bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of resistance to change in children with autism
Authors: Fisher Wayne W. , Felber Jennifer M. , Phillips Lauren A. , Craig Andrew R. , Paden Amber R. , Niemeier Jessica J.
Published: June 2019

“Resistance to change” represents a core symptom of autism that we conceptualized and assessed as resulting in part due to factors known to govern free‐operant choice. During a free‐choice baseline, participants chose between problematic, resistive responses and an appropriate alternative response. During the asymmetrical‐choice condition, we delivered their most highly preferred item if the participant chose the alternative response (i.e., differential reinforcement of alternative behavior [DRA]). During the guided‐ (Experiment 1) and singular‐ (Experiment 2) choice conditions, we prompted participants to choose the alternative response and then delivered their most highly preferred item (i.e., DRA with escape extinction). All participants learned to tolerate (Experiment 1) or choose (Experiment 2) the alternative response when we combined DRA with escape extinction. After exposure to escape extinction, two participants showed strong maintenance effects with DRA alone. We discuss these finding relative to the effects of DRA and escape extinction on resistance to change.
Measurement of nontargeted problem behavior during investigations of resurgence
Authors: Sullivan William E. , Saini Valdeep , DeRosa Nicole M. , Craig Andrew R. , Ringdahl Joel E. , Roane Henry S.
Published: June 2019

Resurgence occurs when a previously extinguished behavior reemerges once a more recently reinforced behavior is placed on extinction. Previous research has suggested that nontargeted responses within the same response class recur alongside target‐response resurgence (e.g., da Silva, Maxwell, & Lattal, 2008; Lieving, Hagopian, Long, & O'Connor, 2004). The purpose of this two‐experiment investigation was to examine target response resurgence while simultaneously measuring the occurrence of nontargeted responses. Three children diagnosed with autism spectrum disorder who displayed multiple topographies of problem behavior participated. In Experiment 1, a three‐phase resurgence procedure was conducted and all three participants displayed target‐response resurgence accompanied by the emergence of nontargeted forms of problem behavior. These findings were replicated in Experiment 2 using a 30‐min assessment procedure. The implications of these findings as they pertain to the treatment of severe problem behavior and utility of a brief relapse assessment are discussed.
An evaluation of praise as a reinforcer for preschoolers' behavior
Authors: Senn Laura Perry , Bayles Makenzie W. , Bruzek Jennifer L.
Published: June 2019

Behavior analysts and educators often recommend using praise, particularly descriptive praise, despite mixed empirical findings to support this recommendation. We evaluated the effectiveness of praise as a reinforcer during a reinforcer assessment using known tasks with preschoolers in Experiment 1. Praise functioned as a reinforcer for 2 of 6 participants; the remaining 4 participants required additional reinforcers (edibles) to show a reinforcement effect. We then compared the effectiveness of descriptive versus general praise for acquisition of unknown tacts and assessed participants' preference for the different types of praise for 4 participants from Experiment 1. Results are discussed within the context of the importance of determining individual efficacy and preference for praise.
An opinion paper of the Cardiology Practice and Research Network of the American College of Clinical Pharmacy: Recommendations for training of cardiovascular pharmacy specialists in postgraduate year 2 residency programs
Authors: Ng Tien M. H. , DiDomenico Robert J. , Ripley Toni L. , Benge Cassandra D. , Buckley Leo F. , Campbell Kristen B. , Hale Genevieve M. , Macaulay Tracy E. , Nappi Jean M. , Pickworth Kerry K. , Short Marintha R.
Published: June 2019

Pharmacists in direct patient care settings are expanding their roles and responsibilities. These changes mandate a deeper and broader understanding of disease states, as well as influencing social, behavioral, and environmental factors. Existing guidelines and accreditation standards related to the training of graduate or cardiovascular pharmacist specialists (ie, Accreditation Council for Graduate Medical Education, American Society of Health‐System Pharmacists, American College of Clinical Pharmacy [ACCP]) provide some guidance on essential competencies. However, they stop short of providing recommendations for how to achieve all the objectives. The purpose of this paper is to build upon existing guidelines/standards, describing our recommendations for pharmacy residency training of a cardiovascular clinical specialist. The paper is broken down into the following sections: (1) Skills and Competencies (Building Clinical Skills, Application of Clinical Knowledge and Skills, Drug Information, Research and Scholarship, Teaching Skills, Interpersonal, Communication, and Presentation Skills), (2) Personal and Professional Growth (Growing Interpersonal Skills, Engaging with the Profession), (3) Program Design (Resident Selection, Preceptors and Mentoring, Expectations for Progress/Milestones, Program and Learning Experience Structure), and (4) Clinical and Therapeutic Content Expertise or Medical Knowledge. After each recommendation, specific details are provided to aid in conceptualizing how each can be achieved. Some recommendations are considered essential whereas others are designated as optional. This paper represents the opinion of the Cardiology Practice and Research Network of the American College of Clinical Pharmacy. It does not necessarily represent an official ACCP commentary, guideline, or statement of policy or position.
Diaphragm‐based optical fiber sensor for pulse wave monitoring and cardiovascular diseases diagnosis
Authors: Wang Jingyi , Liu Kewei , Sun Qizhen , Ni Xiaoling , Ai Fan , Wang Senmao , Yan Zhijun , Liu Deming
Published: June 2019

