bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibiting PNP for the therapy of hyperuricemia in Lesch–Nyhan disease: Preliminary in vitro studies with analogues of immucillin‐G
Authors: Jacomelli Gabriella , Baldini Eva , Mugnaini Claudia , Micheli Vanna , Bernardini Giulia , Santucci Annalisa
Published: February 2019

Lesch‐Nyhan disease (LND) is a rare X‐linked genetic disorder, with complete hypoxanthine‐guanine phosphoribosyltransferase (HGPRT) deficiency, uric acid (UA), hypoxanthine and xanthine accumulation, and a devastating neurologic syndrome. UA excess, causing renal failure, is commonly decreased by xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, yielding a xanthine and hypoxanthine increase. Xanthine accumulation may result in renal stones, while hypoxanthine excess seems involved in the neurological disorder. Inhibition of purine nucleoside phosphorylase (PNP) represents a different strategy for lowering urate. PNP catalyzes the cleavage of purine ribo‐ and d‐ribo‐nucleosides into ribose/deoxyribose phosphate and free bases, starting catabolism to uric acid. Clinical trials demonstrated that PNP inhibitors, initially developed as anticancer drugs, lowered UA in some gouty patients, in association or not with allopurinol. The present study tested the reliability of an analogue of immucillin‐G (C1a), a PNP inhibitor, as a therapy for urate, hypoxanthine, and xanthine excess in LND patients by blocking hypoxanthine production upstream. The therapeutic aim is to limit the administration of XOR inhibitors to LND patients by supplying the PNP inhibitor in low doses, avoiding d‐nucleoside toxicity. We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND hyperuricemia.
Mapping mononuclear phagocytes in blood, lungs, and lymph nodes of sarcoidosis patients
Authors: Lepzien Rico , Rankin Gregory , Pourazar Jamshid , Muala Ala , Eklund Anders , Grunewald Johan , Blomberg Anders , Smed-Sörensen Anna
Published: February 2019

Sarcoidosis is a T-cell driven inflammatory disease characterized by granuloma formation. Mononuclear phagocytes (MNPs)—macrophages, monocytes, and dendritic cells (DCs)—are likely critical in sarcoidosis as they initiate and maintain T cell activation and contribute to granuloma formation by cytokine production. Granulomas manifest primarily in lungs and lung-draining lymph nodes (LLNs) but these compartments are less studied compared to blood and bronchoalveolar lavage (BAL). Sarcoidosis can present with an acute onset (usually Löfgren’s syndrome (LS)) or a gradual onset (non-LS). LS patients typically recover within 2 years while 60% of non-LS patients maintain granulomas for up to 5 years. Here, four LS and seven non-LS patients underwent bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). From each patient, blood, BAL, endobronchial biopsies (EBBs), and LLN samples obtained by EBUS-TBNA were collected and MNPs characterized using multicolor flow cytometry. Six MNP subsets were identified at varying frequencies in the anatomical compartments investigated. Importantly, monocytes and DCs were most mature with migratory potential in BAL and EBBs but not in the LLNs suggesting heterogeneity in MNPs in the compartments typically affected in sarcoidosis. Additionally, in LS patients, frequencies of DC subsets were lower or lacking in LLNs and EBBs, respectively, compared to non-LS patients that may be related to the disease outcome. Our work provides a foundation for future investigations of MNPs in sarcoidosis to identify immune profiles of patients at risk of developing severe disease with the aim to provide early treatment to slow down disease progression.
Fabrication of homogenous three‐dimensional biomimetic tissue for mass spectrometry imaging
Authors: Song Xiaowei , He Jiuming , Li Chao , Sun Chenglong , Pang Xuechao , Zhang Jin , Zang Qingce , Luo Zhigang , Li Xin , Zhang Ruiping , Abliz Zeper
Published: February 2019

Reference samples are essential for mass spectrometric method optimization, data quality control, and target analyte quantitation. However, it is highly challenging to prepare an ideal homogeneous, standard‐spiked tissue sample for mass spectrometry imaging (MSI) research. Herein, we present a standard‐spiked 3D biomimetic tissue model fabricated with native cells, homogenate matrix, and biocompatible polymer. Unlike traditional homogenized tissue surrogates or those constructed with “on‐tissue” or “under‐tissue” micropipetting strategies, this simulated tissue shares both structural integrity of cells and homogeneous properties of matrix. As a result, analyte standards could undergo more in‐depth incorporation and has a more comparable native status with a real tissue. Series of tissue sections made from the 3D tissue model were proven to be feasible and useful for the parameter optimization, analyte quantitation, and calibration curve fitting for the air‐flow assisted desorption electrospray ionization MSI. Additionally, by analyzing the quality control model sections, we proposed a median principal component score calibration and demonstrated that this method can normalize instrumental fluctuations to stable levels in a large‐scale untargeted MSI experiments for the reliable metabolomic biomarker discovery. Thus, these results indicated that the standard‐spiked 3D biomimetic tissue has convincing significance in MSI analysis
Evolutionary concept of inflammatory response and stroke
Authors: Duris K. , Jurajda M.
Published: February 2019

