bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of short‐term predominate breastfeeding on cognitive outcome at 5 years
Authors: Lenehan Sonia M. , Boylan Geraldine B. , Livingstone Vicki , Fogarty Leanna , Twomey Deirdre Marie , Nikolovski Janeta , Irvine Alan D. , Kiely Mairead , Kenny Louise C. , Hourihane Jonathon O.B. , Murray Deirdre M.
Published: September 2019

Aim

Breastfeeding is associated with IQ, school attendance and income. Despite the known benefits of breastfeeding, the rate of exclusive breastfeeding up to 6 months is low globally. We examined the effect of short‐term breastfeeding on long‐term IQ.

Methods

In this secondary analysis of the prospective Cork BASELINE Birth Cohort Study, children were categorised as predominantly breastfed (n = 288) versus exclusively formula‐fed (n = 254) at 2‐months of age. Infants (n = 404) receiving mixed feeding were excluded. Outcome was assessed using the KBIT‐II at 5 years. Multivariable linear regression was used to adjust for confounding variables.

Results

Following adjustment for confounding variables, children, predominately breastfed at 2 months of age, demonstrated increased overall IQ (2.00 points (95% CI: 0.35 to 3.65); P = .018) and non‐verbal IQ at 5 years of age (1.88 points (95% CI: 0.22 to 3.54); P = .027) compared with those never breastfed. No significant relationship was found with verbal IQ (P = .154).

Conclusion

A significant increase in composite and non‐verbal IQ at 5 years of age was associated with short‐term breastfeeding. This study adds to a growing body of evidence that short‐term breastfeeding promotes healthy cognitive development.
Disturbed cardiac mitochondrial and cytosolic calcium handling in a metabolic risk‐related rat model of heart failure with preserved ejection fraction
Authors: Miranda‐Silva Daniela , Wüst Rob C. I. , Conceição Glória , Gonçalves‐Rodrigues Patrícia , Gonçalves Nádia , Gonçalves Alexandre , Kuster Diederik W. D. , Leite‐Moreira Adelino F. , van der Velden Jolanda , de Sousa Beleza Jorge M. , Magalhães José , Stienen Ger J. M. , Falcão‐Pires Inês
Published: September 2019

Aim

Calcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction (HFrEF), but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF).

Methods

We assessed mitochondrial Ca2+ handling in intact cardiomyocytes from Zucker/fatty Spontaneously hypertensive F1 hybrid (ZSF1)‐lean (control) and ZSF1‐obese rats, a metabolic risk‐related model of HFpEF. A mitochondrially targeted Ca2+ indicator (MitoCam) was expressed in cultured adult rat cardiomyocytes. Cytosolic and mitochondrial Ca2+ transients were measured at different stimulation frequencies. Mitochondrial respiration and swelling, and expression of key proteins were determined ex vivo.

Results

At rest, mitochondrial Ca2+ concentration in ZSF1‐obese was larger than in ZSF1‐lean. The diastolic and systolic mitochondrial Ca2+ concentrations increased with stimulation frequency, but the steady‐state levels were larger in ZSF1‐obese. The half‐widths of the contractile responses, the resting cytosolic Ca2+ concentration and the decay half‐times of the cytosolic Ca2+ transients were higher in ZSF1‐obese, likely because of a lower SERCA2a/phospholamban ratio. Mitochondrial respiration was lower, particularly with nicotinamide adenine dinucleotide (NADH) (complex I) substrates, and mitochondrial swelling was larger in ZSF1‐obese.

Conclusion

The free mitochondrial calcium concentration is higher in HFpEF owing to alterations in mitochondrial and cytosolic Ca2+ handling. This coupling between cytosolic and mitochondrial Ca2+ levels may compensate for myocardial ATP supply in vivo under conditions of mild mitochondrial dysfunction. However, if mitochondrial Ca2+ concentration is sustainedly increased, it might trigger mitochondrial permeability transition pore opening.
Higher expression of beclin 1 in human meningiomas is related to better clinical outcome and pathological grade
Authors: Kuo Keng‐Liang , Chen Chien‐Heng , Chen Hsin‐I , Chung Yen‐Yo , Chai Chee‐Yin
Published: September 2019

Meningiomas are common intracranial tumors, and most exhibit optimal prognosis; however, some meningiomas still recur and even develop malignant transformation in the following years, regardless of initial pathological grade. During these years, autophagy raises its significance in tumorigenesis and tumor suppression, both important for tumor development. The aim of this study was to elucidate the relationship between two autophagy markers, LC3B and beclin 1, with clinical and pathological parameters in patients with meningiomas. A total of 77 thin‐sectioned slides, retrospectively collected from meningioma patients, were analyzed and correlated with clinicopathological parameters. We found that expression of beclin 1 rather than LC3B correlated to better prognosis, lower pathological grade, and longer survival. Furthermore, intensity of beclin 1 was also found to be significantly related to the pathological grade. These findings indicated that beclin 1 as a protective factor predicts better prognosis and plays the role of tumor suppression in meningiomas.
Duplicated tramadol use in chronic low back pain: A nationwide cross‐sectional study
Authors: Koo Hyunji , Lee Min Taek , You Seung Hun , Seon Jeong Yeon , Lee Sieun , Jeong Kyeong Hye , Jung Sun‐Young
Published: September 2019

