bluuebunny/crossref_metadata_2025 huggingface dataset:
Disrupted‐in‐schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization
Authors: Kaefer Karola , Malagon‐Vina Hugo , Dickerson Desiree D. , O'Neill Joseph , Trossbach Svenja V. , Korth Carsten , Csicsvari Jozsef
Published: February 2019

Aberrant proteostasis of protein aggregation may lead to behavior disorders including chronic mental illnesses (CMI). Furthermore, the neuronal activity alterations that underlie CMI are not well understood. We recorded the local field potential and single‐unit activity of the hippocampal CA1 region in vivo in rats transgenically overexpressing the Disrupted‐in‐Schizophrenia 1 (DISC1) gene (tgDISC1), modeling sporadic CMI. These tgDISC1 rats have previously been shown to exhibit DISC1 protein aggregation, disturbances in the dopaminergic system and attention‐related deficits. Recordings were performed during exploration of familiar and novel open field environments and during sleep, allowing investigation of neuronal abnormalities in unconstrained behavior. Compared to controls, tgDISC1 place cells exhibited smaller place fields and decreased speed‐modulation of their firing rates, demonstrating altered spatial coding and deficits in encoding location‐independent sensory inputs. Oscillation analyses showed that tgDISC1 pyramidal neurons had higher theta phase locking strength during novelty, limiting their phase coding ability. However, their mean theta phases were more variable at the population level, reducing oscillatory network synchronization. Finally, tgDISC1 pyramidal neurons showed a lack of novelty‐induced shift in their preferred theta and gamma firing phases, indicating deficits in coding of novel environments with oscillatory firing. By combining single cell and neuronal population analyses, we link DISC1 protein pathology with abnormal hippocampal neural coding and network synchrony, and thereby gain a more comprehensive understanding of CMI mechanisms.
Benign breast disease increases breast cancer risk independent of underlying familial risk profile: Findings from a Prospective Family Study Cohort
Authors: Zeinomar Nur , Phillips Kelly‐Anne , Daly Mary B. , Milne Roger L. , Dite Gillian S. , MacInnis Robert J. , Liao Yuyan , Kehm Rebecca D. , Knight Julia A. , Southey Melissa C. , Chung Wendy K. , Giles Graham G. , McLachlan Sue‐Anne , Friedlander Michael L. , Weideman Prue C. , Glendon Gord , Nesci Stephanie ,   kConFab Investigators, Andrulis Irene L. , Buys Saundra S. , John Esther M. , Hopper John L. , Terry Mary Beth
Published: February 2019

Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort, we used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile (FRP), calculated using absolute risk estimates from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. During 176,756 person‐years of follow‐up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis at baseline. A history of BBD was associated with a greater risk of BC: HR = 1.31 (95% CI: 1.14–1.50), and did not differ by underlying FRP, with HRs of 1.35 (95% CI: 1.11–1.65), 1.26 (95% CI: 1.00–1.60), and 1.40 (95% CI: 1.01–1.93), for categories of full‐lifetime BOADICEA score <20%, 20 to <35%, ≥35%, respectively. There was no difference in the association for women with BRCA1 mutations (HR: 1.64; 95% CI: 1.04–2.58), women with BRCA2 mutations (HR: 1.34; 95% CI: 0.78–2.3) or for women without a known BRCA1 or BRCA2 mutation (HR: 1.31; 95% CI: 1.13–1.53) (pinteraction = 0.95). Women with a history of BBD have an increased risk of BC that is independent of, and multiplies, their underlying familial and genetic risk.
SSK modulation performance with relay selection and selection combining
Authors: Ali Shaik Mohammed , Sahu Hemanta Kumar
Published: February 2019

In this letter, the performance of space shift keying (SSK) modulation is analyzed with partial amplify and forward (AF) relay selection (RS) from multiple numbers of relays and selection combining (SC) at the receiver. This scheme selects a single radio frequency (RF) chain from the transmitter to the relay using the RS as well as relay to the receiver using the SC technique. Closed‐form expression for average bit error probability (ABEP) is derived and Numerical and computer simulation results are presented with the discussion. The result derived is compared with the best RS where the best link between the transmitter to the receiver is selected with SC at the receiver. It is revealed that there is an interesting trade‐off between partial RS and best RS with SC at the receiver. However, it is shown that partial RS with SC has almost equal ABEP performance in comparison to best RS with SC with low hardware complexity.
Macrophages significantly enhance wound healing in a vascularized skin model
Authors: Kreimendahl Franziska , Marquardt Yvonne , Apel Christian , Bartneck Matthias , Zwadlo‐Klarwasser Gabriele , Hepp Julia , Jockenhoevel Stefan , Baron Jens Malte
Published: February 2019

