bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and Molecular Phenotyping in Scleromyxedema Pretreatment and Posttreatment With Intravenous Immunoglobulin
Authors: Mecoli Christopher A. , Talbot C. Conover , Fava Andrea , Cheadle Christopher , Boin Francesco , Wigley Fredrick M. , Hummers Laura K.
Published: April 2019

Objective

Scleromyxedema (SMX) is a rare systemic sclerosis mimic that often responds to intravenous immunoglobulin (IVIG) therapy, yet the resulting clinical and biochemical changes have not been well characterized. To better understand the pathogenesis of the disease and the efficacy of IVIG, we sought to explore whether IVIG would introduce a measurable biologic effect corresponding with clinical improvement.

Methods

Fifteen patients with SMX were recruited for the study. Clinical information and peripheral blood mononuclear cells for flow cytometry were obtained immediately before and again 1–2 weeks after patients received IVIG therapy. Ten patients also underwent skin biopsies for gene expression analysis both before and after IVIG therapy. Clinical data included measures of skin involvement (modification of the modified Rodnan skin thickness score [MMRSS] and percentage of body surface area) and several patient‐reported outcome measures assessing patients’ skin.

Results

Posttreatment, the average MMRSS score decreased from mean ± SD 13.6 ± 2.6 to 10.3 ± 1.9; P = 0.003. There were also significant improvements in skin flexibility (mean ± SD 5.4 ± 0.8 to 3.2 ± 0.7; P = 0.003) and softening (mean ± SD 4.9 ± 0.9 to 2.6 ± 0.6; P = 0.022). Baseline levels of Tc17 cells (CD8+CCR6+CXCR3+CCR4–) correlated with the extent of skin involvement as measured by MMRSS pretreatment (r = 0.69, P = 0.012) and decreased after IVIG therapy (mean ± SD 3.4% ± 3.2% to 1.3% ± 1.7%; P = 0.008). Posttreatment analysis of RNA in skin tissue revealed a decrease in gene expression of transforming growth factor β (TGFβ) cytokines as well as several interferon‐inducible proteins.

Conclusion

This open‐label study further supports the evidence that patients with SMX respond both objectively and subjectively to IVIG therapy. Biologic studies suggest a role for T lymphocytes in the pathogenesis of the disease and reveal the potential significance of TGFβ and interferon pathways.
“…Not Having the Real Support That We Need”: Patients’ Experiences With Ambiguity of Systemic Lupus Erythematosus and Erosion of Social Support
Authors: Leung Jerik , Ra Jennifer , Baker Elizabeth A. , Kim Alfred H. J.
Published: April 2019

Objective

The patient‐specific experience of living with systemic lupus erythematosus (SLE) is underreported, particularly when studying factors associated with health‐related quality of life (HRQOL). Recent work has suggested that biomedical interventions are only partially predictive of HRQOL measures. A qualitative analysis of patient‐specific experiences can uncover additional root causes of impaired HRQOL in populations with SLE beyond the scope of quantitative questionnaires.

Methods

Consented adult patients with SLE classified by the American College of Rheumatology or Systemic Lupus International Collaborating Clinics were recruited. Ten semistructured interviews were conducted across six participants. Interviews were audio recorded, transcribed, and analyzed using an iterative process. Findings were presented to an interactive public forum with patients with SLE, family members and friends of patients, and health care professionals to assess accuracy.

Results

Four themes emerged from the interviews: 1) ambiguity, inconsistency, and lack of symptom predictability due to SLE disease courses; 2) poor communication with family, friends, and/or partners and poor bidirectional communication between health care providers and patients (informational support); 3) lack of validation for patients’ experiences (appraisal support); and 4) problematic aspects of social support, including negative support and patients’ inability to reciprocate support because of role changes. Data also indicate a reciprocal association between appraisal and informational sources of support.

Conclusion

Findings indicate that inadequate appraisal and informational support from informal and formal sources are salient factors influencing HRQOL among patients with SLE. Findings also point to the necessity of integrating community organizations, physicians, and friends and family of patients with SLE into capacity‐building interventions aimed at enhancing these sources of social support.
Characterization of a Subset of Patients With Rheumatoid Arthritis for Whom Current Management Strategies are Inadequate
Authors: Bradford Claire M. , McDonnell Thomas , Raj Divya , Robinson George A. , Cole Andrew , Ramakrishnan Shashank , González‐Serrano Rosa , Mak Jasper , Eskiocak Yusuf Cem , Isenberg David A. , Ciurtin Coziana , Jury Elizabeth C. , Manson Jessica J.
Published: April 2019

Objective

A subset of patients with seropositive rheumatoid arthritis (RA) do not mount a C‐reactive protein (CRP) response during flares. We hypothesize that these patients are more likely to experience poor clinical care and less likely to respond to traditional therapy. This study questioned whether this presentation was associated with worse disease outcome and distinct immunological features.

Methods

Using Power Doppler ultrasound, 48 RA patients with active synovitis were recruited; 30 had normal (n)CRP (5 mg/L or less) and 18 had high (h)CRP (more than 5 mg/L) levels. All had equivalent disease burden assessed by other clinical and laboratory parameters.