Arterial pulse wave has been considered as a vital sign in assessment of cardiovascular diseases. Noninvasive pulse sensor with compact structure, immunity to electro‐magnetic interference and high sensitivity is the research focus in recent years. While, optical fiber biosensor is a competitive option to meet these needs. Here, a diaphragm‐based optical fiber pulse sensor was proposed to achieve high‐precision radial pulse wave monitoring. A wearable device was developed, composed of a sports wristband and an aluminum diaphragm‐based optical fiber sensor tip of only 1 cm in diameter, which was highly sensitive to the weak acoustic signal. In particular, coherent phase detection was adopted to improve detection signal‐to‐noise ratio, so as to recover the high‐fidelity pulse waveforms. A clinical experiment was carried out to detect and morphological analyze the pulse waveforms of four subjects, the results of which preliminarily demonstrated the feasibility of pulse diagnosis method. The proposed pulse fiber sensor provides a comfortable way for pulse diagnosis, which is promising in early cardiovascular diseases indicating.
LncRNA CCAT1 promotes autophagy via regulating ATG7 by sponging miR‐181 in hepatocellular carcinoma
Authors: Guo Jianbo , Ma Yingbo , Peng Xueqiang , Jin Hongyuan , Liu Jingang
Published: June 2019

Background

Hepatocellular carcinoma (HCC) is a significant clinical challenge, and the mechanisms underlying HCC pathogenesis remain incompletely understood. Colon cancer associated transcript 1 (CCAT1), is one novel long noncoding RNA (lncRNA) which is upregulated in HCC. Autophagy is a vital process in HCC progression, and it is unknown whether CCAT1 regulates autophagy in HCC.

Materials and methods

Immunofluorescence staining and transmission electron microscopy were used to analyze autophagy activity. Luciferase assay was performed to confirm miRNA‐181a‐5p (miR‐181a‐5p) bind CCAT1 and ATG7.

Results

CCAT1 levels were higher in tissue and cell lines of HCC. In function research, we found that CCAT1 facilitates HCC cell autophagy and cell proliferation. Our results show that, mechanistically, CCAT1 promotes autophagy through functioning as a sponge for miR‐181a‐5p, and then regulating ATG7 expression.

Conclusion

Our findings indicate CCAT1 may play a role in regulating autophagy by sponging miR‐181a‐5p in HCC.
Exosomal microRNA and stroke: A review
Authors: Ghoreishy Abdolreza , Khosravi Alireza , Ghaemmaghami Amir
Published: June 2019

Blood vessels rupture or occlusion in brain results in stroke. Stroke is the major reason for mortality and dysfunction worldwide. Despite several attempts, there are no any approved therapeutic approaches for stroke subjects. The most neuroprotective agents showed the positive effects in preclinical reports, while there are no significant therapeutic impacts in the clinical trials. MicroRNAs (miRNAs) are small noncoding RNAs which involved in the modulation of a variety of cellular and molecular pathways. Given that deregulation of these molecules is related to initiation and progression of stroke. Exosomes are nano‐carriers which are able to transfer different cargos such as miRNAs to recipient cells. Increasing evidence revealed that exosomal miRNAs are one of very important factors which are involved in the pathogenesis of stroke. Hence, more understanding about the role of exosomal miRNAs in stroke pathogenesis could contribute in discovering and developing new therapeutic approaches. Moreover, it has been proved the exosomal miRNAs could be used as noninvasive biomarkers in diagnosis and monitoring response to therapy in subjects with stroke. Herein for first time, we summarized different exosomal miRNAs involved in pathogenesis of stroke.
CRISPR‐Cas system: Toward a more efficient technology for genome editing and beyond
Authors: Ahmadzadeh Vahideh , Farajnia Safar , Baghban Roghayyeh , Rahbarnia Leila , Zarredar Habib
Published: June 2019

Genome engineering technology is of great interest for biomedical research that enables scientists to make specific manipulation in the DNA sequence. Early methods for introducing double‐stranded DNA breaks relies on protein‐based systems. These platforms have enabled fascinating advances, but all are costly and time‐consuming to engineer, preventing these from gaining high‐throughput applications. The CRISPR‐Cas9 system, co‐opted from bacteria, has generated considerable excitement in gene targeting. In this review, we describe gene targeting techniques with an emphasis on recent strategies to improve the specificities of CRISPR‐Cas systems for nuclease and non‐nuclease applications.
Upregulation of miR‐675‐5p induced by lncRNA H19 was associated with tumor progression and development by targeting tumor suppressor p53 in non–small cell lung cancer
Authors: Zheng Zi‐Hui , Wu Dong‐Mei , Fan Shao‐Hua , Zhang Zi‐Feng , Chen Gui‐Quan , Lu Jun
Published: June 2019