Tissue‐engineered dermo‐epidermal skin grafts could be applied for the treatment of large skin wounds or used as an in vitro wound‐healing model. However, there is currently no skin replacement model that includes both, endothelial cells to simulate vascularization, and macrophages to regulate wound healing and tissue regeneration. Here, we describe for the first time a tissue‐engineered, fully vascularized dermo‐epidermal skin graft based on a fibrin hydrogel scaffold, using exclusively human primary cells. We show that endothelial cells and human dermal fibroblasts form capillary‐like structures within the dermis whereas keratinocytes form the epithelial cell layer. Macrophages played a key role in controlling the number of epithelial cells and their morphology after skin injury induced with a CO2 laser. The activation of selected cell types was confirmed by mRNA analysis. Our data underline the important role of macrophages in vascularized skin models for application as in vitro wound healing models or for skin replacement therapy. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1340–1350, 2019.
Incident Fragility Fractures Have a Long-Term Negative Impact on Health-Related Quality of Life of Older People: The Canadian Multicentre Osteoporosis Study
Authors: Borhan Sayem , Papaioannou Alexandra , Gajic-Veljanoski Olga , Kennedy Courtney , Ioannidis George , Berger Claudie , Goltzman David , Josse Robert , Kovacs Christopher S , Hanley David A , Prior Jerilynn C , Morin Suzanne N , Kaiser Stephanie M , Cheung Angela M , Thabane Lehana , Adachi Jonathan ,   for the CaMos Research Group
Published: February 2019

Although the short-term impact of incident fragility fractures on health-related quality of life (HRQL) of older people has been confirmed, we lack long-term evidence. We explored the impact of incident fragility fractures on HRQL, among people aged 50 years and older, using 10-year prospective data from the Canadian Multicentre Osteoporosis Study (CaMos). This study was based on data from 7753 (2187 men and 5566 women) participants of CaMos. The HRQL, measured through the Health Utility Index (HUI), was captured at baseline and year 10. The incident fragility fractures were recorded over 10 years of follow-up at spine, hip, rib, shoulder, pelvis, or forearm. Multivariable regression analysis was conducted to measure the mean difference, termed as deficit, in the HUI scores for participants with and without fractures. We examined the effects of single or multiple fragility fractures, time (fractures that occurred between year 1 to 5 and 6 to 10) and recovery to the prefracture level. Incident spine and hip fractures were associated with significant deficits (varied from –0.19 to –0.07) on the HUI scores. Hip and spine fractures were associated with negative impact on mobility, self-care, and ambulation. Fractures that occurred closer to the follow-up assessment were associated with significant impact on HRQL compared to fractures occurring a long time before it, except for hip fracture (deficits lasted 5 years or longer). Similarly, multiple hip (–0.14), spine (–0.16), and rib (–0.21) fractures significantly impacted the HRQL of women. Women with a hip fracture never recovered to their prefracture level score (OR = 0.41; 95% confidence interval [CI], 0.19 to 0.98). Our analysis suggests that single and multiple hip fractures as well as multiple spine and rib fractures strongly impact the HRQL of older people over a prolonged period of time. © 2019 American Society for Bone and Mineral Research.
Production and recovery of poly‐3‐hydroxybutyrate [P(3HB)] of ultra‐high molecular weight using fed‐batch cultures of Azotobacter vinelandii OPNA strain
Authors: García Andrés , Pérez Diana , Castro Manuel , Urtuvia Viviana , Castillo Tania , Díaz‐Barrera Alvaro , Espín Guadalupe , Peña Carlos
Published: February 2019

BACKGROUND

Poly‐3‐hydroxybutyrate P(3HB) is a bioplastic that is characterized for its biodegradability and biocompatibility and can be used in the biomedical field. The aim of this study was to evaluate the scaling‐up process at pilot level, for the production and recovery of P(3HB) synthesized by Azotobacter vinelandii OPNA strain, based on the use of fed‐batch fermentation coupled to a recovery method using nonhalogenated solvents (ethanol and acetone).

RESULTS

In fed‐batch cultivations at the 3‐L scale, using yeast extract and sucrose of industrial grade with a carbon:nitrogen ratio of 14 and manipulating the agitation rate from 500 to 700 rpm to give a maximal biomass concentration of 33.8 ± 1.5 g L−1, P(3HB) concentrations of 29 ± 4.5 g L−1 were reached. By simulating the gassed volumetric power input observed in the 3‐L bioreactors at the different agitation rates (500 and 700 rpm), a scaling‐up to 30‐L bioreactors was performed. At this scale, the P(3HB) concentration, and productivity were similar or even better than those values obtained at the smaller scale. The production process was coupled to a P(3HB) separation process, in which the polymer was precipitated with ethanol and washed with acetone, reaching a purity close to 95% and a yield of 85%. The P(3HB) obtained was of ultra‐high molecular mass, with values of 5693 ± 615 kDa.