Results

Time to diagnosis and time to first disease‐modifying antirheumatic drug were significantly longer in nCRP compared with hCRP patients (P < 0.05). Significantly more nCRP patients needed escalation to biologics after 2‐year follow‐up (P = 0.01). The inflammatory milieu was also different between the two subgroups. Synergy between inflammatory cytokines observed in hCRP patients was lost in nCRP patients, and nCRP patients had significantly increased regulatory T‐cell (Treg) frequencies that correlated positively with predictors of poor disease outcome. Conversely, hCRP but not nCRP patients demonstrated a significant upregulation of alternative complement pathway factors that correlated negatively with Treg frequency.

Conclusion

Patients with nCRP during flares of RA had an altered immunological profile compared with hCRP patients and experienced diagnostic delays and responded less favorably to conventional treatment.
Robustness of linear time‐varying systems with relaxed excitation
Authors: Efimov Denis , Barabanov Nikita , Ortega Romeo
Published: April 2019

It is a well‐known fact that linear time‐varying systems with a persistently excited state matrix are exponentially converging and input‐to‐state stable with respect to additive perturbations. Recently, several relaxed conditions of persistent excitation have been presented, which ensure an asymptotic convergence rate in the system. In the present work, it is shown that these conditions are similar and that, under such a relaxed excitation, only nonuniform in time input‐to‐state stability and integral input‐to‐state stability properties can be obtained. The results are illustrated by simulations for a problem of estimation in the linear regression model.
Onslaught against 42 CFR Part 2 continues in Congress
Authors: Knopf Alison
Published: April 2019

With the opposition of the American Medical Association (AMA) last fall, any moves in Congress and the federal government to weaken the patient consent provisions of 42 CFR Part 2, the regulation protecting the confidentiality of substance use disorder (SUD) treatment records, were stopped in their tracks — and in the nick of time (see ADAW, Oct. 1, 2018; Oct. 15, 2018). But the groups promoting the complete abandonment of 42 CFR Part 2, replacing it with the Health Insurance Portability and Accountability Act, which itself is targeted for at least partial destruction (see ADAW, Jan. 21, Jan. 28, Feb. 25), are back. There's a new push to try to overhaul 42 CFR Part 2.
Detection of extranodal and spleen involvement by FDG‐PET imaging predicts adverse survival in untreated follicular lymphoma
Authors: St‐Pierre Frédérique , Broski Stephen M. , LaPlant Betsy R. , Ristow Kay , Maurer Matthew J. , Macon William R. , Habermann Thomas M. , Ansell Stephen M. , Thompson Carrie A. , Micallef Ivana N. M. , Nowakowski Grzegorz S. , Witzig Thomas E.
Published: April 2019

Predicting early clinical failure in patients with untreated follicular lymphoma (FL) is important but difficult. This study aimed to determine the incidence and patterns of extranodal (EN) and spleen disease using PET/CT, and assess their utility in predicting early clinical failure. PET/CT images from 613 cases of untreated FL (2003‐2016) were reviewed. The location and number of EN sites, patterns of bone involvement, and splenic involvement were recorded. Outcomes were assessed using event‐free survival (EFS), overall survival (OS), and early clinical failure at 24 months (EFS24). So, 49% (301/613) of patients had PET/CT‐detected EN involvement, and 28% (171/613) had spleen involvement. The presence of ≥2 EN sites, spleen, bone or soft tissue involvement all predicted failure to achieve EFS24. Presence of ≥2 EN sites and bone involvement pattern were also predictive of OS in a univariate analysis. In a multivariate analysis with FLIPI‐2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (HR 1.49 (1.11‐2.00),P= .007; HR 1.71 (1.10‐2.65),P= .017; and HR 1.67 (1.06‐2.62),P= .026, respectively). When the multivariate analysis was performed using PRIMA‐PI factors (marrow and B2M), the number of EN sites was an independent prognostic factor for inferior OS (HR 2.28;P= .05). Baseline PET/CT identifies EN involvement in nearly half of patients with untreated FL. The presence of ≥2 EN sites, bone, soft tissue, or splenic involvement predicts early clinical failure. These results, when combined with other factors, may better identify high‐risk patients and guide therapy.
Tuning the In Vivo Transport of Anticancer Drugs Using Renal‐Clearable Gold Nanoparticles
Authors: Peng Chuanqi , Xu Jing , Yu Mengxiao , Ning Xuhui , Huang Yingyu , Du Bujie , Hernandez Elizabeth , Kapur Payal , Hsieh Jer‐Tsong , Zheng Jie
Published: April 2019

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics. This requires a fundamental understanding of how engineered nanoparticles impact the targeting‐clearance and permeation‐retention paradoxes in the anticancer‐drug delivery. Herein, we systematically investigated how renal‐clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues. Renal‐clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability. The renal‐clearable AuNPs also accelerated body clearance of off‐target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long‐standing paradoxes in the anticancer drug delivery.
Stable, Wavelength‐Tunable Fluorescent Dyes in the NIR‐II Region for In Vivo High‐Contrast Bioimaging and Multiplexed Biosensing
Authors: Lei Zuhai , Sun Caixia , Pei Peng , Wang Shangfeng , Li Dandan , Zhang Xin , Zhang Fan
Published: April 2019

