bluuebunny/crossref_metadata_2025 huggingface dataset:
Essential diseases in prescribing: A national Delphi study towards a core curriculum in pharmacotherapy education
Authors: Jansen B.H.E. , Disselhorst G.W. , Schutte T. , Jansen B. , Rissmann R. , Richir M.C. , Keijsers C.J.P.W. , Vanmolkot F.H.M. , van den Brink A. Maassen , Kramers C. , Vondeling A.M. , Dumont G.J.H. , de Waard‐Siebinga I. , Van Agtmael M.A. , Tichelaar J.
Published: August 2018

Aims

Prescribing is a core skill for junior doctors, yet 8–10% of their prescriptions contain errors. To ensure adequate training in prescribing, it is important to define the diseases for which junior doctors should be competent to prescribe. The aim of the present study was therefore to identify the essential diseases in prescribing for junior doctors.

Methods

A two‐round Delphi consensus study was conducted among medical specialists, general practitioners, junior doctors, pharmacists and pharmacotherapy teachers from all eight academic hospitals in the Netherlands. Using a five‐point Likert scale, the participants indicated for each item on an initial questionnaire whether it should be considered an essential disease for junior doctors. The items for which ≥80% of all respondents agreed or strongly agreed were accepted as essential diseases.

Results

Sixty‐two participants completed the Delphi survey. In total, 63 of 220 items were considered to be essential diseases.

Conclusion

This is the first Delphi consensus study identifying exact conditions that junior doctors must be able to prescribe for. The essential diseases can be used for training in prescribing and assessment of junior doctors' prescribing competence.
Efficacy of retreatment with immunomodulatory drugs and proteasome inhibitors following daratumumab monotherapy in relapsed and refractory multiple myeloma patients
Authors: Oostvogels Rimke , Jak Margot , Raymakers Reinier , Mous Rogier , Minnema Monique C.
Published: August 2018

This single‐centre retrospective observational study analysed the efficacy of retreatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) after treatment with daratumumab monotherapy in patients with relapsed and/or refractory multiple myeloma (RRMM). In total 55 patients were treated with daratumumab monotherapy between 2010 and 2017. From this group 29 (53%) IMiD‐refractory patients were retreated with an IMiD after daratumumab and 6 (11%) PI‐refractory patients were retreated with a PI‐based regimen. For the IMiD‐refractory patients the overall response rate (ORR) was 52% (15/29 patients, partial response or better) upon IMiD retreatment, whereas the ORR to PI retreatment was 67% (4/6 patients) in the PI‐refractory group. The immunomodulatory effects of daratumumab may play a role in these high response rates in previously refractory patients. Due to the >6 month‐long persistence of daratumumab in the plasma the subsequent therapies can effectively be considered as combination therapy. Furthermore, the excellent tolerability of daratumumab treatment may enable patients to recover from prior lines of treatment and receive full dosing of subsequent therapies. In conclusion, a high proportion of RRMM patients benefitted from retreatment with IMiDs and PIs after daratumumab treatment. These retreatment options should therefore be explored in RRMM patients progressing on daratumumab monotherapy.
Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells
Authors: Paulus Aneel , Manna Alak , Akhtar Sharoon , Paulus Shumail M. , Sharma Mayank , Coignet Marie V. , Jiang Liuyan , Roy Vivek , Witzig Thomas E. , Ansell Stephen M. , Allan John , Furman Richard , Aulakh Sonikpreet , Manochakian Rami , Ailawadhi Sikander , Chanan‐Khan Asher A. , Sher Taimur
Published: August 2018

CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti‐CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells.In vitroDara treatment of WM cells (including ibrutinib‐resistant lines) elicited antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), antibody‐dependent cell phagocytosis (ADCP) and direct apoptosis.In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI‐WM1‐xenografted mice. CD38 is reported to augment B‐cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib‐resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single‐agent Dara or ibrutinib. In summary, we are the first to report thein vitroandin vivoanti‐WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co‐targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.
Prostate artery Embolisation Assessment of Safety and feasibilitY (P‐EASY): a potential alternative to long‐term medical therapy for benign prostate hyperplasia
Authors: Brown Nicholas , Walker Duncan , McBean Rhiannon , Pokorny Morgan , Kua Boon , Gianduzzo Troy , Dunglison Nigel , Esler Rachel , Yaxley John
Published: August 2018

Objectives

To assess the safety, short‐term efficacy and early functional results of prostate artery embolisation (PAE), an emerging minimally invasive treatment for symptomatic benign prostate hyperplasia (BPH).

Patients and methods

In all, 51 men with BPH (prostate size >40 mL) causing moderate–severe lower urinary tract symptoms, who had either failed or ceased medical therapy and had declined or were considered unsuitable for surgical intervention, were recruited to this study. All men underwent baseline clinical assessment, PAE, and 3‐month follow‐up. The primary endpoints of this study were safety and feasibility. Safety was measured by the incidence of post‐PAE adverse events and feasibility was defined by technical success. Secondary endpoints were changes in the International Prostate Symptom Score (IPSS) and quality of life (QoL) score at 3 months after PAE.