CONCLUSION

In this study a successful scaling‐up process for the production of P(3HB) of ultra‐high molecular weight at pilot scale was developed. © 2019 Society of Chemical Industry
Regulation of the levels of health promoting compounds: lupeol, mangiferin and phenolic acids in the pulp and peel of mango fruit: a review
Authors: Vithana Mekhala DK , Singh Zora , Johnson Stuart K
Published: February 2019

There is a demand for feasible methodologies that can increase/maintain the levels of health‐promoting phytochemicals in horticultural produce, due to strong evidence that these compounds can reduce risk of chronic diseases. Mango (Mangifera indica L.), ranks fifth among the most cultivated fruit crops in the world, is naturally rich in phytochemicals such as lupeol, mangiferin and phenolic acids (e.g. gallic acid, chlorogenic acid and vanillic acid). Yet, there is still much scope for up‐regulating the levels of these compounds in mango fruit through manipulation of different preharvest and postharvest practices that affect their biosynthesis and degradation. The process of ripening, harvest maturity, physical and chemical elicitor treatments such as low temperature stress, methyl jasmonate (MeJA), salicylic acid (SA) and nitric oxide (NO) and the availability of enzyme cofactors (Mg2+, Mn2+ and Fe2+) required in terpenoid biosynthesis were identified as potential determinants of the concentration of health‐promoting compounds in mango fruit. The effectiveness of these preharvest and postharvest approaches in regulating the levels of lupeol, mangiferin and phenolic acids in the pulp and peel of mango fruit will be discussed. In general spray application of 0.2% iron(II) sulphate (FeSO4) 30 days before harvest, harvest at sprung stage, storage of mature green fruit at 5 °C for 12 days prior to ripening, fumigation of mature green fruit with 10−5 mol L−1 and/or 10−4 mol L−1 MeJA for 24 h or 20 and/or 40 µL L−1 NO for 2 h upregulate the levels of lupeol, mangiferin and phenolic acids in pulp and peel of ripe mango fruit. © 2019 Society of Chemical Industry
Selection of suitable species as a key factor for vegetation restoration of degraded areas in an open‐pit manganese‐ore mine in Southern China using multivariate‐analysis methods
Authors: Hou Xiaoyun , Liu Shiliang , Zhao Shuang , Beazley Robert , Cheng Fangyan , Wu Xue , Xu Jingwei , Dong Shikui
Published: February 2019

Open‐pit mining results in large amounts of degraded lands that require ecological recovery. Adequate‐species selection for ecological recovery is of great importance. In this study, field investigations along the disturbance gradients (marginal area, restoration area, and control area) in a manganese ore deposit of Guangxi in Southern China were carried out. We screened the adequate species from two aspects. In the marginal area, the result of corrected Akaike information criterion revealed that Mn was the most important soil parameter affecting vegetation diversity. Cyclosorus parasiticus (L.) Farwell., Setaria viridis (L.) Beauv., Mimosa sepiaria Benth., and Bidens pilosa L. were selected for their abilities to adapt to high‐Mn‐content soils. In the restoration area and control area, we combined important values and field performance (Dickson quality index, DQI) of species to select adequate species. Miscanthus sinensis Anderss. and Arundinella hirta (Thunb.) Tanaka were selected using the similar DQI (p > 0.05) in both areas. In summary, C. parasiticus (L.) Farwell., S. viridis (L.) Beauv., M. sinensis Anderss., and A. hirta (Thunb.) Tanaka were selected as adequate species because of their high potential to adapt to these disturbed sites. Our results and methodology could have a demonstrating effect for restoration programmes in manganese ore mining areas of China.
Mapping European ecosystem change types in response to land‐use change, extreme climate events, and land degradation
Authors: Horion Stéphanie , Ivits Eva , De Keersmaecker Wanda , Tagesson Torbern , Vogt Jürgen , Fensholt Rasmus
Published: February 2019

Extreme climate events and nonsustainable land use are important drivers altering the functioning of European ecosystems, resulting in loss of the services provided. Yet a consensus method for regular continental scale assessment of ecosystem condition in relation to land degradation (LD) is still lacking. Here, we propose a new remote sensing‐based approach allowing for improved, repeated assessment of changing pressure on terrestrial ecosystems. On the basis of segmented trend analysis of water‐use efficiency (WUE), a map of ecosystem change type (ECT) was produced over Europe for the period 1999 to 2013. Results were related to drought and change in land use and land cover and to known cases of soil degradation (LD case‐studies). More than 30% of the European ecosystems experienced significant changes in WUE, of which more than 20% were categorized as abrupt. Large‐scale positive reversals in WUE were observed over regions with increasing crop yield and intensification of wood production, whereas decreased WUE was observed over grassland areas coinciding with high farmland abandonment. Evidence of drought pressure on ecosystem functioning (EF) was observed, with abrupt changes in functioning observed during major European drought events. The ECTs also provided relevant information on the location and type of change in EF over the LD case studies. We conclude that mapping of gradual and abrupt changes in EF is expected to be valuable tool for ecosystem condition assessment that is essential for assessing the success of reaching the LD neutrality objectives set by the United Nations Convention to Combat Desertification.
Supplementation of All‐Trans‐Retinoic Acid Below Cytotoxic Levels Promotes Adipogenesis in 3T3‐L1 Cells
Authors: Kim Dong‐Hwan , Lee Jeong‐Woong , Lee Kichoon
Published: February 2019

