bluuebunny/crossref_metadata_2025 huggingface dataset:
International Code for Phytolith Nomenclature (ICPN) 2.0
Authors:   International Committee for Phytolith Taxonomy (ICPT), Neumann Katharina , Strömberg Caroline A E , Ball Terry , Albert Rosa Maria , Vrydaghs Luc , Cummings Linda Scott
Published: April 2019

Background

Opal phytoliths (microscopic silica bodies produced in and between the cells of many plants) are a very resilient, often preserved type of plant microfossil. With the exponentially growing number of phytolith studies, standardization of phytolith morphotype names and description is essential. As a first effort in standardization, the International Code for Phytolith Nomenclature 1.0 was published by the ICPN Working Group in Annals of Botany in 2005. A decade of use of the code has prompted the need to revise, update, expand and improve it.

Scope

ICPN 2.0 formulates the principles recommended for naming and describing phytolith morphotypes. According to these principles, it presents the revised names, diagnosis, images and drawings of the morphotypes that were included in ICPN 1.0, plus three others. These 19 morphotypes are those most commonly encountered in phytolith assemblages from modern and fossil soils, sediments and archaeological deposits. An illustrated glossary of common terms for description is also provided.
Evolution of biosequence search algorithms: a brief survey
Authors: Kucherov Gregory
Published: April 2019

Motivation

Although modern high-throughput biomolecular technologies produce various types of data, biosequence data remain at the core of bioinformatic analyses. However, computational techniques for dealing with this data evolved dramatically.

Results

In this bird’s-eye review, we overview the evolution of main algorithmic techniques for comparing and searching biological sequences. We highlight key algorithmic ideas emerged in response to several interconnected factors: shifts of biological analytical paradigm, advent of new sequencing technologies and a substantial increase in size of the available data. We discuss the expansion of alignment-free techniques coming to replace alignment-based algorithms in large-scale analyses. We further emphasize recently emerged and growing applications of sketching methods which support comparison of massive datasets, such as metagenomics samples. Finally, we focus on the transition to population genomics and outline associated algorithmic challenges.
A scale-dependent ‘functional’ assessment of the concept of endemism
Authors: Amori Giovanni , Luiselli Luca
Published: April 2019

Whether a species can be defined as ‘endemic’ or not is very controversial in theoretical terms, because the concepts of ‘endemism’ and ‘area of endemism’ remain much debated among scientists. We propose that it is necessary to consider the body size scale of an organism and the breadth of its distributional range if we want to define a given species as ‘endemic’ or not. Thus, for instance, Madagascar can be an appropriate area of endemism for animals as large and vagile as the fossa (Cryptoprocta ferox), but it is much too large to be considered an ecologically appropriate ‘area of endemism’ for small-sized frogs with limited dispersal abilities. Instead, for these small species it is ecologically more appropriate to consider given forest regions within Madagascar as ‘areas of endemism’. Therefore, we propose a five-step approach in order to define whether a given species can be considered endemic or not within a set of potential candidate species, and we offer a suite of practical examples (African squirrels, African Artiodactyla and a family of freshwater turtles from the Americas) to elucidate the designated concept. We define the new concept presented herein as ‘scale-dependent functional endemism’. The new concept has the benefits of including the ‘ecological characteristics’ of the target species in the concept of ‘endemism’ and being easily repeated, because it is based on rather objective criteria.
Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies
Authors: Hernandez Ciria C , XiangWei Wenshu , Hu Ningning , Shen Dingding , Shen Wangzhen , Lagrange Andre H , Zhang Yujia , Dai Lifang , Ding Changhong , Sun Zhaohui , Hu Jiasheng , Zhu Hongmin , Jiang Yuwu , Macdonald Robert L
Published: April 2019

We performed next generation sequencing on 1696 patients with epilepsy and intellectual disability using a gene panel with 480 epilepsy-related genes including all GABAA receptor subunit genes (GABRs), and we identified six de novo GABR mutations, two novel GABRA5 mutations (c.880G>T, p.V294F and c.1238C>T, p.S413F), two novel GABRA1 mutations (c.778C>T, p.P260S and c.887T>C, p.L296S/c.944G>T, p.W315L) and two known GABRA1 mutations (c.335G>A, p.R112Q and c.343A>G, p.N115D) in six patients with intractable early onset epileptic encephalopathy. The α5(V294F and S413F) and α1(P260S and L296S/W315L) subunit residue substitutions were all in transmembrane domains, while the α1(R112Q and N115R) subunit residue substitutions were in the N-terminal GABA binding domain. Using multidisciplinary approaches, we compared effects of mutant GABAA receptor α5 and α1 subunits on the properties of recombinant α5β3γ2 and α1β3γ2 GABAA receptors in both neuronal and non-neuronal cells and characterized their effects on receptor clustering, biogenesis and channel function. GABAA receptors containing mutant α5 and α1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Our study identified GABRA5 as a causative gene for early onset epileptic encephalopathy and expands the mutant GABRA1 phenotypic spectrum, supporting growing evidence that defects in GABAergic neurotransmission contribute to early onset epileptic encephalopathy phenotypes.
An Efficient Framework for a Third Party Auditor in Cloud Computing Environments
Authors: Mahdavi-Hezavehi S , Alimardani Y , Rahmani R
Published: April 2019