Tramadol is a weak opioid that is commonly used for chronic low back pain (LBP). Despite its effectiveness, duplicated use of tramadol, which may indicate abuse or dependence, may exacerbate potential adverse reactions. This population‐based, cross‐sectional study aimed to investigate the prevalence of duplication of tramadol and its associated factors among patients with LBP. From a Korean nationwide claims database, non‐hospitalized patients aged 40‐99 years with LBP without malignancy were prescribed tramadol during 2014‐2016. Duplication of tramadol was defined as overlapping of prescription days. Among them, we defined “extensive duplication (ED)” when days of tramadol duplication cover 10% or more of the days prescribed tramadol. Patient and healthcare utilization factors associated with ED were examined using a logistic regression model. The study population was 6 417 503 patients. Of these, 13.7% were ED users. The age‐ and sex‐standardized prevalence of using tramadol twice or more a year was 14.06 per 100 people in 2014, 13.74 per 100 people in 2015 and 13.52 per 100 people in 2016. ED occurred more in those in the group aged 70‐79 years (OR 1.12, 95% CI 1.11‐1.13) than 40‐49 years and in those with comorbidities, such as drug abuse (OR 2.99, 95% CI 2.05‐4.36) or depression (OR 1.75, 95% CI 1.72‐1.77). Based on the results of this study, a proper management system is needed to avoid tramadol duplication among older people and patients with drug abuse or depression.
Optimizing spontaneous adverse drug reaction reporting in public healthcare setting in Namibia
Authors: Adenuga Babafunso A. , Kibuule Dan , Rennie Timothy W.
Published: September 2019

Despite the universal scale‐up of pharmacovigilance systems globally, adverse drug reaction (ADR) reporting remains suboptimal among resource‐limited countries. Few studies in sub‐Saharan Africa evaluate the effectiveness of adverse drug reaction (ADR) reporting programmes. A cross‐sectional survey using a self‐administered questionnaire to assess ADR reporting knowledge, attitude and practices among healthcare workers in Namibia's public sector was conducted between September and December 2018. The primary outcome were practices, knowledge and attitude of the respondents towards ADR reporting. Quantitative and qualitative data were analysed using descriptive statistics and thematic analysis, respectively. Of the 197 healthcare workers surveyed, 43.1% were nurses, 63.4% of the respondents knew about the ADR reporting system in Namibia, 76.7% knew the pharmacovigilance/ADR reporting centre in Namibia, while 37.3% had reported an ADR before. Nurses were less likely to be knowledgeable and report ADRs. The independent predictor of ADR reporting was the nursing cadre; adjusted odds ratio (aOR) = 0.17 (95% CI: 0.07, 0.401, P < .01). Pre‐ and in‐service trainings including introduction of electronic reporting platforms were some of the identified ways of optimizing the pharmacovigilance and ADR reporting systems by the respondents. As pharmacovigilance in Namibia relies on spontaneous reporting of ADRs, there is a need for advocacy and workforce strengthening for ADR reporting in the public health sector.
Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer
Authors: Hamaguchi Tetsuya , Denda Tadamichi , Kudo Toshihiro , Sugimoto Naotoshi , Ura Takashi , Yamazaki Kentaro , Fujii Hirofumi , Kajiwara Takeshi , Nakajima Takako Eguchi , Takahashi Shin , Otsu Satoshi , Komatsu Yoshito , Nagashima Fumio , Moriwaki Toshikazu , Esaki Taito , Sato Takeo , Itabashi Michio , Oki Eiji , Sasaki Toru , Chiron Marielle , Yoshino Takayuki
Published: September 2019

Aflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second‐line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty‐two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy‐eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor‐stroma interaction. Plasma levels of biomarkers at baseline and at pre‐dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre‐dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end‐products binding protein, insulin‐like growth factor‐binding protein 1, interleukin‐8, kallikrein 5, pulmonary surfactant‐associated protein D, tissue inhibitor of metalloproteinases 1, tenascin‐C, and tumor necrosis factor receptor 2. None correlated with progression‐free survival or maximum tumor shrinkage. Pre‐dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.
Circulating microRNA‐590‐5p functions as a liquid biopsy marker in non‐small cell lung cancer
Authors: Khandelwal Akanksha , Seam Rajeev Kumar , Gupta Manish , Rana Manjit Kaur , Prakash Hridayesh , Vasquez Karen M. , Jain Aklank
Published: September 2019