The immune system plays an important role under both physiological and pathological conditions. Immune surveillance as well as defense and healing processes are crucial for the organism, but the immune system has a natural tendency to act aggressively when excessively stimulated. We may assume that the immune system is not designed to deal with severe conditions, such as polytrauma or severe stroke, because these are not compatible with life in the wilderness and evolution has no chance to act in such cases. These conditions are associated with exaggerated/deregulated inflammatory response, which may cause more damage than initial pathology. In this article, we would like to sketch a basic concept of the immune system–brain interactions from the evolutionary point of view and to discuss some implications related to stroke.
GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture
Authors: Pilipenko Vladimirs , Narbute Karina , Amara Ines , Trovato Angela , Scuto Maria , Pupure Jolanta , Jansone Baiba , Poikans Janis , Bisenieks Egils , Klusa Vija , Calabrese Vittorio
Published: February 2019

Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer’s disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma‐aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: “free” moiety attached to the position 4 of the 1,4‐dihydropyridine (DHP) ring, and two “crypto” moieties as part of the DHP scaffold. The “free” and “crypto” GABA moieties are linked by a peptide bond (–CONH–), resulting in a peptide‐mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di‐2‐ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA‐A and GABA‐B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide‐like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti‐dementia drugs.
Hardworking coworkers: A multilevel cross‐national look at group work hours and work–family conflict
Authors: Vaziri Hoda , Benson George S. , Salazar Campo Maritza
Published: February 2019

This study investigates the relationship between coworker work hours and perceived work‐to‐family conflict (WFC) in a multinational sample of professional service employees. Building on recent research on the ways in which workgroups influence individual WFC, we demonstrate that the average hours worked by coworkers has a significant relationship to reported WFC independent of an employee's own work hours. Although this finding is universal across the multinational sample, national cultural differences were found to moderate the relationship, such that employees in more collectivist countries are more strongly influenced by average coworker hours than their counterparts in less collectivist countries. The multilevel analysis was conducted using a sample of 7,600 professional service employees in 497 different workgroups across 20 countries. The results provide support for the effect of culture on the relationship between group average hours and perceptions of WFC. We conclude with a discussion of how national culture affects WFC.
Study of a terrestrial Martian analogue: Geochemical characterization of the Meñakoz outcrops (Biscay, Spain)
Authors: Ruiz‐Galende Patricia , Torre‐Fdez Imanol , Aramendia Julene , Gómez‐Nubla Leticia , Castro Kepa , Arana Gorka , Madariaga Juan Manuel
Published: February 2019

The necessity to create databases for the proper interpretation of the results obtained by the rovers that will be sent by ESA to Mars implies the study of terrestrial Martian analogues. In this work, the Meñakoz outcrops, which are basaltic volcanic rocks interbedded with Turonian sediments coming from a Cretaceous submarine volcano outcrop located in Biscay (northern Spain), have been studied and proposed as a Martian analogue. Considering that Raman and near infrared spectroscopies are two of the techniques that will go on‐board the rovers in the next planetary missions, they were used to characterize the samples collected in Meñakoz. As was expected, silicates (phyllosilicates) were the major minerals detected by those techniques in the Meñakoz samples, but also, compounds such as sulfates and oxides could be detected. Phyllosilicates are very important because they are some of the compounds that have been reported to be present on the Mars surface in previous missions and specifically in Oxia Planum, the landing site for the ExoMars 2020 rover of the ESA missions to Mars. This fact provides reasons to propose the emplacement of Meñakoz as Martian analogue.
Estrogen receptor beta expression correlates with proliferation in desmoid tumors
Authors: Santti Kirsi , Ihalainen Hanna , Rönty Mikko , Karlsson Christina , Haglund Caj , Sampo Mika , Tarkkanen Maija , Blomqvist Carl
Published: February 2019

Background and objectives

Estrogen receptor signaling and cyclin D1 have a major role in tumor cell proliferation in breast cancer. Desmoid tumors are rare neoplasms that may respond to endocrine treatment. The present study aimed to investigate the expression levels and the clinical relevance of estrogen receptor beta (ERβ) and cyclin D1 in desmoid tumors.

Methods

This study consists of 83 patients with a surgically treated desmoid tumor. ERβ and cyclin D1 expression was examined by immunohistochemistry in tissue microarrays. Cyclin A and Ki67 were studied in our previous work.

Results

Median ERβ expression was 10.8%. ERβ expression correlated with expression of the proliferation antigens Ki67 (rp = 0.35, P = 0.003), cyclin D1 (rp = 0.34, P = 0.004), and cyclin A (rp = 0.34, P = 0.004). ERβ immunoexpression showed a trend towards predictive impact for recurrence as a continuous variable. Further explorative analysis indicated that very high ERβ expression was related to high risk of relapse (hazard ratio [HR] 2.6; P = 0.02).

