predicting preterm birth, but this is based on a study of very few patients. There were no data that allowed us to compare all three tests together. The accuracy of the results is uncertain, mainly because all the studies are very different. We are aware of four related UK trials that are currently ongoing that plan to include large numbers of women.

KEYWORDS:

ACTIM PARTUS; FETAL FIBRONECTIN; PAMG-1; PARTOSURE; PH(IGFBP-1); PHOSPHORYLATED INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN; PLACENTAL ALPHA MACROGLOBULIN-1; TEST ACCURACY

PMID: 30917097 DOI: 10.3310/hta23130

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8.

Annu Rev Genomics Hum Genet. 2019 Mar 27. doi: 10.1146/annurev-genom-083118-015143. [Epub ahead of print]

Epigenetic Regulation and Risk Factors During the Development of Human Gametes and Early Embryos.

Wang Y1, Liu Q1, Tang F2, Yan L1, Qiao J1.

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Abstract

Drastic epigenetic reprogramming occurs during human gametogenesis and early embryo development. Advances in low-input and single-cell epigenetic techniques have provided powerful tools to dissect the genome-wide dynamics of different epigenetic molecular layers in these processes. In this review, we focus mainly on the most recent progress in understanding the dynamics of DNA methylation, chromatin accessibility, and histone modifications in human gametogenesis and early embryo development. Deficiencies in remodeling of the epigenomes can cause severe developmental defects, infertility, and long-term health issues in offspring. Aspects of the external environment, including assisted reproductive technology procedures, parental diets, and unhealthy parental habits, may disturb the epigenetic reprogramming processes and lead to an aberrant epigenome in the offspring. Here, we review the current knowledge of the potential risk factors of aberrant epigenomes in humans. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 30917080 DOI: 10.1146/annurev-genom-083118-015143

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9.

J Glob Oncol. 2019 Mar;(5):1-10. doi: 10.1200/JGO.18.00193.

Linguistic Validation of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events in Korean.

Cho J1,2, Yoon J1,2, Kim Y2, Oh D2, Kim SJ2, Ahn J2, Suh GY2, Nam SJ2, Mitchell SA3.

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Abstract

PURPOSE:

The aim of this study was to translate and linguistically validate a Korean-language version of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

METHODS:

All 124 PRO-CTCAE items were translated into Korean (PRO-CTCAE-Korean) using International Society for Pharmacoeconomics and Outcomes Research best practices and linguistically validated in a diverse sample of patients undergoing cancer treatment (n = 120) to determine whether the Korean translation captured the original concepts. During the cognitive interviews, participants first completed approximately 60 PRO-CTCAE-Korean questions and were then interviewed to evaluate the conceptual equivalence of the translation to the original PRO-CTCAE English-language source. Interview probes addressed comprehension, clarity, and ease of judgement. Three rounds of interviews were conducted. Items that met the a priori threshold of 10% or more of respondents with comprehension difficulties were considered for rephrasing and retesting.

RESULTS:

A majority of PRO-CTCAE-Korean items were well comprehended in round 1; 14 items posed comprehension difficulties for at least 10% of respondents in round 1. Four symptom terms (mouth and throat sores, feeling like nothing could cheer you up, frequent urination, and pain, swelling, redness at drug injection or intravenous insertion site) were revised and retested in rounds 2 and 3. For the other 10 symptom terms, no suitable alternative phrasing was identified, and the terms were retested in rounds 2 and 3. After rounds 2 and 3, no item presented difficulties in 20% or more of participants.

CONCLUSION:

PRO-CTCAE-Korean has been linguistically validated for use in Korean-speaking populations. Quantitative evaluation of this new measure to establish its measurement properties and responsiveness in Korean speakers undergoing cancer treatment is in progress.

PMID: 30917069 DOI: 10.1200/JGO.18.00193

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10.

Hum Factors. 2019 Mar 27:18720819835088. doi: 10.1177/0018720819835088. [Epub ahead of print]

The Validity of an Oculus Rift to Assess Postural Changes During Balance Tasks.

Marchetto J1, Wright WG1.

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Abstract

OBJECTIVE::

To investigate whether shifts in head position, measured via an Oculus Rift head-mounted display (HMD), is a valid measure of whole-body postural stability.

BACKGROUND::

The inverted single-link pendulum model of balance suggests shifts in whole-body center of mass can be estimated from individual body segments. However, whether head position describes postural stability such as center-of-pressure (COP) remains unclear.

