bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive and brain structural changes in long-term oligodendroglial tumor survivors
Authors: Cayuela Nuria , Jaramillo-Jiménez Esteban , Càmara Estela , Majós Carles , Vidal Noemi , Lucas Anna , Gil-Gil Miguel , Graus Francesc , Bruna Jordi , Simó Marta
Published: July 2019

Background

We identify cognitive impairment and MRI structural brain changes in long-term oligodendroglial tumor survivors treated with radiation therapy (RT) alone (21%) or with chemotherapy (CT) (79%).

Methods

Oligodendroglial tumor patients (based on the World Health Organization [WHO] 2007 classification) who completed RT ± CT at least 2 years before the study initiation, were classified into 3 groups according to the time treatment was completed: Group 1 = 2–5 years (n = 22), Group 2 = 6–10 years (n = 13), and Group 3 >10 years (n = 13). All patients had a cross-sectional neuropsychological evaluation (n = 48) and a longitudinal volumetric analysis (gray matter [GM; n = 34]) between postsurgical and last follow-up MRI. White matter (WM) changes on MRI were assessed using a qualitative scale.

Results

There were no differences regarding tumor or treatment-related characteristics between groups. Six of 22 patients (27.3%) in Group 1; 5/13 (38.5%) in Group 2; and 9/13 (69.2%) in Group 3 had cognitive impairment that was considered severe in 3/22 patients (13.6%) in Group 1; 4/13 (30.8%) in Group 2; and 6/13 (46.2%) in Group 3. Patients in Groups 2 and 3 showed significant GM atrophy and more leukoencephalopathy than Group 1. Cognitive deficits were associated with brain atrophy and WM changes.

Conclusions

Long-term oligodendroglial tumor survivors who underwent standard RT ± CT treatment, mainly >5 years of its completion, present cognitive impairment, especially on memory and executive functions, associated with late GM and WM damage, thus highlighting the need of developing future strategies in patients with oligodendroglial tumor and long expected survival.
Temporal muscle thickness is an independent prognostic marker in patients with progressive glioblastoma: translational imaging analysis of the EORTC 26101 trial
Authors: Furtner Julia , Genbrugge Els , Gorlia Thierry , Bendszus Martin , Nowosielski Martha , Golfinopoulos Vassilis , Weller Michael , van den Bent Martin J , Wick Wolfgang , Preusser Matthias
Published: July 2019

Background

Temporal muscle thickness (TMT) was described as a surrogate marker of skeletal muscle mass. This study aimed to evaluate the prognostic relevance of TMT in patients with progressive glioblastoma.

Methods

TMT was analyzed on cranial MR images of 596 patients with progression of glioblastoma after radiochemotherapy enrolled in the European Organisation for Research and Treatment of Cancer 26101 trial. An optimal TMT cutoff for overall survival (OS) and progression-free survival (PFS) was defined in the training cohort (n = 260, phase II). Patients were grouped as “below” or “above” the TMT cutoff and associations with OS and PFS were tested using the Cox model adjusted for important risk factors. Findings were validated in a test cohort (n = 308, phase III).

Results

An optimal baseline TMT cutoff of 7.2 mm was obtained in the training cohort for both OS and PFS (area under the curve = 0.64). Univariate analyses estimated a hazard ratio (HR) of 0.54 (95% CI: 0.42, 0.70; P < 0.0001) for OS and an HR of 0.49 (95% CI: 0.38, 0.64; P < 0.0001) for PFS for the comparison of training cohort patients above versus below the TMT cutoff. Similar results were obtained in Cox models adjusted for important risk factors with relevance in the trial for OS (HR, 0.54; 95% CI: 0.41, 0.70; P < 0.0001) and PFS (HR, 0.47; 95% CI: 0.36, 0.61; P < 0.0001). Results were confirmed in the validation cohort.

Conclusion

Reduced TMT is an independent negative prognostic parameter in patients with progressive glioblastoma and may help to facilitate patient management by supporting patient stratification for therapeutic interventions or clinical trials.
Gene regulatory network stabilized by pervasive weak repressions: microRNA functions revealed by the May–Wigner theory
Authors: Chen Yuxin , Shen Yang , Lin Pei , Tong Ding , Zhao Yixin , Allesina Stefano , Shen Xu , Wu Chung-I
Published: July 2019

Food web and gene regulatory networks (GRNs) are large biological networks, both of which can be analyzed using the May–Wigner theory. According to the theory, networks as large as mammalian GRNs would require dedicated gene products for stabilization. We propose that microRNAs (miRNAs) are those products. More than 30% of genes are repressed by miRNAs, but most repressions are too weak to have a phenotypic consequence. The theory shows that (i) weak repressions cumulatively enhance the stability of GRNs, and (ii) broad and weak repressions confer greater stability than a few strong ones. Hence, the diffuse actions of miRNAs in mammalian cells appear to function mainly in stabilizing GRNs. The postulated link between mRNA repression and GRN stability can be seen in a different light in yeast, which do not have miRNAs. Yeast cells rely on non-specific RNA nucleases to strongly degrade mRNAs for GRN stability. The strategy is suited to GRNs of small and rapidly dividing yeast cells, but not the larger mammalian cells. In conclusion, the May–Wigner theory, supplanting the analysis of small motifs, provides a mathematical solution to GRN stability, thus linking miRNAs explicitly to ‘developmental canalization’.
Topological domain states and magnetoelectric properties in multiferroic nanostructures
Authors: Tian Guo , Yang Wenda , Chen Deyang , Fan Zhen , Hou Zhipeng , Alexe Marin , Gao Xingsen
Published: July 2019