Results

There were no serious adverse events and all procedures were technically successful. For non‐catheterised patients, improvement in IPSS and QoL was reported in 95.1% of cases (P < 0.001). The mean reductions in IPSS and QoL were 18.8 points (80.7%) (P < 0.001) and 3.8 points (80.6%) (P < 0.001), respectively. Of the 30 non‐indwelling‐catheter‐dependent men on medical therapy, 23 men were able to completely cease all medications, with all but one of the remaining men reporting significant improvements in IPSS and QoL score.

Conclusion

PAE is a technically feasible and safe procedure, with excellent short‐term efficacy. High rates of patient satisfaction were achieved in this study, along with significant reductions in prostate symptoms and improvements in QoL. PAE may be an alternative to long‐term use of medical therapy for symptoms due to BPH.
Effects of non‐euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice
Authors: Iannotti Fabio Arturo , Pagano Ester , Moriello Aniello Schiano , Alvino Filomena Grazia , Sorrentino Nicolina Cristina , D'Orsi Luca , Gazzerro Elisabetta , Capasso Raffaele , De Leonibus Elvira , De Petrocellis Luciano , Di Marzo Vincenzo
Published: August 2018

Background and Purpose

Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, results in chronic inflammation and irreversible skeletal muscle degeneration. Moreover, the associated impairment of autophagy greatly contributes to the aggravation of muscle damage. We explored the possibility of using non‐euphoric compounds present in Cannabis sativa, cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabidivarin (THCV), to reduce inflammation, restore functional autophagy and positively enhance muscle function in vivo.

Experimental Approach

Using quantitative PCR, western blots and [Ca2+]i measurements, we explored the effects of CBD and CBDV on the differentiation of both murine and human skeletal muscle cells as well as their potential interaction with TRP channels. Male dystrophic mdx mice were injected i.p. with CBD or CBDV at different stages of the disease. After treatment, locomotor tests and biochemical analyses were used to evaluate their effects on inflammation and autophagy.

Key Results

CBD and CBDV promoted the differentiation of murine C2C12 myoblast cells into myotubes by increasing [Ca2+]i mostly via TRPV1 activation, an effect that undergoes rapid desensitization. In primary satellite cells and myoblasts isolated from healthy and/or DMD donors, not only CBD and CBDV but also THCV promoted myotube formation, in this case, mostly via TRPA1 activation. In mdx mice, CBD (60 mg·kg−1) and CBDV (60 mg·kg−1) prevented the loss of locomotor activity, reduced inflammation and restored autophagy.

Conclusion and Implications

We provide new insights into plant cannabinoid interactions with TRP channels in skeletal muscle, highlighting a potential opportunity for novel co‐adjuvant therapies to prevent muscle degeneration in DMD patients.

Linked Articles

This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
Successful treatment of established heart failure in mice with recombinant HDL (Milano)
Authors: Aboumsallem Joseph Pierre , Mishra Mudit , Amin Ruhul , Muthuramu Ilayaraja , Kempen Herman , De Geest Bart
Published: August 2018

Background and Purpose

The pleiotropic properties of HDL may exert beneficial effects on the myocardium. The effect of recombinant HDLMilano on established heart failure was evaluated in C57BL/6 mice.

Experimental Approach

Mice were subjected to transverse aortic constriction (TAC) or sham operation at the age of 14 weeks. Eight weeks later, TAC and sham mice were each randomized into three different groups. Reference groups were killed at day 56 after the operation for baseline analysis. Five i.p. injections of recombinant HDLMilano (MDCO‐216), 100 mg·kg−1, or an equivalent volume of control buffer were administered with a 48 h interval starting at day 56. Endpoint analyses in the control buffer groups and in the MDCO‐216 groups were executed at day 65.

Key Results

Lung weight in MDCO‐216 TAC mice was 25.3% lower than in reference TAC mice and 27.9% lower than in control buffer TAC mice and was similar in MDCO‐216 sham mice. MDCO‐216 significantly decreased interstitial fibrosis and increased relative vascularity compared to reference TAC mice and control buffer TAC mice. The peak rate of isovolumetric relaxation in MDCO‐216 TAC mice was 30.4 and 36.3% higher than in reference TAC mice and control buffer TAC mice respectively. Nitro‐oxidative stress and myocardial apoptosis were significantly reduced in MDCO‐216 TAC mice compared to control buffer TAC mice.

Conclusions and Implications

MDCO‐216 improves diastolic function, induces regression of interstitial fibrosis and normalizes lung weight in mice with established heart failure. Recombinant HDL may emerge as a treatment modality in heart failure.
Inhibition of histone deacetylase 7 reverses concentrative nucleoside transporter 2 repression in colorectal cancer by up‐regulating histone acetylation state
Authors: Ye Chaonan , Han Kun , Lei Jinxiu , Zeng Kui , Zeng Su , Ju Haixing , Yu Lushan
Published: August 2018

Background and Purpose

The concentrative nucleoside transporter 2 (CNT2) mediates the uptake of both natural nucleosides and nucleoside‐derived drugs. Therefore, it is important both physiologically and pharmacologically. However, CNT2 expression is significantly repressed in colorectal cancer (CRC). Here, we have elucidated the mechanism(s) underlying CNT2 repression in CRC.