Median cyclin D1 expression was 15.6%. High cyclin D1 expression was associated with high Ki67 and cyclin A expression. Cyclin D1 was not associated with time to recurrence.

Conclusions

ERβ and cyclin D1 immunopositivity correlated with high proliferation in desmoid tumors. High ERβ expression might be predictive for postoperative recurrence.
Enhanced striatopallidal gamma‐aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease
Authors: Perez‐Rosello Tamara , Gelman Simon , Tombaugh Geoffrey , Cachope Roger , Beaumont Vahri , Surmeier D. James
Published: February 2019

Background

Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin gene. This mutation leads to progressive dysfunction that is largely attributable to dysfunction of the striatum. The earliest signs of striatal pathology in HD are found in indirect pathway gamma‐Aminobutyric acid (GABA)‐ergic spiny projection neurons that innervate the external segment of the globus pallidus (GPe). What is less clear is whether the synaptic coupling of spiny projection neurons with GPe neurons changes in HD.

Objectives

The principal goal of this study was to determine whether striatopallidal synaptic transmission was altered in 2 mouse models of HD.

Methods

Striatopallidal synaptic transmission was studied using electrophysiological and optogenetic approaches in ex vivo brain slices from 2 HD models: Q175 heterozygous (het) and R6/2 mice.

Results

Striatopallidal synaptic transmission increased in strength with the progression of behavioral deficits in Q175 and R6/2 mice. The alteration in synaptic transmission was evident in both prototypical and arkypallidal GPe neurons. This change did not appear attributable to an increase in the probability of GABA release but, rather, to an enhancement in the postsynaptic response to GABA released at synaptic sites. This alteration significantly increased the ability of striatopallidal axon terminals to pause ongoing GPe activity.

Conclusions

In 2 mouse models of HD, striatopallidal synaptic transmission increased in parallel with the progression of behavioral deficits. This adaptation could compensate in part for the concomitant deficit in the ability of corticostriatal signals to activate spiny projection neurons and pause GPe activity. © 2019 International Parkinson and Movement Disorder Society
Does the Index of Ideality of Correlation Detect the Better Model Correctly?
Authors: Toropova Alla P. , Toropov Andrey A.
Published: February 2019

The CORAL software is a tool to build up predictive models for various endpoints by means of Quantitative Structure‐Property/Activity Relationships (QSPRs/QSARs). A new criterion for assessment of the predictive potential of QSPR/QSAR models, so‐called Index of Ideality of Correlation (IIC) is applied to improve the software. The ability of the IIC to detect models with better predictive potential is checked up with groups of random splits of data into the structured training set and extrenal validation set. To this end, two endpoints are examined (i) Toxicity towards Fathead minnow (Pimephales promelas); and (ii) drug load capasity of samples “micelle‐polymer”. Applications of the IIC for endpoint represented by traditional Simplified Molecular Input‐Line Entry System (SMILES) together with so‐called quasi‐SMILES has shown the suitability of the IIC be a tool to detect better model.
A mixed methods study of satisfaction with justice and desire for revenge in survivors of the September 11, 2001, attacks on New York City's World Trade Center
Authors: Ayvaci Emine R. , Pollio David E. , Sonis Jeffrey , Bhatti Saira M. , North Carol S.
Published: February 2019

Objective

This study used mixed methods to investigate satisfaction with justice and desire for revenge in a sample of employees from New York City agencies affected by the 9/11 attacks on the World Trade Center.

Methods

A volunteer sample of 196 employees of eight affected agencies provided a short essay about what justice means to them in relation to the 9/11 attacks, followed by 20 quantitative questions covering personal experiences and perceptions of 9/11‐related justice. Wilcoxon rank sum tests were performed for bivariate comparisons of quantitative items and qualitative thematic codes. Mixed methods analysis was used to inspect the associations of the content of all text coded for themes with quantitative categories within and across domains.

Results

Only the revenge domain showed a significant association between the quantitative category and the qualitative theme. The quantitative revenge category was positively associated with the qualitative justice through safety theme. Examination of qualitative content provided insights into the relationships with quantitative constructs.

Conclusion

Qualitative and mixed methods research on justice and revenge in mass casualty settings add new findings to the existing literature and have the potential to contribute to the interpretation and potential expansion of topic areas assessed by quantitative scales.
N‐linked mannose glycoconjugates on shrimp thrombospondin, pmTSP‐II, and their involvement in the sperm acrosome reaction
Authors: Timklay Wauranittha , Magerd Sirilug , Sato Chihiro , Somrit Monsicha , Watthammawut Atthaboon , Senarai Thanyaporn , Weerachatyanukul Wattana , Kitajima Ken , Asuvapongpatana Somluk
Published: February 2019