Cloud Service Providers supply services to clients in terms of their demands. They need to be constantly under monitoring for their services with respect to consensus agreements between clients and service providers. A Third Party Auditor or TPA as a trusted organization appears to be necessary to monitor executing agreements of cloud services. Using a third party as an extra component creates cost overheads for clients in a cloud environment. Thus, introducing a cost efficient framework for a cloud environment which includes a third party is an eminent achievement to make a TPA feasible and practical in cloud environments. In this paper, we propose a TPA framework for monitoring service level agreements between cloud service providers and cloud clients using several cloud resources. This framework employs different types of service deployments from various cloud service providers excluding the cloud service provider which is being monitored. Then, we demonstrate that the framework can mitigate costs of a third party auditor in a cloud environment. Simulations of trends for costs exhibits cost efficiency of at least forty percent over ten years when a TPA follows our proposed framework in comparison to other frameworks. Finally, we provide an analysis to compare characteristics of our framework with other frameworks and discuss the advantages of our proposed framework. Our results indicate that TPA as a component of the framework not only reduces overall costs of its presentation in a cloud environment but additionally improves management efficiency and security.
Agreement between gadolinium-enhanced cardiac magnetic resonance and electro-anatomical maps in patients with non-ischaemic dilated cardiomyopathy and ventricular arrhythmias
Authors: Torri Federica , Czimbalmos Csilla , Bertagnolli Livio , Oebel Sabrina , Bollmann Andreas , Paetsch Ingo , Jahnke Cosima , Arya Arash , Merkely Bela , Hindricks Gerhard , Dinov Borislav
Published: April 2019

Aims

We sought to investigate the overlap between late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) and electro-anatomical maps (EAM) of patients with non-ischaemic dilated cardiomyopathy (NIDCM) and how it relates with the outcomes after catheter ablation of ventricular arrhythmias (VA).

Methods and results

We identified 50 patients with NIDCM who received CMR and ablation for VA. Late gadolinium enhancement was detected in 16 (32%) patients, mostly in those presenting with sustained ventricular tachycardia (VT): 15 patients. Low-voltage areas (<1.5 mV) were observed in 23 (46%) cases; in 7 (14%) cases without evidence of LGE. Using a threshold of 1.5 mV, a good and partially good agreement between the bipolar EAM and LGE-CMR was observed in only 4 (8%) and 9 (18%) patients, respectively. With further adjustments of EAM to match the LGE, we defined new cut-off limits of median 1.5 and 5 mV for bipolar and unipolar maps, respectively. Most VT exits (12 out of 16 patients) were found in areas with LGE. VT exits were found in segments without LGE in two patients with VT recurrence as well as in two patients without recurrence, P = 0.77. In patients with VT recurrence, the LGE volume was significantly larger than in those without recurrence: 12% ± 5.8% vs. 6.9% ± 3.4%; P = 0.049.

Conclusions

In NIDCM, the agreement between LGE and bipolar EAM was fairly poor but can be improved with adjustment of the thresholds for EAM according to the amount of LGE. The outcomes were related to the volume of LGE.
Deep sedation for transvenous lead extraction: a large single-centre experience
Authors: Bode Kerstin , Whittaker Peter , Lucas Johannes , Müssigbrodt Andreas , Hindricks Gerhard , Richter Sergio , Doering Michael
Published: April 2019

Aims

Transvenous lead extraction for cardiac implantable electronic devices (CIED) is of growing importance. Nevertheless, the optimal anaesthetic approach, general anaesthesia vs. deep sedation (DS), remains unresolved. We describe our tertiary centre experience of the feasibility and safety of DS.

Methods and results

Extraction procedures were performed in the electrophysiology (EP) laboratory by two experienced electrophysiologists. We used intravenous Fentanyl, Midazolam, and Propofol for DS. A stepwise approach with locking stylets, dilator sheaths, and mechanical sheaths via subclavian, femoral, or internal jugular venous access was utilized. Patient characteristics and procedural data were collected. Logistic regression models were used to identify parameters associated with sedation-related complications. Extraction of 476 leads (dwelling time/patient 88 ± 49 months, 30% ICD leads) was performed in 220 patients (64 ± 17 years, 80% male). Deep sedation was initiated with bolus administration of Fentanyl, Midazolam, and Propofol; mean doses 0.34 ± 0.12 μg/kg, 24.3 ± 6.8 μg/kg, and 0.26 ± 0.13 mg/kg, respectively. Deep sedation was maintained with continuous Propofol infusion (initial dose 3.7 ± 1.1 mg/kg/h; subsequently increased to 4.7 ± 1.2 mg/kg/h with 3.9 ± 2.6 adjustments) and boluses of Midazolam and Fentanyl as indicated. Sedation-related episodes of hypotension, requiring vasopressors, and hypoxia, requiring additional airway management, occurred in 25 (11.4%) and 5 (2.3%) patients, respectively. These were managed without adverse consequences. Five patients (2.3%) experienced major intraprocedural complications; there were no procedure-related deaths. All of our logistic regression models indicated intraprocedural support was associated with administration higher Fentanyl doses.