Experimental Approach

Repression of CNT2 in tumour samples from patients with CRC was identified using Western blot and RT‐qPCR. The histone acetylation state at the CNT2 promoter region was then evaluated with chromatin immunoprecipitation and trichostatin A (TSA) treatment. To find the key enzyme responsible for hypoacetylation at the CNT2 promoter region, siRNA knockdown and RT‐qPCR were used. Effects of combining HDAC inhibitors and cladribine were studied in HCT15 and HT29 cells.

Key Results

Histone deacetylase 7 was significantly up‐regulated in CRC, leading to histone hypoacetylation at the CNT2 promoter region, especially at sites H3K9Ac, H3K18Ac and H4Ac. This hypoacetylation condensed the chromatin structure and reduced CNT2 expression. All these effects were reversed by treatment with TSA, a histone deacetylase inhibitor. In HCT15 and HT29 cells, inhibition of histone deacetylase increased cell uptake and decreased IC50 for cladribine.

Conclusions and Implications

Histone hypoacetylation due to increased levels of histone deacetylase 7 results in CNT2 repression in CRC tumour tissue and could lead to decreased uptake of and consequent resistance to nucleoside anti‐cancer agents. Such resistance could be overcome by combining inhibitors of histone deacetylase with the nucleoside anti‐cancer agent.
A systematic approach for new technology development by using a biomimicry‐based TRIZ contradiction matrix
Authors: Lim Chaeguk , Yun Dooseob , Park Inchae , Yoon Byungun
Published: August 2018

The concept of biomimicry is to bring innovative ideas from nature to find new solutions for technology development or product design. However, there are few studies on proposing a method that connects nature's solutions to technology development in a systematic manner. Since previous studies assume that nature is fundamentally different from technologies, biological approaches should be separated from a technological TRIZ to solve technological problems. This research aims at proposing a systematic process to construct a biomimicry‐based TRIZ contradiction matrix that can be utilized to devise innovative ideas for new technology development by solving a contradictory problem based on biological solutions. To build a contradiction matrix that reflects both technological and biological views, inventive principles in biomimicry fields are extracted by text mining and matched in a cell of an existing TRIZ contradiction matrix by latent dirichlet allocation (LDA). In addition, a biomimicry‐based technology development process is suggested by using 40 inventive principles, 39 engineering parameters of the TRIZ contradiction matrix, and biomimicry cases. The proposed approach can be used as a tool to assist practitioners in solving technological problems and developing new technology by considering biological solutions as well as technological solutions.
Designing radical innovations of meanings for society: Envisioning new scenarios for smart mobility
Authors: Dell'Era Claudio , Altuna Naiara , Verganti Roberto
Published: August 2018

The design‐driven innovation literature focuses on meanings that people give to products and services. This paper investigates how new meanings can be designed and proposed to society rather than to individuals in the particular context of smart mobility. Smart mobility is characterized by a wide range of digital technologies that aim to make all mobility services within a city or territory more accessible and easy to use for citizens. At the same time, to effectively create value, the opportunities digital technologies offer must meet the needs of emerging lifestyles. In modern life, people manifest their interest in the semantic dimension by embracing solutions that are personally constructive and aligned with their cultural values. From an empirical point of view, this paper relies on two case studies that illustrate radical innovation of meanings in the smart mobility domain. Both case studies suggest a multi‐level perspective: on the one hand, they address landscape pressure and the need for more sustainable solutions for future mobility; on the other hand, they propose a new understanding of transport and travel.
Integrated fluorescent cytology with nano‐biologics in peritoneally disseminated gastric cancer
Authors: Watanabe Megumi , Kagawa Shunsuke , Kuwada Kazuya , Hashimoto Yuuri , Shigeyasu Kunitoshi , Ishida Michihiro , Sakamoto Shuichi , Ito Atene , Kikuchi Satoru , Kuroda Shinji , Kishimoto Hiroyuki , Tomida Shuta , Yoshida Ryuichi , Tazawa Hiroshi , Urata Yasuo , Fujiwara Toshiyoshi
Published: August 2018

Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology‐positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology‐positive gastric cancer patients, using a green fluorescent protein (GFP)‐expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP‐401). The fluorescence emitted from TelomeScan‐positive cells was successfully quantified using a multi‐mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology‐positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus‐guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.
Prenatal exposure to dental amalgam and risk of symptoms of attention‐deficit and hyperactivity disorder (ADHD)
Authors: Lygre Gunvor B. , Aase Heidi , Haug Kjell , Lie Stein A. , Björkman Lars
Published: August 2018

Background

ADHD is multifactorial, including both genetic and environmental factors. The safety of amalgam used in dental treatment has been discussed due to its content of mercury and potential risks for negative neurodevelopmental consequences in the offspring. The aim of the study was to investigate possible associations between symptoms related to ADHD in children of three and five years of age and prenatal exposure to mercury from mothers’ amalgam fillings.

Methods

Data from the Norwegian Mother and Child Cohort Study (MoBa) were used. Data were collected by questionnaires sent to participating women in week 17 (Q1) and 30 (Q3) of pregnancy and when the child was three (Q6) and five years of age (Q7). Information about exposure to amalgam during pregnancy was obtained from Q3. Information about symptoms related to ADHD was obtained from Q6 and Q7. Valid data were obtained for 42 163 children at three years of age and 23 392 children at five years of age. Logistic regression models, including mothers’ age, education, body mass index, parity, smoking and alcohol consumption during pregnancy, were used to estimate the association between ADHD symptoms and prenatal exposure to amalgam fillings.