Glycoconjugates in egg extracellular matrices are known to serve several functions in reproductive processes. Here, the presence of N‐linked mannose (Man) glycoconjugates on shrimp thrombospondin (
pmTSP‐II) and their physiological functions were investigated in the black tiger shrimp
Penaeus monodon. A molecular analysis of
pmTSP‐II demonstrated anchorage sites for
N‐linked glycans in both the chitin‐binding and TSP3 domains. The presence of Man residues was verified by concanavalin A lectin histochemistry on the purified fraction of
pmTSP‐II (250 kDa with protease inhibitor). The function of the Man glycoconjugates was evident by the Con A interference with the
pmTSP‐II‐induced acrosome reaction (AR) as well as by the ability to recover the induction of the AR by the inclusion of Mans in the treatment mixture. In addition, the recombinant proteins of the three signature
pmTSP‐II domains expressed in
E. coli (lacking glycosylation) and mannosidase‐treated
pmTSP‐II showed a minimal ability to initiate the AR response. Together, these results provide evidence of the pivotal role that Man‐linked
pmTSP‐II plays in modulating the shrimp sperm AR, a novel role for a TSP family protein in shrimp reproductive biology.
Constructing boundary structures of rock blocks
Authors: Zheng Yinhe , Xia Lu , Yu Qingchun
Published: February 2019

Determining rock‐block structures is important for modeling jointed rock masses. This paper presents a method to construct the boundary structures of complex blocks by eliminating fictitious surfaces. The planes involved in forming a complex block are retrieved, and the boundary polygons on each plane are determined using a series of Boolean operations. A regulation method is used to adjust the resulting polygons so that the regulated outer boundary structures can be used directly in the contact‐detection algorithms. The interior fracture boundaries that are not explicitly associated with the formation of blocks are also constructed. These boundary surfaces are valued in hydraulic models to provide conductive channels of fluids in rock masses. The proposed method extends previous developments on block‐identification algorithms, and the constructed boundary structures can be used directly in the modeling process of most discrete models. The program implemented based on this method has been used to study the stability and morphology of blocks in the Three Gorges Project, and several examples are given to further demonstrate the ability and performance of the proposed method.
Enteral Nutrition in the Mechanically Ventilated Patient
Authors: Allen Karen , Hoffman Leah
Published: February 2019

Mechanically ventilated patients are unable to take food orally and therefore are dependent on enteral nutrition for provision of both energy and protein requirements. Enteral nutrition is supportive therapy and may impact patient outcomes in the intensive care unit. Early enteral nutrition has been shown to decrease complications and hospital length of stay and improve the prognosis at discharge. Nutrition support is unique for patients on mechanical ventilation and, as recently published literature shows, should be tailored to the individuals’ underlying pathology. This review will discuss the most current literature and recommendations for enteral nutrition in patients receiving mechanical ventilation.
Genetic Architecture of Human Obesity Traits in the Rhesus Macaque
Authors: Raboin Michael J. , Letaw John , Mitchell Asia D. , Toffey David , McKelvey Jessica , Roberts Charles T. , Curran Joanne E. , Vinson Amanda
Published: February 2019

Objective

Whereas the metabolic consequences of obesity have been studied extensively in the rhesus macaque, corollary genetic studies of obesity are nonexistent. This study assessed genetic contributions to spontaneous adiposity in this species.

Methods

Phenotypic variation by age class and sex for BMI, waist to height ratio, waist to thigh ratio, and waist circumference was assessed in 583 macaques. Total and sex‐specific heritability for all traits was estimated, including waist to thigh ratio adjusted for BMI, as well as genotypic and phenotypic correlations. In addition, functional genetic variation at BDNF, FTO, LEP, LEPR, MC4R, PCSK1, POMC, and SIM1 was assessed in four animals with extreme spontaneous adiposity.

Results

Trait heritability in the combined sample was low to moderate (0.14‐0.32), whereas sex‐specific heritability was more substantial (0.20‐0.67). Heritability was greater in females for all traits except BMI. All traits were robustly correlated, with genetic correlations of 0.63 to 0.93 indicating substantial pleiotropy. Likely functional variants were discovered in the four macaques at all eight human obesity genes, including six missense mutations in BDNF, FTO, LEP, LEPR, and PCSK1 and, notably, one nonsense mutation in LEPR.

Conclusions

A moderate polygenic contribution to adiposity in rhesus macaques was found, as well as mutations with potentially larger effects in multiple genes that influence obesity in humans.
Synthesis of novel thermosetting imide compounds having phenylethynyl carbonyl groups at both terminal ends and production of new network polymers based on the imide compounds
Authors: Kimura Hajime , Ohtsuka Keiko , Yonekawa Morio , Matsumoto Akihiro
Published: February 2019