Despite the availability of various diagnostic procedures, a tissue biopsy is still indispensable for the routine diagnosis of lung cancer. However, inaccurate diagnoses can occur, leading to inefficient cancer management. In this context, use of circulating microRNAs (miRNAs) may serve as diagnostic tools as liquid biopsies, and as biomarkers to better understand the molecular mechanisms involved in the progression of cancer. We identified miR‐590‐5p as a potential prognostic marker in the progression of non‐small cell lung cancer (NSCLC). We were able to detect this miRNA in blood plasma samples of NSCLC patients through quantitative real‐time PCR. Our data showed an ~7.5‐fold downregulation of miR‐590‐5p in NSCLC patients compared to healthy controls, which correlated with several clinicopathological features. Further, overexpression of miR‐590‐5p led to decreased cell viability, proliferation, colony formation, migration, and invasion potential of lung cancer cells, whereas its knockdown showed the opposite effect. In addition, the levels of several proteins involved in the epithelial‐to‐mesenchymal transition negatively correlated with miR‐590‐5p levels in lung adenocarcinoma cells and tumors of NSCLC patients. Further, dual‐luciferase reporter assays identified STAT3 as a direct target of miR‐590‐5p, which negatively regulated STAT3 activation and its downstream signaling molecules (eg, Cyclin D1, c‐Myc, Vimentin, and β‐catenin) involved in tumorigenesis. Taken together, our study suggests that miR‐590‐5p functions as a tumor suppressor in NSCLC through regulating the STAT3 pathway, and may serve as a useful biomarker for the diagnosis/prognosis of NSCLC, and as a potential therapeutic target for the treatment of NSCLC.
Ara h 7 isoforms share many linear epitopes: Are 3D epitopes crucial to elucidate divergent abilities?
Authors: Ehlers Anna M. , Klinge Marco , Suer Waltraud , Weimann Yvonne , Knulst André C. , Besa Frithjof , Le Thuy‐My , Otten Henny G.
Published: September 2019

Background

The peanut allergens Ara h 2, h 6, and h 7 are potent allergens and can trigger severe reactions. Ara h 7 consists of three isoforms differing in their ability to induce basophil degranulation, whereas the ability of Ara h 7.0201 is comparable to Ara h 2 and 6 as shown in previous literature.

Objective

To identify linear epitopes of Ara h 7.0101, Ara h 7.0201 and Ara h 7.0301 recognized by IgE and IgG4 from patients sensitized to Ara h 7 and to investigate their potential to elucidate divergent abilities of the Ara h 7 isoforms in inducing basophil activation.

Methods

Linear epitopes recognized by IgE and IgG4 were mapped by peptide microarray analysis containing 15‐mer peptides of Ara h 2.0201, 6, 7.0101, 7.0201 and 7.0301 and 39 peanut allergic patients sensitized to Ara h 7 (discovery). For validation, 20‐mer peptides containing the minimal epitope and surrounding amino acids were incubated with 25 sensitized patients and 10 controls (validation).

Results

Three out of 14 linear epitopes were unique for each isoform (Ara h 7.0101: aa 97‐109; Ara h 7.0201: aa 122‐133; Ara h 7.0301: aa 65‐74) but scarcely recognized by IgE. The main linear IgE epitope (aa 51‐57) located in the long flexible loop of all Ara h 7 isoforms was bound by antibodies from 31% of the patients (discovery and validation cohort). Regarding IgG4, 55% of the patients recognized an epitope present on all isoforms (aa 55‐65), whereas epitope aa 129‐137, only present on Ara h 7.0101/0.0301, was recognized by 38% of the patients. Recognition was highly individual, although 20% of the patients recognized any linear epitope neither by IgE nor by IgG4 despite a low mean z‐score of ≥ 1.7. Remarkably, only 50% of the patients recognized one or more epitopes by IgE.

Conclusion & Clinical Relevance

Ara h 7 isoforms share many linear epitopes being easily accessible for antibody binding. Unique epitopes, essential to elucidate divergent potencies, were scarcely recognized, suggesting a crucial involvement of conformational epitopes.
A preclinical model links osseo‐densification due to misfit and osseo‐destruction due to stress/strain
Authors: Coyac Benjamin R. , Leahy Brian , Salvi Giuseppe , Hoffmann Waldemar , Brunski John B. , Helms Jill A.
Published: September 2019

Objective

Primary stability is a prerequisite for implant osseointegration. Some degree of misfit between an implant and its osteotomy is required to ensure primary stability, and this is typically achieved by undersizing an implant osteotomy. In this preclinical study, we aimed at understanding the relationship between misfit, insertion torque, implant stability, and their cumulative short‐ and longer‐term effects on peri‐implant bone.

Materials and methods

We placed implants in maxillary extraction sites of a rat; in the control group, these implants had minimal misfit while those in the test group had a high degree of misfit and therefore osseo‐densified the peri‐implant bone.

Results

Compared to controls, the misfit‐induced stresses produced by osseo‐densification led to micro‐fractures in the peri‐implant bone and an extensive zone of dying osteocytes. High interfacial pressures produced a pro‐resorptive environment as shown by tartrate‐resistant acid phosphatase activity and cathepsin K immunostaining (IHC). The lack of alkaline phosphatase activity and collagen I IHC supported the absence of new bone formation. Collectively, micro‐computed tomography imaging, quantification of bone–implant contact (BIC), vimentin, and IL1‐β IHCs demonstrated that implant failure occurred soon afterward, which presented as a crater‐like lesion filled with fibrous, inflamed granulation tissue around the test implants.

Conclusion

By controlling every other risk indicator, we confirmed how excessive osseo‐densification can lead directly to osseo‐destruction.
Development evaluation in authoritarian states: A case from Kazakhstan
Authors: Knox Colin
Published: September 2019

Motivation

Authoritarian states receive development funding from international donors for programmes and interventions, some aimed at improving their governance systems. This article reports on the evaluation of an EU‐funded programme in Kazakhstan, seen as the most progressive reformer in Central Asia. The EU Programme was aimed at enhancing Kazakhstan’s business competitiveness through better regulation and civil service modernization.