Results

No significant associations between number of teeth with amalgam filling, amalgam fillings placed or removed during pregnancy, and symptoms related to ADHD in children of three and five years of age were found.

Conclusions

In a large, prospective cohort study, we found no indication of increased risk of ADHD‐related symptoms in children prenatally exposed to mother's amalgam fillings.
Dental caries and anthropometric measures in a sample of 5‐ to 9‐year‐old children in Dhaka, Bangladesh
Authors: Mishu Masuma Pervin , Tsakos Georgios , Heilmann Anja , Watt Richard G.
Published: August 2018

Aim

This study aimed to assess associations between dental caries and anthropometric measures among a sample of children aged 5‐9 years in Dhaka, Bangladesh.

Methods

A cross‐sectional observational study was conducted among 5‐ to 9‐year‐old children in Dhaka, Bangladesh. Data were collected from children and their parents attending the Dhaka Dental College Hospital and from three nearby primary schools. The outcome measures were as follows: age and sex adjusted height‐z‐scores (HAZ), weight‐z‐scores (WAZ) and BMI‐z‐scores (BAZ). Multiple linear regressions were used to assess the associations between caries and anthropometric measures, adjusted for maternal education, family income, study setting, birth weight and childhood diseases as potential confounders.

Results

The final sample comprised 788 children, and the overall response rate was 96.7%. The majority (73.2%) had experience of dental caries. The mean dmft + DMFT score was 2.84 (95% CI 2.64, 3.03) and 35.8% experienced dental sepsis. Dental caries and sepsis were negatively associated with HAZ, WAZ and BAZ scores. After adjustment for potential confounders, children with severe levels of caries had lower HAZ scores (coefficient: −0.40; 95% CI −0.69, −0.10), lower WAZ scores (coefficient: −0.59; 95% CI −0.94, −0.24) and lower BAZ scores (coefficient: −0.50; 95% CI −0.87, −0.13) than those who were caries free. Children with moderate levels of caries also had lower WAZ scores (coefficient: −0.43; 95% CI −0.72, −0.15) and lower BAZ scores (coefficient: −0.43; 95% CI −0.72, −0.13) than caries‐free children. Children with dental sepsis had lower HAZ (coefficient: −0.23; 95% CI −0.42, −0.03), WAZ (coefficient: −0.33; 95% CI −0.56, −0.10) and BAZ scores (coefficient: −0.29; 95% CI −0.53, −0.05) than dental sepsis‐free children.

Conclusions

Dental caries was associated with lower height, weight and BMI among this sample of Bangladeshi children, even after adjusting for age and sex and a number of potential confounders.
Efficacy and safety of allergen immunotherapy in patients with allergy to molds: A systematic review
Authors: Di Bona Danilo , Frisenda Flavia , Albanesi Marcello , Di Lorenzo Gabriele , Caiaffa Maria Filomena , Macchia Luigi
Published: August 2018

Background

Allergen immunotherapy (AIT) with mould extracts has been performed for many years but the final demonstration of its clinical efficacy is still missing, due to the small number of studies and their inconsistent results.

Objective

To systematically review efficacy and safety of AIT for the treatment of respiratory allergies to moulds.

Design

The primary outcomes were safety and reduction of symptoms (Symptom Score, SS) and medication use (Medication Score, MS) in patients treated with AIT compared to controls. The strength of the evidence was graded based on the risk of bias, consistency and magnitude of effect, according to the GRADE Working Group's guide.

Data sources

Medline, Web of Science and the Cochrane Library (through September 2017) supplemented with manual searches of reference lists.

Eligibility criteria

Randomized studies of intervention comparing AIT to placebo/pharmacotherapy. Studies not reporting on our outcome of interest or without a control population were excluded.

Results

Nine studies (168 children, 99 adults; median sample size, 27) met the inclusion criteria. The risk of bias was moderate‐to‐high in all but one study. Low strength evidence supports the assumption that AIT is effective in reducing symptoms and medication use, with only four of nine studies reporting higher benefit of AIT vs. comparators. The highest benefit of AIT compared to pharmacotherapy/placebo was reported in studies with a longer follow‐up (SMD for MS from −3.96 to −3.97 in favour of AIT) and low risk of bias (VAS for SS: 66.3 ± 13 in AIT group; 186.6 ± 39 in comparators; P < 0.05). No difference was reported with respect to study sample size, route of administration, age of participants. Generalised adverse reactions were reported in 12.5% of participants treated with sublingual immunotherapy, and 37.2% of participants treated with subcutaneous immunotherapy.

Conclusions

Low strength evidence suggests that mould AIT is efficacious for the treatment of respiratory allergies. High‐quality studies with an adequate sample size are needed.
Inhibition of H3K27me3 demethylases attenuates asthma by reversing the shift in airway smooth muscle phenotype
Authors: Yu Qijun , Yu Xiaowei , Zhao Wenxue , Zhu Manni , Wang Zhengxia , Zhang Jiaxiang , Huang Mao , Zeng Xiaoning
Published: August 2018

Background

The shift in airway smooth muscle cells (ASMCs) phenotype between proliferation and contraction during asthma has been reported recently, highlighting a role of ASMCs plasticity in the pathophysiology of asthma. As an event involved in epigenetic post‐translational modification, histone H3 lysine27 (H3K27) demethylation has attracted significant attention with respect to the epigenetic changes in diverse cells; however, little is known about its contribution to the switching of ASMCs phenotype in asthma.