METHOD::

Participants ( N = 10) performed six conditions while wearing an HMD and performing a previously validated virtual reality (VR)-based balance assessment. COP was recorded with a Wii Balance Board force plate (WBB), while an HMD recorded linear and angular head displacement. Visual input was presented in the HMD (stable scene, dark scene, or dynamic scene) and somatosensory information (with or without foam) was varied across each condition. The HMD time series data were compared with the criterion-measure WBB.

RESULTS::

Significant correlations were found between COP measures (standard deviation, range, sway area, velocity) and head-centered angular and linear displacements (roll, pitch, mediolateral and anteroposterior directions).

CONCLUSIONS::

The Oculus Rift HMD shows promise as a measure of postural stability without additional posturography equipment. These findings support the application of VR HMD technology for assessment of postural stability across a variety of challenging conditions.

APPLICATION::

The human factors and ergonomic benefit of such an approach is in its portability, low cost, and widespread availability for clinic and home-based investigation of postural disturbances. Fall injury affects millions of people annually, so assessment of fall risk and treatment of the underlying causes has enormous public health benefit.

KEYWORDS:

balance; fall-risk; medical devices; posture; virtual environments

PMID: 30917062 DOI: 10.1177/0018720819835088

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11.

Issues Ment Health Nurs. 2019 Mar 27:1-9. doi: 10.1080/01612840.2018.1528321. [Epub ahead of print]

Understanding Mental Health Nurses' Perceptions of Barcode Medication Administration: A Qualitative Descriptive Study.

Xie N1, Kalia K1, Strudwick G1, Lau F2.

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Abstract

Barcode medication administration (BCMA) technology has been challenging for mental health nurses to incorporate into their clinical practice despite the potentially positive benefits of using the technology for improving patient safety. A review of the literature identified a number of practices that nurses can use to improve adoption of the technology, however, these practices have been primarily used in non-mental health contexts. Therefore, the purpose of this study was to understand mental health nurses' perceptions of practices identified from the literature to improve BCMA adoption in a mental health inpatient setting. Using a qualitative descriptive approach, ten (n = 10) interviews were conducted with direct care mental health nurses working at a mental health and addiction academic teaching hospital in Canada. Data analysis consisted of a conventional content analysis of the interview transcripts by two independent coders. The following five themes emerged from the transcripts: 1) safety, 2) clinical workflow, 3) education, 4) accountability, and 5) strategies. Sub-themes were also identified within the themes of safety and clinical workflow. Insights gleaned from this study warrant acknowledgement and consideration when implementing strategies to increase BCMA compliance within mental health contexts.

PMID: 30917055 DOI: 10.1080/01612840.2018.1528321

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12.

J Food Prot. 2019 Apr;82(4):696-702. doi: 10.4315/0362-028X.JFP-18-499.

Quantification of the β2-Adrenergic Feed Additives Ractopamine and Salbutamol by Reductive Amination-Assisted Modification.

Shen PT1, Wu YY2, Chang YT2, Cheng CW3, Huang MF2, Chen Z4, Shiue YL5, Liang SS2,5,6.

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Abstract

A reductive amination-assisted method was used to synthesize standards and internal standards of ractopamine and salbutamol. Standard and internal standard analogs were fabricated by isotopic formaldehydes and sodium cyanoborohydride. A quantitative method of modified ractopamine and salbutamol was successfully validated. The reductive amination-assisted method enhances the signal for MS detection.

KEYWORDS:

Ractopamine; Reductive amination; Salbutamol; Tandem mass spectrometry; β-Adrenergic agonist

PMID: 30917042 DOI: 10.4315/0362-028X.JFP-18-499

Select item 30916938

13.

Chem Rev. 2019 Mar 27. doi: 10.1021/acs.chemrev.8b00593. [Epub ahead of print]

Electrospinning and Electrospun Nanofibers: Methods, Materials, and Applications.

Xue J1, Wu T1, Dai Y2, Xia Y1,3.