A novel thermosetting imide compound having a respective phenylethynyl carbonyl group at both terminal ends was newly synthesized from an acid anhydride having a phenylethynyl carbonyl group and various diamine compounds. The thermosetting behavior of the obtained novel thermosetting imide compound having phenylethynyl carbonyl groups was analyzed through differential scanning calorimetry measurements and infrared spectroscopic analysis. As a result, it became clear that a curing reaction of phenylethynyl carbonyl groups proceeds at approximately 200°C and that the curing reaction thereof proceeds at a temperature that is lower by 150°C or more compared with that of phenylethynyl groups. Examination of the polymerization reaction of the imide compounds having phenylethynyl carbonyl groups using model compounds revealed that a reaction that imparted an alkene C=C and polycyclic aromatic structure progressed. Moreover, a network polymer obtained from a thermosetting imide compound having respective phenylethynyl carbonyl groups at both terminal ends exhibited extremely superior heat resistance and thermal decomposition resistance. These superior thermal properties are thought to be due to the strong molecular interaction (molecular packing) that results from the polycyclic aromatic structures and alkenes produced through polymerization of the phenylethynyl carbonyl groups and to the suppression of the movement of the molecular chains.
Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?
Authors: Maarbjerg Sabine F. , Thorsted Anders , Kristoffersson Anders , Friberg Lena E. , Nielsen Elisabet I. , Wang Mikala , Brock Birgitte , Schrøder Henrik
Published: February 2019

Background

Data on piperacillin–tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens.

Procedure

This prospective pharmacokinetic study was conducted from April 2016 to January 2018. Children with cancer receiving empiric piperacillin–tazobactam to treat infections were included. Piperacillin–tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4× MIC. MIC50 and MIC90 were defined based on an intrainstitutional MIC range.

Results

A total of 482 piperacillin concentrations were obtained from 43 children (aged 1–18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC50 (2.0 mg/L), MIC90 (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4× MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC ≤ 8 mg/L.

Conclusions

Our data revealed insufficient PTA with standard IA of piperacillin–tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA.
Effects of medication intake in early pregnancy on the fetal fraction of cell‐free DNA testing
Authors: Kuhlmann‐Capek Maggie , Chiossi Giuseppe , Singh Prapti , Monsivais Luis , Lozovyy Violetta , Gallagher Lauren , Kirsch Nathan , Florence Elizabeth , Petruzzi Victoria , Chang Jeffrey , Buenaventura Sofia , Walden Paul , Gardner Benjamin , Munn Mary , Costantine Maged
Published: February 2019

Objectives

To determine the association between medications intake in early pregnancy and variation in the fetal fraction (FF) in pregnant women undergoing cell‐free DNA (cfDNA) testing.

Methods

We performed a retrospective cohort study of women (n = 1051) undergoing cfDNA testing at an academic center. The exposed group included women taking medications (n = 400; 38.1%), while the nonexposed group consisted of women taking no medications (n = 651; 61.9%). Our primary outcome was FF. We performed univariate and multivariate analyses as appropriate.

Results

The FFs were 8.8% (6.6‐12.1), 8.7% (6.3‐11.6), and 7.7% (5.1‐9.3) among women taking 0, 1, and two or more medications, respectively (P < 0.01). Using multivariable linear mixed effects model, the mean FF was significantly lower among those taking two or more medications compared with the nonexposed group. FF was directly correlated with gestational age at the time of cfDNA testing and inversely correlated with maternal obesity. Exposure to metformin was associated with 1.8% (0.2‐3.4) lower mean FF when compared with the nonexposed group (P = 0.02). Obesity and intake of two or more medications were associated with higher hazard ratio of having a low FF less than 4%.

Conclusions

Exposure to metformin or two or more medications was associated with decreased FF, and obesity is associated with delay in achieving adequate FF percentage. These findings should be considered while counseling patients on test limitations.
A mixed methods analysis of clozapine errors reported to the National Reporting and Learning System
Authors: Dabba Keval , Elswood Matthew , Ameer Ahmed , Gerrett David , Maidment Ian
Published: February 2019

Purpose

To review and analyse medication errors related to clozapine, an atypical antipsychotic, that were reported to the National Reporting and Learning System (NRLS).

Methods

Following extraction of one year of clozapine related errors from the NRLS, a qualitative analysis (thematic analysis and re‐classification) and quantitative analysis was performed.

An incident was considered a clozapine error if there was a failure in its medication process (i.e. an error in the prescribing, dispensing, preparing, administering, monitoring or advising of clozapine).

Results

“Issues with stock/supply/ordering” was the most common theme derived from the qualitative thematic analysis (n = 338), followed by wrong dose/strength/frequency (n = 221) and medication omissions (n = 202). Most errors occurred in the “administration/supply” medication stage. Over half of reported clozapine incidents involved people 26 to 55 years old (n = 830) and 82% of errors were reported by mental health services (n = 1270). Only 1.5% of reports were classed as moderate/severe harm.