Conclusion

Transvenous lead extraction under DS in the EP laboratory is a safe procedure with high success rates when performed by experienced staff.
Validation of an ampicillin selection protocol to enrich for mutants of Listeria monocytogenes unable to replicate on fresh produce
Authors: Jayeola Victor , Parsons C , Gorski L , Kathariou S
Published: April 2019

Several outbreaks of listeriosis have implicated fresh produce but genetic factors required for growth of Listeria monocytogenes on produce remain poorly characterized. Based on the fact that β-lactam antibiotics only kill bacterial cells that are growing, we hypothesized that ampicillin selection can enrich for L. monocytogenes mutants unable to grow on produce. For validation, we examined relative recovery of L. monocytogenes strain 2011L-2858 and its cold-sensitive mutant L1E4 following inoculation of cantaloupe rind fragments with 1:1 mixture of the strains and incubation at 4°C with or without ampicillin. Listeria monocytogenes from rind fragments inoculated with the mixed cultures and incubated in the presence of ampicillin were used to inoculate fresh rind fragments for a second round of enrichment. In the presence of ampicillin, the proportion of L1E4 increased from 55% on day 0 to 78% on day 14, with higher recovery (85% after 14 days) in the second round of enrichment. These data suggested that L1E4 was enriched on cantaloupe rind fragments while growing cells of the wildtype were killed by ampicillin. Application of this protocol to transposon mutant libraries from three L. monocytogenes strains yielded several mutants unable to grow on cantaloupe. Thus, ampicillin selection can facilitate discovery of genes essential for growth of L. monocytogenes on fresh produce.
Wind load estimation on an open-grown European oak tree
Authors: Angelou Nikolas , Dellwik Ebba , Mann Jakob
Published: April 2019

In this study, we investigate the relationship between the mean wind-induced load on an open-grown oak tree and the mean wind speed. The estimation of the wind load is based on bending moment observations on the stem, using strain gauges installed close to the base of the tree. The measurement campaign included periods where the crown was both with and without foliage. A new post-processing method to compensate for time- and temperature-dependent drifts of long-term strain gauge measurements is presented. The time-scale, at which the method is applied, is determined from the observed high coherence between the wind speed and the induced bending moments. The analysis shows that the wind load on the tree is proportional to the wind speed raised to an exponent of 1.60–1.68 and 1.90–2.01 in the case of a crown with and without leaves, respectively. The results indicate that the presence of foliage increases the wind-induced load by a factor of 2–3. The impact of the wind speed range on these results is discussed and compared to the measured wind deficit in the lee of the tree. The application of this method can potentially be extended to other tree mounted sensors.
Exploring Elder Neglect: New Theoretical Perspectives and Diagnostic Challenges
Authors: Stodolska Agata , Parnicka Agnieszka , Tobiasz-Adamczyk Beata , Grodzicki Tomasz
Published: April 2019

Background and Objectives

Neglect of older adults is a complex and important social problem which is difficult to detect. The aim of this review is to explore and categorize different characteristics of elder neglect, to facilitate a uniform conceptualization and provide recommendations for identification of the phenomenon.

Research Design and Methods

Articles published between January 1990 and February 2019, both from developed and developing countries, were taken into consideration. The literature search was performed in PubMed, Web of Science, and CINAHL using keywords related to elder abuse and neglect. Articles regarding the concept of elder neglect, identifying or measuring this phenomenon were reviewed. The identified indicators were presented according to the Maslow’s hierarchy of needs.

Results

From 7,207 articles found in the initial search, 63 relevant studies were selected for the final analysis. Indicators most frequently used by researchers (functionality, physical appearance and health, social and psychological background, mental health, and environment) correspond to different aspects of needs. Caregiver’s responsibility, satisfaction of needs, and risk of harm are the core elements to consider in identification of neglect.

Discussion and Implications

The identified elements and categories of indicators provide the framework for developing standard definitions and measures of elder neglect. The proposed diagram demonstrates gaps in identification and can be useful in detecting potential neglect in various categories of needs. Further research on perceptions and prevalence of elder neglect in different countries would be helpful for cross-country analysis as well as for adaptation of the instruments to cultural specifics.
Docosahexaenoic acid reduces microglia phagocytic activity via miR-124 and induces neuroprotection in rodent models of spinal cord contusion injury
Authors: Yip Ping K , Bowes Amy L , Hall Jodie C E , Burguillos Miguel A , Ip T H Richard , Baskerville Tracey , Liu Zhuo-Hao , Mohamed Moumin A E K , Getachew Fanuelle , Lindsay Anna D , Najeeb Saif-Ur-Rehman , Popovich Phillip G , Priestley John V , Michael-Titus Adina T
Published: April 2019