Vitamin A, referred to as retinol, is an essential nutrient that affects the cell growth and differentiation including adipogenesis. Although previous studies using supraphysiological doses (over 1 μM) of all‐trans‐retinoic acid (atRA) demonstrated antiadipogenic activity, effects of atRA at various levels on differentiation of 3T3‐L1 preadipocytes have not been extensively investigated. Our study showed that the amount of cellular triacylglycerol (TAG) and intensities of Oil‐Red‐O staining were decreased by supplementing atRA (1 and 10 μM) but increased by low concentrations of atRA (0.01 to 100 nM) compared with the control. Also PPARγ and FABP4 were gradually overexpressed by atRA up to 1 nM but decreased at over 1 nM concentrations. Moreover, mitotic clonal expansion (MCE) and consequential growth‐arrest were analyzed as important steps in adipogenesis of 3T3‐L1 cells. The 1 nM group showed more cell proliferation and thereafter a higher ratio of the G0/G1 phase on Day 2. Protein levels of S/G2‐phase factors were dose dependently increased by atRA up to 1 nM on Day 1, but the factors were highly expressed in higher doses on Day 2. G0/G1 markers were higher at the higher doses of atRA on Day 1; whereas, they were highly expressed in mild or medium doses on Day 2. These data indicate that atRA controls adipogenesis with accompanied changes in cell proliferation and follow‐up growth‐arrest. These results indicate that atRA can function both as a negative and positive regulator of adipogenesis depending on dosages, providing a strategy for achieving proper nutritional balance for treatment of obesity.
Service supply chains for population health: Overcoming fragmentation of service delivery ecosystems
Authors: Rouse William B. , Johns Michael M.E. , Pepe Kara M.
Published: February 2019

Introduction

Population health involves integration of health, education, and social services to keep a defined population healthy, to address health challenges holistically, and to assist with the realities of being mortal. The fragmentation of the US population health delivery system is addressed. The impacts of this fragmentation on the treatment of substance abuse in the United States are considered. Innovations needed to overcome this fragmentation are proposed.

Approach

Treatment capacity issues, including scheduling practices, are discussed. Costs of treatment and lack of treatment are considered. Models of integrated care delivery are reviewed. Potential innovations from systems science, behavioral economics, and social networks are considered. The implications of these innovations are discussed in terms of information technology (IT) systems and governance.

Conclusions

Enormous savings are possible with more integrated treatment. Based on a range of empirical findings, it is argued that investments of these resources in integrated delivery of care have the potential to dramatically improve health outcomes, thereby significantly reducing the costs of population health.
Reversible Bonding of Aromatic Thermosetting Copolyesters for In‐Space Assembly
Authors: Meyer Jacob L. , Bakir Mete , Lan Pixiang , Economy James , Jasiuk Iwona , Bonhomme Gaëtan , Polycarpou Andreas A.
Published: February 2019

Reversible bonding is an attractive option for assembly and disassembly of reconfigurable space structures due to the simplicity of the fastening concept. Interchain transesterifications reaction [ITR—a type of dynamic covalent exchange reactions afforded by aromatic thermosetting copolyesters (ATSP)] between two ATSP coatings can successfully be used as a reversible bonding concept, provided that the mode of debonding is completely cohesive (rather than adhesive or delaminatory from metal substrate). An optimization study is carried out on the ITR bonding for which ATSP coating is applied on 7075 aluminum substrates and bond/debond experiments are carried out using a custom‐built tool kit. The toolkit enables precise control over bonding pressure, temperature, and contact time. Bonding conditions are optimized to produce complete cohesive failure with maximized bonding strength. Optimized bonding parameters are successfully implemented to realize 50 cycles of bond/debond process without compromising adhesive strength. Experiments show a debonding strength of 28.7 MPa for the 51st cycle at room temperature—significantly in excess of prior highest reversible bonding strength results found in the literature. These results, in addition to the high thermal stability and glass transition temperature of the base polymer, indicate viability of this reversible bonding concept for in‐space assembly.
Waterproof and Breathable Electrospun Nanofibrous Membranes
Authors: Yu Xi , Wu Xiaohui , Si Yang , Wang Xianfeng , Yu Jianyong , Ding Bin
Published: February 2019

Waterproof and breathable (W&B) membranes combine fascinating properties of resistance to liquid water penetration and transmitting of water vapor, playing a key role in addressing problems related to health, resources, and energy. Electrospinning is an efficient and advanced way to construct nanofibrous materials with easily tailored wettability and adjustable pore structure, therefore providing an ideal strategy for constructing W&B membranes. In this review, recent progress on electrospun W&B membranes is summarized, involving materials design and fabrication, basic properties of electrospun W&B membranes associated with waterproofness and breathability, as well as their applications. In addition, challenges and future trends of electrospun W&B membranes are discussed.
Sensitivity and Specificity of Diagnostic Criteria for Progressive Supranuclear Palsy
Authors: Ali Farwa , Martin Peter R. , Botha Hugo , Ahlskog J. Eric , Bower James H. , Masumoto Joseph Y. , Maraganore Demetrius , Hassan Anhar , Eggers Scott , Boeve Bradley F. , Knopman David S. , Drubach Daniel , Petersen Ronald C. , Dunkley Erika Driver , van Gerpen Jay , Uitti Ryan , Whitwell Jennifer L. , Dickson Dennis W. , Josephs Keith A.
Published: February 2019

Background

In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times.