Multiferroic nanostructures have been attracting tremendous attention over the past decade, due to their rich cross-coupling effects and prospective electronic applications. In particular, the emergence of some exotic phenomena in size-confined multiferroic systems, including topological domain states such as vortices, center domains, and skyrmion bubble domains, has opened a new avenue to a number of intriguing physical properties and functionalities, and thus underpins a wide range of applications in future nanoelectronic devices. It is also highly appreciated that nano-domain engineering provides a pathway to control the magnetoelectric properties, which is promising for future energy-efficient spintronic devices. In recent years, this field, still in its infancy, has witnessed a rapid development and a number of challenges too. In this article, we shall review the recent advances in the emergent domain-related exotic phenomena in multiferroic nanostructures. Specific attention is paid to the topological domain structures and related novel physical behaviors as well as the electric-field-driven magnetic switching via domain engineering. This review will end with a discussion of future challenges and potential directions.
Structures and electronic properties of domain walls in BiFeO3 thin films
Authors: Huyan Huaixun , Li Linze , Addiego Christopher , Gao Wenpei , Pan Xiaoqing
Published: July 2019

Domain walls (DWs) in ferroelectrics are atomically sharp and can be created, erased, and reconfigured within the same physical volume of ferroelectric matrix by external electric fields. They possess a myriad of novel properties and functionalities that are absent in the bulk of the domains, and thus could become an essential element in next-generation nanodevices based on ferroelectrics. The knowledge about the structure and properties of ferroelectric DWs not only advances the fundamental understanding of ferroelectrics, but also provides guidance for the design of ferroelectric-based devices. In this article, we provide a review of structures and properties of DWs in one of the most widely studied ferroelectric systems, BiFeO3 thin films. We correlate their conductivity and photovoltaic properties to the atomic-scale structure and dynamic behaviors of DWs.
Definitions, regulations, and new frontiers for dietary fiber and whole grains
Authors: Korczak Renee , Slavin Joanne L
Published: July 2019

The aim of this article is to review the definitions and regulations for dietary fiber and whole grains worldwide and to discuss barriers to meeting recommended intake levels. Plant foods, such as whole grains, that are rich in dietary fiber are universally recommended in dietary guidance. Foods rich in dietary fiber are recommended for all, but dietary recommendations for whole grains and dietary fiber depend on definitions and regulations. Official recommendations for dietary fiber in the United States and Canada are denoted by dietary reference intakes (DRIs), which are developed by the Institute of Medicine. An adequate intake (AI) for dietary fiber was based on prospective cohort studies of dietary fiber intake and cardiovascular disease risk that found 14 grams of dietary fiber per 1000 kilocalories protected against cardiovascular disease (CVD). This value was used to set AIs for dietary fiber across the life cycle based on recommended calorie intakes. Actual intakes of dietary fiber are generally about half of the recommended levels. Recommendations for whole grain intake are equally challenging, as definitions for whole grain foods are needed to set recommendations. The 2005 Dietary Guidelines for Americans recommended that half of all grain servings be whole grains, but usual intakes are generally less than 1 serving per day, rather than the recommended 3 servings per day. Scientific support for whole grain recommendations is based on the same prospective cohort studies and links to CVD protection used to inform dietary fiber guidance. Thus, dietary fiber is a recommended nutrient and whole grains are a recommended dietary pattern in dietary guidance in North America and around the world. Challenges for attaining recommended intakes of dietary fiber and whole grains include low-carbohydrate diets, low-gluten diets, and public health recommendations to avoid processed foods.
Heats of combustion of the main carbohydrates contained in plant-source foods
Authors: Sánchez-Peña María Judith , Martínez-Navarro Ana Guadalupe , Márquez-Sandoval Fabiola , Gutiérrez-Pulido Humberto , Pacheco-Moisés Fermín Paul , González-Ortiz Luis Javier
Published: July 2019

In a previous review, the experiments of American chemist W.O. Atwater were critically examined, with the findings demonstrating certain weaknesses that could compromise the validity of the values currently used for metabolizable energy. An examination of published works on the heat of combustion of carbohydrates reveals 2 types of weaknesses: the inaccuracy and imprecision of the calorimetric data used, and the averaging procedure employed to estimate such representative values. The present review focuses on the first type of weakness, namely the inaccuracy and imprecision of the calorimetric data used in previous studies. An exhaustive bibliographic search yielded almost 100 heat of combustion values for some of the 6 main carbohydrates contained in plant-source foods (glucose, fructose, sucrose, maltose, starch, and cellulose). These heats of combustion were subjected to rigorous statistical analysis to propose the following for each carbohydrate: (1) an interval (termed a bibliographic interval) that very likely includes the actual heat of combustion value and (2) a “representative value” (calculated to produce the minimum level of inaccuracy). In addition, an estimation of the maximum level of inaccuracy that could be expected when using such a representative value is reported.
Patient-centred care in an occupational medicine clinic
Authors: Lari S , Thompson A M S , Spilchuk V , Afanasyeva M , Holness D L
Published: July 2019

Background

Patient-centred care (PCC) has been associated with improved patient satisfaction outcomes in a variety of clinical settings. There is a paucity of research addressing the concept of PCC in an occupational medicine context.