Objective

To investigate the role of trimethylated H3K27 (H3k27me3) demethylation in ASM remodelling as well as the underling mechanism.

Methods

Mice were exposed five times a week to house dust mite (HDM) extract for 5 weeks. Lung function was measured following the final HDM challenge. Airway inflammation and remodelling were then assessed in lungs of individual mice. Human ASMCs were purchased from Sciencell Research Laboratories. Proliferation, synthesis, migration and contraction of ASMCs were analysed, respectively.

Results

We observed demethylation at H3k27me3 sites in lungs harvested from mice exposed to HDM extract. Administration of a selective inhibitor of H3K27 demethylase (GSK‐J4) could ameliorate the classical hallmarks of asthma, such as airway hyperresponsiveness, airway inflammation and remodelling. We established a proliferative as well as a contractive model of human ASMCs to explore the impacts of H3K27 demethylase inhibition on ASMCs phenotype. Our results indicated that GSK‐J4 decreased ASMCs proliferation and migration elicited by PDGF through the Akt/JNK signalling; GSK‐J4 also prevented the upregulation of contractile proteins in ASMCs induced by TGF‐β through the Smad3 pathway.

Conclusions

Inhibition of H3K27me3 demethylation alleviated the development of asthmatic airway disease in vivo and modulated ASMCs phenotype in vitro. Collectively, our findings highlight a role of H3K27me3 demethylation in experimental asthma and ASMCs phenotype switch.
Molecular genetics of hypospadias and cryptorchidism recent developments
Authors: Kalfa Nicolas , Gaspari Laura , Ollivier Margot , Philibert Pascal , Bergougnoux Anne , Paris Francoise , Sultan Charles
Published: August 2018

During the last decade, a tremendous amount of work has been devoted to the study of the molecular genetics of isolated hypospadias and cryptorchidism, two minor forms of disorders of sex development (DSD). Beyond the genes involved in gonadal determination and sex differentiation, including those underlying androgen biosynthesis and signaling, new genes have been identified through genome‐wide association study and familial clustering. Even if no single genetic defect can explain the whole spectrum of DSD, these recent studies reinforce the strong role of the genetic background in the occurrence of these defects. The timing of signaling disruption may explain the different phenotypes.
Degeneration of white matter and gray matter revealed by diffusion tensor imaging and pathological mechanism after spinal cord injury in canine
Authors: Liu Chang‐Bin , Yang De‐Gang , Zhang Xin , Zhang Wen‐Hao , Li Da‐Peng , Zhang Chao , Qin Chuan , Du Liang‐Jie , Li Jun , Gao Feng , Zhang Jie , Zuo Zhen‐Tao , Yang Ming‐Liang , Li Jian‐Jun
Published: August 2018

Aim

Exploration of the mechanism of spinal cord degeneration may be the key to treatment of spinal cord injury (SCI). This study aimed to investigate the degeneration of white matter and gray matter and pathological mechanism in canine after SCI.

Methods

Diffusion tensor imaging (DTI) was performed on canine models with normal (n = 5) and injured (n = 7) spinal cords using a 3.0T MRI scanner at precontusion and 3 hours, 24 hours, 6 weeks, and 12 weeks postcontusion. The tissue sections were stained using H&E and immunohistochemistry.

Results

For white matter, fractional anisotropy (FA) values significantly decreased in lesion epicenter, caudal segment 1 cm away from epicenter, and caudal segment 2 cm away from epicenter (P = 0.003, P = 0.004, and P = 0.013, respectively) after SCI. Apparent diffusion coefficient (ADC) values were initially decreased and then increased in lesion epicenter and caudal segment 1 cm away from epicenter (P < 0.001 and P = 0.010, respectively). There are no significant changes in FA and ADC values in rostral segments (P > 0.05). For gray matter, ADC values decreased initially and then increased in lesion epicenter (P < 0.001), and overall trend decreased in caudal segment 1 cm away from epicenter (P = 0.039). FA values did not change significantly (P > 0.05). Pathological examination confirmed the dynamic changes of DTI parameters.

Conclusion

Diffusion tensor imaging is more sensitive to degeneration of white matter than gray matter, and the white matter degeneration may be not symmetrical which meant the caudal degradation appeared to be more severe than the rostral one.
The delta‐opioid receptor and Parkinson’s disease
Authors: Huang Jin‐Zhong , Ren Yi , Xu Yuan , Chen Tao , Xia Terry C. , Li Zhuo‐Ri , Zhao Jian‐Nong , Hua Fei , Sheng Shi‐Ying , Xia Ying
Published: August 2018

Parkinson’s disease (PD) is a common degenerative neurological disease leading to a series of familial, medical, and social problems. Although it is known that the major characteristics of PD pathophysiology are the dysfunction of basal ganglia due to injury/loss of dopaminergic neurons in the substantia nigra pars compacta dopaminergic and exhaustion of corpus striatum dopamine, therapeutic modalities for PD are limited in clinical settings up to date. It is of utmost importance to better understand PD pathophysiology and explore new solutions for this serious neurodegenerative disorder. Our recent work and those of others suggest that the delta‐opioid receptor (DOR) is neuroprotective and serves an antiparkinsonism role in the brain. This review summarizes recent progress in this field and explores potential mechanisms for DOR‐mediated antiparkinsonism.
No net loss for people and biodiversity
Authors: Griffiths Victoria F. , Bull Joseph W. , Baker Julia , Milner‐Gulland E.J.
Published: August 2018