Lung cancer is the main cause of cancer‐related death, and the proportion of non–small cell lung cancer (NSCLC) on lung cancer is 85%, while more than 80% lung cancer patients are diagnosed with chronic obstructive pulmonary disease (COPD). In this study, we aimed to explore the potential mechanism of COPD induced NSCLC. Luciferase assay and reverse transcription‐polymerase chain reaction (RT‐PCR) were conducted to study the regulatory relationship between P53 and microRNA‐675 (miR‐675). Real‐time PCR, Western‐blot analysis, and MTT assay were performed to explore the impact of H19 and miR‐675 in the signaling pathway involved in COPD induced NSCLC. In NSCLC patients with COPD, H19 and miR‐675 levels were strikingly upregulated while P53 level was significantly downregulated. P53 was identified as a target gene of miR‐675, and H19 remarkably upregulated miR‐675, while H19 siRNA notably inhibited miR‐675. In addition, miR‐675 and H19 dramatically suppressed the expression of P53 and Bax while inducing the expression of Bcl‐2. Finally, H19 and miR‐675 induced proliferation of A549 and MRC‐5 cells. These finding indicated that COPD (hypoxia)‐induced H19 promoted expression of miR‐675 associated with NSCLC though target apoptosis‐related protein P53, BAX, and Bcl‐2.
Long noncoding RNA OIP5‐AS1 aggravates cell proliferation, migration in gastric cancer by epigenetically silencing NLRP6 expression via binding EZH2
Authors: Bai Yunlei , Li Sheng
Published: June 2019

The critical role of long noncoding RNAs (lncRNAs) in the development of multiple cancers has been revealed either functioning as a tumor initiator or a cancer suppressor. A widely recognized OIP5 antisense RNA 1 (lncRNA OIP5‐AS1) has been validated to be an essential regulator of the tumorigenesis of various malignancies. Whereas, the potential role and the exact mechanism of lncRNA OIP5‐AS1 by which OIP5‐AS1 mediates gastric cancer (GC) progression remains vague. Therefore, first our work probed its expression levels in GC cell lines and related normal cells by real‐time quantitative polymerase chain reaction. The heightened level of OIP5‐AS1 was detected in GC cell lines. In terms of its cellular effects, we performed a series of functional experiments and as presented in the assays, the proliferative potential and motility was diminished. However, more apoptotic cells were induced with the introduction of OIP5‐AS1 silencing. Meanwhile, higher Nod‐like receptor pyrin domain‐containing protein 6 (NLRP6) and enhancer of zeste homolog 2 (EZH2) expression in the GC cells was monitored. Besides, OIP5‐AS1 was disclosed to locate mainly in the nucleus. In terms of mechanism, OIP5‐AS1 directly bound to EZH2 and obstructed NLRP6 expression, speeding up GC progression.
MicroRNA‐323‐3p promotes myogenesis by targeting Smad2
Authors: Qin Jin , Sun Yunmei , Liu Shuge , Zhao Rui , Zhang Qiyue , Pang Weijun
Published: June 2019

Skeletal muscle is an important and complex organ with multiple biological functions in humans and animals. Proliferation and differentiation of myoblasts are the key steps during the development of skeletal muscle. MicroRNA (miRNA) is a class of 21‐nucleotide noncoding RNAs regulating gene expression by combining with the 3′‐untranslated region of target messenger RNA. Many studies in recent years have suggested that miRNAs play a critical role in myogenesis. Through high‐throughput sequencing, we found that miR‐323‐3p showed significant changes in the longissimus dorsi muscle of Rongchang pigs in different age groups. In this study, we discovered that overexpression of miR‐323‐3p repressed myoblast proliferation and promoted differentiation, whereas the inhibitor of miR‐323‐3p displayed the opposite results. Furthermore, we predicted Smad2 as the target gene of miR‐323‐3p and found that miR‐323‐3p directly modulated the expression level of Smad2. Then luciferase reporter assays verified that Smad2 was a target gene of miR‐323‐3p during the differentiation of myoblasts. These findings reveal that miR‐323‐3p is a positive regulator of myogenesis by targeting Smad2. This provides a novel mechanism of miRNAs in myogenesis.
The inhibition of BDNF/TrkB/PI3K/Akt signal mediated by AG1601 promotes apoptosis in malignant glioma
Authors: Yin Hongqiang , Jiang Yu , Zhang Yinguo , Ge Hui , Yang Zhuo
Published: June 2019

Malignant glioma is the most aggressive primary brain tumor and has a poor survival rate. Even if extensive methods are preformed to treat glioma, the mortality rate is still very high. It is necessary for discovering and developing new drugs for malignant glioma treatment. AG1601 is one of AG‐series drugs, including AG1031 and AG1503, and it has been optimized on the original basis. In our study, we found that AG1601 markedly inhibited proliferation and promoted C6 glioma cell apoptosis in vitro. AG1601 also reduced the size and weight of glioma in vivo. The growth ability of glioma was significantly inhibited after treatment with AG1601. It also showed that the expression levels of BDNF/TrkB/PI3K/Akt signal related proteins were obviously decreased in C6 glioma cells after treatment with AG1601 in vivo and in vitro. We also found that BDNF, as the activator of BDNF/TrkB/PI3K/Akt signal, reversed the anti‐proliferation and pro‐apoptosis of C6 glioma cells caused by AG1601. K252a, a specific inhibitor of TrkB, and AG1601 in combination aggravated C6 glioma cell apoptosis. These results indicate that AG1601 has good effects on the anti‐proliferation and pro‐apoptosis of malignant glioma via BDNF/TrkB/PI3K/Akt signal and could be considered as a potential drug in treating malignant glioma.
Association and in silico investigations of miR‐302c insertion/deletion variant as a novel biomarker with susceptibility to gastric cancer
Authors: Raad Mohammad , Bayat Amir , Sharafshah Alireza , Amiri Ali Zahedi , Zohour Mostafa Montazer , Ahmadvand Mohammad
Published: June 2019