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Abstract

Electrospinning is a versatile and viable technique for generating ultrathin fibers. Remarkable progress has been made with regard to the development of electrospinning methods and engineering of electrospun nanofibers to suit or enable various applications. We aim to provide a comprehensive overview of electrospinning, including the principle, methods, materials, and applications. We begin with a brief introduction to the early history of electrospinning, followed by discussion of its principle and typical apparatus. We then discuss its renaissance over the past two decades as a powerful technology for the production of nanofibers with diversified compositions, structures, and properties. Afterward, we discuss the applications of electrospun nanofibers, including their use as "smart" mats, filtration membranes, catalytic supports, energy harvesting/conversion/storage components, and photonic and electronic devices, as well as biomedical scaffolds. We highlight the most relevant and recent advances related to the applications of electrospun nanofibers by focusing on the most representative examples. We also offer perspectives on the challenges, opportunities, and new directions for future development. At the end, we discuss approaches to the scale-up production of electrospun nanofibers and briefly discuss various types of commercial products based on electrospun nanofibers that have found widespread use in our everyday life.

PMID: 30916938 DOI: 10.1021/acs.chemrev.8b00593

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14.

APMIS. 2019 Mar 27. doi: 10.1111/apm.12946. [Epub ahead of print]

The synthetic antimicrobial peptide LTX21 induces inflammatory responses in a human whole blood model and a murine peritoneum model.

Granslo HN1,2, Aarag Fredheim EG1,3, Esaiassen E1,2, Christophersen L4, Jensen PØ4, Mollnes TE5,6,7, Moser C4, Flaegstad T1,2, Klingenberg C1,2, Cavanagh JP1.

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Abstract

The global spread of antimicrobial resistance and the increasing number of immune-compromised patients are major challenges in modern medicine. Targeting bacterial virulence or the human host immune system to increase host defence are important strategies in the search for novel antimicrobial drugs. We investigated the inflammatory response of the synthetic short antimicrobial peptide LTX21 in two model systems: a human whole blood ex vivo model and in a murine in vivo peritoneum model - both reflecting early innate immune response. In the whole blood model, LTX21 increased secretion of a range of different cytokines, decreased the level of tumour necrosis factor (TNF), and activated the complement system. In a haemolysis assay, we found 2.5% haemolysis at a LTX21 concentration of 500 mg/L. In the murine model, increased influx of white blood cells (WBC) and polymorphonuclear neutrophils (PMN) in the murine peritoneal cavity was observed after treatment with LTX21. In addition, LTX21 increased monocyte chemoattractant protein-1 (MCP-1). In conclusion, LTX21 affected the inflammatory response; the increase in cytokine secretion, complement activation and WBC influx indicates an activated inflammatory response. The present results indicate impact of LTX21 on host-pathogen interplay. Whether this will also affect the course of infection has to be investigated. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

LTX21; cationic peptides; human whole blood model; murine model

PMID: 30916807 DOI: 10.1111/apm.12946

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15.

Biol Reprod. 2019 Mar 27. pii: ioz044. doi: 10.1093/biolre/ioz044. [Epub ahead of print]

MiR-664-2 impacts pubertal development in a precocious-puberty rat model through targeting the NMDA receptor-1.

Ju M1, Yang L2, Zhu J1, Chen Z1, Zhang M1, Yu J1, Tian Z1.

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Abstract

Precocious puberty commonly results from premature activation of the hypothalamic-pituitary-gonadal axis (HPGA). Gonadotropin-releasing hormone (GnRH) is the initial trigger for HPGA activation and plays an important role in puberty onset. N-methyl-D-aspartate (NMDA) can promote pulsatile GnRH secretion and accelerates puberty onset. However, the mechanism of N-methyl-D-aspartate receptors (NMDARs) in precocious puberty (PP) pathogenesis remains obscure. We found that serum GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen (E2) levels, hypothalamic NMDAR1 and GnRH mRNA expression peaked at the vaginal opening (VO) day. Next, the hypothalamic NMDAR1 mRNA and protein levels in rats treated with danazol, a chemical commonly effecting on the reproductive system, were significantly increased at the VO day (PND 24) compared to controls, accompanied by enhanced serum GnRH, LH, FSH, and E2 levels. Further, microRNA-664-2 (miR-664-2) was selected after bioinformatics analysis and approved in primary hypothalamic neurons, which binds to the 3'-untranslated regions (3'-UTR) of NMDAR1. Consistently, the miR-664-2 expression in hypothalamus of the Danazol group was decreased compared to Vehicle. Our results suggested that attenuated miR-664-2 might participate in precocious puberty pathogenesis through enhancing the NMDAR1 signaling.

© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction.

