bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of the long‐acting ivermectin formulation in sheep: Further insight into potential pharmacokinetic interactions
Authors: Ballent Mariana , Maté Maria Laura , Dominguez Paula , Virkel Guillermo , Albérich Melanie , Lespine Anne , Lanusse Carlos , Lifschitz Adrian Luis
Published: December 2018

The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long‐acting (LA) formulation to sheep and its impact on potential drug‐drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 μg/kg) and as LA formulation at 630 μg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long‐lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated Cmax and AUC0‐t values of the IVM‐LA formulation were 1.47‐ and 3.35‐fold higher compared with IVM 1% formulation, respectively. The T1/2ab and Tmax collected after administration of the LA formulation were 2‐ and 3.5‐fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7‐fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post‐administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug‐drug interactions is a further contribution to the field.
II. MEASURES: SECURE BASE BEHAVIOR, CO‐CONSTRUCTION, AND ATTACHMENT SCRIPTS
Authors: Posada Germán E. , Waters Harriet S.
Published: December 2018

In order to examine the interplay between behavioral and cognitive representations of attachment during early childhood, we compiled both behavior‐based and more cognitive‐based attachment measures for this age range. The behavior‐based measures were observational Q‐set methodologies already established in the literature. Measures of attachment representations for the children and mothers were narrative‐based procedures, that is, established storytelling tasks for obtaining attachment narratives from children and adults. For assessing maternal co‐construction processes, we developed two new co‐construction tasks that required joint storytelling of attachment relevant storylines in one case, and joint conversations about emotion‐laden situations in the other. All of these measures are based on the central secure base construct of attachment theory. Behavioral measures assess secure base use and support. Attachment narratives collected from both children and parents are scored for secure base script knowledge. Maternal co‐construction is assessed in terms of cognitive processes that enhance and promote attachment script knowledge.
Loop assembly: a simple and open system for recursive fabrication of DNA circuits
Authors: Pollak Bernardo , Cerda Ariel , Delmans Mihails , Álamos Simón , Moyano Tomás , West Anthony , Gutiérrez Rodrigo A. , Patron Nicola J. , Federici Fernán , Haseloff Jim
Published: December 2018

High‐efficiency methods for DNA assembly have enabled the routine assembly of synthetic DNAs of increased size and complexity. However, these techniques require customization, elaborate vector sets or serial manipulations for the different stages of assembly.

We have developed Loop assembly based on a recursive approach to DNA fabrication. The system makes use of two Type IIS restriction endonucleases and corresponding vector sets for efficient and parallel assembly of large DNA circuits. Standardized level 0 parts can be assembled into circuits containing 1, 4, 16 or more genes by looping between the two vector sets. The vectors also contain modular sites for hybrid assembly using sequence overlap methods.

Loop assembly enables efficient and versatile DNA fabrication for plant transformation. We show the construction of plasmids up to 16 genes and 38 kb with high efficiency (> 80%). We have characterized Loop assembly on over 200 different DNA constructs and validated the fidelity of the method by high‐throughput Illumina plasmid sequencing.

Our method provides a simple generalized solution for DNA construction with standardized parts. The cloning system is provided under an OpenMTA license for unrestricted sharing and open access.
A minimally invasive hybrid approach for cardiac resynchronization of the systemic right ventricle
Authors: Moore Jeremy P. , Gallotti Roberto G. , Shannon Kevin M. , Biniwale Reshma
Published: December 2018

Background

Patients with systemic right ventricle (RV) often develop progressive heart failure and may benefit from cardiac resynchronization therapy (CRT); however, the optimal strategy for CRT has not been defined.

Methods

A retrospective review of all the patients with systemic RV failure undergoing a hybrid transcatheter‐surgical approach was performed. Procedural technique and outcomes are reported.

Results

Six patients underwent detailed electroanatomical mapping of the systemic RV followed by a new hybrid approach targeting latest endocardial activation, which was followed by focused epicardial mapping. The exact site of latest endocardial activation was variable but localized to the basolateral RV in all cases. Sites of latest activation tended to be more superior during contralateral ventricular pacing versus intact atrioventricular conduction (P = 0.06). Latest endocardial activation at the targeted site occurred at 157 ms (interquartile range [IQR] = 120‐181 ms) and corresponding epicardial activation at 174 ms (IQR = 140‐198 ms), after the onset of the QRS complex. Following the hybrid CRT, the QRS duration decreased from a median of 193 to 147 ms and the fractional area of change increased from a median of 15.5% to 30% (P < 0.001). Patients were discharged to home after a median of 4 days. Of the three patients who were initially referred for transplant evaluation, two (66%) of them no longer met the criteria following CRT.