Gastric cancer (GC) is the fifth most prevalent malignant tumor and the third most frequent cause of cancer mortality worldwide. rs199971565 is an insertion/deletion (INDEL) located in microRNA‐302c (miR‐302c) seed site, which may affect its function and biogenesis. There is no genetic association study investigating this INDEL with any disease till now. Thus, the current study was conducted to investigate the association of rs199971565 with susceptibility to GC in an Iranian population. In addition, in silico studies were performed to reveal the possible functional significance of this INDEL. A total of 378 subjects were genotyped through amplification refractory mutation system PCR (ARMS‐PCR) after DNA extraction from peripheral blood by the salting out procedure. Also, in silico analyses were performed through databases and web tools including MiRNASNP V2.0, miRWalk V2.0, miRTarBase, DAVID V6.8, RNAfold, PHDcleave, miRmap, and STarMir. Results revealed that there was an association between rs199971565 and the incidence risk of GC under a recessive (P = .04, odds ratio [OR] = 18.73; 95% confidence interval [CI] = 1.07‐326.95) model of inheritance. Also, compared to the Ins allele, the Del allele significantly increased the risk of GC (P = .01, OR = 2.02; 95% CI = 1.11‐3.66). Further analyses showed no significant association in age and sex between two study groups (P = .216 and P = .798, respectively). In conclusion, for the first time, this study indicated the association and in silico investigations of rs199971565 and suggested it as a novel INDEL biomarker located in the seed site of miR‐302c, which may have crucial roles in the susceptibility to GC and its incidence risk.
Analytical comparison between two hematological analyzer systems: Mindray BC‐5180 vs Sysmex XN‐1000
Authors: Wang Jing , Zhao Shengmei , Su Zhenguo , Liu Xiangdong
Published: June 2019

Background

To compare the Mindray BC‐5180 and Sysmex XN‐1000 instruments by analyzing the results of complete blood count in the external quality assessment in Shandong Province in 2018.

Methods

In the external quality assessment, 10 batches of quality control materials were issued throughout the year. The test items were WBC, RBC, Hb, PLT, and HCT. The laboratories using Mindray BC‐5180 and Sysmex XN‐1000 were screened, and the results were analyzed by t test, Passing‐Bablok regression analysis, and Bland‐Altman analysis.

Results

Thirty‐six laboratories using Mindray BC‐5180 instruments and thirty‐six laboratories using Sysmex XN‐1000 instruments were screened, and the average difference between the two instruments results is not significant (P > 0.05, t test). Passing‐Bablok regression analysis showed that the 95% confidence interval of the regression equation interception of each test item included 0, and the 95% confidence interval of the slope contained 1, r > 0.98, which showed that the correlation is good. The Bland‐Altman analysis showed that both instruments had more than 95% of the points within the 95% consistency limit (WBC97.2%, RBC95.6%, PLT97.2%, Hb96.7%, HCT97.5%). Within the consistency limit, the absolute value of the difference between the Mindray BC‐5180 instrument and the Sysmex XN‐1000 instrument is WBC 0.14%, RBC 0.26%, PLT 2.7%, and Hb 1.9%. HCT is 0.69%, and the difference is clinically acceptable.

Conclusion

It can be considered that the two instruments have good correlation and consistency, and the two instruments can replace each other.
Microtubule‐interfering agents, spindle defects, and interkinetochore tension
Authors: Qi Feifei , Zhou Jun , Liu Min
Published: June 2019

Microtubule‐interfering agents have been very useful both as biological tools in studying mitosis and as chemotherapeutic agents against cancer. It remains poorly understood how these agents converge on the spindle assembly checkpoint (SAC) to halt mitotic progression, while inhibiting microtubule dynamics by different mechanisms. Cells arrested at mitosis by various microtubule‐interfering agents exhibit strikingly different defects in the mitotic spindle. However, all the arrested cells possess the 3F3/2 phosphoepitope at the sister kinetochores of chromosomes, indicating the decrease of tension across the paired kinetochores. In addition, microtubule‐interfering agents result in a comparable reduction in the distance between sister kinetochores, suggesting that these agents decrease interkinetochore tension to similar degrees. Here, we discuss recent progress that suggests impairment of kinetochore‐microtubule attachment and reduction of interkinetochore tension as common mechanisms underlying the persistent SAC activation in response to diverse microtubule‐interfering agents.
Inhalation Aerosol Therapy in the Treatment of Chronic Rhinosinusitis: A Prospective Randomized Study
Authors: Velepič Marko , Manestar Dubravko , Perković Ivona , Škalamera Dunja , Braut Tamara
Published: June 2019

The purpose of the study was to compare treatment of chronic rhinosinusitis (CRS) with topical glucocorticoids and saline irrigation versus aerosol inhalation therapy. Patients diagnosed with CRS were randomly divided into 2 groups. In the first group, patients were treated with topical glucocorticoids (mometasone furoate, 100 µg in each nostril once daily) and saline irrigation (150 mL twice a day) for 2 weeks. In the second group, patients were treated with inhalation aerosol therapy composed of essential oils, saline, glucocorticoids, and antibiotics, once daily 5 times per week (Monday through Friday), for 2 weeks. The effect of the treatments was compared between the 2 groups. In the first group there was no significant improvement in the Glasgow Health Status Inventory (GHSI) (P = .29). In the second group the improvement in GHSI score was significant (P = .037). It was shown that in the first group the Glasgow Benefit Inventory score was significantly lower than in the second group (P = .002), which means that the improvement in the health status after the therapy was better in the second group. A Lund‐Kennedy score showed statistical improvement in both groups (both P < .001). Improvement was also compared between the groups. The results were not significant (P = .11). The authors concluded that, in this preliminary research, inhalation aerosol therapy composed of essential oils, saline, glucocorticoids, and antibiotics led to better subjective results than intranasal glucocorticoid therapy and saline irrigation in the treatment of CRS. Further investigations with more participants, longer periods of treatment, and different validation tools are needed to confirm our results.
Optimization of the 3D electro‐Fenton process in removal of acid orange 10 from aqueous solutions by response surface methodology
Authors: Mohammadi Hamed , Alinejad Abdolazim , Khajeh Mahsa , Darvishmotevalli Mohammad , Moradnia Maryam , Tehrani Ashraf Mazaheri , Hosseindost Gholamreza , Zare Mohammad Reza , Mengelizadeh Nezamaddin
Published: June 2019