Small‐molecule organic fluorophores, spectrally active in the 900–1700 nm region, with tunable wavelength and sensing properties are sought‐after for in vivo optical imaging and biosensing. A panel of fluorescent dyes (CX) has been developed to meet this challenge. CX dyes exhibit the wavelength tunability of cyanine dyes and have a rigidified polymethine chain to guarantee their stability. They are chemo‐ and photo‐stable in an aqueous environment and have tunable optical properties with maximal absorbing/emitting wavelength at 1089/1140 nm. They show great potential in high‐contrast in vivo bioimaging and multicolor detection with negligible optical cross talk. Förster resonance energy transfer (FRET) between CX dyes was demonstrated in deep tissue, providing an approach for monitoring drug‐induced hepatotoxicity by detection of OONO−. This report presents a series of NIR‐II dyes with promising spectroscopic properties for high‐contrast bioimaging and multiplexed biosensing.
Molecular simulation of hydrodesulfurization of coal tar using Pd/ZSM‐5/γ‐Al2O3 catalyst
Authors: Chu Ruizhi , Wang Jian , Meng Xianliang , Yu Shi , Zhang Guifeng , Wang Minglei , Li Xiao , Wu Guoguang , Bai Lei
Published: April 2019

In this study, all‐atom model of Pd/ZSM‐5/γ‐Al2O3 was developed and validated by comparing the experimental results of nitrogen adsorption isotherm, pore structure parameters, and powder X‐ray diffraction to our simulation results. Coal tar was simulated using dibenzothiophene (DBT), and tetralin (THN) in our study, and the product of coal tar hydrodesulfurization was modeled by H2S and n‐hexane (Hex). The adsorption and diffusion of the DBT, THN, and Hex on Pd/ZSM‐5/γ‐Al2O3 were investigated, and the simulation results were verified by differential thermogravimetric and X‐ray photoelectron spectroscopy results. The results demonstrated that DBT and THN mainly adsorbed to mesopores, and part of THN could also adsorb to micropores. Note that the mesopores allow the reactions of DBT, THN, and Hex to take place as they have large enough size, and micropores limit those reactions as those model molecules hardly adsorbed to micropores. In addition the acidity of the carrier weakens the heat of adsorption of H2S, making it easier to diffuse out of the catalyst and protect the active site. And our simulation results also show that the diffusion coefficient of H2S was much higher than other chemicals. As a consequence, the multichannel design and the choice of acidic carrier improved the sulfur tolerance of the catalyst.
Long‐Term Outcome of Ustekinumab Therapy for Behçet's Disease
Authors: Mirouse Adrien , Barete Stéphane , Desbois Anne‐Claire , Comarmond Cloé , Sène Damien , Domont Fanny , Bodaghi Bahram , Ferfar Yasmina , Cacoub Patrice , Saadoun David ,   for the French Behçet's Network
Published: April 2019

Objective

Oral ulcers, the hallmark lesion of Behçet's disease (BD), can be disabling and resistant to conventional treatment, and there is a need for safe and effective treatment. We undertook this study to investigate the long‐term safety and efficacy of ustekinumab therapy for BD‐related oral ulcers that are resistant to colchicine.

Methods

This multicenter, prospective, open‐label study included 30 patients who fulfilled the criteria of the International Study Group for BD and who were diagnosed as having active oral ulcers resistant to colchicine. Patients were treated subcutaneously with ustekinumab 90 mg at inclusion, at week 4, and then once every 12 weeks. Each patient was assessed longitudinally for the presence and number of oral ulcers, and median numbers of oral ulcers (with interquartile range [IQR]) were calculated. The primary efficacy end point was the proportion of patients at week 12 who experienced complete response, defined as having no oral ulcers.

Results

The median number of oral ulcers per patient during ustekinumab therapy was significantly lower at week 12 compared to baseline (0 [IQR 0–1] versus 2 [IQR 2–3]; P < 0.0001). Complete response was achieved in 60.0% and 88.9% of patients at weeks 12 and 24, respectively. The median Behçet's Syndrome Activity Score (in which higher scores indicate more active disease) was significantly lower at weeks 12 and 24 (17.5 [IQR 10–42.5] and 10 [IQR 8–11], respectively) versus baseline (70 [IQR 50–70]; P < 0.0001). After a median follow‐up of 12 months (IQR 6–16 months), 26 patients (86.7%) were still receiving ustekinumab treatment. Reasons for ustekinumab discontinuation included BD flare (n = 3) and side effects (n = 1). Seven patients (23.3%) experienced adverse events, including headaches (n = 4) and asthenia (n = 2), with no serious side effects.

Conclusion

Ustekinumab seems to be effective in treating BD‐related oral ulcers that are resistant to treatment with colchicine.
Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis
Authors: Gibson Kristen M. , Morishita Kimberly A. , Dancey Paul , Moorehead Paul , Drögemöller Britt , Han Xiaohua , Graham Jinko , Hancock Robert E. W. , Foell Dirk , Benseler Susanne , Luqmani Rashid , Yeung Rae S. M. , Shenoi Susan , Bohm Marek , Rosenberg Alan M. , Ross Colin J. , Cabral David A. , Brown Kelly L. ,   on behalf of the PedVas Investigators Network
Published: April 2019

Objective

Individuals with deficiency of adenosine deaminase 2 (DADA2), a recently recognized autosomal recessive disease, present with various systemic vascular and inflammatory manifestations, often with young age at disease onset or with early onset of recurrent strokes. Their clinical features and histologic findings overlap with those of childhood‐onset polyarteritis nodosa (PAN), a primary “idiopathic” systemic vasculitis. Despite similar clinical presentation, individuals with DADA2 may respond better to biologic therapy than to traditional immunosuppression. The aim of this study was to screen an international registry of children with systemic primary vasculitis for variants in ADA2.