Conclusion

Issues with availability, stock, and supply were found to be the most common causes. This usually entailed a lack of stock to fulfil a patient's dose/supply. Such incidents could potentially be reduced by improved management of the supply process, and liaison between pharmacy and clinical staff. The implementation of emergency drug cupboards at the discretion of an on‐call pharmacist may prove to be a preventative measure for such errors. Despite the potential adverse effects associated with clozapine, very few incidents led to moderate/severe harm. Encouragement of NRLS reporting is recommended for incidents of all degrees of harm.
PLGA‐based in situ‐forming system: degradation behavior in the presence of hydroxyapatite nanoparticles
Authors: Radfar Neda , Mobedi Hamid , Behnamghader Aliasghar , Mashak Arezou
Published: February 2019

The degradation behavior of poly(lactic‐co‐glycolic acid) (PLGA) is important for its application as a biomaterial. In this work, the influence of nano‐hydroxyapatite (nano‐HA) on the degradation behavior of PLGA matrix was studied. PLGA‐based in situ forming system containing nano‐HA was prepared using the immersion precipitation method and the polymer hydrolysis was investigated in a phosphate buffer (pH 7.4) at 37°C. The pH values in the testing medium were evaluated to quantify the degradation process. Gel permeation chromatography and scanning electron microscopy techniques were employed to monitor changing of the weight‐average molecular weight (MW) and the body structures of PLGA matrices, respectively. To model the MW changes, a first‐order degradation model was employed. The formed PLGA matrices had different porosities that effected water penetration into the matrices following the hydrolysis process. The obtained degradation rate constant using a mathematical model for PLGA matrices with different nano‐HA content was about from 2.5 to 4.5 times lower than neat PLGA matrix. POLYM. ENG. SCI., 59:1028–1035, 2019. © 2019 Society of Plastics Engineers
Ventilatory and Pharmacotherapeutic Strategies for Management of Adult Patients on Extracorporeal Life Support
Authors: Dzierba Amy L. , Abrams Darryl , Muir Justin , Brodie Daniel
Published: February 2019

Extracorporeal life support (ECLS) can provide mechanical support for patients with severe life‐threatening cardiac or respiratory failure. ECLS is a complex therapy that has increased in use over several decades owing to advances in technology. In concert with this growth, there is an increased need to understand the complexity of this technology to augment the effectiveness of ECLS and minimize complications such as ventilator‐induced lung injury, bleeding, thrombosis, infections, and inadequate drug dosing. The purpose of this review was to discuss management strategies in adult patients receiving ECLS and provide recommendations on ventilator management, provision of adequate analgesia and sedation, treatment and prevention of infections, and anticoagulation.
Does origin determine environmental impacts? Not for bamboos
Authors: Canavan Susan , Kumschick Sabrina , Le Roux Johannes J. , Richardson David M. , Wilson John R.U.
Published: February 2019

Societal Impact Statement

Non‐native species can cause considerable negative impacts in natural ecosystems. Such impacts often are directly due to the fact that these species occur in habitats where they did not evolve. We explored this for bamboos and found that, contrary to the situation in many other plant groups, biogeographic origin was not a strong predictor of the type and severity of environmental impacts caused. We argue that impacts from bamboos are a response to land transformation and disturbance of forest habitats by humans. Therefore, the threats posed by bamboos to highly disturbed forest systems should be the same wherever bamboos are present or planted, and management should adopt similar approaches.

Negative environmental impacts can result from the human‐mediated breakdown of biogeographic boundaries that historically shaped species distributions leading to rapid population expansions, that is, from biological invasions. However, the alteration of natural ecosystems by humans has created opportunities for both native and non‐native species to become weedy. We assessed whether origin status (native or non‐native) matters for the type and magnitude of environmental impacts caused by bamboos (Poaceae: Bambusoideae).

We used a systematic global literature search and the International Union for Conservation of Nature's (IUCN) Environmental Impact Classification of Alien Taxa (EICAT) scheme as the basis for scoring impacts of bamboo species.

We found that the type and severity of recorded impacts were similar in the native and non‐native ranges of weedy bamboos, and that the habitats in which impacts are most often reported (i.e., temperate and tropical forests) were also the same.

Origin was not a strong predictor of environmental impacts for bamboos. Rather, impacts are likely to be a response to human‐mediated land transformation and disturbance of forests. Further research on the mechanisms whereby bamboos impact other species is needed to guide management strategies in their native ranges and as input to risk assessments for new introductions and plantings.
Theory and practice of cushion curve: A supplementary discussion
Authors: Ge Changfeng
Published: February 2019

The practice of developing cushion curves has been applied for many years. Known for its tedious development, the process does not correlate to cushion configurations too. This study reviewed conventional theories, practice of cushion curves, and simplified methods, including the conversion from quasi‐static compression chart to cushion curves, and testing‐extrapolated methods based on several applicable tests. In addition, the study examined the effect of configuration on cushion curves. Discussion indicated that the theories of cushion curves are based on two fundamental properties in physics: energy conversion and Newton's second law. Energy density‐based test‐extrapolation approaches reduced the development time significantly without compromising the accuracy of the cushion curves. The edge and corner cushion structure showed a similar pattern to the conventional flat cushion curve, but were shifted horizontally to the right. This paper recommends packaging engineers to apply C‐e curves as the basis of the cushion curves to design cushioning. Finally, energy dissipated during platen drop test is discussed to explain the deformation process in relation to dynamic stress‐strain curve and cushion curve.
Test method for enhanced mechanical shock fragility statistics accuracy
Authors: Horiguchi Shogo , Saito Katsuhiko
Published: February 2019