Purpose

This article addresses two research questions. What was the impact of the EU‐funded intervention? What role, if any, did the evaluation play in reflective policy learning for the future?

Approach and Methods

The research draws on quantitative and qualitative evidence. This involved analysing secondary data sources on the effectiveness of governance over time in Kazakhstan and interviews for 34 key stakeholders on the impact of the EU interventions.

Findings

We find no significant improvements in governance over time. While the donor responded in a flexible way to meet the changing strategic goals of the state (which were at the personal behest of the President), this did not help to embed evaluation as part of the policy cycle for future learning. The key beneficiary here was the Government of Kazakhstan.

Policy implications

Wider systemic change from upward accountability to downward accountability to citizens is needed to make evaluation relevant for authoritarian states. Upward accountability to the President is a feature of authoritarian regimes, which precludes citizens from being able to hold the state to account. Without these systemic changes, autocracies simply engage in development evaluation as a perfunctory exercise to meet donor requirements.
Factors predictive of the presence of a CSF1R mutation in patients with leukoencephalopathy
Authors: Kondo Y. , Matsushima A. , Nagasaki S. , Nakamura K. , Sekijima Y. , Yoshida K.
Published: September 2019

Background and purpose

The purpose was to identify statistically factors that correlate with the presence of a colony‐stimulating factor 1 receptor (CSF1R) mutation and to reevaluate the accuracy of the current diagnostic criteria for CSF1R‐related leukoencephalopathy.

Methods

CSF1R testing was conducted on 145 consecutive leukoencephalopathy cases who were clinically suspected of having adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia. From these, 135 cases whose detailed clinical information was available were enrolled. Forward logistic stepwise regression was performed to generate a probability model to predict a positive CSF1R mutation result. The current diagnostic criteria were also applied to our cohort and their sensitivity and specificity were calculated.

Results

Twenty‐eight CSF1R‐mutation‐positive cases and 107 CSF1R‐mutation‐negative cases were identified. Our probability model suggested that factors raising the probability of a CSF1R‐mutation‐positive result were younger onset, parkinsonism, thinning of the corpus callosum and diffusion‐restricted lesions. It also showed that involuntary movements and brainstem or cerebellar atrophy were negative predictors of a CSF1R‐mutation‐positive result. In our cohort, the sensitivity and specificity for ‘probable’ or ‘possible’ CSF1R‐related leukoencephalopathy were 81% and 14%, respectively.

Conclusions

Clinical and brain imaging features predictive of the presence of a CSF1R mutation are proposed. Consideration of these factors will help prioritize patients for CSF1R testing.
Founder effects and species introductions: A host versus parasite perspective
Authors: Blakeslee April M. H. , Haram Linsey E. , Altman Irit , Kennedy Kristin , Ruiz Gregory M. , Miller A. Whitman
Published: September 2019

Species colonizations (both natural and anthropogenic) can be associated with genetic founder effects, where founding populations demonstrate significant genetic bottlenecks compared to native populations. Yet, many successfully established free‐living species exhibit little reduction in genetic diversity—possibly due to multiple founding events and/or high propagule pressure during introductions. Less clear, however, is whether parasites may show differential signatures to their free‐living  hosts. Parasites with indirect life cycles may particularly be more prone to founder effects (i.e., more genetically depauperate) because of inherently smaller founding populations and complex life cycles. We investigated this question in native (east coast) and introduced (west coast) North American populations of a host snail Tritia obsoleta (formerly Ilyanassa obsoleta, the eastern mudsnail) and four trematode parasite species that obligately infect it. We examined genetic diversity, gene flow, and population structure using two molecular markers (mitochondrial and nuclear) for the host and the parasites. In the host snail, we found little to no evidence of genetic founder effects, while the trematode parasites showed significantly lower genetic diversity in the introduced versus native ranges. Moreover, the parasite's final host influenced infection prevalence and genetic diversity: Trematode species that utilized fish as final hosts demonstrated lower parasite diversity and heightened founder effects in the introduced range than those trematodes using birds as final hosts. In addition, inter‐regional gene flow was strongest for comparisons that included the putative historical source region (mid‐Atlantic populations of the US east coast). Overall, our results broaden understanding of the role that colonization events (including recent anthropogenic introductions) have on genetic diversity in non‐native organisms by also evaluating less studied groups like parasites.
Berberine ameliorates non‐steroidal anti‐inflammatory drugs‐induced intestinal injury by the repair of enteric nervous system
Authors: Chao Guanqun , Ye Fangxu , Yuan Yuan , Zhang Shuo
Published: September 2019