Conclusions

Whereas latest endocardial activation for the systemic RV appears to localize to the basolateral region, the optimal lead position may be variable. An approach utilizing endocardial mapping followed by a limited surgical incision and confirmation of latest activation may result in minimally invasive surgery and a favorable acute CRT response.
Investigating skin age analysis to reduce tanning intentions among adolescents: A pilot study
Authors: Weight Alexa B. , Forbes Brayden R. , Whittier Samuel A. , Truong Amanda , Klein Stephanie Z.
Published: December 2018

As skin cancer rates continue to rise, targeted efforts to reduce excessive exposure to ultraviolet radiation are crucial. Adolescents are a high‐risk population for intentional tanning; thus, we sought to determine whether the novel use of skin age analysis with ultraviolet (UV) photography would be an effective tool for reducing intentions to tan in adolescents with a calculated skin age (measured by complexion analysis software) that exceeds their actual age. Surveying 85 students in this study, skin age difference above zero was associated with reduced intentions to tan (P = 0.006) and high‐risk sun exposure behaviors were identified. This provides rationale for skin age analysis as a potentially effective intervention in decreasing intentions to tan in this high‐risk young population.
Genome‐wide association analysis of resistance to wheat spindle streak mosaic virus in bread wheat
Authors: Hourcade D. , Bogard M. , Bonnefoy M. , Savignard F. , Mohamadi F. , Lafarge S. , Du Cheyron P. , Mangel N. , Cohan J. P.
Published: December 2018

Wheat spindle streak mosaic virus (WSSMV) is a major concern for cereal crops in Europe and North America. A strong increase in the occurrence of WSSMV has been observed in each French region where susceptible cultivars are cultivated. Most European bread wheat cultivars are resistant, but assessing the status of newly registered cultivars or breeding lines regarding WSSMV resistance is of importance. This paper describes a genome‐wide association study carried out on a panel of 163 cultivars and tested for their resistance to WSSMV. Two regions on chromosomes 5B and 7D showed minor effects on WSSMV resistance. More importantly, a large genomic region on chromosome 2D explained most of the resistance to WSSMV. More than 99% of the cultivars carrying the AA genotype at the most associated marker (Excalibur_c15426_661) were resistant to WSSMV, while 100% of the cultivars showing the GG genotype were susceptible. This large genomic region of 45.8 Mb was found distal to the centromere and showed very high linkage disequilibrium. It is hypothesized that this region may be an alien introgression originating from a wild related species. This region contains a total of 2605 predicted genes based on the Chinese Spring IWGSC RefSeq v. 1.0 including genes potentially involved in plant disease resistance. A kompetitive allele‐specific PCR (KASP) single‐nucleotide polymorphism (SNP) marker was designed in order to identify breeding lines or registered cultivars resistant to WSSMV.
Platelet transfusion practices in immune thrombocytopenia related hospitalizations
Authors: Goel Ruchika , Chopra Saurav , Tobian Aaron A. R. , Ness Paul M. , Frank Steven M. , Cushing Melissa , Vasovic Ljiljana , Kaicker Shipra , Takemoto Clifford , Josephson Cassandra D. , Nellis Marianne , Bussel James , Krishnamurti Lakshmanan
Published: December 2018

BACKGROUND

The role of platelet transfusions in management of Immune Thrombocytopenia (ITP) remains controversial. Current guidelines recommend that platelet transfusions in ITP be reserved for catastrophic hemorrhage or invasive surgical procedures. This study assesses the nationwide platelet transfusion practices in hospitalized children and adults with ITP.

STUDY DESIGN AND METHODS

We studied hospitalizations with ITP as the primary admitting diagnosis from 2010–2014 in National Inpatient Sample (NIS), the largest all‐payer inpatient database. Univariate and multivariable logistic regression analyses were used to determine factors predicting platelet transfusions. Sampling weights were applied to generate nationally representative estimates. Propensity score matching was used to perform sensitivity analyses.