Methods

The coding exons of ADA2 were sequenced in 60 children and adolescents with a diagnosis of PAN, cutaneous PAN, or unclassifiable vasculitis (UCV), any chronic vasculitis with onset at age 5 years or younger, or history of stroke. The functional consequences of the identified variants were assessed by ADA2 enzyme assay and immunoblotting.

Results

Nine children with DADA2 (5 with PAN, 3 with UCV, and 1 with antineutrophil cytoplasmic antibody–associated vasculitis) were identified. Among them, 1 patient had no rare variants in the coding region of ADA2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). The clinical phenotype varied widely.

Conclusion

These findings support previous observations indicating that DADA2 has extensive genotypic and phenotypic variability. Thus, screening ADA2 among children with vasculitic rash, UCV, PAN, or unexplained, early‐onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA2.
Plasmid Copy Number of pTRKH3 in Lactococcus lactis is Increased by Modification of the repDE Ribosome‐Binding Site
Authors: Duarte Sofia O. D. , Martins Maria C. , Andrade Sílvia M. , Prazeres Duarte M. F. , Monteiro Gabriel A.
Published: April 2019

Plasmids for DNA vaccination are exclusively produced in the Gram‐negative Escherichia coli. One important drawback of this system is the presence of lipopolysaccharides. The generally recognized as safe Lactococcus lactis (L. lactis) would constitute a safer alternative for plasmid production. A key requirement for the establishment of a cost‐effective L. lactis‐based plasmid manufacturing is the availability of high‐copy number plasmids. Unfortunately, the highest copy number reported in Gram‐positive bacteria for the pAMβ1 replicon is around 100 copies. The purpose of this work is to engineer the repDE ribosome‐binding site (RBS) of the pTRKH3 plasmid by site‐directed mutagenesis in order to increase the plasmid copy number in L. lactis LMG19460 cells. The pTRKH3‐b mutant is the most promising candidate, achieving 215 copies of plasmid per chromosome, a 3.5‐fold increase when compared to the nonmodified pTRKH3, probably due to a stronger RBS sequence, a messenger RNA secondary structure that promotes the RepDE expression, an ideal intermediate amount of transcriptional repressors and the presence of a duplicated region that added an additional RBS sequence and one new in‐frame start codon. pTRKH3‐b is a promising high‐copy number shuttle plasmid that will contribute to turn lactic acid bacteria into a safer and economically viable alternative as DNA vaccines producers.
Effect of flurbiprofen axetil on postoperative delirium for elderly patients
Authors: Wang Xifan , Wang Yu , Hu Yanan , Wang Liping , Zhao Wenshuai , Wei Lanying , Chen Hong , Han Fei
Published: April 2019

Objectives

Proinflammatory cytokines triggered by surgery and postoperative pain are major causes of postoperative delirium (POD). This study investigated the effects of flurbiprofen axetil on POD when used for postoperative analgesia after major noncardiac surgery in elderly patients.

Methods

Patients over 65 years old were randomly divided into two groups: the sufentanil group (S group), in which 150 μg of sufentanil was used in the patient‐controlled analgesia (PCA) pump for 3 days; the sufentanil combined with flurbiprofen axetil group (SF group), in which 150 μg of sufentanil was combined with 300 mg of flurbiprofen axetil in the PCA pump for 3 days. The Confusion Assessment Method scale was used for POD evaluation. The pain intensity, side effects, and risk factors (age, gender, surgical position, and category of surgery) for POD were evaluated.

Results

Ultimately, 140 patients were included. The overall incidence of POD was not significantly different between the S and SF groups. The incidence of POD was significantly lower in the SF group than in the S group among patients over 70 years (5.1% vs. 20.7%, p = 0.045, odds ratio = 0.146, 95% confidence interval = 0.020–1.041). The incidence of POD was no difference in patients classified by the category of surgery, surgical position, or gender between groups. Sufentanil and flurbiprofen axetil in the PCA pump was completely used within 72 hr. The pain intensity, consumed sufentanil dosage of the PCA, and the side effects was not different between groups.

Conclusions

Flurbiprofen axetil might reduce POD in patients over 70 years undergoing major noncardiac surgery.
Modification of the first constant domain of heavy chain enabled effective folding of functional anti‐forskolin antigen‐binding fragment for sensitive quantitative analysis
Authors: Yusakul Gorawit , Sakamoto Seiichi , Tanaka Hiroyuki , Morimoto Satoshi
Published: April 2019