Microglia are activated after spinal cord injury (SCI), but their phagocytic mechanisms and link to neuroprotection remain incompletely characterized. Docosahexaenoic acid (DHA) has been shown to have significant neuroprotective effects after hemisection and compression SCI and can directly affect microglia in these injury models. In rodent contusion SCI, we demonstrate that DHA (500 nmol/kg) administered acutely post-injury confers neuroprotection and enhances locomotor recovery, and also exerts a complex modulation of the microglial response to injury. In rodents, at 7 days after SCI, the level of phagocytosed myelin within Iba1-positive or P2Y12-positive cells was significantly lower after DHA treatment, and this occurred in parallel with an increase in intracellular miR-124 expression. Furthermore, intraspinal administration of a miR-124 inhibitor significantly reduced the DHA-induced decrease in myelin phagocytosis in mice at 7 days post-SCI. In rat spinal primary microglia cultures, DHA reduced the phagocytic response to myelin, which was associated with an increase in miR-124, but not miR-155. A similar response was observed in a microglia cell line (BV2) treated with DHA, and the effect was blocked by a miR-124 inhibitor. Furthermore, the phagocytic response of BV2 cells to stressed neurones was also reduced in the presence of DHA. In peripheral monocyte-derived macrophages, the expression of the M1, but not the M0 or M2 phenotype, was reduced by DHA, but the phagocytic activation was not altered. These findings show that DHA induces neuroprotection in contusion injury. Furthermore, the improved outcome is via a miR-124-dependent reduction in the phagocytic response of microglia.
Smoking, drinking, diet and physical activity—modifiable lifestyle risk factors and their associations with age to first chronic disease
Authors: Ng Ryan , Sutradhar Rinku , Yao Zhan , Wodchis Walter P , Rosella Laura C
Published: April 2019

Background

This study examined the incidence of a person’s first diagnosis of a selected chronic disease, and the relationships between modifiable lifestyle risk factors and age to first of six chronic diseases.

Methods

Ontario respondents from 2001 to 2010 of the Canadian Community Health Survey were followed up with administrative data until 2014 for congestive heart failure, chronic obstructive respiratory disease, diabetes, lung cancer, myocardial infarction and stroke. By sex, the cumulative incidence function of age to first chronic disease was calculated for the six chronic diseases individually and compositely. The associations between modifiable lifestyle risk factors (alcohol, body mass index, smoking, diet, physical inactivity) and age to first chronic disease were estimated using cause-specific Cox proportional hazards models and Fine-Gray competing risk models.

Results

Diabetes was the most common disease. By age 70.5 years (2015 world life expectancy), 50.9% of females and 58.1% of males had at least one disease and few had a death free of the selected diseases (3.4% females; 5.4% males). Of the lifestyle factors, heavy smoking had the strongest association with the risk of experiencing at least one chronic disease (cause-specific hazard ratio = 3.86; 95% confidence interval = 3.46, 4.31). The lifestyle factors were modelled for each disease separately, and the associations varied by chronic disease and sex.

Conclusions

We found that most individuals will have at least one of the six chronic diseases before dying. This study provides a novel approach using competing risk methods to examine the incidence of chronic diseases relative to the life course and how their incidences are associated with lifestyle behaviours.
Linear algebra-based controller for trajectory tracking in mobile robots with additive uncertainties estimation
Authors: Scaglia G J E , Serrano M E , Godoy S A , Rossomando F
Published: April 2019

This paper addresses trajectory tracking problem in mobile robots considering additive uncertainties. The controller design method is based on linear algebra theory. Numerical estimation techniques are used to estimate the uncertainty value in each sample time. The controller is calibrated by stochastic way using the Monte Carlo Experiment. In addition, the proof of convergence to zero of the tracking error is included. The theoretical results are validated by simulation and experimental tests. The controller proposed shows that it can be used to reduce the effect of additive uncertainties in the tracking error.
The Twelfth Moment of Dirichlet L-functions with Smooth Moduli
Authors: Nunes Ramon M
Published: April 2019

We prove an analogue of Heath-Brown’s bound on the 12th moment of the Riemann zeta function for Dirichlet $L$-functions with smooth moduli.
Monocyte subsets involved in the development of systemic lupus erythematosus and rheumatoid arthritis
Authors: Hirose Sachiko , Lin Qingshun , Ohtsuji Mareki , Nishimura Hiroyuki , Verbeek J Sjef
Published: April 2019

AbstractMonocytes are evolutionally conserved innate immune cells that play essential roles for the protection of the host against pathogens and also produce several inflammatory cytokines. Thus, the aberrant functioning of monocytes may affect not only host defense but also the development of inflammatory diseases. Monocytes are a heterogeneous population with phenotypical and functional differences. Most recent studies have shown that monocytes are divided into three subsets, namely classical, intermediate and non-classical subsets, both in humans and mice. Accumulating evidence showed that monocyte activation is associated with the disease progression in autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, it remains to be determined how monocytes contribute to the disease process and which subset is involved. In this review, we discuss the pathogenic role of monocyte subsets in SLE and RA on the basis of current studies by ourselves and others to shed light on the suitability of monocyte-targeted therapies in these diseases.
‘Antibiotic footprint’ as a communication tool to aid reduction of antibiotic consumption
Authors: Limmathurotsakul Direk , Sandoe Jonathan A T , Barrett David C , Corley Michael , Hsu Li Yang , Mendelson Marc , Collignon Peter , Laxminarayan Ramanan , Peacock Sharon J , Howard Philip
Published: April 2019