Aims

To assess patient perception and compare physician and patient perceptions of patient centredness of the care at a specialty occupational medicine clinic.

Methods

An observational study design using the Patient Perception of Patient Centeredness Questionnaire (PPPC) at an ambulatory tertiary care occupational health clinic. Results were analysed using a standardized coding system. Summary scores were compared to results reported in a primary care setting. Patient and physician scores were compared to detect physician–patient differences in perceived patient centredness of care.

Results

Of 47 eligible patients 37 consented to participate and seven were excluded due to incomplete data. Summary scores of patient perceptions of patient centredness were similar but somewhat better than scores reported in a primary care setting. Perceived patient centredness of care was high and there was minimal discordance between patient and physician scores.

Conclusions

This study demonstrated that PCC can be measured in an occupational health setting. In an ambulatory tertiary care occupational health clinic there was a high degree of patient centredness of care which may be explained by a variety of factors. Future research should consider whether similar findings exist in other occupational medicine practice settings.
Select Committees and Brexit: Parliamentary Influence in a Divisive Policy Area
Authors: Lynch Philip , Whitaker Richard
Published: July 2019

In this first comprehensive study of House of Commons departmental select committees and Brexit, we analyse the incidence of divisions (i.e. formal votes) on Brexit-related issues in select committees, showing that unanimity remains the norm with the exception of the Exiting the EU Committee, which is the most divided select committee of recent times. We add to the literature on select committee influence by adapting Russell and Benton’s (2011) methodology to examine government responses to committee recommendations on Brexit. We show that most have been partially accepted but that the level of policy change, rather than divisions on recommendations, is the main factor explaining variation, with greater success for recommendations suggesting a lower degree of change. Committees have also had indirect influence, shaping the agenda and bringing information into the public domain.
Q-type asteroids: Possibility of non-fresh weathered surfaces
Authors: Hasegawa Sunao , Hiroi Takahiro , Ohtsuka Katsuhito , Ishiguro Masateru , Kuroda Daisuke , Ito Takashi , Sasaki Sho
Published: July 2019

Itokawa particles, which are samples recovered from the S-complex asteroid 25143 Itokawa by the Hayabusa spacecraft, demonstrate that S-complex asteroids are parent bodies of ordinary chondrite meteorites. Furthermore, they clarify that the space-weathering age of the Itokawa surface is of the order of several thousand years. Traditionally, Q-type asteroids have been considered fresh-surfaced. However, as the space-weathering timescale is approximately three orders of magnitude lesser than the conventionally considered age, the previously proposed formation mechanisms of Q-type asteroids cannot sufficiently explain the surface refreshening. In this study, we propose a new hypothesis on the surface state of Q-type asteroids: Q-type asteroids have a non-fresh weathered surface with a paucity of fine particles. For verifying this hypothesis, laboratory experiments on the space weathering of ordinary chondrites are performed. Based on the results of these experiments, we found that large (more than $100\, \mu \mathrm{m}$) ordinary chondritic particles with space weathering exhibit spectra consistent with Q-type asteroids.
Multifactorial and Species-Specific Feedback Regulation of the RNA Surveillance Pathway Nonsense-Mediated Decay in Plants
Authors: Kesarwani Anil K , Lee Hsin-Chieh , Ricca Patrizia G , Sullivan Gabriele , Faiss Natalie , Wagner Gabriele , Wunderling Anna , Wachter Andreas
Published: July 2019

Nonsense-mediated decay (NMD) is an RNA surveillance mechanism that detects aberrant transcript features and triggers degradation of erroneous as well as physiological RNAs. Originally considered to be constitutive, NMD is now recognized to be tightly controlled in response to inherent signals and diverse stresses. To gain a better understanding of NMD regulation and its functional implications, we systematically examined feedback control of the central NMD components in two dicot and one monocot species. On the basis of the analysis of transcript features, turnover rates and steady-state levels, up-frameshift (UPF) 1, UPF3 and suppressor of morphological defects on genitalia (SMG) 7, but not UPF2, are under feedback control in both dicots. In the monocot investigated in this study, only SMG7 was slightly induced upon NMD inhibition. The detection of the endogenous NMD factor proteins in Arabidopsis thaliana substantiated a negative correlation between NMD activity and SMG7 amounts. Furthermore, evidence was provided that SMG7 is required for the dephosphorylation of UPF1. Our comprehensive and comparative study of NMD feedback control in plants reveals complex and species-specific attenuation of this RNA surveillance pathway, with critical implications for the numerous functions of NMD in physiology and stress responses.
Unravelling GSNOR-Mediated S-Nitrosylation and Multiple Developmental Programs in Tomato Plants
Authors: Gong Biao , Yan Yanyan , Zhang Lili , Cheng Fei , Liu Zhen , Shi Qinghua
Published: July 2019