The study was to detect the role of GDNF, PGP9.5 (a neuronal marker), and GFAP (EGCs’ marker) in the mechanism of non‐steroidal anti‐inflammatory drugs (NSAIDs) related to intestinal injury and to clarify the protective effect of berberine in the treatment of NSAID‐induced small intestinal disease. Forty male SD rats were divided randomly into five groups (A–E): Group A: control group; Group B: model group received diclofenac sodium 7.5 mg/(kg*day) for 5 days; Group C–E: berberine low, medium and high dose groups were treated by 7.5 mg/(kg*day) diclofenac sodium for 5 days then received berberine 25 mg/(kg*day), 50 mg/(kg*day), and 75 mg/(kg*day), respectively, between the sixth and eighth day. Intestinal mucosa was taken on the ninth day to observe the general, histological injuries, and to measure the intestinal epithelial thickness. Then, immunohistochemistry was performed to detect the expression of PGP9.5 and GFAP, and Western blot was performed to detect GDNF expression. The histological score and the general score in the model group were, respectively, 5.75 ± 1.04 and 4.83 ± 0.92. Scores in berberine medium and high berberine group were lower compared with the model group (P < 0.05). The intestinal epithelial thickness in the model group was lower than in the control group and the berberine groups (P < 0.05). PGP9.5, GFAP, and GDNF content in the model group and the three berberine groups were significantly lower than in the control groups (P < 0.05). PGP9.5, GFAP, and GDNF content in the control group and the three berberine groups were higher compared with the model groups (P < 0.05). Berberine can protect the intestinal mucosa of NSAID users, and the mechanism is associated with the reparation of the enteric nervous system via upregulating the expression of PGP9.5, GFAP, and GDNF.
Multisite rate control analysis identifies ribosomal scanning as the sole high‐capacity/low‐flux‐control step in mRNA translation
Authors: Firczuk Helena , Teahan James , Mendes Pedro , McCarthy John E.G.
Published: September 2019

Control of complex intracellular pathways such as protein synthesis is critical to organism survival, but is poorly understood. Translation of a reading frame in eukaryotic mRNA is preceded by a scanning process in which a subset of translation factors helps guide ribosomes to the start codon. Here, we perform comparative analysis of the control status of this scanning step that sits between recruitment of the small ribosomal subunit to the m7GpppG‐capped 5′end of mRNA and of the control exerted by downstream phases of polypeptide initiation, elongation and termination. We have utilized a detailed predictive model as guidance for designing quantitative experimental interrogation of control in the yeast translation initiation pathway. We have built a synthetic orthogonal copper‐responsive regulatory promoter (PCuR3) that is used here together with the tet07 regulatory system in a novel dual‐site in vivo rate control analysis strategy. Combining this two‐site strategy with calibrated mass spectrometry to determine translation factor abundance values, we have tested model‐based predictions of rate control properties of the in vivo system. We conclude from the results that the components of the translation machinery that promote scanning collectively function as a low‐flux‐control system with a capacity to transfer ribosomes into the core process of polypeptide production that exceeds the respective capacities of the steps of polypeptide initiation, elongation and termination. In contrast, the step immediately prior to scanning, that is, ribosome recruitment via the mRNA 5′ cap‐binding complex, is a high‐flux‐control step.
Animal models of leukodystrophy: a new perspective for the development of therapies
Authors: Rutherford Holly A. , Hamilton Noémie
Published: September 2019

The leukodystrophies are a family of heritable disorders characterised by white matter degeneration, accompanied by variable clinical symptoms including loss of motor function and cognitive decline. Now thought to include over 50 distinct disorders, there are a vast array of mechanisms underlying the pathology of these monogenic conditions and, accordingly, a range of animal models relating to each disorder. While both murine and zebrafish models continue to aid in the development of potential therapies, many of these models fail to truly recapitulate the human condition – thus leaving substantial weaknesses in our understanding of leukodystrophy pathogenesis. Additionally, the heterogeneity in leukodystrophy presentation – both in patients and in vivo models – often results in a narrow focus on single disorders in isolation across much of the literature. Thus, this review aims to synthesise prominent research regarding the most common leukodystrophies in order to provide an overview of key animal models and their utility in developing novel treatments. We begin by discussing the ongoing revolution across the leukodystrophy field following the rise of next generation sequencing, before focusing more extensively on existing animal models from the mouse and zebrafish fields. Finally, we explore how these preclinical models have shaped the development of therapeutic strategies currently in development. We propose future directions for the field and suggest a more critical view of the dogma which has underpinned leukodystrophy research for decades.
Economic Impact of Headache and Psychiatric Comorbidities on Healthcare Expenditures Among Children in the United States: A Retrospective Cross‐Sectional Study
Authors: Law Emily F. , Palermo Tonya M. , Zhou Chuan , Groenewald Cornelius B.
Published: September 2019

Objective

To examine the annual healthcare expenditures associated with childhood headache in the United States, and to evaluate whether psychiatric comorbidities increase the impact of headache on expenditures.

Background

Headache is prevalent in childhood and co‐occurs with anxiety disorders, depressive disorders, and attention deficit/hyperactivity disorder (ADHD), which may increase cost of illness.

Methods

We conducted a secondary data analysis using a nationally representative sample of 34,633 children ages 2‐17 from the 2012‐2015 Medical Expenditure Panel Surveys (MEPS), of which 779 (weighted 2.6%) were identified as having headache based on health service use associated with headache. Using a comprehensive cost‐of‐illness approach, we assessed the incremental expenditures associated with headache and determined excess expenditures associated with psychiatric comorbidities using standard adjusted 2‐part expenditure models.

Results

Annual total healthcare expenditures were estimated to be 24.3% higher, 95% CI [1,55], in our headache group ($3036, 95% CI [2374,3699] vs $2350, 95% CI [2140,2559]). Total national expenditures associated with pediatric headache in the United States were estimated at $1.1 billion annually, 95% CI [.04, 2.2 billion]. Depression and ADHD were associated with higher incremental expenditures for the headache group (depression: $1815, 95% CI[676,2953] vs $1409, 95% CI[697,2112]; ADHD: $4742, 95% CI[1659,7825] vs $2935, 95% CI[1977,3894]); however, interactions between psychiatric comorbidities and headache did not reach statistical significance.