Methods

Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3‐year cutoff.

Results

A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes.

Conclusion

The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society
Emerging links between pediatric lysosomal storage diseases and adult parkinsonism
Authors: Ysselstein Daniel , Shulman Joshua M. , Krainc Dimitri
Published: February 2019

Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal‐recessive or X‐linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in accumulation of nondegraded substrates. Although lysosomal storage disorders are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany many lysosomal storage disorders. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between lysosomal storage disorders and adult‐onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher's disease and are among the most common and potent risk factors for PD. However, recently, many additional lysosomal storage disorder genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of PD and guide development of new therapeutic strategies. We systematically review the emerging genetic links between lysosomal storage disorders and PD. © 2019 International Parkinson and Movement Disorder Society
Exome sequencing in families with chronic central serous chorioretinopathy
Authors: Schellevis Rosa L. , van Dijk Elon H. C. , Breukink Myrte B. , Keunen Jan E. E. , Santen Gijs W. E. , Hoyng Carel B. , de Jong Eiko K. , Boon Camiel J. F. , den Hollander Anneke I.
Published: February 2019

Background

Central serous chorioretinopathy (CSC) is a chorioretinal disease characterized by fluid accumulation between the neuroretina and retinal pigment epithelium with unknown etiology. Family studies have suggested a heritable component for CSC with an autosomal dominant inheritance pattern. Therefore, exome sequencing was performed on familial cCSC to indentify the genetic components contributing to familial cCSC.

Methods

Exome sequencing was performed on 72 individuals of 18 families with CSC. In these families, we determined whether rare genetic variants (minor allele frequency < 1%) were segregated with CSC and also performed familial gene‐burden analysis.

Results

In total, 11 variants segregated in two out of 18 families. One of these variants, c.4145C>T; p.T1382I (rs61758735) in the PTPRB gene, was also associated with CSC in a large case–control cohort sequenced previously (p = 0.009). Additionally, in 28 genes two or more different heterozygous variants segregated in two or more families, but no gene showed consistent associations in both the family gene‐burden results and gene‐burden analysis in the case–control cohort.

Conclusion

We identified potential candidate genes for familial CSC and managed to exclude Mendelian inheritance of variants in one or a limited number of genes. Instead, familial CSC may be a heterogeneous Mendelian disease caused by variants in many different genes, or alternatively CSC may represent a complex disease to which both environmental factors and genetics contribute.
Identification of New Potent Acetylcholinesterase Inhibitors Using Virtual Screening and in vitro Approaches
Authors: Mokrani El Hassen , Bensegueni Abderrahmane , Chaput Ludovic , Beauvineau Claire , Djeghim Hanane , Mouawad Liliane
Published: February 2019

Acetylcholinesterase (AChE) is currently the most favorable target for the symptomatic treatment and reduction of Alzheimer's disease (AD). In order to identify new potent inhibitors of this enzyme, we describe herein a new structure‐based virtual screening (SBVS) using the Institut Curie‐CNRS chemical library (ICCL), which contained at the screening date 14307 compounds. The strategy undertaken in this work consisted of the use of several docking programs in SBVS calculations followed by the application of a consensus method (vSDC) and a scrupulous visual analysis. It allowed us to obtain a high degree of success, with a yield of almost 86 %, since 12 hits were identified among only 14 molecules tested in vitro. Still more remarkably, 6 of these hits were more active than galantamine, the reference inhibitor. These hits were predicted to have good ADMET properties. The two most promising compounds can serve as leads for AD treatment.
Vegan and Animal Meal Composition and Timing Influence Glucose and Lipid Related Postprandial Metabolic Profiles
Authors: Draper Colleen Fogarty , Tini Giulia , Vassallo Irene , Godin Jean Philippe , Su MingMing , Jia Wei , Beaumont Maurice , Moco Sofia , Martin Francois‐Pierre
Published: February 2019

Scope

Flexitarian dieting is increasingly associated with health benefits. The study of postprandial metabolic response to vegan and animal diets is essential to decipher how specific diet components may mediate metabolic changes.

Methods and results

A randomized, crossover, controlled vegan versus animal diet challenge is conducted on 21 healthy participants. Postprandial metabolic measurements are conducted at seven timepoints. Area under the curve analysis of the vegan diet response demonstrates higher glucose (EE 0.35), insulin (EE 0.38), triglycerides (EE 0.72), and nine amino acids at breakfast (EE 4.72–209.32); and six lower health‐promoting fatty acids at lunch (EE −0.1035 to −0.13) (p < 0.05).