The assembly between heavy and light chains is a critical step of immunoglobulin (Ig) and fragment antigen‐binding (Fab) antibody expression and of their binding activity. The genes encoding Fab were obtained from hybridoma cells secreting monoclonal antibody (MAb, IgG2b) against adenylate cyclase activator forskolin (FOR). The subclass of the first constant domain of heavy chain (CH1) of IgG2b was modified to IgG1 via overlap extension polymerase chain reaction and expressed via Escherichia coli bacterial system. Since both Fabs (IgG2b and IgG1) were expressed as inclusion bodies, functional analysis was performed after in vitro refolding via stepwise dialysis. The result indicated that the folding efficiency between VH‐CH1 and VL‐CL was improved by the CH1 modification from IgG2b to IgG1 subclass, although their specificity for FOR was not altered. Effective folding of IgG1 was also observed when they were expressed in the hemolymph of silkworm larvae using the Bombyx mori nuclear polyhedrosis virus bacmid system. An indirect competitive enzyme‐linked immunosorbent assay (icELISA) was then developed for the determination of FOR using effectively prepared Fab IgG1. The sensitivity of FOR determination was in the range of 3.91–62.5 ng/mL with less than 9% relative standard deviation, implying the sensitive and reliable analysis of developed icELISA. In addition, high accuracy of the icELISA was supported by the results of spiked‐and‐recovery tests, ranging from 100.2 to 102.3%. Therefore, Fab could be utilized reliably for icELISA instead of the more expensive MAb. Collectively, this approach improved productivity of Fab and reduced the cost of antibody production.
Teaching and learning evidence‐based practices: Promoting dialogue for counsellors and psychotherapists
Authors: Allan Robert
Published: April 2019

Background

This paper expands on research themes that explored counsellors’ experience with learning an evidence‐based practice (EBP), to discuss clinical and training implications for educators, counsellors and psychotherapists teaching or learning an evidence‐based approach. Counsellors also have an ethical responsibility to ensure our work is as beneficial as possible and there are opportunities to promote a research culture within an evidence‐based approach and stronger researcher‐practitioner alliances. For programme managers, funders and government departments, there is an increased pressure to allocate resources on an explicit, rational basis and in consideration of consumer rights.

Objective/Method

Drawing from the existing research literature about EBPs, the author's teaching and training experience and research with counsellors learning an EBP, a method for promoting discussion about EBPs is proposed with students and trainees.

Conclusion

The tensions created by counselling and psychotherapy practices versus the practicalities of conducting research on a counselling approach for the purpose of peer‐reviewed publications, offer unique opportunities for educators and practitioners to consider how they best want to engage with EBPs. In this paper, educators and practitioners are offered a series of considerations to help guide their engagement with evidence‐based approaches.
Vancomycin‐induced linear IgA bullous dermatosis (LABD)—an atypical presentation
Authors: Visentainer Lorena , Massuda Juliana Yumi , Cintra Maria Letícia , Magalhães Renata Ferreira
Published: April 2019

Key clinical message

We report an uncommon presentation of bullous dermatosis by linear IgA. There are few cases reported in the literature with this form of presentation starting with mucosal lesions and then evolving into a similar bullous pemphigoid pattern. In addition, we emphasize the importance of direct immunofluorescence for the definitive diagnosis.
Emery‐Dreifuss muscular dystrophy type 4: A new SYNE1 mutation associated with hypertrophic cardiomyopathy masked by a perinatal distress‐related spastic diplegia
Authors: Sandra Mastroianno , Maria Pia Leone , Stefano Castellana , Pietro Palumbo , Crociani Paola , Aldo Russo , Giuseppe Di Stolfo , Massimo Carella
Published: April 2019

Hypertrophic cardiomyopathy could be part of a more complex syndrome like Emery‐Dreifuss muscular dystrophy type 4. Genetic analysis allowed to identify a de novo heterozygous missense mutation in SYNE1 gene (chr6:152665253:G > C), supporting physician to reach a correct diagnosis in patient affected by cardiomyopathy associated with a difficult clinical scenario.
Euglycemic diabetic ketoacidosis in association with dapagliflozin use after gastric sleeve surgery in a patient with type II diabetes mellitus
Authors: Banakh Iouri , Kung Ross , Gupta Sachin , Matthiesson Kati , Tiruvoipati Ravindranath
Published: April 2019

Key Clinical Message

Sodium–glucose cotransporter 2 inhibitors (SGLT2Is) can be associated with euglycemic diabetic ketoacidosis (eDKA). Severe metabolic acidosis with extreme electrolyte abnormalities can occur with nonsignificant blood glucose elevations in SGLT2I‐treated patients. Additional risk factors for eDKA include prolonged fasting, major illness, large weight loss, and reductions in insulin doses.
Detection of Histone H2AX Phosphorylation on Ser‐139 as an Indicator of DNA Damage
Authors: Zhao Hong , Huang Xuan , Halicka H. Dorota , Darzynkiewicz Zbigniew
Published: April 2019

This unit describes immunocytochemical detection of histone H2AX phosphorylated on Ser‐139 (γH2AX) to reveal DNA damage, particularly when the damage involves the presence of DNA double‐strand breaks (DSBs). These breaks often result from DNA damage induced by ionizing radiation or by treatment with anticancer drugs such as DNA topoisomerase inhibitors. Furthermore, DSBs are generated in the course of DNA fragmentation during apoptosis. The unit presents strategies to distinguish radiation‐ or drug‐induced DNA breaks from those intrinsically formed in untreated cells or associated with apoptosis. The protocol describes immunocytochemical detection of γH2AX combined with measurement of DNA content to identify cells that have DNA damage and concurrently to assess their cell‐cycle phase. The detection is based on indirect immunofluorescence using FITC– or Alexa Fluor 488–labeled antibody, with DNA counterstained with propidium iodide and cellular RNA removed with RNase A. © 2019 by John Wiley & Sons, Inc.
Analyst coverage and forecast accuracy when CSR reports improve stakeholder engagement: The Global Reporting Initiative‐International Finance Corporation disclosure strategy
Authors: García‐Sánchez Isabel María , Gómez‐Miranda María‐Elena , David Fátima , Rodríguez‐Ariza Lazaro
Published: April 2019