Nitric oxide (NO) impacts multiple developmental events and stress responses in plants. S-nitrosylation, regulated by S-nitrosoglutathione reductase (GSNOR), is considered as an important route for NO bioactivity. However, genetic evidence for GSNOR-mediated plant development and S-nitrosylation remains elusive in crop species. Genetic and site-specific nitrosoproteomic approach was used to obtain GSNOR-mediated phenotype and S-nitrosylated network. Knockdown of GSNOR increased the endogenous NO level and S-nitrosylation, resulting in higher germination rate, inhibition of root and hypocotyl growth, decreased photosynthesis, reduced plant growth, altered plant architecture, dysplastic pollen grains, and low fructification rate and fruit yield. For nitrosoproteomic analysis, 395 endogenously S-nitrosylated proteins with 554 S-nitrosylation sites were identified within a wide range of biological processes, especially for energy metabolism. Physiological and exogenous energy-support testing were consistent with the omic result, suggesting that GSNOR-mediated S-nitrosylation of energy metabolism plays key roles in impacting plant growth and development. Taken together, GSNOR is actively involved in the regulation of multiple developmental processes related to agronomically important traits. In addition, our results provide valuable resources and new clues for the study of S-nitrosylation-regulated metabolism in plants.
Competing Endogenous RNA Networks Underlying Anatomical and Physiological Characteristics of Poplar Wood in Acclimation to Low Nitrogen Availability
Authors: Lu Yan , Deng Shurong , Li Zhuorong , Wu Jiangting , Liu Qifeng , Liu Wenzhe , Yu Wen-Jian , Zhang Yuhong , Shi Wenguang , Zhou Jing , Li Hong , Polle Andrea , Luo Zhi-Bin
Published: July 2019

Although poplar plantations are often established on nitrogen (N)-poor soil, the physiological and molecular mechanisms underlying wood properties of poplars in acclimation to low N availability remain largely unknown. To investigate wood properties of poplars in acclimation to low N, Populus ï¿½ canescens saplings were exposed to either 50 (low N) or 500 (normal N) ï¿½M NH4NO3 for 2 months. Low N resulted in decreased xylem width and cell layers of the xylem (the number of cells counted along the ray parenchyma on the stem cross section), narrower lumina of vessels and fibers, greater thickness of double fiber walls (the walls between two adjacent fiber cells), more hemicellulose and lignin deposition, and reduced cellulose accumulation in poplar wood. Consistently, concentrations of gibberellins involved in cell size determination and the abundance of various metabolites including amino acids, carbohydrates and precursors for cell wall biosynthesis were decreased in low N-supplied wood. In line with these anatomical and physiological changes, a number of mRNAs, long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) were significantly differentially expressed. Competing endogenous RNA regulatory networks were identified in the wood of low N-treated poplars. Overall, these results indicate that miRNAs–lncRNAs–mRNAs networks are involved in regulating wood properties and physiological processes of poplars in acclimation to low N availability.
Pain, Anxiety, and Depression in the First Two Years Following Transport-Related Major Trauma: A Population-Based, Prospective Registry Cohort Study
Authors: Giummarra Melita J , Simpson Pamela , Gabbe Belinda J
Published: July 2019

Objectives

This study aimed to characterize the population prevalence of pain and mental health problems postinjury and to identify risk factors that could improve service delivery to optimize recovery of at-risk patients.

Methods

This population-based registry cohort study included 5,350 adult survivors of transport-related major trauma injuries from the Victorian State Trauma Registry. Outcome profiles were generated separately for pain and mental health outcomes using the “pain or discomfort” and “anxiety or depression” items of the EuroQol Five Dimensions Three-Level questionnaire at six, 12, and 24 months postinjury. Profiles were “resilient” (no problems at every follow-up), “recovered” (problems at six- and/or 12-month follow-up that later resolved), “worsening” (problems at 12 and/or 24 months after no problems at six and/or 12 months), and “persistent” (problems at every follow-up).

Results

Most participants had persistent (pain/discomfort, N = 2,171, 39.7%; anxiety/depression, N = 1,428, 26.2%) and resilient profiles (pain/discomfort, N = 1,220, 22.3%; anxiety/depression, N = 2,055, 37.7%), followed by recovered (pain/discomfort, N = 1,116, 20.4%; anxiety/depression, N = 1,025, 18.8%) and worsening profiles (pain/discomfort, N = 956, 17.5%; anxiety/depression, N = 948, 17.4%). Adjusted multinomial logistic regressions showed increased risk of problems (persistent, worsening, or resolved) vs no problems (resilient) in relation to female sex, middle age, neighborhood disadvantage, pre-injury unemployment, pre-injury disability, and spinal cord injury. People living in rural areas, motorcyclists, pedal cyclists, and people with head, chest, and abdominal injuries had lower risk of problems.

Discussion

Targeted interventions delivered to people with the risk factors identified may help to attenuate the severity and impact of pain and mental health problems after transport injury.
Effects of Rescheduling Hydrocodone on Opioid Prescribing in Ohio
Authors: Liu Yingna , Baker Olesya , Schuur Jeremiah D , Weiner Scott G
Published: July 2019

Background

We quantified opioid prescribing after the 2014 rescheduling of hydrocodone from schedule III to II in the United States using a state-wide prescription database and studied trends three years before and after the policy change, focusing on certain specialties.