Governments, businesses, and lenders worldwide are adopting an objective of no net loss (NNL) of biodiversity that is often partly achieved through biodiversity offsetting within a hierarchy of mitigation actions. Offsets aim to balance residual losses of biodiversity caused by development in one location with commensurate gains at another. Although ecological challenges to achieve NNL are debated, the associated gains and losses for local stakeholders have received less attention. International best practice calls for offsets to make people no worse off than before implementation of the project, but there is a lack of clarity concerning how to achieve this with regard to people's use and nonuse values for biodiversity, especially given the inevitable trade‐offs when compensating biodiversity losses with gains elsewhere. This is particularly challenging for countries where poor people depend on natural resources. Badly planned offsets can exacerbate poverty, and development and offset impacts can vary across spatial‐temporal scales and by location, gender, and livelihood. We conceptualize the no‐worse‐off principle in the context of NNL of biodiversity, by exploring for whom and how the principle can be achieved. Changes in the spatial and temporal distribution of biodiversity‐related social impacts of a development and its associated offset can lead to social inequity and negatively impact people's well‐being. The level of aggregation (regional, village, interest group, household, and individual) at which these social impacts are measured and balanced can again exacerbate inequity in a system. We propose that a determination that people are no worse off, and preferably better off, after a development and biodiversity offset project than they were before the project should be based on the perceptions of project‐affected people (assessed at an appropriate level of aggregation); that their well‐being associated with biodiversity losses and gains should be at least as good as it was before the project; and that this level of well‐being should be maintained throughout the project life cycle. Employing this principle could help ensure people are no worse off as a result of interventions to achieve biodiversity NNL.
Exploring deep neural networks for multitarget stance detection
Authors: Sobhani Parinaz , Inkpen Diana , Zhu Xiaodan
Published: August 2018

Detecting subjectivity expressed toward concerned targets is an interesting problem and has received intensive study. Previous work often treated each target independently, ignoring the potential (sometimes very strong) dependency that could exist among targets (eg, the subjectivity expressed toward two products or two political candidates in an election). In this paper, we relieve such an independence assumption in order to jointly model the subjectivity expressed toward multiple targets. We propose and show that an attention‐based encoder‐decoder framework is very effective for this problem, outperforming several alternatives that jointly learn dependent subjectivity through cascading classification or multitask learning, as well as models that independently predict subjectivity toward individual targets.
The pulmonary artery‐aorta ratio: Is it related to quality of life in chronic obstructive pulmonary disease?
Authors: Ghobadi Hassan , Janbazi Hamid , Matin Somaieh , Lari Shahrzad M. , Ansarin Khalil
Published: August 2018

Introduction

Little is known about the relationship between health status and pulmonary artery diameter in chronic obstructive pulmonary disease (COPD) patients. The aim of this study was to evaluate correlation between pulmonary artery‐aorta ratio (P‐A ratio) and health status of the individuals, using COPD assessment test (CAT).

Materials and Methods

In a cross‐sectional study, 112 COPD patients were recruited. The severity of COPD was determined by global initiative for obstructive lung disease (GOLD). After digital chest CT scan, the P‐A ratio was measured at the level of bifurcation and compared with CAT score, GOLD stage, exacerbation rate and Modified Medical Research Council (MMRC) score.

Results

The average P‐A ratio was 0.89 ± 0.16 and 62.5% of patients had ratio less than one. The P‐A ratio correlates significantly with different GOLD stages, CAT score and MMRC score (P < .001, P < .001, P < .001, respectively). Compared patients with low P‐A ratio (<1), those with high P‐A ratio (≥ 1) showed higher CAT score [11.94 ± 5.94 vs 25.17 ± 5.84] (P < .001). The P‐A ratio was significantly higher in frequent (≥2) comparing low (<2) exacerbations [1.07 ± 0.07 vs 0.77 ± 0.06] (P < .001).

Conclusion

Significant correlations were found between P‐A ratio and GOLD, exacerbation rate and health status, using CAT of patients with COPD. These findings also may suggest the potential role of P‐A ratio, in the management of COPD patients.
A case‐control study of the genetic polymorphism of IL6 and HAPE risk in a Chinese Han population
Authors: He Xue , Wang Li , Zhu Linhao , Yuan Dongya , He Yongjun , Jin Tianbo
Published: August 2018

Aims

The role of inflammatory cytokines in High‐altitude pulmonary edema (HAPE) remains unclear. The purpose of this study was to evaluate the role of IL4 and IL6 gene polymorphism in the development of HAPE in Chinese people.

Methods

In the present study, we screened ten polymorphisms of IL4 and IL6 gene in 265 HAPE and 303 healthy volunteers. Genotypes were determined using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression.