Conclusions

Glycemic and lipid parameters vary irrespective of diet type, demonstrating that vegan and animal meals contain health‐promoting and suboptimal nutrient combinations. The vegan breakfast produces the same pattern of elevated branched chain amino acids, insulin, and glucose as the animal diet from the fasting results, reflecting the low protein load in the animal and the higher branched‐chain amino acid load of the vegan breakfast. Liberalization of the vegan menu to vegetarian and the animal menu to a Nordic‐based diet can result in optimal metabolic signatures for both flexitarian diet strategies in future research.
Disentangling the Effects of Monounsaturated Fatty Acids from Other Components of a Mediterranean Diet on Serum Metabolite Profiles: A Randomized Fully Controlled Dietary Intervention in Healthy Subjects at Risk of the Metabolic Syndrome
Authors: Michielsen Charlotte C. J. R. , Hangelbroek Roland W.J. , Feskens Edith J. M. , Afman Lydia A.
Published: February 2019

Scope

The Mediterranean (MED) diet has been associated with a decreased risk of cardiovascular diseases. It is unclear whether this health effect can be mainly contributed to high intakes of monounsaturated fatty acids (MUFA), characteristic for the MED diet, or whether other components of a MED diet also play an important role.

Methods and Results

A randomized fully controlled parallel trial is performed to examine the effects of the consumption of a saturated fatty acid rich diet, a MUFA‐rich diet, or a MED diet for 8 weeks on metabolite profiles, in 47 subjects at risk of the metabolic syndrome. A total of 162 serum metabolites are assessed before and after the intervention by using a targeted NMR platform. Fifty‐two metabolites are changed during the intervention (false discovery rate [FDR]p < 0.05). Both the MUFA and MED diet decrease exactly the same fractions of LDL, including particle number, lipid, phospholipid, and free cholesterol fraction (FDRp < 0.05). The MED diet additionally decreases the larger subclasses of very‐low‐density lipoprotein (VLDL), related VLDL fractions, VLDL‐triglycerides, and serum‐triglycerides (FDRp < 0.05).

Conclusion

The findings clearly demonstrate that the MUFA component is responsible for reducing LDL subclasses and fractions, and therefore causes an antiatherogenic lipid profile. Interestingly, consumption of the other components in the MED diet show additional health effects.
Exam‐level dose monitoring in CT: Quality metric consideration for multiple series acquisitions
Authors: Li Xinhua , Yang Kai , Liu Bob
Published: February 2019

Purpose

Multi‐series CT examination is common in the clinic, but no metric is agreed upon to report the overall dose from such an examination. This work proposes a relevant metric for tracking patient dose from multi‐series examinations and illustrates the evaluation method through explanatory examples.

Materials and methods

In each acquisition series, a previously reported method was used to evaluate the cross‐sectional average dose along the z‐axis of a water phantom, with inputs of CTDIvol, scan length, tube current, and patient water‐equivalent diameter. With a multi‐series examination, the dose at each z‐location was accumulated over all acquisition series. This method was applied to four clinical CT examinations. In three abdominal/pelvic examinations (patient weight, 107, 79, 79 kg), tube current modulation was applied in five acquisition series with scan lengths of 30–41.8 cm, while tube current was fixed in other series with short scan lengths (1.0, 7.9 cm). In another CT‐guided liver ablation procedure (patient weight, 114 kg), 22 series were acquired with constant mA and scan lengths of 1–30 cm. The maximum value of the overall dose profile of each examination was compared to five dose quantities, including CTDIvol,sum and SSDEsum by the ACR CT Dose Index Registry, scan length‐weighted CTDIvol and SSDE by a CT dose monitoring platform, and “max z location CTDIvol” by a CT manufacturer.

Results

A simple graphic display of dose as a function of the z‐axis location was presented for each acquisition series and for the whole examination. Differences up to 43.4% and 42.8%, or down to −93.5%, −93.5%, and −49.0%, were observed between the maximum value of the overall dose profile and five dose quantities (in the above order), respectively.

Conclusion

The overall dose profile gives a complete description of z‐axis dose distribution for the studied CT examinations under a wide range of patient variables and acquisition conditions, including multiple acquisition series. Simple visualization of the doses across and beyond the scan ranges may provide a new tool for CT dose optimization.
The Effect of Medical Marijuana Laws on the Health and Labor Supply of Older Adults: Evidence from the Health and Retirement Study
Authors: Nicholas Lauren Hersch , Maclean Johanna Catherine
Published: February 2019

Older adults are at elevated risk of reducing labor supply due to poor health, partly because of high rates of symptoms that may be alleviated by medical marijuana. Yet, surprisingly little is known about how this group responds to medical marijuana laws (MMLs). We quantify the effects of state medical marijuana laws on the health and labor supply of adults age 51 and older, focusing on the 55 percent with one or more medical conditions with symptoms that may respond to medical marijuana. We use longitudinal data from the Health and Retirement Study to estimate event study and differences‐in‐differences regression models. Three principle findings emerge from our analysis. First, active state medical marijuana laws lead to lower pain and better self‐assessed health among older adults. Second, state medical marijuana laws lead to increases in older adult labor supply, with effects concentrated on the intensive margin. Third, the effects of MMLs are largest among older adults with a health condition that would qualify for legal medical marijuana use under current state laws. Findings highlight the role of health policy in supporting work among older adults and the importance of including older adults in assessments of state medical marijuana laws.
Bone marrow biopsy in the initial staging of Ewing sarcoma: Experience from a single institution
Authors: Cesari Marilena , Righi Alberto , Colangeli Marco , Gambarotti Marco , Spinnato Paolo , Ferraro Andrea , Longhi Alessandra , Abate Massimo Eraldo , Palmerini Emanuela , Paioli Anna , Ferrari Cristina , Donati Davide Maria , Picci Piero , Ferrari Stefano
Published: February 2019

Background

Ewing sarcoma (ES) is the second most common bone tumor in adolescents and children. Staging workup for ES includes imaging and bone marrow biopsy (BMB). The effective role of BMB is now under discussion.