Conclusion

Youth with headache exert a considerable economic burden on families, healthcare systems, and society. Due to the limitations in methods used to classify youth with headache in MEPS, our findings may underestimate the true prevalence and cost of pediatric headache in the United States. Further research with larger sample sizes is needed to understand the impact of psychiatric comorbidities on healthcare expenditures in this population.
Clinical applications, accuracy and limitations of guided endodontics: a systematic review
Authors: Moreno‐Rabié C. , Torres A. , Lambrechts P. , Jacobs R.
Published: September 2019

Background

The novel concept of guided endodontics has been reported as an effective method to obtain safe and reliable results in root canal treatment.

Aim

To evaluate by means of a systematic review the clinical applications, accuracy and limitations of guided endodontic treatment.

Data sources

A search of the literature was performed on PubMed, Embase, Web of Science and Cochrane Library databases, until 25 April 2019. No language or year restrictions were applied.

Study eligibility criteria

Articles that answered the research question, including case reports, in vitro and ex vivo studies were included. Data extraction was performed independently by two reviewers.

Study appraisal

Quality assessment was done using STROBE, CARE and Modified CONSORT guidelines for observational, case reports and pre‐clinical studies, respectively.

Results

A total of 22 articles, including fifteen case reports, six pre‐clinical studies (in vitro and ex vivo studies) and one observational study, were included.

Limitations and Conclusions

Even though the level of evidence is low, and the methodology described among studies heterogeneous, all articles describe guided access cavity preparation and guided surgery as being highly accurate and successful techniques when comparing the drilled path to the planned treatment. More studies with a larger number of patients are necessary to obtain significant conclusions.
New waste‐based clinkers for the preparation of low‐energy cements. A step forward toward circular economy
Authors: Martínez‐Martínez Sergio , Pérez‐Villarejo Luis , Eliche‐Quesada Dolores , Sánchez‐Soto Pedro J. , Christogerou Angeliki , Kanellopoulou Dimitra G. , Angelopoulos George N.
Published: September 2019

This paper describes the use of industrial wastes arising from different production processes of the ceramic and marble industries as raw materials for the design and formulation of new cement clinkers with a high content of dicalcium silicate (Belite). The aim was to reintroduce these wastes in the industrial sector and take advantage of them for a greater environmental benefit, as indicated by the principles of the circular economy. Formulations containing 2.5, 5 and 10 wt% of chamotte and marble sludge, respectively, and a waste‐free formulation have been designed to obtain clinkers with a content of dicalcium silicate higher than 60 wt%. The different blends have been studied up to a maximum temperature of 1390°C by Thermal Analysis. Other techniques such as XRD, XRF, Modified Bogue Equation, Quality Indexes (LSF, AM, SM) and Optical Microscopy have been used for the study and characterization of industrial wastes, the raw materials and the high belite‐type cement dosages. The results indicate that this type of cements can be designed using different types of wastes and in this way reduce the environmental impacts caused by the extraction of raw materials and the deposition of the wastes in landfills, improving the circular economy of the construction industry.
Simulation of glass furnace with increased production by increasing fuel supply and introducing electric boosting
Authors: Li Luyao , Han Jianjun , Lin Huey‐Jiuan , Ruan Jian , Wang Jing , Zhao Xiujian
Published: September 2019

Based on the furnace with production of 600 t/d, two methods of increasing fuel supply and introducing electric boosting are investigated to increase glass production. The heat flux from combustion chamber to glass tank, temperature distribution of glass furnace, and the glass convection flow are presented, which influences the performance of glass furnace. The glass quality is evaluated with the melting index and mixing index, while the efficiencies of batch melting process and fining process are evaluated with the sand dissolution index and fining index, respectively. The results show that the method of increasing fuel supply is appropriate and efficient to increase the production less than 650 t/d. To further increase production about 700 t/d, the method of introducing electric power is preferred on the condition that the glass quality and lifetime of glass furnace are ensured. Optimization of furnace design and electric boosting parameters are required for the production more than 700 t/d. This investigation is expected to guide the optimized design of glass furnace to increase glass production.
Oxidative stability of vegetable purees enriched with n‐3‐LC‐PUFA microalgal biomass: impact of type of vegetable
Authors: Gheysen Lore , Durnez Nicky , Devaere Jolien , Bernaerts Tom , Van Loey Ann , De Cooman Luc , Foubert Imogen
Published: September 2019

Vegetable purees can be interesting food products to enrich with omega‐3 long‐chain polyunsaturated fatty acids (n‐3‐LC‐PUFA), since they are important carriers of nutrients and fibres and essential in a healthy diet. Due to their large number of double bounds, n‐3‐LC‐PUFA are highly susceptible to lipid oxidation. Different vegetable purees, containing different types and amounts of endogenous antioxidants, may possibly show differences in oxidative stability. This study contributes to obtain more insight into the impact of the type of vegetable (broccoli, carrot or tomato) on the oxidative stability of purees enriched with heterotrophic (Schizochytrium) n‐3‐LC‐PUFA‐rich microalgal biomass. Therefore, different vegetable purees enriched with microalgae were compared with each other and analysed for their amount lipid oxidation products and antioxidants. Broccoli and tomato puree enriched with Schizochytrium showed a higher oxidative stability compared to enriched carrot puree. However, all of these Schizochytrium‐enriched purees were prone to oxidation.
Effects of malondialdehyde‐induced protein oxidation on the structural characteristics of rice protein
Authors: Li Fang , Wu Xiao‐Juan , Wu Wei
Published: September 2019