BACKGROUND

In recent decades, rapid population growth and industrial development have led to the release of toxic compounds into water resources. Several technologies have been proposed to address the problem, and among them, the 3D electro‐Fenton process has found great popularity due to its high efficiency and simple operation. In the 3D electro‐Fenton process, the type of particle electrode is one of the most important factors owing to its impact on the reduction of energy consumption and generation of reactive species. In the present study, the optimization of the 3D electro‐Fenton process coupled with iron‐coated nickel foam (NF‐Fe), as a new particle electrode, in the removal of acid orange 10 was investigated using response surface methodology (RSM).

RESULTS

The RSM results showed that the quadratic model has a high R2 and high F‐value based on ANOVA analysis. The optimum efficiency of dye removal (99.15%) was obtained at pH 5.6, an NF‐Fe dosage of 0.68 g L−1, a time of 34.6 min, and current density of 23.62 mA cm−2. Comparative tests showed the high efficiency of the 3D electro‐Fenton process compared to other electrochemical systems. Quenching experiments demonstrated the production of different reactive species in the 3D process. The stability experiment proved that the NF‐Fe has a high potential to improve the long‐term degradation of dye.

CONCLUSIONS

Due to its high efficiency, production of more reactive species and excellent stability of the NF‐Fe electrode, this 3D electro‐Fenton process is an excellent option for removal of dye from aqueous solutions. © 2019 Society of Chemical Industry
Comprehensive review and future perspectives on the photocatalytic hydrogen production
Authors: Corredor Juan , Rivero María J , Rangel Carmen M , Gloaguen Frederic , Ortiz Inmaculada
Published: June 2019

Hydrogen represents a renewable energy alternative that may positively contribute to get over the global energy crisis while at the same time reducing its environmental burden. Overcoming the challenge of reaching this potential could be helped by careful choice of hydrogen (H2) sources. Photocatalytic generation of H2, although a minor alternative, appears to be a very good option at the time that liquid wastes are being degraded; therefore, this approach has given rise to an increasing number of interesting studies.
Here, we aim to provide an integrated overview of the different photocatalytic, heterogeneous, homogeneous and hybrid systems. First, we categorize the units and mechanisms that take part in the photocatalytic process, and secondly we analyze their role and draw comparative conclusions. Thus, we analyze the role of (i) the electron source to carry out proton reduction, (ii) the proton source, which can be free protons in the medium or a proton donor compound, (iii) the catalyst nature and concentration, and (iv) the photosensitizer nature and concentration. We also provide an analysis of the influence of the solvent, especially in homogenous systems as well as the influence of pH. We provide a comparison of the photocatalytic performance, highlighting the advantages and disadvantages, of different systems. Thus, this review is, on the one hand, an update on the state of the art of photocatalytic generation of H2 from a full perspective that integrates homogeneous, heterogeneous and hybrid systems, and, on the other, a source of useful information for future research. © 2019 Society of Chemical Industry
Is there section deformation resulting in differential change of nuclear numerical densities along the z axis of thick methacrylate or paraffin sections?
Authors: Xu Wei , Guo Yang , Xiang Yu , Yang Zheng‐Wei
Published: June 2019

The optical disector, a three‐dimensional counting frame or probe in stereology, is often positioned in the middle (depth) of a thick section for unbiased nuclear counting. Using 30–40 μm thick methacrylate or paraffin sections for nuclear counting of neurons with the optical disector, however, some studies showed markedly higher nuclear densities at 10% of the section thickness near the top or bottom surface of the section, suggestive of deformation of section along its z axis and thus affecting the number estimation. To verify the findings, this study obtained two sets of 12–14 methacrylate sections (average thicknesses 21.7 and 29.4 μm) and two sets of 12 paraffin sections (average thicknesses 13.8 and 29.2 μm) from mature rat testes. Each section was used to count round spermatid nuclei in the seminiferous epithelium densely packed with the cells, using 3–4 consecutive disectors placed vertically (along the z axis of the section) from the top surface of the section, through the whole section thickness (two sets of methacrylate and paraffin sections) or in 80–83% of the thickness (other sections). The results demonstrated that, overall, there were no considerable nonuniform changes of the nuclear densities along the z axis of the sections.
The cephalic morphology of the troglobiontic cholevine species Troglocharinus ferreri (Coleoptera, Leiodidae)
Authors: Luo Xiao‐Zhu , Antunes‐Carvalho Caio , Wipfler Benjamin , Ribera Ignacio , Beutel Rolf G.
Published: June 2019