Methods

We used Ohio’s state prescription drug monitoring program database, which includes all filled schedule II and III prescriptions regardless of payer or pharmacy, to conduct an interrupted time series analysis of the nine most prescribed opioids: hydrocodone, oxycodone, tramadol, codeine, and others. We analyzed hydrocodone prescribing trends for the physician specialties of internal medicine, anesthesiology, and emergency medicine. We evaluated trends 37 months before and after the rescheduling change.

Results

Rescheduling was associated with a hydrocodone level change of –26,358 (95% confidence interval [CI] = –36,700 to –16,016) prescriptions (–5.8%) and an additional decrease in prescriptions of –1,568 (95% CI = –2,296 to –839) per month (–0.8%). Codeine prescribing temporarily increased, at a level change of 6,304 (95% CI = 3,003 to 9,606) prescriptions (18.5%), indicating a substitution effect. Hydrocodone prescriptions by specialty were associated with a level change of –805 (95% CI = –1,280 to –330) prescriptions (–8.5%) for anesthesiologists and a level change of –14,619 (95% CI = –23,710 to –5,528) prescriptions (–10.2%) for internists. There was no effect on prescriptions by emergency physicians.

Conclusions

The 2014 federal rescheduling of hydrocodone was associated with declines in hydrocodone prescriptions in Ohio beyond what had already been occurring, and hydrocodone may have been briefly substituted with codeine. These results indicate that rescheduling did have a lasting effect but affected prescribing specialties variably.
Is the Brief-BESTest Brief Enough? Suggested Modifications Based on Structural Validity and Internal Consistency
Authors: Godi Marco , Giardini Marica , Arcolin Ilaria , Ferrante Simona , Nardone Antonio , Corna Stefano , Colombo Roberto
Published: July 2019

Background

The Brief Balance Evaluation Systems Test (Brief-BESTest) could be a useful tool for balance assessment. Although some psychometric characteristics have been examined, others still need to be clarified.

Objective

The objective was to assess the structural validity, convergent validity, discriminant validity, and internal consistency of the Brief-BESTest in neurological patients.

Design

This was a cross-sectional study.

Methods

Data were from 416 patients with neurological disease and related balance disorders. Patients were assessed with the 5-levels Activities-Specific Balance Confidence Scale (ABC 5-levels), Brief-BESTest, and some simple balance tests (ie, 1-leg stance, Timed “Up & Go” test, functional reach, and a fall history questionnaire). Three Brief-BESTest models were examined through confirmatory factor analysis, and the following indexes were calculated: Comparative Fit Index, Tucker-Lewis Index, and root-mean-square error of approximation. Convergent validity was assessed by calculating the correlation between Brief-BESTest and ABC 5-levels total scores. Receiver operating characteristics assessed the ability of each model to differentiate between people with falls and those without falls. Internal consistency was measured with Cronbach α and coefficient ω.

Results

Confirmatory factor analysis showed model 3 (Comparative Fit Index = 0.97; Tucker-Lewis Index = 0.95; root-mean-square error of approximation = 0.05), with item 1 removed and error covariance between items 3 and 4 and between items 5 and 6, to have a significantly better structure than models 1 and 2. The correlation between Brief-BESTest and ABC 5-levels was 0.61 (Spearman ρ) for all 3 models. The area under the curve of the receiver operating characteristics showed an acceptable accuracy (0.72) in distinguishing patients with a history of falls from those without a history of falls (95% confidence interval = 0.66–0.78) for all models and was superior to the areas under the curve of other simple balance tests (1-leg stance, Timed “Up & Go” test, functional reach). Cronbach α was good for Brief-BESTest models 1 (0.92) and 3 (0.92), but ω was greater than 0.80 only for model 3.

Limitations

The sample was heterogeneous.

Conclusions

The Brief-BESTest, after some changes, shows good validity and internal consistency in patients affected by different balance disorders.
Ambiguity, Volatility, and Credit Risk
Authors: Augustin Patrick , Izhakian Yehuda
Published: July 2019

We explore the implications of ambiguity for the pricing of credit default swaps (CDSs). A model of heterogeneous investors with independent preferences for ambiguity and risk shows that, because CDS contracts are assets in zero net supply, the net credit risk exposure of the marginal investor determines the sign of the impact of ambiguity on CDS spreads. We find that ambiguity has an economically significant negative impact on CDS spreads, on average, suggesting that the marginal investor is a net buyer of credit protection. A 1-standard-deviation increase in ambiguity is estimated to decrease CDS spreads by approximately 6%. (JEL C65, D81, D83, G13, G22)

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
The association between lymphopenia and serious infection risk in rheumatoid arthritis
Authors: Subesinghe Sujith , Kleymann Alexander , Rutherford Andrew Ian , Bechman Katie , Norton Sam , Benjamin Galloway James
Published: July 2019

Objectives

To investigate the relationship between occurrence of serious infection (SI) and lymphocyte counts in patients with RA using data from a single centre.

Methods

We used routinely captured data from a single tertiary rheumatology centre to explore the relationship between lymphopenia and SI risk. Adult RA patients were included over a 5-year follow-up period. Admissions due to confirmed SI were considered. SI rate with 95% confidence intervals was calculated. The association between SI with baseline lymphocyte counts, time-averaged lymphocyte counts throughout all follow-up, and a nadir lymphocyte count was assessed using Cox proportional hazards regression. The relationship between lymphopenia over time and SI was analysed using a mixed-effect model of lymphocyte counts prior to SI.