Aware of the information needs of stakeholders, and of the important deficiencies often present in corporate social responsibility (CSR) reports on economic, social, and environmental issues, companies leading in sustainability have initiated a new communication strategy in which their CSR reports take into account both the Global Reporting Initiative (GRI) guidelines and the International Finance Corporation (IFC) Performance Standards, in an approach termed the GRI‐IFC disclosure strategy. We examine whether this innovative practice provides a better reflection of a firm's social and environmental dimensions and therefore improves the forecasts made by financial analysts, who are significant stakeholders in this respect. Our analysis of an unbalanced sample of 750 international companies, located in 19 countries and operating in 22 business sectors during the years 2011–2016, in which a logistic regression is applied to the panel data, reveals the existence of a two‐way relationship between the adoption of the GRI‐IFC disclosure strategy and the level of analyst coverage. Moreover, the use of this strategy, and the resulting increase in coverage, has a positive impact on the accuracy of analysts' forecasts.
Intelligent Image De‐Blurring for Imaging Flow Cytometry
Authors: Zhang Fangzheng , Lei Cheng , Huang Chun‐Jung , Kobayashi Hirofumi , Sun Chia‐Wei , Goda Keisuke
Published: April 2019

By virtue of the combined merits of optical microscopy and flow cytometry, imaging flow cytometry is a powerful tool for rapid, high‐content analysis of single cells in large heterogeneous populations. However, its efficiency (defined by the ratio of the number of clearly imaged cells to the total cell population) is not high (typically 50–80%), due to out‐of‐focus image blurring caused by imperfect fluidic focusing of cells, a common drawback that not only reduces the number of cell images useable for high‐content analysis but also increases the probability of false events and missed rare cells. To address this challenge and expand the efficacy of imaging flow cytometry, here, we propose and demonstrate intelligent deblurring of out‐of‐focus cell images in imaging flow cytometry. Specifically, by using our machine learning algorithms, we show an 11% increase in variance and a 95% increase in first‐order gradient summation of cell images taken with an optofluidic time‐stretch microscope. Without strict hardware requirements, our intelligent de‐blurring method provides a promising solution to the out‐of‐focus blurring problem of imaging flow cytometers and holds promise for significantly improving their performance. © 2019 International Society for Advancement of Cytometry
Fine‐needle aspiration cytology and cell block in diagnosis and subtyping of hepatoblastoma
Authors: Subramanian Kalaivani Selvi , Chikhale Mangesh , Barwad Adarsh , Gochhait Debasis , Toi Pampa Ch , Siddaraju Neelaiah
Published: April 2019

Hepatoblastoma (HB) constitutes less than 1% of all pediatric malignancies and is the most common malignant tumor of liver in children. The fine‐needle aspiration cytological (FNAC) diagnosis and sub‐typing of this tumor is challenging, which is of critical importance from its treatment point of view. All cases with a clinicoradiological impression of “HB” during the study period of 1 year were subjected to ultrasound‐guided (USG) FNAC and cell blocks were prepared in all cases. Detailed cytopathological examination was carried out based on the cytomorphological pattern and the cell blocks were used to correlate the findings and the final diagnoses were confirmed with the histopathological findings. Four cases were included during this study period. All were children, whose age ranged from 3 months to 10 years. All of them presented with mass per abdomen and increased serum alfa‐feto protein (AFP) levels. On a detailed cytological examination, the clinical impression of HB was confirmed in all four cases with a subsequent histological correlation. Based on their distinct cytomorphological pattern, three of them were accurately sub‐typed as“fetal type,” wile the fourth was an “embryonal type of HB.” All four cases had the evidence of extramedullary hematopoeisis. We conclude that a precise preoperative FNAC diagnosis with accurate sub‐typing of HB is possible purely on cytomorphologic basis which has prognostic and therapeutic implications. Cell blocks are of great use for ancillary studies. Extramedullary hematopoiesis serves as an important “clue” in diagnosis.
Variability in content and dissolution profiles of MDMA tablets collected in the UK between 2001 and 2018 – A potential risk to users?
Authors: Couchman Lewis , Frinculescu Anca , Sobreira Catarina , Shine Trevor , Ramsey John , Hecht Max , Kipper Karin , Holt David , Johnston Atholl
Published: April 2019