Leiodidae are the second largest subterranean radiation of beetles at family rank. To explore morphological trends linked with troglobiontic habits and characters with potential phylogenetic significance, the head of the cave‐dwelling species Troglocharinus ferreri (Cholevinae, Leptodirini) was examined in detail. Overall, the general pattern is similar to what is found in Catops ventricosus (Cholevini). Shared apomorphic features include a fully exposed anterolateral concavity containing the antennal socket, a distinct bead above this depression, a bilobed lip‐like structure anterad the labrum, a flat elevated portion of the ventral mandibular surface, and a ventral process at the proximomesal edge of this mandibular area. The tentorial structures are well‐developed as in C. ventricosus, with a large laminatentorium and somewhat shortened dorsal arms. The mouthparts are largely unmodified, with the exception of unusually well‐developed extrinsic maxillary muscles. Features of T. ferreri obviously linked with subterranean habits are the complete lack of compound eyes, circumocular ridges, and optic lobes. A series of characters is similar to conditions found in other genera of Leptodirini: the head capsule completely lacks a protruding ocular region, a distinct neck is missing, the transverse occipital crest is indistinct, and the antennae are elongate and lack a distinct club. Two different trends of cephalic transformations occur in troglobiontic Leptodirini, with some genera like Troglocharinus and Leptodirus having elongated head capsules and antennae, and others having broadened, more transverse heads. In contrast, the modifications are more uniform in the closely related Ptomaphagini, with a pattern distinctly differing from Leptodirini: the head is transverse, with a distinctly protruding ocular region, a distinct transverse occipital crest, and a very narrow neck region.
Protist diversity and community assembly in surface sediments of the South China Sea
Authors: Wu Wenxue , Huang Bangqin
Published: June 2019

Protists are pivotal components of marine ecosystems in terms of their high diversity, but protist communities have been poorly explored in benthic environments. Here, we investigated protist diversity and community assembly in surface sediments in the South China Sea (SCS) at a basin scale. Pyrosequencing of 18S rDNA was performed for a total of six samples taken from the surface seafloor at water depths ranging from 79 to 2,939 m. We found that Cercozoa was the dominant group, accounting for an average of 39.9% and 25.3% of the reads and operational taxonomic units (OTUs), respectively. The Cercozoa taxa were highly diverse, comprising 14 phylogenetic clades, six of which were affiliated with unknown groups belonging to Filosa and Endomyxa. Fungi were also an important group in both read‐ (18.1% on average) and OTU‐derived (9.3% on average) results. Moreover, the turnover patterns of the protist communities were differently explained by species sorting (53.3%), dispersal limitation (33.3%), mass effects (0%), and drift (13.3%). In summary, our findings show that the basin‐wide protist communities in the surface sediments of the SCS are primarily dominated by Cercozoa and are mainly assembled by species sorting and dispersal limitation.
Epigenetic polypharmacology: A new frontier for epi‐drug discovery
Authors: Tomaselli Daniela , Lucidi Alessia , Rotili Dante , Mai Antonello
Published: June 2019

Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.
Identification of gene variants in 130 Han Chinese patients with hypospadias by targeted next‐generation sequencing
Authors: Zhang Wanyu , Shi Jinxiu , Zhang Chenhui , Jiang Xincheng , Wang Junqi , Wang Wei , Wang Defen , Ni Jihong , Chen Lifen , Lu Wenli , Xiao Yuan , Ye Weijing , Dong Zhiya
Published: June 2019

Background

Hypospadias is a common congenital malformation of male external genitalia, which mainly manifests as an abnormal urethral opening on the ventral side of the penis. The etiology and clinical phenotype of hypospadias is highly heterogeneous, and its clinical diagnosis is challenging. Currently, over 70% of patients have an unknown etiology. Here, we performed a targeted analysis of gene mutations in 130 patients with hypospadias of unknown etiology to find the precise genetic cause.

Methods

We developed a targeted next‐generation sequencing (NGS) panel, encompassing the exon coding regions of 105 genes involved in external genitalia and urogenital tract development and performed sequencing analysis on 130 children with hypospadias of unknown etiology.

Results

In total, 25 patients with hypospadias (19.2%) were found to have 20 mutations among the nine genes involved in external genitalia and urogenital tract development, including 16 reported and four novel mutation sites. Twenty‐two patients (16.9%) had diagnostic variants. Multiple genetic mutations were identified in three of the 25 patients. Hypospadias combined with micropenis was the most common phenotype (68%) in 25 patients.

Conclusions

Higher frequency mutations were identified in SRD5A2 (52%) and AR (24%) in our patient cohort. Middle or posterior hypospadias with micropenis may be significant indicators of genetic variations. Polygenic inheritance may be a rare genetic cause of hypospadias.
A convolutional neural network for ultra‐low‐dose CT denoising and emphysema screening
Authors: Zhao Tingting , McNitt‐Gray Michael , Ruan Dan
Published: June 2019

Purpose

Reducing dose level to achieve ALARA is an important task in diagnostic and therapeutic applications of computed tomography (CT) imaging. Effective image quality enhancement strategies are crucial to compensate for the degradation caused by dose reduction. In the past few years, deep learning approaches have demonstrated promising denoising performance on natural/synthetic images. This study tailors a neural network model for (ultra‐)low‐dose CT denoising, and assesses its performance in enhancing CT image quality and emphysema quantification.