Results

This analysis included 1095 patients with 205 SIs during 2016 person-years of follow-up. The SI rate was 4.61/100 patient-years (95% CI: 3.76, 5.65). Compared with patients with nadir lymphocyte counts >1.5 × 109 cells/l, nadir lymphopenia <1 × 109 cells/l was significantly associated with higher SI risk (HR 3.28; 95% CI: 1.59, 6.76), increasing to HR 8.08 (95% CI: 3.74, 17.44) in patients with lymphopenia <0.5 × 109 cells/l. Lymphocyte counts were observed to be reduced in the 30-day period prior to SI.

Conclusion

Lymphocyte counts below <1.0 × 109 cells/l were associated with higher SI risk in RA patients; the strongest association between lymphopenia and SI was observed when lymphocyte counts were below <0.5 × 109 cells/l. Lymphopenia may be used as a measure to stratify patients at risk of SI.
Comparative safety of biologic versus conventional synthetic DMARDs in rheumatoid arthritis with COPD: a real-world population study
Authors: Hudson Marie , Dell’Aniello Sophie , Shen Sophie , Simon Teresa A , Ernst Pierre , Suissa Samy
Published: July 2019

Objectives

Abatacept, a biologic DMARD, was associated with respiratory adverse events in a small subgroup of RA patients with chronic obstructive pulmonary disease (COPD) in a trial. Whether this potential risk is specific to abatacept or extends to all biologics and targeted synthetic DMARDs (tsDMARDs) is unclear. We assessed the risk of adverse respiratory events associated with biologic and tsDMARDs compared with conventional synthetic DMARDs (csDMARDs) among RA patients with concomitant COPD in a large, real-world cohort.

Methods

We used a prevalent new-user design to study RA patients with COPD in the US-based MarketScan databases. New users of biologic DMARDs and/or tsDMARDs were matched on time-conditional propensity scores to new users of csDMARDs. Adverse respiratory events were estimated using Cox models comparing current use of biologic/tsDMARDs with csDMARDs.

Results

The cohort included 7424 patients initiating biologic/tsDMARDs and 7424 matched patients initiating csDMARDs. The adjusted hazard ratio of hospitalized COPD exacerbation comparing biologic/tsDMARD vs csDMARD was 0.76 (95% CI: 0.55, 1.06), while it was 1.02 (95% CI: 0.82, 1.27) for bronchitis, 1.21 (95% CI: 0.92, 1.58) for hospitalized pneumonia or influenza and 0.99 (95% CI: 0.87, 1.12) for outpatient pneumonia or influenza. The hazard ratio of the combined end point of COPD exacerbation, bronchitis and hospitalized pneumonia or influenza was 1.04 (95% CI: 0.89, 1.21).

Conclusion

In this large, real-world comparative safety study, biologic and tsDMARDs, including abatacept, were not associated with an increased risk of adverse respiratory events when compared with csDMARDs in patients with RA and COPD.
EFFECTIVE DOSE AND RISK ESTIMATES IN ADULT PATIENTS FROM FOUR RADIOLOGICAL PROCEDURES EXTRAPOLATED OVER TWO POPULATIONS AT SOME SELECTED CENTERS IN LAGOS STATE, NIGERIA
Authors: Balogun F A , Adeyemi F O , Balogun B O , Oketayo O O , Olowookere C J , Fasan-Odunsi A O
Published: July 2019

In this study, risk of exposure to adult patients in some common radiological procedures was estimated at selected diagnostic centers in Lagos State, Nigeria using estimated average effective doses. The results showed that pelvis lateral (LAT) examination with the lowest estimated mean effective dose level (2.61) recorded the highest probability of cancer incidence and mortality occurrences, while lumbar anteroposterior (AP) had the lowest (3.61). A high sum total of probability of fatal cancers and the total weighted probability of non-fatal cancer in a single exposure to low-dose ionizing radiation were recorded in pelvic procedure among others. Also, a high-percentage mortality increase of solid cancers was recorded in chest PA examination (53.7%), while the lowest was in lumbar spine radiography (with lumbar AP = 0.14%, lumbar LAT = 0.15%). The data obtained suggested the possibility of having higher percentage mortality and cancer-related incidence in the chest.
Police Warriors and Police Guardians: Race, Masculinity, and the Construction of Gun Violence
Authors: Carlson Jennifer
Published: July 2019