RESULTS

From 2010 to 2014, there were 78,376 admissions with ITP as the primary admission diagnosis (mean ± SD age: 45 ± 27 years; females 56%, children [age < 18 years] 22%) and 282,285 with ITP as one of all the admission diagnoses. Overall, 27% admissions with ITP as primary (children 4%) and 15% admissions with ITP as one of all the diagnoses documented at least one platelet transfusion. On multivariable adjustment the following factors were associated with worsening disease severity and a higher odds of platelet transfusion, adult age (adjOR = 9.03, 95% CI = 7.40–11.02), male gender (adjOR = 1.21, 95% CI = 1.11–1.31), bleeding occurrence (intracranial/gastrointestinal/genitourinary/epistaxis) (adjOR = 1.78, 95% CI = 1.61–1.96), admission to rural non‐teaching hospital (adjOR = 1.85, 95% CI = 1.52–2.22), and small bed‐size hospital (adjOR = 1.23, 95% CI = 1.05–1.45). Of admissions reporting platelet transfusions, only 26% reported a bleeding complication, and 11% had a major operating‐room surgery/procedure. Overall, 65% of transfused patients had neither bleeding nor a major operative procedure during the hospitalization. Admissions with platelet transfusions had a significantly longer mean length of hospitalization 2.2 days (95% CI = 1.96–2.41, p < 0.001), and accrued higher mean total hospital charges; $31,150 USD (95% CI = 27,644–34,656, p < 0.001). However, platelet transfusions were not associated with in‐hospital mortality (adjOR = 1.02, 95% CI = 0.73–1.45, p = 0.892).

CONCLUSION

Platelets are administered to a small fraction of the hospitalized ITP patients. In a majority of these cases however, platelet usage does not appear to be concordant with the current guidelines or associated with improvement in clinical outcomes.
Diary Keeping in Writing Education
Authors: Dincel Betul Keray , Savur Hilmi
Published: December 2018

One of the many types of texts that can be used in writing education is the diary. In this study, the opinions of the Turkish language teacher candidates about diary keeping and their diaries kept for two months in which they could freely express their thoughts were analyzed. It is a qualitative study in which thirty-four participants' diaries were examined, and semi-structured interviews were conducted with seventeen randomly selected candidates. It is observed that the topics dealt by the teacher candidates in their diaries mainly focused on themes such as education-teaching activities, life, feelings, thoughts, relatives, nature, important days, diary, problems, personal development, and writing skills. The emerging codes from these interviews were grouped as: Diary, problems, personal development, and writing skills. The results of this research reveal that candidates who regularly keep a diary begin to question their lives and try to manage them better. Moreover, it was shown that diary keeping, which is regular writing, has an important role in the development of writing ability.
The Effects of Natural Grass Turf on Some Motoric Characteristics of Young Soccer Players
Authors: Caglayan Atakan
Published: December 2018

The aim of this study is to examine the effect of soccer training on natural turfs on strength, speed, power and balance characteristics in prepubertal children. Twenty-two male athletes chosen from the 12-13 age group who play soccer in the youth team of an amateur soccer club from Istanbul, Turkey volunteered to participate in our study. In the study, 30 m sprint, Y-balance, standing long jump and vertical jump tests were done as pre- and post-tests. The same training program was assigned to the players, who were separated into two groups. One group was trained on synthetic grass turf (SG) while the other group was trained on natural grass turf (NG) for eight weeks. As a result of the statistical analyses, significant improvements were observed in all parameters between pre-and post-test measurements of both SG and NG groups (p<0.05). When the developmental differences of the groups were examined, statistical improvement was found in the standing long jump parameter in favor of the group that trained on Natural Grass turf (p=0.037). In conclusion, depending on the characteristics of the soccer game, enhancements were observed on both surfaces. However, the challenge effect of natural grass turf was more effective than that of synthetic grass turf on leg strength improvement. It is considered that as a result of continuing their soccer trainings on natural grass turfs, young players can improve their performance and can avoid possible injuries.
Redefinition of the little-known genus Ceuthothrombium (Acari: Neothrombiidae), with description of a new species ectoparasitic on a centipede from Iran
Authors: Majidi Maryam , Hajiqanbar Hamidreza , Saboori Alireza
Published: December 2018