KEYWORDS:

NMDAR1; hypothalamic-pituitary-gonadal axis; miR-664-2; precocious puberty

PMID: 30916745 DOI: 10.1093/biolre/ioz044

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16.

JAMA Dermatol. 2019 Mar 27. doi: 10.1001/jamadermatol.2018.5360. [Epub ahead of print]

Evaluation of Prospective HLA-B*13:01 Screening to Prevent Dapsone Hypersensitivity Syndrome in Patients With Leprosy.

Liu H1,2,3,4, Wang Z1,3, Bao F1,3, Wang C1,3, Sun L1,3, Zhang H1,3, Yu G1,3, Mi Z1,3, Li J1,3, Li L1,3, Zhao Q1,3, Yue Z1,3, Zhao W1,3, Yu W1,3, Cao J1,3, Xiong F1,3, Wang Y1,3, Chai Z1,3, Cheng X1,3, Zhang Y1,3, Fu F1,3, Lang X1,3, Wang X1,3, Irwanto A5, Krismawati H6, Fu X1,3, Sun Y1,3, You J1, Liu J1, Pan Q1,3, Chu T1, Liu D1, Chen S1, Shen J7, Yan L7, Zhang G7, Liu J5, Zhang F1,2,3,4; and the Dapsone Hypersensitivity Syndrome Prevention Working Group, Xiong L8, Yang J8, Li J9, Ke W9, Li M9, Ning Y10, Xiong J10, Li M11, Xiong M11, Yang B11, Duan Q12, Wang H12, Li W12, Kuang Y13, Li J13, Wang L14, Cao Q14, Xiao P15, Xiao B15, Zhang L16, Lin Z17, Wang Y17, Shen Y18, Yan L18, Wu W19, Zheng H20, Zhan X21, Li W21, Shang X22, Xu Y23, Liu Q23.

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Abstract

IMPORTANCE:

Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone.

OBJECTIVE:

To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01-positive leprosy.

DESIGN, SETTING, AND PARTICIPANTS:

A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events.

EXPOSURES:

Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT.

MAIN OUTCOMES AND MEASURES:

The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control.

RESULTS:

Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01-negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10-5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status.

CONCLUSIONS AND RELEVANCE:

Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01-positive leprosy may significantly reduce the incidence of DHS in the Chinese population.

PMID: 30916737 DOI: 10.1001/jamadermatol.2018.5360

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Select item 30916723

17.

JAMA Dermatol. 2019 Mar 27. doi: 10.1001/jamadermatol.2019.0008. [Epub ahead of print]

Application of Topical Phosphodiesterase 4 Inhibitors in Mild to Moderate Atopic Dermatitis: A Systematic Review and Meta-analysis.

Yang H1, Wang J2, Zhang X2, Zhang Y3, Qin ZL4, Wang H1, Luo XY1.

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Abstract

IMPORTANCE:

Topical medication is the central treatment for patients with atopic dermatitis (AD), but the options are limited. Phosphodiesterase 4 (PDE4) inhibitors are a new candidate for AD therapy.

OBJECTIVE:

To evaluate the efficacy and safety of topical PDE4 inhibitors in mild to moderate AD.

DATA SOURCES:

Clinical trials were identified from MEDLINE, Embase, Cochrane Controlled Register of Trials, Chinese medical databases (Wanfang, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Science and Technology Journal Database), ClinicalTrials.gov, and other trial registries from inception to August 15, 2018. No restrictions on languages were placed.

STUDY SELECTION:

Only double-blind randomized clinical trials with topical PDE4 inhibitors vs topical vehicle treatment for patients with mild to moderate AD were included.

DATA EXTRACTION AND SYNTHESIS:

Two reviewers independently extracted study features, intervention details, and outcomes. A meta-analysis was performed using the random-effects model. The Cochrane Collaboration's risk of bias assessment tool was used to assess the risk of bias. Funnel plots and Egger tests were used to assess the publication bias.

MAIN OUTCOMES AND MEASURES:

Changes from baseline in target lesion score were expressed in terms of standardized mean differences (SMDs) with 95% CIs. Outcomes of investigators' assessment and safety were expressed in terms of relative risk with 95% CIs.