This paper draws on 79 in-depth interviews with police chiefs in Arizona, California, and Michigan to advance sociological understandings of race, masculinity, and policing. While the bulk of scholarship on public law enforcement focuses on urban settings, this paper juxtaposes police’s perceptions of urban, suburban, and rural gun violence. It details how police chiefs construct criminal gun violence according to two overarching tropes: (1) gang- and drug-related gun violence involving black and brown perpetrators and victims in urban spaces and (2) active shooting-related gun violence involving white perpetrators and victims in suburban and rural spaces. The analysis shows that police understand their own guns in part through reference to these tropes, embracing two racially distinct styles of police masculinity: the “warrior” and the “guardian.” Whereas the “warrior” brand of police masculinity emphasizes aggressive enforcement against (black and brown) perpetrators, the “guardian” brand of police masculinity emphasizes assertive protection on behalf of (white) victims. Detailing masculinity as a bifurcated axis along which racialized policing is enacted and amplified, this study broadens scholarly understandings of public law enforcement as a race-making institution and suggests the limitations of police reforms that fail to address whiteness as shaping public law enforcement.
An Integrative Approach Using Phylogenomics and High-Resolution X-Ray Computed Tomography for Species Delimitation in Cryptic Taxa
Authors: Chaplin Kirilee , Sumner Joanna , Hipsley Christy A , Melville Jane
Published: July 2019

Morphologically cryptic taxa have proved to be a long-standing challenge for taxonomists. Lineages that show strong genomic structuring across the landscape but are phenotypically similar pose a conundrum, with traditional morphological analyses of these cryptic lineages struggling to keep up with species delimitation advances. Micro X-ray computed tomography (CT) combined with geometric morphometric analyses provides a promising avenue for identification of morphologically cryptic taxa, given its ability to detect subtle differences in anatomical structures. However, this approach has yet to be used in combination with genomic data in a comparative analytical framework to distinguish cryptic taxa. We present an integrative approach incorporating genomic and geometric morphometric evidence to assess the species delimitation of grassland earless dragons (Tympanocryptis spp.) in north-eastern Australia. Using mitochondrial and nuclear genes (ND2 and RAG1, respectively), along with $>$8500 SNPs (nuclear single nucleotide polymorphisms), we assess the evolutionary independence of target lineages and several closely related species. We then integrate phylogenomic data with osteological cranial variation between lineages using landmark-based analyses of three-dimensional CT models. High levels of genomic differentiation between the three target lineages were uncovered, also supported by significant osteological differences. By incorporating multiple lines of evidence, we provide strong support for three undescribed cryptic lineages of Tympanocryptis in north-eastern Australia that warrant taxonomic review. Our approach demonstrates the successful application of CT with integrative taxonomic approaches for cryptic species delimitation, which is broadly applicable across vertebrates containing morphologically similar yet genetically distinct lineages. Additionally, we provide a review of recent integrative taxonomic approaches for cryptic species delimitation and an assessment of how our approach can value-add to taxonomic research.
Graphical representation of functions using technology: a window to teacher knowledge
Authors: Rocha Helena
Published: July 2019

Using technology to get a graphical representation of functions requires the choice of a suitable viewing window. The literature suggests teachers’ knowledge as being central in this process, but does not tell us much about how the teachers should manage this. This study aims to improve understanding about the teachers’ choices related to the viewing window on the study of functions. It also intends to illustrate how this analysis can be a useful way to access aspects of teachers’ knowledge based on the framework of Knowledge for Teaching Mathematics with Technology (KTMT). The study adopts a qualitative methodological approach, undertaking case studies of two teachers. The findings recognize the importance of carefully sequencing the students’ contact with this kind of situation and the impact of the viewing window over the teachers’ choices of tasks, pointing to the relevance of considering situations where the students actually face the difficulties. This highlights the relation of teachers’ choices of viewing window to their knowledge of different KTMT’s domains, and specifically the relevance of knowledge of different ways to change the window; of the difficulties faced by the students; of the most suitable tasks (and required viewing window) at each moment; of the impact of the viewing window on the appearance of a graph and of the different situations associated, from the mathematical point of view.
2,4,6-Tribromophenol Exposure Decreases P-Glycoprotein Transport at the Blood-Brain Barrier
Authors: Trexler Andrew W , Knudsen Gabriel A , Nicklisch Sascha C T , Birnbaum Linda S , Cannon Ronald E
Published: July 2019

2,4,6-Tribromophenol (TBP, CAS No. 118-79-6) is a brominated chemical used in the production of flame-retardant epoxy resins and as a wood preservative. In marine environments, TBP is incorporated into shellfish and consumed by predatory fish. Food processing and water treatment facilities produce TBP as a byproduct. 2,4,6-Tribromophenol has been detected in human blood and breast milk. Biologically, TBP interferes with estrogen and thyroid hormone signaling, which regulate important transporters of the blood-brain barrier (BBB). The BBB is a selectively permeable barrier characterized by brain microvessels which are composed of endothelial cells mortared by tight-junction proteins. ATP-binding cassette (ABC) efflux transporters on the luminal membrane facilitate the removal of unwanted endobiotics and xenobiotics from the brain. In this study, we examined the in vivo and ex vivo effects of TBP on two important transporters of the BBB: P-glycoprotein (P-gp, ABCB1) and Multidrug Resistance-associated Protein 2 (MRP2, ABCC2), using male and female rats and mice. 2,4,6-Tribromophenol exposure ex vivo resulted in a time- (1–3 h) and dose- (1–100 nM) dependent decrease in P-gp transport activity. MRP2 transport activity was unchanged under identical conditions. Immunofluorescence and western blotting measured decreases in P-gp expression after TBP treatment. ATPase assays indicate that TBP is not a substrate and does not directly interact with P-gp. In vivo dosing with TBP (0.4 µmol/kg) produced decreases in P-gp transport. Co-treatment with selective protein kinase C (PKC) inhibitors prevented the TBP-mediated decreases in P-gp transport activity.
Comparison of Zebrafish Larvae and hiPSC Cardiomyocytes for Predicting Drug-Induced Cardiotoxicity in Humans
Authors: Dyballa Sylvia , Miñana Rafael , Rubio-Brotons Maria , Cornet Carles , Pederzani Tiziana , Escaramis Georgia , Garcia-Serna Ricard , Mestres Jordi , Terriente Javier
Published: July 2019

Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high-throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive, and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction, and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.
Optimising the use of molecular tools for the diagnosis of yaws
Authors: Munson Morgan , Creswell Benjamin , Kondobala Kofi , Ganiwu Bawa , Lomotey Rita Dede , Oppong Paul , Agyeman Frederick Opoku , Kotye Nana , Diwura Mukaila , Ako Ebenezer Padi , Simpson Shirley Victoria , Addo Kennedy Kwasi , Pickering Harry , Handley Becca L , Houghton Joanna , Kwakye Cynthia , Marks Michael
Published: July 2019

Background

Yaws is a neglected tropical disease and results in lesions of skin, soft tissues and bones. PCR plays an important part in surveillance.

Methods

Children suspected to have yaws were enrolled. From the largest lesion, paired swabs were collected, one in transport medium and one as a dry swab. In children with multiple lesions we collected additional swabs from up to four subsequent lesions. Swabs in transport medium were maintained in a cold chain while dry swabs were stored at ambient temperature. Swabs were tested by PCR for Treponema pallidum and Haemophilus ducreyi.

Results

Of 55 individuals, 10 (18%) had at least one positive PCR for T. pallidum and 12 (22%) had at least one positive result for H. ducreyi. Concordance was 100% between swabs in transport medium and dry swabs. One patient had PCR-confirmed yaws on the swab of a third lesion when both the first and second lesions were PCR-negative.

Conclusions

Storing swabs in transport medium and transporting in a cold chain did not improve yield, however, detection of T. pallidum is increased by swabbing additional lesions. As the target for yaws is eradication, approaches to sample collection need revisiting to ensure cases are not missed.
Molecular data support the placement of the enigmatic Cheguevaria as a subfamily of Lampyridae (Insecta: Coleoptera)
Authors: Ferreira Vinicius S , Keller Oliver , Branham Marc A , Ivie Michael A
Published: July 2019

Since the description of the genus Cheguevaria as incertae sedis (Lampyridae), the placement of these beetles has been uncertain. This study is the first to address the placement of this genus based on a molecular phylogenetic analysis. We used three genes (18S rRNA, rrnl mitochondrial DNA and cox1 mitochondrial DNA) and a maximum likelihood approach with W-IQ-TREE to support Cheguevaria as a member of the Lampyridae and recognize it as the sole genus in the new subfamily Cheguevariinae stat. nov.
Combination of a δ-opioid Receptor Agonist and Loperamide Produces Peripherally-mediated Analgesic Synergy in Mice
Authors: Bruce Daniel J. , Peterson Cristina D. , Kitto Kelley F. , Akgün Eyup , Lazzaroni Sophia , Portoghese Phillip S. , Fairbanks Carolyn A. , Wilcox George L.
Published: July 2019

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

The long-term use of opioids for analgesia carries significant risk for tolerance, addiction, and diversion. These adverse effects are largely mediated by μ-opioid receptors in the central nervous system. Based on the authors’ previous observation that morphine and δ-opioid receptor agonists synergize in spinal cord in a protein kinase Cε–dependent manner, they predicted that this μ-opioid receptor–δ-opioid receptor synergy would take place in the central terminals of nociceptive afferent fibers and generalize to their peripheral terminals. Therefore, the authors hypothesized that loperamide, a highly efficacious μ-opioid receptor agonist that is excluded from the central nervous system, and oxymorphindole, a δ-opioid receptor agonist that was shown to synergize with morphine spinally, would synergistically reverse complete Freund’s adjuvant–induced hyperalgesia.

Methods

Using the Hargreaves assay for thermal nociception, the von Frey assay for mechanical nociception and the complete Freund’s adjuvant–induced model of inflammatory pain, we tested the antinociceptive and antihyperalgesic effect of loperamide, oxymorphindole, or the loperamide–oxymorphindole combination. Animals (Institute for Cancer Research [ICR] CD1 strain mice; n = 511) received drug by systemic injection, intraplantar injection to the injured paw, or a transdermal solution on the injured paw. Dose–response curves for each route of administration and each nociceptive test were generated, and analgesic synergy was assessed by isobolographic analysis.

Results

In naïve animals, the loperamide–oxymorphindole combination ED50 value was 10 times lower than the theoretical additive ED50 value whether given systemically or locally. In inflamed animals, the combination was 150 times more potent systemically, and 84 times more potent locally. All combinations showed statistically significant synergy when compared to the theoretical additive values, as verified by isobolographic analysis. The antihyperalgesia was ablated by a peripherally-restricted opioid antagonist.

Conclusions

From these data we conclude that the loperamide–oxymorphindole combination synergistically reverses complete Freund’s adjuvant–induced inflammatory hyperalgesia. The authors also conclude that this interaction is mediated by opioid receptors located in the peripheral nervous system.