‘Superbugs’, bacteria that have become resistant to antibiotics, have been in numerous media headlines, raising awareness of antibiotic resistance and leading to multiple action plans from policymakers worldwide. However, many commonly used terms, such as ‘the war against superbugs’, risk misleading people to request ‘new’ or ‘stronger’ antibiotics from their doctors, veterinary surgeons or pharmacists, rather than addressing a fundamental issue: the misuse and overuse of antibiotics in humans and animals. Simple measures of antibiotic consumption are needed for mass communication. In this article, we describe the concept of the ‘antibiotic footprint’ as a tool to communicate to the public the magnitude of antibiotic use in humans, animals and industry, and how it could support the reduction of overuse and misuse of antibiotics worldwide. We propose that people need to make appropriate changes in behaviour that reduce their direct and indirect consumption of antibiotics.
Pharmacokinetics of tenofovir monoester and association with intracellular tenofovir diphosphate following single-dose tenofovir disoproxil fumarate
Authors: Brooks Kristina M , Ibrahim Mustafa E , Castillo-Mancilla Jose R , MaWhinney Samantha , Alexander Keisha , Tilden Scott , Kerr Becky Jo , Ellison Lucas , McHugh Cricket , Bushman Lane R , Kiser Jennifer J , Hosek Sybil , Huhn Gregory D , Anderson Peter L
Published: April 2019

Background

Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported.

Methods

Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models.

Results

Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) Tmax of 0.5 h (0.25–2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0–4 was 93.3 ng·h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng·h/mL (30.0%). Tenofovir monoester AUC0–∞ (but not tenofovir AUC0–∞) was a significant predictor of tenofovir diphosphate in both PBMC (P = 0.015) and DBS (P = 0.005), increasing by 3.8% (95% CI 0.8%–6.8%) and 4.3% (95% CI 1.5%–7.2%), respectively, for every 10 ng·h/mL increase in tenofovir monoester.

Conclusions

Tenofovir monoester Cmax and AUC0–4 were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.
Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis
Authors: Alghanem S S , Touw D J , Thomson A H
Published: April 2019

Objectives

To determine the outcomes of weight- and height-based tobramycin dosing regimens for patients with cystic fibrosis (CF).

Methods

A simulated dataset of 5000 patients based on 331 patients with CF was created using NONMEM. Pharmacokinetic (PK) parameters were derived for each patient from a published model using Monte Carlo simulation. The abilities of 10 and 12 mg/kg/day and 3 and 4 mg/cm/day to achieve standard and extended Cmax (20–30 and 20–40 mg/L) and AUC0–24 (80–120 and 80–150 mg·h/L) targets were evaluated. PK/pharmacodynamic (PK/PD) indices were a Cmax/MIC ratio ≥10 and an AUC0–24/MIC ratio ≥110. For these indices and a range of MICs, cumulative fractions of response (CFRs) for Pseudomonas aeruginosa were also determined.

Results

More patients achieved standard Cmax and AUC0–24 targets with 3 mg/cm/day (64% and 62%, respectively) than with 10 mg/kg/day (43% and 48%, respectively). AUC0–24 estimates >120 mg·h/L were more common with weight-based dosing. With higher doses, 72% achieved high target peaks with 4 mg/cm/day and 65% with 12 mg/kg/day. For the Cmax/MIC index, the maximal MIC for the target microorganism was 2 mg/L with lower doses, 2.5 mg/L with higher doses and 0.5 mg/L for AUC0–24/MIC-based regimens. The CFR for all regimens was >90% for Cmax targets and 66% to 79% for AUC0–24 targets.

Conclusions

A tobramycin dose of 3 mg/cm/day rather than 10 mg/kg/day achieved similar PK/PD outcomes but dose and AUC0–24 ranges were narrower and the incidence of high AUC0–24 values was lower. Height-based doses should therefore be considered for patients with CF.
Do Covariances Between Maternal Behavior and Embryonic Physiology Drive Sex-Ratio Evolution Under Environmental Sex Determination?
Authors: Janzen Fredric J , Delaney David M , Mitchell Timothy S , Warner Daniel A
Published: April 2019