The genus Ceuthothrombium Robaux, Webb & Campbell, 1976 is redefined based on data of the original description and a new species from Jahrom, Iran. The discovery of a new species from Iran showed a variation between characters considered for the genus and some new features were considered as well. Also, Ceuthothrombium scolopendrae sp. nov. (Acari: Trombidiformes: Neothrombiidae) is described and illustrated, as an ectoparasite of the centipede Scolopendra canidens Newport (Scolopendromorpha: Scolopendridae) from Jahrom, southern Iran.
Effective approach to epidemic containment using link equations in complex networks
Authors: Matamalas Joan T. , Arenas Alex , Gómez Sergio
Published: December 2018

Assessing the importance of each connection in a network for the spreading of epidemics allows the largest containment up to date.
The development of lower-atmosphere turbulence early in a solar flare
Authors: Jeffrey N. L. S. , Fletcher L. , Labrosse N. , Simões P. J. A.
Published: December 2018

IRIS observation of the initiation of a solar flare suggests that turbulence helps to heat the Sun’s lower atmosphere.
Noncoding regions are the main source of targetable tumor-specific antigens
Authors: Laumont Céline M. , Vincent Krystel , Hesnard Leslie , Audemard Éric , Bonneil Éric , Laverdure Jean-Philippe , Gendron Patrick , Courcelles Mathieu , Hardy Marie-Pierre , Côté Caroline , Durette Chantal , St-Pierre Charles , Benhammadi Mohamed , Lanoix Joël , Vobecky Suzanne , Haddad Elie , Lemieux Sébastien , Thibault Pierre , Perreault Claude
Published: December 2018

A proteogenomic method identifies potentially actionable tumor-specific antigens and shows that most of them are not coded by classic exons.
A Case-Control Study of Real-Life Experience with Ceftolozane-Tazobactam in Patients with Hematologic Malignancy and Pseudomonas aeruginosa Infection
Authors: Fernández-Cruz Ana , Alba Natalia , Semiglia-Chong María Auxiliadora , Padilla Belén , Rodríguez-Macías Gabriela , Kwon Mi , Cercenado Emilia , Chamorro-de-Vega Esther , Machado Marina , Pérez-Lago Laura , García de Viedma Darío , Díez Martín José Luis , Muñoz Patricia
Published: December 2018

We present our experience in patients with hematologic malignancy and
Pseudomonas aeruginosa
infection treated with ceftolozane-tazobactam. We performed a single-center case-control study comparing patients with hematologic malignancy and
P. aeruginosa
infection treated with ceftolozane-tazobactam (study group) with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy.
Novel Two-Component System MacRS Is a Pleiotropic Regulator That Controls Multiple Morphogenic Membrane Protein Genes in
Streptomyces coelicolor
Authors: Liu Meng , Zhang Peipei , Zhu Yanping , Lu Ting , Wang Yemin , Cao Guangxiang , Shi Mei , Chen Xiu-lan , Tao Meifeng , Pang Xiuhua
Published: December 2018

TCSs help bacteria adapt to environmental stresses by altering gene expression. However, the roles and corresponding regulatory mechanisms of most TCSs in the
Streptomyces
model strain
S. coelicolor
are unknown. We investigated the previously uncharacterized MacRS TCS and identified the core DNA recognition sequence, two seven-nucleotide inverted repeats, for the DNA-binding protein MacR. We further found that MacR directly controls a group of membrane proteins, including MmpA-C, which are novel morphogenic factors that delay formation of aerial mycelium. We also discovered that these membrane proteins interact with one another and that other
Streptomyces
species have conserved MacRS homologs. Our findings suggest a conserved role for MacRS in morphogenesis and/or other membrane-associated activities. Additionally, our study showed that MacRS impacts, albeit indirectly, the production of the signature metabolite actinorhodin, further suggesting that MacRS and its homologs function as novel pleiotropic regulatory systems in
Streptomyces
.
Tick-Borne Flaviviruses, with a Focus on Powassan Virus
Authors: Kemenesi Gábor , Bányai Krisztián
Published: December 2018

The tick-borne pathogen Powassan virus is a rare cause of encephalitis in North America and the Russian Far East. The number of documented cases described since the discovery of Powassan virus in 1958 may be <150, although detection of cases has increased over the past decade.
Milk feed osmolality and adverse events in newborn infants and animals: a systematic review
Authors: Ellis Zoë-Marie , Tan Hui Shan Grace , Embleton Nicolas D , Sangild Per Torp , van Elburg Ruurd M
Published: December 2018

Background

High feed osmolality (or osmolarity) is often suggested to be linked with adverse gastrointestinal events in preterm infants.