Methods

The noise statistics in low‐dose CT images has its unique characteristics and differs from that used in general denoising models. In this study, we first simulate the paired ultra‐low‐dose and targeted high‐quality image of reference, with a well‐validated pipeline. These paired images are used to train a denoising convolutional neural network (DnCNN) with residual mapping. The performance of the DnCNN tailored to CT denoising (DnCNN‐CT) is assessed over various dose reduction levels, with respect to both image quality and emphysema scoring quantification. The possible over‐smoothing behavior of DnCNN and its impact on different subcohort of patients are also investigated.

Results

Performance evaluation results showed that DnCNN‐CT provided significant image quality enhancement, especially for very‐low‐dose level. With DnCNN‐CT denoising on 3%‐dose cases, the peak signal‐to‐noise ratio improved by 8 dB and the structure similarity index increased by 0.15. This outperformed the original DnCNN and the state‐of‐the‐art nonlocal‐mean‐type denoising scheme. Emphysema mask was also investigated, where lung voxels of abnormally low attenuation coefficient were marked as potential emphysema. Emphysema mask generated after DnCNN‐CT denoising on 3%‐dose image was demonstrated to agree well with that from the full‐dose reference. Despite over‐smoothing in DnCNN denoising, which contributed to slight underestimation of emphysema score compared to the reference, such minor overcorrection did not affect clinical conclusions. The proposed method provided effective detection for cases with appreciable emphysema while serving as a reasonable correction for normal cases without emphysema.

Conclusions

This work provides a tailored DnCNN for (ultra‐)low‐dose CT denoising, and demonstrates significant improvement on both the image quality and the clinical emphysema quantification accuracy over various dose levels. The clinical conclusion of emphysema obtained from the denoised low‐dose images agrees well with that from the full‐dose ones.
A thermally polarized 129Xe phantom for quality assurance in multi‐center hyperpolarized gas MRI studies
Authors: Bier Elianna A. , Nouls John C. , Wang Ziyi , He Mu , Schrank Geoff , Morales‐Medina Naomi , Hashoian Ralph , Svetlik Harvey , Mugler John P. , Driehuys Bastiaan
Published: June 2019

Purpose

Hyperpolarized 129Xe MR is increasingly being adopted worldwide, but no standards exist for assessing or comparing performance at different 129Xe imaging centers. Therefore, we sought to develop a thermally polarized xenon phantom assembly, approximating the size of a human torso, along with an associated imaging protocol to enable rapid quality‐assurance imaging.

Methods

MR‐compatible pressure vessels, with an internal volume of 5.85 L, were constructed from pressure‐rated, engineering grade PE4710 high‐density polyethylene. They were filled with a mixture of 61% natural xenon and 39% oxygen to approximately 11.6 bar and placed in a loader shell filled with a 0.56% saline solution to mimic the human chest. Imaging employed a 2D spoiled gradient‐echo sequence using non‐slice‐selective excitation (TR/TE = 750/6.13 ms, flip angle = 74°, FOV = 40 × 440 mm, matrix = 64 × 32, bandwidth = 30 Hz/pixel, averages = 4), resulting in a 1.6 min acquisition. System characterization and imaging were performed at 8 different MRI centers.

Results

At 3 Telsa, 129Xe in the pressure vessels was characterized by T1 = 580.5 ± 8.3 ms, linewidth = 0.21 ppm, and chemical shift = +10.2 ppm. The phantom assembly was used to obtain transmit voltage calibrations and 2D and 3D images across multiple coil and scanner configurations at 8 sites. Across the 5 sites that employed a standard flexible chest coil, the SNR was 12.4 ± 1.8.

Conclusion

The high‐density polyethylene pressure vessels filled with thermally polarized xenon and associated loader shell combine to form a phantom assembly that enables spectroscopic and imaging acquisitions that can be used for testing, quality assurance, and performance tracking—capabilities essential for standardizing hyperpolarized 129Xe MRI within and across institutions.
A randomized study comparing regular care with a nurse‐led clinic based on tight disease activity control and person‐centred care in patients with rheumatoid arthritis with moderate/high disease activity: A 6‐month evaluation
Authors: Bergsten Ulrika , Almehed Katarina , Baigi Amir , Jacobsson Lennart T.H.
Published: June 2019

Introduction

A recent survey showed that 27% of rheumatoid arthritis (RA) patients had inadequately controlled disease activity. Hence, there is a need for new strategies aiming at improving patient outcomes. The aim of the present study was to evaluate the effect of a nurse‐led clinic with frequent visits, treat‐to‐target and person‐centred care of patients with established RA and moderate‐to‐high disease activity compared with patients receiving regular care.

Methods

The study was a randomized, controlled trial over 26 weeks, with a nonrandomized extension to week 50. Patients were randomized to an intervention group (IG; nurse‐led clinic) based on person‐centred care, frequent visits and “treat to target”, or to a control group (CG) which visited the clinic according to care as usual. The primary outcome was the difference in the DAS28 change between the IG and the CG groups.

Results

A total of 332 patients were screened for eligibility, of which 70 were randomly assigned to either the IG (n = 36) or the CG (n = 34) group. The primary outcome was not met, although patients in the IG group tended to improve more than those in the CG group (difference: 0.43 (95% confidence interval [CI] –0.27, 1.13). In both the IG and CG groups, delta‐DAS28 improved significantly. The European League Against Rheumatology moderate or good response was achieved by 76% (95% CI 58, 89) in the IG and 49% (95% CI 32, 65) in the CG group.