3,4‐Methylenedioxymethamphetamine (MDMA, Ecstasy) tablets are widely used recreationally, and not only vary in appearance, but also in MDMA content. Recently, the prevalence of high‐content tablets is of concern to public health authorities. To compare UK data with other countries, we evaluated MDMA content of 412 tablets collected from the UK, 2001–2018, and investigated within‐batch content variability for a sub‐set of these samples. In addition, we investigated dissolution profiles of tablets using pharmaceutical industry‐standard dissolution experiments on 247 tablets. All analyses were carried out using liquid chromatography−tandem mass spectrometry (LC–MS/MS). Our data supported other studies, in that recent samples (2016–2018) tend to have higher MDMA content compared to earlier years. In 2018, the median MDMA content exceeded 100 mg free‐base for the first time. Dramatic within‐batch content variability (up to 136 mg difference) was also demonstrated. Statistical evaluation of dissolution profiles at 15‐minutes allowed tablets to be categorized as fast‐, intermediate‐, or slow‐releasing, but no tablet characteristics correlated with dissolution classification. Hence, there would be no way of users knowing a priori whether a tablet is more likely to be fast or slow‐releasing. Further, within‐batch variation in dissolution rate was observed. Rapid assessment of MDMA content alone provides important data for harm reduction, but does not account for variability in (a) the remainder of tablets in a batch, or (b) MDMA dissolution profiles. Clinical manifestations of MDMA toxicity, especially for high‐content, slow‐releasing tablets, may be delayed or prolonged, and there is a significant risk of users re‐dosing if absorption is delayed.
Gas chromatography−mass spectrometry analysis of non‐hydrolyzed sulfated steroids by degradation product formation
Authors: Polet Michael , Van Gansbeke Wim , Albertsdóttir Aðalheiður Dóra , Coppieters Gilles , Deventer Koen , Van Eenoo Peter
Published: April 2019

Steroid detection and identification remain key issues in toxicology, drug testing, medical diagnostics, food safety control, and doping control. In this study, we evaluate the capabilities and usefulness of analyzing non‐hydrolyzed sulfated steroids with gas chromatography−mass spectrometry (GC–MS) instead of the conventionally applied liquid chromatography−mass spectrometry (LC–MS) approach. Sulfates of 31 steroids were synthesized and their MS and chromatographic behavior studied by chemical ionization−GC−triple quadrupole MS (CI−GC‐TQMS) and low energy−electron ionization−GC−quadrupole time‐of‐flight−MS (LE−EI−GC−QTOF−MS). The collected data shows that the sulfate group is cleaved off in the injection port of the GC–MS, forming two isomers. In CI, the dominant species (ie, [MH – H2SO4]+ or [MH – H4S2O8]+ for bis‐sulfates) is very abundant due to the limited amount of fragmentation, making it an ideal precursor ion for MS/MS. In LE−EI, [M – H2SO4].+ and/or [M – H2SO4 – CH3].+ are the dominant species in most cases. Based on the common GC–MS behavior of non‐hydrolyzed sulfated steroids, two applications were evaluated and compared with the conventionally applied LC–MS approach; (a) discovery of (new) sulfated steroid metabolites of mesterolone and (b) expanding anabolic androgenic steroid abuse detection windows. GC–MS and LC–MS analysis of non‐hydrolyzed sulfated steroids offered comparable sensitivities, superseding these of GC–MS after hydrolysis. For non‐hydrolyzed sulfated steroids, GC–MS offers a higher structural elucidating power and a more straightforward inclusion in screening methods than LC–MS.
Genetic variation and possible origins of weedy rice found in California
Authors: De Leon Teresa B. , Karn Elizabeth , Al‐Khatib Kassim , Espino Luis , Blank Timothy , Andaya Cynthia B. , Andaya Virgilio C. , Brim‐DeForest Whitney
Published: April 2019

Control of weeds in cultivated crops is a pivotal component in successful crop production allowing higher yield and higher quality. In rice‐growing regions worldwide, weedy rice (Oryza sativa f. spontanea Rosh.) is a weed related to cultivated rice which infests rice fields. With populations across the globe evolving a suite of phenotypic traits characteristic of weeds and of cultivated rice, varying hypotheses exist on the origin of weedy rice. Here, we investigated the genetic diversity and possible origin of weedy rice in California using 98 simple sequence repeat (SSR) markers and an Rc gene‐specific marker. By employing phylogenetic clustering analysis, we show that four to five genetically distinct biotypes of weedy rice exist in California. Analysis of population structure and genetic distance among individuals reveals diverse evolutionary origins of California weedy rice biotypes, with ancestry derived from indica, aus, and japonica cultivated rice as well as possible contributions from weedy rice from the southern United States and wild rice. Because this diverse parentage primarily consists of weedy, wild, and cultivated rice not found in California, most existing weedy rice biotypes likely originated outside California.
Measuring function and structure of urban headwater streams with citizen scientists
Authors: Kielstra Brian W. , Chau Joyce , Richardson John S.
Published: April 2019