An optimum cushioning package, which is neither excessive nor inadequate, must be designed to ensure cushioning performance that maintains an acceptable failure rate during transportation while also minimizing packaging costs. For this purpose, statistics pertaining to transport hazards and product shock strength must be engaged. The proposed study presents a test method to enhance the statistical accuracy of mechanical shock fragility of products. Sample statistics are invariably unknown; hence, optimum test‐setting values cannot be determined at the beginning. The proposed test method has been devised for determining optimum test‐setting values of the (n + 1)th sample using statistics of n samples being tested. An improvement in the estimation accuracy of the variation coefficient for the critical‐velocity‐change test was confirmed via simulations performed using the proposed method. Optimization of the test‐setting value has also been experimentally confirmed. A comparison of histograms and statistics obtained using experimental results has demonstrated that the proposed method can better estimate distribution shapes compared with the simple method. An example of the application of experimental results to stress‐strength models has also been described. The observed result has a considerable influence on the design of cushioning packages, thereby demonstrating effectiveness of the proposed method.
A mixed finite‐element, finite‐volume, semi‐implicit discretization for atmospheric dynamics: Cartesian geometry
Authors: Melvin Thomas , Benacchio Tommaso , Shipway Ben , Wood Nigel , Thuburn John , Cotter Colin
Published: February 2019

To meet the challenges posed by future generations of massively parallel supercomputers, a reformulation of the dynamical core for the Met Office's weather and climate model is presented. This new dynamical core uses explicit finite‐volume type discretizations for the transport of scalar fields coupled with an iterated‐implicit, mixed finite‐element discretization for all other terms. The target model aims to maintain the accuracy, stability and mimetic properties of the existing Met Office model independent of the chosen mesh while improving the conservation properties of the model. This paper details that proposed formulation and, as a first step towards complete testing, demonstrates its performance for a number of test cases in (the context of) a Cartesian domain. The new model is shown to produce similar results to both the existing semi‐implicit semi‐Lagrangian model used at the Met Office and other models in the literature on a range of bubble tests and orographically forced flows in two and three dimensions.
Bulk and structural convergence at convection‐resolving scales in real‐case simulations of summertime moist convection over land
Authors: Panosetti Davide , Schlemmer Linda , Schär Christoph
Published: February 2019

Convection‐resolving models (CRMs) are established as a solid framework to simulate moist convection in both numerical weather prediction and regional‐scale climate projections. However, capturing the different scales of the governing processes is challenging. Previous studies have shown that the size and properties of individual clouds and updraughts do not converge until horizontal grid spacings (Δx) of (100 m). We refer to this as structural convergence. On the other hand, a few recent studies have demonstrated that domain‐averaged and integrated tendencies related to a large ensemble of convective cells converge at the kilometre scale. We refer to this as bulk convergence.

This study investigates both the bulk convergence of the mean diurnal cycle and spatial distribution of precipitation, clouds and convective transport, and structural convergence of cloud‐scale statistics in real‐case convection‐resolving simulations. Two nine‐day episodes of quasi‐periodic diurnal moist convection are simulated at Δx = 8.8, 4.4, 2.2, 1.1 km and 550 m over the Alps and over Central Germany to compare the results in the presence and in the absence of a mesoscale orographic forcing.

Results reveal that bulk convergence is systematically achieved in both episodes for the spatial distribution of the analysed quantities. For their mean diurnal cycle, bulk convergence is generally observed in simulations over the Alps, but not over Central Germany, indicating that the presence of a mesoscale orographic forcing reduces the resolution sensitivity of the bulk flow properties. Structural convergence is confirmed to be not yet fully achieved at the kilometre scale. In particular, the size and strength of the simulated convective updraughts and the size of the smallest clouds are largely determined by Δx.
On the feasibility of quantifying sodium channel Nav1.6 protein in mouse brain using targeted ultra‐high‐performance/electrospray ionization multiple reaction monitoring mass spectrometry
Authors: Sojo Luis E. , Kwan Rainbow , Dang Cathy , Tung Matthew , Li Jenny
Published: February 2019

Rationale

Nav1.6 is a transmembrane voltage gated sodium channel implicated in various forms of epilepsy. Modulation of its activity in epilepsy animal models can be accomplished using inhibitors which may result in changes in its expression. There is a need to generate reliable quantitative measurements of Nav1.6 expression in animal models. This research explores the feasibility of quantifying Nav1.6 expression in mouse brains using targeted multiple reaction monitoring (MRM) mass spectrometry.

Methods

A combination of in silico tryptic Nav1.6 peptides and MRM transitions were used to select target peptides. This was followed by a simple proteomic work‐up including plasma membrane isolation, trypsin‐based proteolysis and ultra‐high‐performance/electrospray ionization tandem mass spectrometry (UHPLC/ESI‐MS/MS) to detect the presence of Nav1.6 in induced HEK293 cells. The unique Nav1.6 peptide, DSLFIPR, was selected as probe for quantifying Nav1.6 levels in brains from C57BL/6J wild‐type mice as well as two kinds of mutants including Scn8aN1768D/+ and heterozygous null Scn8a+/− mice using isotope dilution targeted mass spectrometry.