Results

Two single‐nucleotide polymorphisms (SNPs) in the IL6 gene were significantly associated with HAPE. Rs1800796 and rs1524107 (G vs C, OR = 1.31, 95%CI = 1.01‐1.69, P = .041 and T vs C, OR = 1.35, 95%CI = 1.05‐1.74, P = .020, respectively). However, there did not found any association for IL4 gene.

Conclusion

Inflammatory cytokines may play a role in the progress of HAPE. These polymorphisms could be genetic markers for predicting the susceptibility to HAPE.
Clinical impact of pretreatment prognostic nutritional index (PNI) in small cell lung cancer patients treated with platinum‐based chemotherapy
Authors: Jin Shi , Cao Shoubo , Xu Shanqi , Wang Chunyan , Meng Qingwei , Yu Yan
Published: August 2018

Introduction

Numbers of prognostic factors of small cell lung cancer (SCLC) have been demonstrated in previous studies. However, the identification of biomarkers with easy access, convenience, and low consumption is of great value in clinics.

Objectives

In order to find such a biomarker, a single institution study with 1156 SCLC patients was retrospectively conducted to assess the prognostic value of prognostic nutritional index (PNI) on SCLC patients treated with platinum‐based chemotherapy.

Methods

The optimal cut‐off values were determined by a receiver operating characteristic (ROC) curve analysis. Univariate and multivariate analyses were used to assess their prognostic values for overall survival (OS).

Results

On univariate analysis, age, smoking history, tumor stage, PNI, radiotherapy, and surgery were significantly associated with OS. Age, stage, PNI, radiotherapy, and surgery held statistical significance on multivariate analysis. High PNI was closely associated with younger age, limited disease, and radiotherapy. PNI was also demonstrated to be an independent prognostic factor in subgroups analysis, especially in patients with age ≤ 60, no smoking history, no family history of tumor, and no radiotherapy.

Conclusions

Age ≤ 60 years, limited disease, high PNI, radiotherapy, and surgery were independent positive prognostic factors of SCLC patients treated with chemotherapy. PNI was a good biomarker for the assessment of SCLC prognosis for its easy access, convenience to be calculated, and low consumption. Pretreatment PNI can better predict the prognosis of SCLC, especially in patients with age ≤ 60, no smoking history, no family history of tumor, and no radiotherapy.
Impact of baseline characteristics on extensive‐stage SCLC patients treated with etoposide/carboplatin: A secondary analysis of a phase III study
Authors: Abdel‐Rahman Omar
Published: August 2018

Background

The purpose of the current study is to investigate the impact of baseline characteristics on the outcomes of extensive‐stage small cell lung cancer (SCLC) patients recruited into a clinical trial.

Methods

This is a secondary analysis of the control arm (etoposide/carboplatin arm) of the ‘NCT00363415’ study which is a phase III study conducted between 2006 and 2007. Univariate analysis of factors affecting overall and progression‐free survival (PFS) was conducted through Cox regression analysis [including age, race, gender, Eastern Cooperative Oncology Group performance score, body mass index, Lactate dehydrogenase, number of metastatic sites and brain metastases]. Factors with P < .05 in the univariate analysis were then included in the multivariate analysis.

Results

All patients within the control arm (etoposide/carboplatin) were included in the analysis (N = 455 patients). The following factors were predictive of worse overall survival (OS) in univariate analysis (P < .05): performance score = 2, LDH > upper limit of normal and ≥3 metastatic sites. Multivariate Cox regression analysis incorporating these three factors showed that only number of metastatic sites predicts worse OS (P < .0001). Likewise, the following factors were associated with worse PFS in univariate analysis (P < .05): performance score = 2 and ≥ 3 metastatic sites predict worse PFS (P < .05). Multivariate analysis incorporating these two factors showed that only number of metastatic sites predicts worse PFS (P < .0001).

Conclusion

Number of metastatic sites is the most important predictive factor for overall and PFS among patients with extensive‐stage SCLC treated with systemic chemotherapy within a clinical trial.
Knowledge, attitudes, and planned practice of HIV‐positive to HIV‐positive transplantation in US transplant centers
Authors: Van Pilsum Rasmussen Sarah E. , Bowring Mary Grace , Shaffer Ashton A. , Henderson Macey L. , Massie Allan , Tobian Aaron A. R. , Segev Dorry L. , Durand Christine M.
Published: August 2018

Background

HIV+ donor organs can now be transplanted into HIV+ recipients (HIV D+/R+) following the HIV Organ Policy Equity (HOPE) Act. Implementation of the HOPE Act requires transplant center awareness and support of HIV D+/R+ transplants.

Methods

To assess center‐level barriers to implementation, we surveyed 209 transplant centers on knowledge, attitudes, and planned HIV D+/R+ protocols.

Results

Responding centers (n = 114; 56%) represented all UNOS regions. Fifty centers (93 organ programs) planned HIV D+/R+ protocols (kidney n = 48, liver n = 34, pancreas n = 8, heart n = 2, lung = 1), primarily in the eastern United States (28/50). Most (91.2%) were aware that HIV D+/R+ transplantation is legal; 21.4% were unaware of research restrictions. Respondents generally agreed with HOPE research criteria except the required experience with ≥5 HIV+ transplants by organ type. Centers planning HIV D+/R+ protocols had higher transplant volume, HIV+ recipient volume, increased infectious risk donor utilization, and local HIV prevalence (P < 0.01). Centers not planning HIV D+/R+ protocols were more likely to believe their HIV+ candidates would not accept HIV+ donor organs (P < 0.001). Most centers (83.2%) supported HIV+ living donation.