Headwater streams accumulate, process, and export organic materials for use in downstream environments. Decomposition of organic material, an important ecosystem function, may be sensitive to land cover changes in urbanizing regions since headwater stream processes tend to be tightly coupled with riparian and catchment characteristics. Headwaters represent 70–80% of total stream length in watersheds but are disproportionately converted to drainage infrastructure or buried with urban development. Cumulatively, this loss may result in substantial changes to physical and biological downstream processes. From a monitoring perspective, headwaters are largely ignored compared with fishable/navigable waterways for planning decisions, so their structural and functional variability is not well understood. Here, we engaged citizen scientists to contribute data on this variability and to evaluate the sensitivity of standardized cotton‐strip decomposition rates to multiscale factors across headwaters with varying landscape conditions in the Greater Toronto Area (York Region), Canada. These factors included stream, riparian vegetation, and catchment characteristics. We expected decomposition rates to be similarly sensitive to local‐ and catchment‐scale factors because of the strong links between headwater catchment and stream processes. We also expected a hump‐shaped distribution of decomposition rates across a gradient of urban cover, with stimulating effects at low to moderate cover but deleterious effects at high urban cover. We found that decomposition rate was most sensitive to local‐scale factors (e.g., strip burial, stream velocity, and both local upland riparian vegetation density and topography) rather than whole catchment properties. We did not find the expected hump‐shaped distribution with urban cover and suggest that more mechanistic studies are needed for understanding cotton‐strip decomposition to control for local factors in determining the scale at which decomposition rate is most sensitive to land cover change.
When Fluorescence Is not a Particle: The Tissue Translocation of Microplastics in Daphnia magna Seems an Artifact
Authors: Schür Christoph , Rist Sinja , Baun Anders , Mayer Philipp , Hartmann Nanna B. , Wagner Martin
Published: April 2019

Previous research reported the translocation of nano- and microplastics from the gastrointestinal tract to tissues in Daphnia magna, most prominently of fluorescent polystyrene beads to lipid droplets. For particles >300 nm, such transfer is biologically implausible as the peritrophic membrane retains these in the daphnid gut. We used confocal laser scanning microscopy to study tissue transfer applying the setup from a previous study (neonates exposed to 20 and 1000 nm polystyrene beads at 2 µg L–1 for 4 and 24 h), the same setup with a fructose-based clearing, and a setup with a 1000-fold higher concentration (2 mg L–1). We used passive sampling to investigate whether the beads leach the fluorescent dye. Although the 1000 nm beads were visible in the gut at both exposure concentrations, the 20 nm beads were detectable at 2 mg L–1 only. At this concentration, we observed fluorescence in lipid droplets in daphnids exposed to both particle types. However, this did not colocalize with the 1000 nm beads, which remained visible in the gut. We further confirmed the leaching of the fluorescent dye using a passive sampler, a method that can also be applied in future studies. In summary, we cannot replicate the original study but demonstrate that the fluorescence in the lipid droplets of D. magna results from leaching of the dye. Thus, the use of fluorescence as a surrogate for particles can lead to artifacts in uptake and translocation studies. This highlights the need to confirm the stability of the fluorescence label or to localize particles using alternative methods. Environ Toxicol Chem 2019;38:1495–1503. © 2019 SETAC

Open Practices

The present study has earned Open Data/Materials badges for making publicly available the digitally shareable data necessary to reproduce the reported results. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki.
Optimal provisioning and scheduling of analytics as a service in cloud computing
Authors: Shenbaga Moorthy Rajalakshmi , Pabitha P.
Published: April 2019

We propose an analytic request‐centric multiobjective provisioning and scheduling method based on hybrid particle swarm optimization, called analytics‐as‐a‐service (AaaS) provisioning and resource scheduling (APARS) system, to optimally provision analytics service and schedule cloud resources by taking into account of user specified constraints. Analytics‐as‐a‐service provisioning and resource scheduling is employed to maximize accuracy of the analytic service and minimize the execution time and cost of the analytic request by combining multiobjectives with the constraint of minimal deadline and budget. Provisioning AaaS and scheduling cloud resources for analytic request is challenging as the analytic request requires scaling up and down of cloud resources dynamically. Thus, this domain invites a rigid system that can provide optimal analytics using cloud services for specified quality of service parameters. Our proposed system can handle diverse set of analytic requests with the goal of minimizing execution time, cost, critical performance, load balancing level and maximizing resource utilization, AaaS utilization, and success rate. The proposed APARS system is tested and evaluated under different use cases and compared with other metaheuristic algorithms, and we found that the results to be convincing our claims. The experimentation is carried out for various scenarios and the proposed APARS is evaluated with other metaheuristic algorithm. Simulation results validate the APARS system and show that the proposed method performs better than other existing methods with various use cases.
Energy and delay aware massive access management in machine‐to‐machine communications
Authors: Tagarian Zahra , Shahgholi Ghahfarokhi Behrouze
Published: April 2019

Machine‐to‐machine (M2M) communication is a challenging topic in the Internet‐of‐Things era. The increasing growth of machines and high rate of packet production have result in massive access to the network. Therefore, one of the media access control (MAC) challenges in 5G cellular networks is the management of massive access to the wireless media regarding quality‐of‐service (QoS) requirements and battery restrictions of the machines. Delay is one of the QoS requirements that should be guaranteed in most applications. To the best of our knowledge, previous studies on scheduled MAC mechanisms have not addressed energy efficiency and delay requirements appropriately. In this paper, the problem of scheduled massive access management has been considered with the aim of simultaneously meeting delay requirements of machines and increasing energy efficiency. The proposed solution exploits gateways to reuse the spectrum dedicated to M2M communications and introduces a clustering algorithm to allocate radio resources to the machines appropriately. Moreover, an optimization problem is defined and solved using genetic algorithms (GA) to adjust the optimal transmission power of machines, aiming at maximizing the energy efficiency. To preserve delay constraints, the proposed method exploits an existing scheduling algorithm. Simulation results demonstrate more than 50% reduction in probability of packet delay violation for various classes of service and in mean packet delay compared to the baseline method. The results have also shown more than 20% improvement in energy efficiency of proposed method compared to the baseline.