RESULTS:

Seven studies were identified, which included 1869 patients with mild to moderate AD. Overall, compared with the topical vehicle control, topical application of PDE4 inhibitors was associated with a significant decrease in target lesion score (SMD -0.40; 95% CI, -0.61 to -0.18; P < .001) and a higher response rate in investigators' assessment of clear or almost clear skin (relative risk, 1.50; 95% CI, 1.33-1.70; P < .001). There was no difference in treatment-related adverse events or in adverse events that required discontinuation of therapy. Subgroup analyses indicated that after 14 and 28 days of therapy with PDE4 inhibitors, target lesion score was significantly decreased. However, these beneficial effects were displayed only for the PDE4 inhibitors crisaborole and AN2898 (crisaborole at day 14: SMD, -0.59; 95% CI, -1.15 to -0.02; P = .04; AN2898 at day 14: SMD, -0.76; 95% CI, -1.38 to -0.13; P = .02; crisaborole at day 28: SMD, -0.86; 95% CI, -1.44 to -0.28; P = .004; AN2898 at day 28: SMD, -0.68; 95% CI, -1.30 to -0.05; P = .03). Heterogeneity was not significant across studies.

CONCLUSIONS AND RELEVANCE:

This meta-analysis suggests that topical PDE4 inhibitors are a safe and effective treatment for mild to moderate AD. Current evidence supports the use of crisaborole or AN2898 as the choice of maintenance or sequential therapy for mild to moderate AD.

PMID: 30916723 DOI: 10.1001/jamadermatol.2019.0008

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18.

Analyst. 2019 Mar 27. doi: 10.1039/c9an00200f. [Epub ahead of print]

Base excision repair mediated cascading triple-signal amplification for the sensitive detection of human alkyladenine DNA glycosylase.

Zhang H1, Wang L1, Xie Y2, Zuo X3, Chen H1, Chen X1.

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Abstract

DNA glycosylase (DG) plays a significant role in repairing DNA lesions, and the dysregulation of DG activity is associated with a variety of human pathologies. Thus, the detection of DG activity is essential for biomedical research and clinical diagnosis. Herein, we develop a facile fluorometric method based on the base excision repair (BER) mediated cascading triple-signal amplification for the sensitive detection of DG. The presence of human alkyladenine DNA glycosylase (hAAG) can initiate the cleavage of the substrate at the mismatched deoxyinosine site by endonuclease IV (Endo IV), resulting in the breaking of the DNA substrate. The cleaved DNA substrate functions as both a primer and a template to initiate strand displacement amplification (SDA) to release primers. The released primers can further bind to a circular template to induce an exponential primer generation rolling circle amplification (PG-RCA) reaction, producing a large number of primers. The primers that resulted from the SDA and PG-RCA reaction can induce the subsequent recycling cleavage of signal probes, leading to the generation of a fluorescence signal. Taking advantage of the high amplification efficiency of triple-signal amplification and the low background signal resulting from single uracil repair-mediated inhibition of nonspecific amplification, this method exhibits a low detection limit of 0.026 U mL-1 and a large dynamic range of 4 orders of magnitude for hAAG. Moreover, this method has distinct advantages of simplicity and low cost, and it can further quantify the hAAG activity from HeLa cell extracts, holding great potential in clinical diagnosis and biomedical research.

PMID: 30916676 DOI: 10.1039/c9an00200f

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Select item 30916665

19.

JMIR Res Protoc. 2019 Mar 27;8(3):e12808. doi: 10.2196/12808.

Identification of Motor Symptoms Related to Parkinson Disease Using Motion-Tracking Sensors at Home (KÄVELI): Protocol for an Observational Case-Control Study.

Jauhiainen M1, Puustinen J2,3,4, Mehrang S1, Ruokolainen J5, Holm A6,7,8, Vehkaoja A1, Nieminen H1.

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Abstract

BACKGROUND:

Clinical characterization of motion in patients with Parkinson disease (PD) is challenging: symptom progression, suitability of medication, and level of independence in the home environment can vary across time and patients. Appointments at the neurological outpatient clinic provide a limited understanding of the overall situation. In order to follow up these variations, longer-term measurements performed outside of the clinic setting could help optimize and personalize therapies. Several wearable sensors have been used to estimate the severity of symptoms in PD; however, longitudinal recordings, even for a short duration of a few days, are rare. Home recordings have the potential benefit of providing a more thorough and objective follow-up of the disease while providing more information about the possible need to change medications or consider invasive treatments.

OBJECTIVE:

The primary objective of this study is to collect a dataset for developing methods to detect PD-related symptoms that are visible in walking patterns at home. The movement data are collected continuously and remotely at home during the normal lives of patients with PD as well as controls. The secondary objective is to use the dataset to study whether the registered medication intakes can be identified from the collected movement data by looking for and analyzing short-term changes in walking patterns.