Aim

To systematically review the literature on milk feed osmolality and adverse gastrointestinal events in newborn and low birthweight infants and animals.

Methods

MEDLINE, Embase, CAB Abstracts, Current Contents, BIOSIS Previews and SciSearch were searched from inception to May 2018 to identify potentially relevant studies. Inclusion criteria: randomised controlled or observational studies of newborn and low birthweight infants or animals investigating the effects of milk-based feeds with different osmolalities. Only full-text, English-language papers were included.

Results

Ten human and six animal studies met the inclusion criteria. Of human studies, seven reported no differences in adverse events with varying feed osmolalities; one reported delayed gastric emptying with feed osmolarity of 539 mOsm/L compared with lower levels; one reported higher necrotising enterocolitis (NEC) incidence with feed osmolarity of 650 mOsm/L compared with 359 mOsm/L; one found higher NEC incidence with the lowest feed osmolality (326 mOsm/kg compared with 385 mOsm/kg). Of animal studies, two reported delayed gastric emptying with feed osmolarity >624 mOsm/L, one reported decreased survival due to dehydration with dietary osmolarities ≥765 mOsmol/L and none reported increased NEC incidence with differing feed osmolalities. No clear mechanisms were found, and diet composition differences limited the interpretations regarding the independent impact of osmolality.

Conclusions

There is no consistent evidence that differences in feed osmolality in the range 300–500 mOsm/kg are associated with adverse gastrointestinal symptoms in neonates.
Combination of multimodal imaging features predictive of choroidal nevus transformation into melanoma
Authors: Dalvin Lauren A , Shields Carol L , Ancona-Lezama David Arturo , Yu Michael D , Di Nicola Maura , Williams Jr Basil K , Lucio-Alvarez J Antonio , Ang Su Mae , Maloney Sean M , Welch R Joel , Shields Jerry A
Published: December 2018

Aim

To characterise combinations of multimodal imaging risk factors and predictive value for choroidal nevus transformation into melanoma.

Methods

This is a retrospective review of multimodal imaging features for 3806 choroidal nevi from 1 January 2007 through 1 January 2017. Kaplan-Meier estimates and Cox regression analyses were used to calculate 5-year percentages of growth to melanoma and HR.

Results

Using multimodal imaging, six risk factors predictive of choroidal nevus transformation into melanoma were identified, namely tumour thickness >2 mm, subretinal fluid, symptoms of visual acuity loss to 20/50 or worse, orange pigment, hollow acoustic density and tumour largest basal diameter >5 mm. Kaplan-Meier 5-year estimated tumour growth was found in 1% of nevi with no risk factors, 11% (range 9%–37%) with one factor, 22% (12%–68%) with two factors, 34% (21%–100%) with three factors, 51% (0%–100%) with four factors and 55% (0%–100%) with five factors. HR for growth was 0.1 with no factor, 2.1–7.8 with one factor, 1.8–12.1 with two factors, 4.0–24.4 with three factors, 4.6–170.0 with four factors and 12.0–595.0 with five factors. The highest HR with each combination of two, three, four or five risk factors always included symptoms of visual acuity loss and orange pigment.

Conclusion

Six risk factors for choroidal nevus transformation into melanoma by multimodal imaging have been identified. Risk for transformation into melanoma is 1% when no factors are present, and approaches 100% with specific combinations of three or more risk factors. Understanding how combinations of factors influence risk of transformation into melanoma can guide counselling and treatment decisions.
Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study
Authors: Abrahami Devin , Douros Antonios , Yin Hui , Yu Oriana HY , Faillie Jean-Luc , Montastruc François , Platt Robert W , Bouganim Nathaniel , Azoulay Laurent
Published: December 2018

Objective

To determine whether use of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.

Design

Population based cohort study.

Setting

General practices contributing data to the UK Clinical Practice Research Datalink.

Participants

154 162 adults newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2017, followed until 31 March 2018.