Conclusions

Disease activity tended to improve more with the nurse‐led intervention compared with regular care, although the difference was not significant, probably partly due to the lack of statistical power.
Longitudinal Changes in Measures of Body Fat and Diet Among Adult Tsimane’ Forager‐Horticulturalists of Bolivia, 2002‐2010
Authors: Bethancourt Hilary J. , Leonard William R. , Tanner Susan , Schultz Alan F. , Rosinger Asher Y.
Published: June 2019

Objective

This study examined changes in body fat and diet among Tsimane’ forager‐horticulturalists and assessed how dietary shifts relate to increases in adiposity between 2002 and 2010.

Methods

Longitudinal anthropometric and household‐level dietary recall data from 365 men and 339 women aged ≥20 years in the Tsimane’ Amazonian Panel Study were used. Multilevel mixed‐effects models estimated how BMI, body fat percentage, waist circumference, skinfolds, and fat‐free mass relate to household consumption of crops, hunted or fished foods, domesticated animal products, cooking oil, and refined grains and sugar.

Results

Women’s prevalence of overweight and obesity increased from 22.6% and 2.4% in 2002 to 28.8% and 8.9% in 2010, respectively, and BMI increased by 0.60% ± 0.12% per year (P < 0.001). Increases in fat‐free mass accounted for some of this observed weight gain among women. Men’s prevalence of overweight and obesity increased from 16.2% and 0.7% to 25.0% and 2.2%, respectively, and BMI increased by 0.22% ± 0.09% per year (P = 0.009). Household use of cooking oil increased and was positively associated with female BMI. Consumption of domesticated animal products did not change significantly but was positively associated with female BMI and male waist circumference.

Conclusions

Even small increases in energy‐dense market‐based foods can contribute to adiposity gains among a moderately active, subsistence‐based population.
Pregnancy loss after amniocentesis in monochorionic and dichorionic twin pregnancies: Results from a large population‐based dataset
Authors: Sperling Jeffrey D. , Zlatnik Marya G. , Norton Mary E. , Currier Robert J.
Published: June 2019

Objective

To determine the loss rate after amniocentesis in twins.

Methods

This cohort study evaluated twin pregnancies with serum screening through the California Prenatal Screening Program. The primary outcome was loss of one or both twins at any gestational age. Exclusions were chromosomal/structural abnormalities, selective fetal reduction, terminations, neonatal deaths, ovum donation, and incomplete data. Loss rates were compared between three groups: (a) screen negative and no amniocentesis, (b) screen positive and accepted, or (c) declined amniocentesis. Multivariate logistic analysis generated adjusted odds ratios (aOR).

Results

Thirty‐six thousand eight hundred twenty‐one twin pregnancies had screening: 2698 (7.3%) were screen positive for aneuploidy or neural tube defects (NTD). Among screen‐positive women, 861 (31.9%) were offered amniocentesis and 274 (31.8%) accepted. The post‐procedure loss rate among screen‐negative women was lower than among screen‐positive women (3.0% vs 7.4%; P < .001; aOR 2.62; 95% CI, 1.16‐2.99). Among screen‐positive women, the loss rate was similar for those who underwent amniocentesis and for those who declined (8.8% vs 6.8%; .32; aOR 1.32; 95% CI, 0.66‐1.91).

Conclusion

Twins that are screen positive for aneuploidy or NTD have an increased risk of pregnancy loss. Those who are screen positive and undergo amniocentesis do not have an increased loss rate.
A European multicentre drug utilisation study of the impact of regulatory measures on prescribing of codeine for pain in children
Authors: Hedenmalm Karin , Blake Kevin , Donegan Katherine , Macia Miguel‐Angel , Gil Miguel , Williams Julie , Montero Dolores , Candore Gianmario , Morales Daniel , Kurz Xavier , Arlett Peter
Published: June 2019

Purpose

In June 2013, following recommendations from the World Health Organization (WHO) and Food and Drug Administration (FDA), the European Medicines Agency agreed updates to the codeine product information regarding use for pain in children younger than 12 years and children undergoing tonsillectomy or adenoidectomy (TA) for obstructive sleep apnoea. This study was conducted to (a) assess effectiveness of these measures on codeine prescribing in the “real‐world” setting and (b) test feasibility of a study using a common protocol by regulators with access to databases.

Methods

The study was performed using BIFAP (Spain), CPRD (UK), and IMS® Disease Analyzer (France and Germany) databases. Prescribers included general practitioners (GPs) (France and UK), GPs and paediatricians together (Spain), and GPs, paediatricians, and ear, nose, and throat (ENT) specialists separately (Germany). Between January 2010 and June 2015, prevalence of codeine prescribing was obtained every 6 months, and a time series analysis (joinpoint) was performed. Codeine prescribing within ±30 days of TA was also identified. Furthermore, doses, durations, and prior prescribing of other analgesics were investigated.

Results

Over the 5‐year period, codeine prescribing decreased in children younger than 12 years (by 84% in France and Spain, 44% in GP practices in Germany, and 33% in the United Kingdom). The temporal pattern was compatible with the regulatory intervention in France and the United Kingdom, whereas a decrease throughout the study period was seen in Germany and Spain. Decreased prescribing associated with TA was suggested in ENT practices in Germany.

Conclusions

Codeine prescribing for children decreased in line with introduced regulatory measures. Multidatabase studies assessing impact of measures by EU regulators are feasible.