Fisherian sex-ratio theory predicts sexual species should have a balanced primary sex ratio. However, organisms with environmental sex determination (ESD) are particularly vulnerable to experiencing skewed sex ratios when environmental conditions vary. Theoretical work has modeled sex-ratio dynamics for animals with ESD with regard to 2 traits predicted to be responsive to sex-ratio selection: 1) maternal oviposition behavior and 2) sensitivity of embryonic sex determination to environmental conditions, and much research has since focused on how these traits influence offspring sex ratios. However, relatively few studies have provided estimates of univariate quantitative genetic parameters for these 2 traits, and the existence of phenotypic or genetic covariances among these traits has not been assessed. Here, we leverage studies on 3 species of reptiles (2 turtle species and a lizard) with temperature-dependent sex determination (TSD) to assess phenotypic covariances between measures of maternal oviposition behavior and thermal sensitivity of the sex-determining pathway. These studies quantified maternal behaviors that relate to nest temperature and sex ratio of offspring incubated under controlled conditions. A positive covariance between these traits would enhance the efficiency of sex-ratio selection when primary sex ratio is unbalanced. However, we detected no such covariance between measures of these categories of traits in the 3 study species. These results suggest that maternal oviposition behavior and thermal sensitivity of sex determination in embryos might evolve independently. Such information is critical to understand how animals with TSD will respond to rapidly changing environments that induce sex-ratio selection.
Internal Conflicts and Shadow Economies
Authors: Peksen Dursun , Early Bryan
Published: April 2019

Existing scholarship on the political economy of political violence, to date, has mostly focused on how formal economies shape or are shaped by conflict and overlooked the informal sector. In this article, we posit that intrastate conflicts are likely to fuel the growth of shadow economies by harming the formal economic sector, undermining governments’ ability to regulate their economies, and fostering illicit trade. We also hypothesize that the effect of internal conflicts spreads across national boundaries, increasing the amount of shadow sector activity in neighboring states. Results from a global analysis spanning from 1971 to 2012 provide significant evidence that internal conflicts positively contribute to the growth of informal economies in conflict states and their neighbors. Additional analyses also show that the growth of shadow economies does not contribute to the outbreak of intrastate conflicts. Our findings have important implications for understanding the transformative economic consequences of violent conflicts and the longer-term economic legacies they might leave.
Role of nitric oxide in plant responses to heavy metal stress: exogenous application versus endogenous production
Authors: Terrón-Camero Laura C , Peláez-Vico M Ángeles , Del-Val Coral , Sandalio Luisa M , Romero-Puertas María C
Published: April 2019

Anthropogenic activities, such as industrial processes, mining, and agriculture, lead to an increase in heavy metal concentrations in soil, water, and air. Given their stability in the environment, heavy metals are difficult to eliminate and can constitute a human health risk by entering the food chain through uptake by crop plants. An excess of heavy metals is toxic for plants, which have various mechanisms to prevent their accumulation. However, once metals enter the plant, oxidative damage sometimes occurs, which can lead to plant death. Initial production of nitric oxide (NO), which may play a role in plant perception, signalling, and stress acclimation, has been shown to protect against heavy metals. Very little is known about NO-dependent mechanisms downstream from signalling pathways in plant responses to heavy metal stress. In this review, using bioinformatic techniques, we analyse studies of the involvement of NO in plant responses to heavy metal stress, its possible role as a cytoprotective molecule, and its relationship with reactive oxygen species. Some conclusions are drawn and future research perspectives are outlined to further elucidate the signalling mechanisms underlying the role of NO in plant responses to heavy metal stress.
‘Scraggy’ dark haloes around bulge-less spiral
Authors: Karachentsev I D , Karachentseva V E
Published: April 2019

We use a sample of 220 face-on bulge-less galaxies situated in the low-density environment to estimate their total mass via orbital motions of supposed rare satellites. Our inspection reveals 43 dwarf companions having the mean projected separation of 130 kpc and the mean-square velocity difference of 96 km s−1. For them, we obtain the mean orbital-mass-to-K-band luminosity ratio of 20 ± 3. Seven bulge-less spirals in the Local Volume are also characterized by the low mean ratio, Morb/LK = 22 ± 5. We conclude that bulge-less Sc–Scd–Sd galaxies have poor dark haloes, about two times lower than that of bulgy spiral galaxies of the same stellar mass.
Atmospheric mass-loss from high-velocity giant impacts
Authors: Yalinewich Almog , Schlichting Hilke
Published: April 2019

Using moving mesh hydrodynamic simulations, we determine the shock propagation and resulting ground velocities for a planet hit by a high-velocity impactor. We use our results to determine the atmospheric mass-loss caused by the resulting ground motion due to the impact shock wave. We find that there are two distinct shock propagation regimes. In the limit in which the impactor is significantly smaller than the target (Ri << Rt), the solutions are self-similar and the shock velocity at a fixed point on the target scale as $m_{\rm i}^{2/3}$, where mi is the mass of the impactor. In addition, the ground velocities follow a universal profile given by vg/vi = (14.2x2 − 25.3x + 11.3)/(x2 − 2.5x + 1.9) + 2ln Ri/Rt, where x = sin (θ/2), θ is the latitude on the target measured from the impact site, and vg and vi are the ground velocity and impact velocity, respectively. In contrast, in the limit in which the impactor is comparable to the size of the target (Ri ∼ Rt), we find that shock velocities decline with the mass of the impactor significantly more weakly than $m_{\rm i}^{2/3}$. We use the resulting surface velocity profiles to calculate the atmospheric mass-loss for a large range of impactor masses and impact velocities and apply them to the Kepler-36 system and the Moon forming impact. Finally, we present and generalize our results in terms of the vg/vi and the impactor to target size ratio (Ri/Rt) such that they can easily be applied to other collision scenarios.
Stability and sub-cellular localization of DNA polymerase β is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress
Authors: Fang Qingming , Andrews Joel , Sharma Nidhi , Wilk Anna , Clark Jennifer , Slyskova Jana , Koczor Christopher A , Lans Hannes , Prakash Aishwarya , Sobol Robert W
Published: April 2019