Malondialdehyde (MDA) was selected to represent a secondary by‐product of lipid peroxidation during rice ageing. This study aimed to investigate the effects of MDA modification on the structural characteristics of rice protein. The results showed that as MDA concentration increased, rice protein carbonyl and disulphide groups increased, but sulphydryl content decreased. The blue shift of maximum fluorescence peak, the decrease of rice protein intrinsic fluorescence intensity and the reduction of surface hydrophobicity indicated the formation of protein aggregates caused by MDA oxidative modification. The results of molecular weight distribution and particle size distribution showed that MDA modification resulted in the formation of soluble protein aggregates, and the decrease of rice protein solubility indicated that insoluble protein aggregates were formed. Results of protein electrophoresis showed that MDA modification contributed to rice protein aggregation via non‐disulphide covalent bonds. The results showed that rice protein gradually aggregated with increasing MDA concentration.
Siglec‐F is induced by granulocyte–macrophage colony‐stimulating factor and enhances interleukin‐4‐induced expression of arginase‐1 in mouse macrophages
Authors: Tateyama Hiroyuki , Murase Yusuke , Higuchi Hiroshi , Inasaka Yui , Kaneoka Hidenori , Iijima Shinji , Nishijima Ken‐ichi
Published: September 2019

Siglecs are cell surface lectins that recognize sialic acids and are primarily expressed in hematopoietic cells. Previous studies showed that some Siglecs regulate macrophage function. In the present study, we examined the induction and putative roles of mouse Siglec‐F in bone‐marrow‐derived macrophages in mice. A quantitative RT‐PCR analysis showed that the basal expression of Siglec‐F was weak in bone‐marrow‐derived macrophages differentiated by macrophage colony‐stimulating factor. However, a 24‐hr stimulation with granulocyte–macrophage colony‐stimulating factor (GM‐CSF) enhanced Siglec‐F expression. GM‐CSF also enhanced Siglec‐F expression in thioglycollate‐induced peritoneal macrophages. The inhibition of signal transducer and activator of transcription 5 (STAT5), but not that of phosphoinositide 3‐kinase or mitogen‐activated protein kinase kinase, significantly reduced the induction of Siglec‐F. Interleukin‐3, which uses a common β‐chain shared with the GM‐CSF receptor to stimulate the STAT5 pathway, also enhanced Siglec‐F expression. The knockdown of Siglec‐F by a specific small interfering RNA enhanced GM‐CSF‐induced STAT5 phosphorylation, suggesting that Siglec‐F down‐regulates its own expression upon prolonged GM‐CSF stimulation. Furthermore, the knockdown of Siglec‐F reduced the STAT6 phosphorylation and expression of arginase‐1 in interleukin‐4‐stimulated macrophages. These results suggest that Siglec‐F fine‐tunes the immune responses of macrophages.
Returns to scale and asset prices
Authors: Chen Hung‐Kun , Chan Konan , Wang Yanzhi
Published: September 2019

The q‐theory of investment is proposed to explain firm growth effects, where previous papers identify a negative effect of firm growth, including asset growth, real investment and net share issuance, on future stock returns. This paper uses returns to scale from the production function to test the dynamic q‐theory, which predicts that the firm growth effect is theoretically weaker for firms with decreasing returns to scale (DRS) than for non‐DRS firms. Our empirical results generally support the prediction of dynamic q‐theory. However, we find that the dynamic q‐theory explains little of the value, momentum and ROE effects from the standpoint of returns to scale.
Forest structure determines spatial changes in avian communities along an elevational gradient in tropical Africa
Authors: Hořák David , Ferenc Michal , Sedláček Ondřej , Motombi Francis Njie , Svoboda Miroslav , Altman Jan , Albrecht Tomáš , Djomo Nana Eric , Janeček Štěpán , Dančák Martin , Majeský Ľuboš , Lltonga Elias Ndive , Doležal Jiří
Published: September 2019

Aim

To test if tree species richness and forest structure drive spatial variation in avian communities along a tropical elevation gradient and to present information about the role of detailed forest parameters.

Location

A 2,000‐m long elevational gradient of tropical forest on Mt. Cameroon, west‐central Africa.

Taxon

Birds and trees.

Methods

We performed bird censuses and vegetation mapping at the same plots across six forested sites at elevations of 350, 650, 1,100, 1,500, 1,850, and 2,200 m a.s.l., with 16 plots per elevation. We tested the effects of elevation, forest structure and tree diversity on the species richness, functional diversity and β‐diversity of birds (Bray–Curtis dissimilarity). We used conditional inference trees based on random forests (RF) to investigate these relationships across all elevation sites as well as within elevations.