Results

The feasibility of using targeted MRM for quantifying Nav1.6 expression in mice brains was demonstrated. Expression of Nav1.6 in brains (hippocampi) from wild‐type and mutant Scn8aN1768D/+ mice were found to be around 0.40 fmol/μg. Mutant null Scn8a+/− heterozygous mice, on the other hand, showed levels of 0.22 fmol/μg as expected based on this particular mutation which only generates 50% of the expression in wild‐type mice. Nav1.6‐overexpressed HEK293 cells showed 3.7 fmol/μg of Nav1.6 expression, suitable for screening new compounds for Nav1.6 blocking activity.

Conclusions

The results of the present feasibility study support the use of DSLFIPIR for quantification of Nav1.6 in brain tissues using UHPL/ESI‐MS/MS.
Two new defatted beef reference materials, CAAS‐1801 and CAAS‐1802, for carbon and nitrogen stable isotope ratio measurements
Authors: Zhao Shanshan , Zhao Yan , Rogers Karyne M. , Chen Ailiang , Zhang Tian , Yang Shuming
Published: February 2019

Rationale

Isotope reference materials are essential to enable reliable and comparable isotope data across multiple laboratories. Although many reference materials already exist, the best reference materials should mimic the unknown samples, so new reference materials continue to evolve with the development of isotope research in new product areas.

Methods

Two defatted beef reference materials, CAAS‐1801 and CAAS‐1802, with substantially different δ13C values (due to difference in dietary intake), have been prepared as reference materials for stable C and N isotope analysis of meat tissue. Homogeneity, and short‐ and long‐term stability tests of these reference materials have been performed. The δ13C and δ15N values of both materials were measured for two‐point isotopic normalization against international reference materials by elemental analyzer/isotope ratio mass spectrometry (EA/IRMS). A total of nine international laboratories were selected for the joint evaluation. Cochran statistical analysis yielded the values reported here.

Results

The defatted beef reference material CAAS‐1801 from Heilongjiang province has a δ13C value of −13.58 ± 0.56‰ relative to VPDB and a δ15N value of 4.23 ± 0.56‰ relative to N2 in air. The defatted beef reference material CAAS‐1802 from Sichuan province has a δ13C value of −25.03 ± 0.45‰ and a δ15N value of 4.36 ± 0.69‰.

Conclusions

The two defatted beef reference materials were found to be isotopically stable across a range of ambient temperatures, and to have low volatility and toxicity, which enables them to be useful as stable isotope reference materials in the field of authentication and traceability of meat.
An atypical pneumonia
Authors: Gerhardy Benjamin
Published: February 2019

We describe a patient with underlying HIV presenting with progressive respiratory distress and acute renal failure. A unifying diagnosis of microscopic polyangiitis was made. Following immunosuppression induction with plasma exchange and intravenous corticosteroid and subsequent maintenance immunosuppression with intravenous cyclophosphamide in conjunction with renal replacement therapy he achieved remission. To our knowledge this is the first documented case of microscopic polyangiitis occurring in the context of underlying HIV, and raises interesting possibilities regarding the development of vasculitis in this patient.
Molecular Rearrangement of Trinuclear Cu(I)‐NHC: Synthesis of Mono, Binuclear and Polymeric Cu(I)‐NHCs
Authors: Santra Biswajit
Published: February 2019

A trinuclear Cu(I)‐NHC [Cu3(py2im)3](PF6)3 (1) has been synthesized in a very short period of time (5‐10 min) in multi‐gram scale using less expensive Cu(OAc)2⋅H2O and py2imH⋅PF6 in presence of L‐ascorbic acid in CH3OH under aerobic conditions at room temperature. Further, a very facile synthetic route has been developed to obtain a mononuclear [Cu(py2im)(phen)](PF6) (3), binuclear [Cu2(py2im)3](PF6)2 (2) and 1D polymeric chain of Cu(I)‐NHC {[Cu(py2im)(4,4′‐bpy)](PF6)}n (4), {[Cu(py2im)(bpe)](PF6)}n (5), {[Cu(py2im)(bpe)](PF6)}n.{[Cu2(py2im)3](PF6)}n (6) and {[Cu(py2im)(azpy)](PF6)}n (7) from a trinuclear Cu(I)‐NHC cluster (1) using additional linear bridging co‐ligands such as 4,4′‐bipyridine (bpy), trans‐1,2‐bis(4‐pyridyl)ethene (bpe), 4,4′‐azobispyridine (azpy) etc. In CH3CN, 4 and 5 were rearranged to adamantanoid core 3D Cu(I)‐MOF {[Cu(bpy)2](PF6)}n (8) and {[Cu(bpe)2](PF6)}n (9), respectively. X‐ray crystallographic structure of 6 exhibits two molecules of 2 which was trapped between two polymeric chains.