Protein–protein interactions regulate many essential enzymatic processes in the cell. Somatic mutations outside of an enzyme active site can therefore impact cellular function by disruption of critical protein–protein interactions. In our investigation of the cellular impact of the T304I cancer mutation of DNA Polymerase β (Polβ), we find that mutation of this surface threonine residue impacts critical Polβ protein–protein interactions. We show that proteasome-mediated degradation of Polβ is regulated by both ubiquitin-dependent and ubiquitin-independent processes via unique protein–protein interactions. The ubiquitin-independent proteasome pathway regulates the stability of Polβ in the cytosol via interaction between Polβ and NAD(P)H quinone dehydrogenase 1 (NQO1) in an NADH-dependent manner. Conversely, the interaction of Polβ with the scaffold protein X-ray repair cross complementing 1 (XRCC1) plays a role in the localization of Polβ to the nuclear compartment and regulates the stability of Polβ via a ubiquitin-dependent pathway. Further, we find that oxidative stress promotes the dissociation of the Polβ/NQO1 complex, enhancing the interaction of Polβ with XRCC1. Our results reveal that somatic mutations such as T304I in Polβ impact critical protein–protein interactions, altering the stability and sub-cellular localization of Polβ and providing mechanistic insight into how key protein–protein interactions regulate cellular responses to stress.
Principles and strategies for involving patients in research in chronic kidney disease: report from national workshops
Authors: Gutman Talia , Tong Allison , Howell Martin , Dansie Kathryn , Hawley Carmel M , Craig Jonathan C , Jesudason Shilpanjali , Chapman Jeremy R , Johnson David W , Murphy Lisa , Reidlinger Donna , Crowe Sally , Duncanson Emily , Muthuramalingam Shyamsundar , Scholes-Robertson Nicole , Williamson Amber , McDonald Stephen
Published: April 2019

Background

There is widespread recognition that research will be more impactful if it arises from partnerships between patients and researchers, but evidence on best practice for achieving this remains limited.

Methods

We convened workshops in three Australian cities involving 105 patients/caregivers and 43 clinicians/researchers. In facilitated breakout groups, participants discussed principles and strategies for effective patient involvement in chronic kidney disease research. Transcripts were analysed thematically

Results

Five major themes emerged. ‘Respecting consumer expertise and commitment’ involved valuing unique and diverse experiential knowledge, clarifying expectations and responsibilities, equipping for meaningful involvement and keeping patients ‘in the loop’. ‘Attuning to individual context’ required a preference-based multipronged approach to engagement, reducing the burden of involvement and being sensitive to the patient journey. ‘Harnessing existing relationships and infrastructure’ meant partnering with trusted clinicians, increasing research exposure in clinical settings, mentoring patient to patient and extending reach through established networks. ‘Developing a coordinated approach’ enabled power in the collective and united voice, a systematic approach for equitable inclusion and streamlining access to opportunities and trustworthy information. ‘Fostering a patient-centred culture’ encompassed building a community, facilitating knowledge exchange and translation, empowering health ownership, providing an opportunity to give back and cultivating trust through transparency.

Conclusions

Partnering with patients in research requires respect and recognition of their unique, diverse and complementary experiential expertise. Establishing a supportive, respectful research culture, responding to their individual context, coordinating existing infrastructure and centralizing the flow of information may facilitate patient involvement as active partners in research.
Improved neuropsychological outcomes following proton therapy relative to X-ray therapy for pediatric brain tumor patients
Authors: Gross Jeffrey P , Powell Stephanie , Zelko Frank , Hartsell William , Goldman Stewart , Fangusaro Jason , Lulla Rishi R , Smiley Natasha Pillay , Chang John Han-Chih , Gondi Vinai
Published: April 2019

Background

Survivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent X-ray radiotherapy (XRT) versus proton radiotherapy (PRT).

Methods

Pediatric patients who underwent either XRT or PRT and received posttreatment age-appropriate neuropsychological evaluation—including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning—were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time.

Results

Between 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%), or posterior fossa (53.6%) compartments received radiation and had posttreatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated SES and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs 2.6 y, P < 0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (β = 10.6, P = 0.048) and processing speed (β = 14.4, P = 0.007) relative to XRT, with trend toward higher verbal IQ (β = 9.9, P = 0.06) and general adaptive functioning (β = 11.4, P = 0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ (P = 0.01) and IQ (P = 0.04) following PRT, with trend toward improved processing speed (P = 0.09).