Procedure

A monoinstitutional retrospective analysis reviewed clinical charts, imaging, and histology of patients with diagnosis of ES treated at the Rizzoli Institute between 1998 and 2017.

Results

The cohort included 504 cases of ES of bone; 137 (27%) had metastases at diagnosis, while the remaining 367 had localized disease. Twelve patients had a positive BMB (2.4%). Eleven had distant metastases detected at initial workup staging with imaging assessment: six patients presented with bone metastases, five with both bone and lung metastases. Only one patient with ES of the foot (second metatarsus) was found to have bone marrow involvement with negative imaging evaluation (0.3%).

Conclusions

On the basis of our data, we suggest reconsidering the effective role of BMB in initial staging workup for patients with ES with no signs of metastases by modern imaging techniques. In metastatic disease, the assessment of the bone marrow status may remain useful to identify a group of patients at very high risk who could benefit from different treatment strategies.
Results of a multicenter universal newborn screening program for sickle cell disease in Italy: A call to action
Authors: Colombatti Raffaella , Martella Maddalena , Cattaneo Laura , Viola Giampietro , Cappellari Anita , Bergamo Chiara , Azzena Silvia , Schiavon Sara , Baraldi Eugenio , Dalla Barba Beatrice , Trafojer Ursula , Corti Paola , Uggeri Marzia , Tagliabue Paolo Emilio , Zorloni Chiara , Bracchi Michela , Biondi Andrea , Basso Giuseppe , Masera Nicoletta , Sainati Laura
Published: February 2019

Background

Sickle cell disease (SCD) is a chronic multisystem disorder requiring comprehensive care that includes newborn screening (NBS) as the first step of care. Italy still lacks a national SCD NBS program and policy on blood disorders. Pilot single‐center screening programs and a regional targeted screening have been implemented so far, but more evidence is needed in order to impact health policies.

Population and methods

NBS was offered to parents of newborns in gynecology clinics in Padova and Monza, tertiary care university hospitals in northern Italy. High‐performance liquid chromatography (HPLC) was performed as the first test on samples collected on Guthrie cards. Molecular analysis of the beta‐globin gene was performed on positive samples.

Results

A total of 5466 newborns were enrolled; for 5439, informed consents were obtained. A similar family origin was seen in the two centers (65% Italians, 9% mixed couples, 26% immigrants). Compared with SCD NBS programs in the United States and Europe, our results show a similar incidence of SCD patients and carriers. All SCD patients had a Sub‐Saharan family background; HbS carriers were 15% Caucasians (Italian, Albanians) and 10% from other areas (North Africa–India–South America); carriers of other hemoglobin variants were mainly (47%) from other areas.

Conclusions

Our results demonstrate the feasibility of a multicentric NBS program for SCD, give information on HbS epidemiology in two Northern Italian Areas, and support previous European recommendation for a universal NBS program for SCD in Italy: a high incidence of patients and carriers has been detected, with a high percentage of Caucasian carriers, impossible to identify in a targeted NBS.
Variation of the prevalence of pediatric polypharmacy: A scoping review
Authors: Baker Courtney , Feinstein James A. , Ma Xuan , Bolen Shari , Dawson Neal V. , Golchin Negar , Horace Alexis , Kleinman Lawrence C. , Meropol Sharon B. , Pestana Knight Elia M. , Winterstein Almut G. , Bakaki Paul M.
Published: February 2019

Purpose

To examine the range of prevalence of pediatric polypharmacy in literature through a scoping review, focusing on factors that contribute to its heterogeneity in order to improve the design and reporting of quality improvement, pharmacovigilance, and research studies.

Methods

We searched Ovid Medline, PubMed, EMBASE, CINAHL, Ovid PsycINFO, Cochrane CENTRAL, and Web of Science Core Collection databases for studies with concepts of children and polypharmacy, along with a hand search of the bibliographies of six reviews and 30 included studies. We extracted information regarding study design, disease conditions, and prevalence of polypharmacy.

Results

Two hundred eighty‐four studies reported prevalence of polypharmacy. They were more likely to be conducted in North America (37.7%), published after 2010 (44.4%), cross‐sectional (67.3%), in outpatient settings (59.5%). Prevalence ranged from 0.9% to 98.4%, median 39.7% (interquartile range [IQR] 22.0%‐54.0%). Studies from Asia reported the highest median prevalence of 45.4% (IQR 27.3%‐61.0%) while studies from North America reported the lowest median prevalence of 30.4% (IQR 14.7%‐50.2%). Prevalence decreased over time: median 45.6% before 2001, 38.1% during 2001 to 2010, and 34% during 2011 to 2017. Studies involving children under 12 years had a higher median prevalence (46.9%) than adolescent studies (33.7%). Inpatient setting studies had a higher median prevalence (50.3%) than studies in outpatient settings (38.8%). Community level samples, higher number and duration of medications defining polypharmacy, and psychotropic medications were associated with lower prevalence.