METHODS:

This paper described the protocol for an observational case-control study that measures activity using three different devices: (1) a smartphone with a built-in accelerometer, gyroscope, and phone orientation sensor, (2) a Movesense smart sensor to measure movement data from the wrist, and (3) a Forciot smart insole to measure the forces applied on the feet. The measurements are first collected during the appointment at the clinic conducted by a trained clinical physiotherapist. Subsequently, the subjects wear the smartphone at home for 3 consecutive days. Wrist and insole sensors are not used in the home recordings.

RESULTS:

Data collection began in March 2018. Subject recruitment and data collection will continue in spring 2019. The intended sample size was 150 subjects. In 2018, we collected a sample of 103 subjects, 66 of whom were diagnosed with PD.

CONCLUSIONS:

This study aims to produce an extensive movement-sensor dataset recorded from patients with PD in various phases of the disease as well as from a group of control subjects for effective and impactful comparison studies. The study also aims to develop data analysis methods to monitor PD symptoms and the effects of medication intake during normal life and outside of the clinic setting. Further applications of these methods may include using them as tools for health care professionals to monitor PD remotely and applying them to other movement disorders.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT03366558; https://clinicaltrials.gov/ct2/show/NCT03366558.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):

DERR1-10.2196/12808.

©Milla Jauhiainen, Juha Puustinen, Saeed Mehrang, Jari Ruokolainen, Anu Holm, Antti Vehkaoja, Hannu Nieminen. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 27.03.2019.

KEYWORDS:

Parkinson disease; gait; home monitoring; mobile phone; movement analysis; smartphone; wearable sensors

PMID: 30916665 DOI: 10.2196/12808

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20.

J Med Internet Res. 2019 Mar 27;21(3):e9240. doi: 10.2196/jmir.9240.

Design and Evaluation of Personalized Motivational Messages by a Virtual Agent that Assists in Post-Traumatic Stress Disorder Therapy.

Tielman ML1, Neerincx MA1,2, Brinkman WP1.

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Abstract

BACKGROUND:

Systems incorporating virtual agents can play a major role in electronic-mental (e-mental) health care, as barriers to care still prevent some patients from receiving the help they need. To properly assist the users of these systems, a virtual agent needs to promote motivation. This can be done by offering motivational messages.

OBJECTIVE:

The objective of this study was two-fold. The first was to build a motivational message system for a virtual agent assisting in post-traumatic stress disorder (PTSD) therapy based on domain knowledge from experts. The second was to test the hypotheses that (1) computer-generated motivating messages influence users' motivation to continue with therapy, trust in a good therapy outcome, and the feeling of being heard by the agent and (2) personalized messages outperform generic messages on these factors.

METHODS:

A system capable of generating motivational messages was built by analyzing expert (N=13) knowledge on what types of motivational statements to use in what situation. To test the 2 hypotheses, a Web-based study was performed (N=207). Participants were asked to imagine they were in a certain situation, specified by the progression of their symptoms and initial trust in a good therapy outcome. After this, they received a message from a virtual agent containing either personalized motivation as generated by the system, general motivation, or no motivational content. They were asked how this message changed their motivation to continue and trust in a good outcome as well as how much they felt they were being heard by the agent.

RESULTS:

Overall, findings confirmed the first hypothesis, as well as the second hypothesis for the measure feeling of being heard by the agent. Personalization of the messages was also shown to be important in those situations where the symptoms were getting worse. In these situations, personalized messages outperformed general messages both in terms of motivation to continue and trust in a good therapy outcome.

CONCLUSIONS:

Expert input can successfully be used to develop a personalized motivational message system. Messages generated by such a system seem to improve people's motivation and trust in PTSD therapy as well as the user's feeling of being heard by a virtual agent. Given the importance of motivation, trust, and therapeutic alliance for successful therapy, we anticipate that the proposed system can improve adherence in e-mental therapy for PTSD and that it can provide a blueprint for the development of an adaptive system for persuasive messages based on expert input.

©Myrthe L Tielman, Mark A Neerincx, Willem-Paul Brinkman. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 27.03.2019.

KEYWORDS:

PTSD; computer assisted therapy; mental health; motivation; trust; user-computer interface

PMID: 30916660 DOI: 10.2196/jmir.9240

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