Conclusions

PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.
Silicosis and pulmonary tuberculosis in deceased female South African miners
Authors: Ndlovu N , Richards G , Vorajee N , Murray J
Published: April 2019

Background

Implementation of South Africa’s 2002 Mining Charter increased women’s participation in underground mining. However, occupational lung diseases (OLDs) in female gold miners have not been studied.

Aims

To compare autopsy-diagnosed pulmonary silicosis, lymph gland silicosis (a precursor of pulmonary silicosis) and active pulmonary tuberculosis (PTB) in South African gold miners.

Methods

The law allows for autopsies on miners for OLD compensation. Information is stored on the Pathology Automation (PATHAUT) database. We selected records of deceased miners who had worked only in gold mines, started employment from 2002, and were autopsied between 2005 and 2015. Using descriptive statistics, we compared demographic and employment characteristics, and disease proportions by sex.

Results

The study comprised 847 gold miners: 68 women and 779 men. There were no statistically significant differences in proportions of autopsy-diagnosed pulmonary silicosis [3 (4%) in women and 54 (7%) in men], lymph gland silicosis [11 (16%) and 171 (22%)] or PTB [29 (43%) and 254 (33%)]. Age and employment duration in women and men with disease were similar. Most miners with pulmonary silicosis had started employment from 2003 [315 (77%)] and worked for under 10 years.

Conclusion

It is important to report research findings by sex. Proportions of silicosis and PTB were comparable in women and men, suggesting similar exposures. Silicosis detection after short employment indicates inadequate dust control, particularly as most entered the industry after implementation of interventions to control silica dust in 2003.
Kidney and inferior vena cava abnormalities with leg thromboses (KILT) syndrome: A case report and literature review
Authors: Rughani Prita , Yeung Frances , Halgren Camilla Raya , Cada Michaela , Schwartz Sarah
Published: April 2019

Venous thromboembolism (VTE) is now increasingly recognized within paediatrics. A Canadian VTE registry has estimated the incidence as 0.7 to 1.0 per 100,000 population, with a peak in infancy and adolescence. Congenital inferior vena cava agenesis (IVCA) is an important risk factor that may be unfamiliar to paediatricians. Several case reports have since described an association between IVCA, VTE, and renal hypoplasia, which has been referred to as KILT syndrome (Kidney and IVC abnormalities with Leg Thromboses). We describe the first reported paediatric case of KILT syndrome in Canada. In any young patient presenting with a spontaneous DVT, particularly, if it is bilateral in nature with no co-existing risk factors for thrombus formation, we recommend investigating for the possibility of an underlying congenital vena cava anomaly. The use of prolonged anticoagulant therapy is supported by the inherent life-long risk of recurrent thrombosis associated with IVC anomalies.
Economic Impact of Adherence to Pain Treatment Guidelines in Chronic Pain Patients
Authors: Margolis Jay M , Princic Nicole , Smith David M , Abraham Lucy , Cappelleri Joseph C , Shah Sonali N , Park Peter W
Published: April 2019

Objectives

This research compared health care resource use (HCRU) and costs for pharmacotherapy prescribing that was adherent vs nonadherent to published pain management guidelines. Conditions included osteoarthritis (OA) and gout (GT) for nociceptive/inflammatory pain, painful diabetic peripheral neuropathy (pDPN) and post-herpetic neuralgia (PHN) for neuropathic pain, and fibromyalgia (FM) for sensory hypersensitivity pain.

Methods

This retrospective cohort study used claims from MarketScan Commercial and Medicare Databases identifying adults newly diagnosed with OA, GT, pDPN, PHN, or FM during July 1, 2006, to June 30, 2013, with 12-month continuous coverage before and after initial (index) diagnosis. Patients were grouped according to their pharmacotherapy pattern as adherent, nonadherent, or “unsure” according to published pain management guidelines using a claims-based algorithm. Adherent and nonadherent populations were compared descriptively and using multivariate statistical analyses for controlling bias.

Results

Final cohort sizes were 441,465 OA, 76,361 GT, 10,645 pDPN, 4,010 PHN, and 150,321 FM, with adherence to guidelines found in 51.1% of OA, 25% of GT, 59.5% of pDPN, 54.9% of PHN, and 33.5% of FM. Adherent cohorts had significantly (P < 0.05) fewer emergency department (ED) visits and lower proportions with hospitalizations or ED visits. Mean health care costs increased following diagnosis across all conditions; however, adherent cohorts had significantly lower increases in adjusted costs pre-index to postindex (OA $5,286 vs $9,532; GT $3,631 vs $7,873; pDPN $9,578 vs $16,337; PHN $2,975 vs $5,146; FM $2,911 vs $3,708; all P < 0.001; adherent vs nonadherent, respectively).

Conclusions

Adherence to pain management guidelines was associated with significantly lower HCRU and costs compared with nonadherence to guidelines.