Results

Both tree and bird species richness declined monotonically with elevation. Vegetation structure correlated with elevation, and all vegetation attributes significantly differed among elevations. The RF explained 70% of the variance in avian species richness, with the most important predictors being elevation, proportion of dead trees, tree species richness and herb layer coverage. We found that elevation (and shrub layer) was a particularly important predictor of avian functional diversity. We identified no important predictor of bird species richness after standardization within elevations, and the proportion of dead trees was the sole important predictor of functional diversity. Within‐elevation β‐diversity in avian community composition was determined by the dissimilarity of the tree community and differences in leaf area index, solar radiation and spatial distance. The functional dissimilarity was best explained by leaf area index.

Main conclusions

Apart from elevation itself, spatial distance even within elevations correlated with compositional and functional variation among avian assemblages. Forest structural traits can have a significant influence on distribution of birds. Thus, gaps in the spatial distribution of species such as along elevations might be caused by fine‐scale recognition of suitable habitats.
Left atrial appendage closure: A therapy uniquely suited for specific populations of patients with atrial fibrillation
Authors: Black‐Maier Eric , Piccini Jonathan P. , Granger Christopher B.
Published: September 2019

Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and confers a fivefold increased risk for stroke. Cardioembolic stroke secondary to AF is a devastating event, but is largely preventable with appropriate oral anticoagulation (OAC). The PROTECT and PREVAIL trials demonstrated that the WATCHMAN left atrial appendage closure (LAAC) device in combination with short‐term warfarin therapy is noninferior to long‐term warfarin with respect to a composite endpoint of stroke, cardiovascular death, and systemic embolism. Importantly, the WATCHMAN confers a significant reduction in life‐threatening bleeding compared to OAC. Although direct‐acting oral anticoagulant (DOAC) are superior to warfarin in eligible patients, several important AF populations exist in whom left atrial appendage (LAA) closure may be preferable to DOAC. Populations warranting strong consideration of LAAC include patients with contraindications to DOAC, end‐stage renal disease, prior intracranial hemorrhage, recurrent gastrointestinal bleeding, and patients undergoing transcatheter aortic valve replacement or left atrial electrical isolation. Device‐related thrombosis is an important complication of LAAC, and DOAC may be preferential to warfarin for prevention and treatment of this complication remains unexplored. Prospective clinical trials comparing DOAC to LAAC in these unique populations are either ongoing or needed.
The gut microbiome alterations in allergic and inflammatory skin diseases – an update
Authors: Polkowska‐Pruszyńska B. , Gerkowicz A. , Krasowska D.
Published: September 2019

The human microbiome is a wide range of microorganisms residing in and on our body. The homeostasis between host immune system and the microbial environment allows mutual benefits and protection. Physiological bacterial colonization is essential for the establishment of organism immunity. The human microbiota ecosystem can be divided into several compartments, out of which intestinal flora strongly affects our health and plays a crucial role in the pathophysiology of many diseases. The gastrointestinal tract, being a major guardian of the immune system, maintains the homeostasis with the commensal microorganisms by tolerating the typical flora antigens. The dysbiosis may trigger an inflammatory response followed by tissue damage or autoimmune processes. The gut microbiome alterations are linked to the pathogenesis of the allergic, cardiovascular, gastrointestinal, metabolic, neurodevelopmental, psychiatric and neurodegenerative diseases and cancer. Moreover, there is increasing evidence connecting the skin condition with the gastrointestinal microbiome, which has been described as the skin–gut axis. The aim of this study was to review the literature regarding the role of the gut microbiome alterations in the pathogenesis of selected allergic and inflammatory skin diseases.
Nodular skin lesions: correlation of reflectance confocal microscopy and optical coherence tomography features
Authors: Garbarino F. , Migliorati S. , Farnetani F. , De Pace B. , Ciardo S. , Manfredini M. , Reggiani Bonetti L. , Kaleci S. , Chester J. , Pellacani G.
Published: September 2019

Background

Nodular lesions have common clinical appearance but different prognoses. Differential diagnosis between melanoma (MM), basal cell carcinoma (BCC) and dermal naevus (DN) poses a challenge in clinical practice. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) are promising non‐invasive imaging techniques, potentially able to decrease redundant biopsies. RCM allows in vivo visualization of skin down to the papillary dermis at almost histological resolution, while OCT, particularly dynamic OCT (D‐OCT), provides images deeper within the dermis and reveals the vascular pattern.

Objectives

To identify correlating features observed with RCM and OCT associated with the different nodular lesion diagnoses.

Methods

We retrospectively assessed 68 nodular lesions (30 MM, 20 BCC and 18 DN) with RCM and subsequently OCT. At the end of the study, evaluations were matched with histopathological diagnosis and statistical analysis was performed.

Results

In MM, 57% (17/30) evidenced both cerebriform nests at RCM and icicle‐shaped structures at OCT, with higher average Breslow index. In 80% of BCCs with basaloid islands at RCM, OCT showed ovoid structures. More than half of DN (56%) showed hyporeflective nests at OCT and either dense nests or dense and sparse nests at RCM.

Conclusions

The combined use of RCM and OCT offers a better understanding of the morphological architecture of nodular lesions, correlating RCM parameters with OCT and vice versa, assisting in turn with early differential diagnosis of malignant and benign nodular lesions. The correlation between icicle‐shaped structures and cerebriform nests in MM and their association with Breslow index requires future research.