Conclusions

Although many programs plan HIV D+/R+ transplantation, center‐level barriers remain including geographic clustering of kidney/liver programs and concerns about HIV+ candidate willingness to accept HIV+ donor organs.
Donor‐derived hepatitis C in the era of increasing intravenous drug use: A report of the Disease Transmission Advisory Committee
Authors: Kaul Daniel R. , Tlusty Susan M. , Michaels Marian G. , Limaye Ajit P. , Wolfe Cameron R.
Published: August 2018

The opioid epidemic has resulted in a potential increase in donors in the testing window period for hepatitis C virus (HCV). We analyzed HCV reports to the Disease Transmission Advisory Committee (DTAC) between 2008 and 2016 to estimate the risk of HCV transmission. In 15 of 95 (16%) reports, at least one recipient developed proven/probable donor‐derived HCV resulting in 32 infected recipients. Seven transmissions occurred during the nucleic acid testing (NAT) window period; four occurred during serological window period. The other four transmission occurred due to human error (3) and false‐negative serology (1). All seronegative‐exposed liver and lung recipients contracted HCV; 18/21 (86%) kidney and 3/4 (75%) heart recipients developed HCV. Four transmitting donors died of intravenous drug overdose, three in 2016 and one in 2012. Among donors with a history of intravenous drug use (IVDU), drug intoxication as a mechanism of death, or increased risk status, and negative screening HCV testing, the risk of transmission to a recipient was about 1 in 1000. The overall risk of transmitting HCV from NAT‐negative donors with IVDU is low and consistent with modeling data. This information may be helpful to clinicians counseling potential recipients offered these organs.
Transplant‐associated thrombotic microangiopathy: Incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation
Authors: Gavriilaki Eleni , Sakellari Ioanna , Batsis Ioannis , Mallouri Despina , Bousiou Zoi , Vardi Anna , Yannaki Evangelia , Constantinou Varnavas , Tsompanakou Aliki , Vadikoliou Chrysanthi , Kaloyannidis Panayotis , Bamihas Gerasimos , Anagnostopoulos Achilles
Published: August 2018

Renewed interest has emerged in transplant‐associated thrombotic microangiopathy (TA‐TMA) with novel prognostic, diagnostic, and treatment algorithms. We aimed to investigate the incidence, prognostic factors, morbidity, and mortality of TA‐TMA in allogeneic hematopoietic cell transplantation (HCT) recipients. We enrolled consecutive HCT recipients (1990‐2017). Among 758 patients, 116 (15.5%) were diagnosed with TA‐TMA. In the multivariate analysis, TBI‐based conditioning, viral infections, acute and chronic GVHD remained independent predictors of TA‐TMA. With a median follow‐up of 23 (range 0.1‐329) months, TA‐TMA resulted in significantly lower overall survival (OS). In the multivariate analysis, TA‐TMA remained an independent predictor of OS, along with relapse, acute, and chronic GVHD. Among 116 TA‐TMA patients, 70 developed renal (56) and/or neurologic (26) dysfunction that would be necessary for TA‐TMA diagnosis according to the Bone Marrow Transplant Clinical Trials Network criteria. TA‐TMA patients with renal dysfunction showed increased rates of acute GVHD, but no difference in OS compared to patients without renal dysfunction. However, neurologic dysfunction resulted in significantly lower OS. In conclusion, TA‐TMA is associated with increased morbidity and mortality in allogeneic transplant recipients. Successful prevention and treatment strategies of infections and GVHD need to be timely employed to improve survival in this complex setting.
Distinctive features of low‐grade myofibroblastic sarcoma on aspiration cytology: A case report
Authors: Taweevisit Mana , Thorner Paul Scott
Published: August 2018

Fine needle aspiration of a parotid mass in a 66 year old male showed spindle‐shaped cells interpreted as the myoepithelial component of a pleomorphic adenoma. Pathologic examination of the resection specimen showed, instead, a low‐grade myofibroblastic sarcoma. Review of the cytological material revealed features that should aid in the recognition of this entity.
Basistherapie bei atopischer Dermatitis – Neues und Bewährtes
Authors: Chylla Ricarda , Schnopp Christina , Volz Thomas
Published: August 2018

Die Basistherapie stellt eine tragende Säule in der Behandlung der atopischen Dermatitis dar. Sie ist unabhängig vom Schweregrad der Erkrankung in allen Stadien indiziert. Eine konsequente Basistherapie trägt entscheidend zur Wiederherstellung der gestörten Barrierefunktion, zur Reduktion der Xerosis und des Juckreizes bei. Überdies konnte eine Einsparung von topischen Steroiden durch eine gleichzeitig durchgeführte Basistherapie bei akuter atopischer Dermatitis gezeigt werden. Im Langzeitmanagement der Erkrankung führt sie zu einem verlängerten rezidivfreien Intervall. Neuere Studien zeigen einen protektiven Effekt einer früh begonnenen Basistherapie hinsichtlich der Entwicklung einer atopischen Dermatitis. Im folgenden Review sollen diese Aspekte unter Berücksichtigung klassischer Basistherapeutika und neuerer Entwicklungen aufgezeigt werden.