Conclusions

The prevalence of pediatric polypharmacy is high and variable. Studies reporting pediatric polypharmacy should account for context, design, polypharmacy definition, and medications evaluated.
Effectiveness of Once/Day Dolutegravir Plus Boosted Darunavir as a Switch Strategy in Heavily Treated Patients with Human Immunodeficiency Virus
Authors: Navarro Jordi , Santos José Ramón , Silva Ana , Burgos Joaquin , Falcó Vicenç , Ribera Esteban , Imaz Arkaitz , Curran Adrian
Published: February 2019

Study Objective

Dual therapy with once/day dolutegravir (DTG) plus boosted darunavir (DRV/b) may be a suitable and effective strategy with a high genetic barrier to resistance in patients infected with human immunodeficiency virus (HIV). Our aim was to evaluate the effectiveness of DTG plus DRV/b (DTG+DRV/b) as a switch strategy in HIV‐infected patients, irrespective of their history of virologic failure (VF).

Design

Multicenter retrospective cohort study.

Setting

Human immunodeficiency outpatient treatment clinics at three university hospitals in Spain.

Patients

Fifty HIV‐infected adults who had a stable antiretroviral treatment (ART) regimen and an undetectable viral load for at least 6 months, and whose ART was switched to once/day DTG+DRV/b between January 2015 and January 2018 were included in the analysis. Historical genotype at the time of VF was available in 44 patients.

Measurements and Main Results

Patients were followed until VF or treatment discontinuation for any reason. The primary outcome was the percentage of patients with a viral load of 50 copies/mL or lower at the last follow‐up visit. Secondary outcomes included changes in CD4+ cell count, lipid profile, and renal function. Of the 50 patients included, median time of viral suppression was 52 months (interquartile range [IQR] 18–103 mo) and nadir CD4+ 89 cells/mm3 (IQR 37–241 cells/mm3). Patients had a history of a median of 8 ART combinations (IQR 4–11 combinations) and 3 VFs (IQR 2–8 VFs). The historical genotypes from 44 patients showed 41 patients (93.2%) with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance‐associated mutations (RAMs), 32 (72.7%) with nonnucleoside reverse transcriptase inhibitor (NNRTI) RAMs, and 12 (27.3%) with primary protease inhibitor (PI) RAMs; 7 (15.9%) had darunavir RAMs, and no patients had baseline integrase strand transfer inhibitor RAMs. Thirty‐seven patients (84.1%) had resistance to at least two antiretroviral classes. After a median of 25 months (IQR 17–28 mo) of follow‐up, 49 patients (98%) maintained a viral load of 50 copies/mL or lower, and 1 patient (2%) had VF. No new RAMs emerged at VF. At week 4, serum creatinine concentration increased a median of 0.12 mg/dl (0.03–0.23 mg/dl). At last visit, total cholesterol and low‐density lipoprotein cholesterol levels increased by a median of 9 mg/dl (IQR −18 to 40 mg/dl) and 16 mg/dl (IQR −9 to 40 mg/dl), respectively, whereas CD4+ cell count remained stable (median +13 cell/mm3).

Conclusion

In this cohort of heavily treated HIV‐infected patients with virologic suppression, switching to the combination of DTG+DRV/b was a convenient regimen that was highly effective and had good tolerability.
Periprocedural Neuroendovascular Antiplatelet Strategies for Thrombosis Prevention in Clopidogrel‐Hyporesponsive Patients
Authors: Barra Megan E. , Berger Karen , Tesoro Eljim P. , Brophy Gretchen M.
Published: February 2019

Patients undergoing neuroendovascular procedures such as cerebral aneurysm coiling and intracranial stent deployment are frequently treated with antiplatelet agents to prevent thrombotic complications. The combination of aspirin and a P2Y12 inhibitor such as clopidogrel is often initiated days before elective procedures or as loading doses for emergent procedures; however, some patients may still experience thrombotic complications. Patients identified as clopidogrel hyporesponders are more likely to experience poor outcomes and may require changes to their regimens. Historically, high‐dose clopidogrel regimens were used in response to subtherapeutic results of platelet function assays and point‐of‐care testing despite limited supporting data. Recently, more data have emerged using alternative P2Y12 inhibitors such as prasugrel and ticagrelor. Dosing for neuroendovascular conditions is often extrapolated from the cardiac literature, although outcomes in cardiac patients may not be relevant to neurologic patients, making prophylactic treatment recommendations challenging for these patients. This review summarizes the literature for antiplatelet prophylaxis in patients undergoing neuroendovascular device placement, focusing on alternative regimens for clopidogrel hyporesponders.