Main outcome measures

Use of DPP-4 inhibitors and GLP-1 receptor agonists was modelled as a time varying variable and compared with use of other second or third line antidiabetic drugs. All exposures were lagged by one year to account for cancer latency and to minimise reverse causality. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of incident cholangiocarcinoma associated with use of DPP-4 inhibitors and GLP-1 receptor agonists, separately. A post hoc pharmacovigilance analysis was conducted using the World Health Organization’s global individual case safety report database, VigiBase, to estimate reporting odds ratios of cholangiocarcinoma.

Results

During 614 274 person years of follow-up, 105 incident cholangiocarcinoma events occurred (rate 17.1 per 100 000 person years). Use of DPP-4 inhibitors was associated with a 77% increased hazard of cholangiocarcinoma (hazard ratio 1.77, 95% confidence interval 1.04 to 3.01). Use of GLP-1 receptor agonists was associated with an increased hazard with a wide confidence interval (hazard ratio 1.97, 0.83 to 4.66). In the pharmacovigilance analysis, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased reporting odds ratios for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones (1.63, 1.00 to 2.66, 4.73, 2.95 to 7.58, respectively).

Conclusion

Compared with use of other second or third line antidiabetic drugs, use of DPP-4 inhibitors, and possibly GLP-1 receptor agonists, might be associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.
Views of UK doctors in training on the timing of choosing a clinical specialty: quantitative and qualitative analysis of surveys 3 years after graduation
Authors: Lachish Shelly , Goldacre Michael J , Lambert Trevor William
Published: December 2018

Background

Workforce studies show a declining proportion of UK junior doctors proceeding directly to specialist training, with many taking career breaks. Doctors may be choosing to delay this important career decision.

Aim

To assess doctors’ views on the timing of choosing a clinical specialty.

Methods

Surveys of two cohorts of UK-trained doctors 3 years after qualification, in 2011 and 2015.

Results

Presented with the statement ‘I had to choose my career specialty too soon after qualification’, 61% agreed (27% strongly) and 22% disagreed (3% strongly disagreed). Doctors least certain about their choice of specialty were most likely to agree (81%), compared with those who were more confident (72%) or were definite regarding their choice of long-term specialty (54%). Doctors not in higher specialist training were more likely to agree with this statement than those who were (72% vs 59%). Graduate medical school entrants (ie, those who had completed prior degrees) were less likely to agree than non-graduates (56% vs 62%). Qualitative analysis of free text comments identified three themes as reasons why doctors felt rushed into choosing their future career: insufficient exposure to a wide range of specialties; a desire for a greater breadth of experience of medicine in general; and inadequate career advice.

Conclusions

Most UK-trained doctors feel rushed into choosing their long-term career specialty. Doctors find this difficult because they lack sufficient medical experience and adequate career advice to make sound choices. Workforce trainers and planners should enable greater flexibility in training pathways and should further improve existing career guidance.
Diagnostic accuracy of inflammatory back pain for axial spondyloarthritis in rheumatological care
Authors: Poddubnyy Denis , Callhoff Johanna , Spiller Inge , Listing Joachim , Braun Juergen , Sieper Joachim , Rudwaleit Martin
Published: December 2018

Objective﻿

Inflammatory back pain (IBP), the key symptom of axial spondyloarthritis (axSpA), including ankylosing spondylitis, has been proposed as a screening test for patients presenting with chronic back pain in primary care. The diagnostic accuracy of IBP in the rheumatology setting is unknown.

Methods

Six rheumatology centres, representing secondary and tertiary rheumatology care, included routinely referred patients with consecutive chronic back pain with suspicion of axSpA. IBP (diagnostic test) was assessed in each centre by an independent (blinded) rheumatologist; a second (unblinded) rheumatologist made the diagnosis (axSpA or no-axSpA), which served as reference standard.

Results

Of 461 routinely referred patients, 403 received a final diagnosis. IBP was present in 67.3%, and 44.6% (180/403) were diagnosed as axSpA. The sensitivity of IBP according to various definitions (global judgement, Calin, Berlin, Assessment of SpondyloArthritis international Society criteria for IBP) was 74.4%–81.1 % and comparable to published figures, whereas the specificity was unexpectedly low (25.1%–43.9%). The resulting positive likelihood ratios (LR+) were 1.1–1.4 and without major differences between sets of IBP criteria. The presence of IBP according to various definitions increased the probability of axSpA by 2.5%–8.4% only (from 44.6% to 47.1%–53.0%).

Conclusions

The diagnostic utility of IBP in the rheumatology setting was smaller than expected. However, this was counterbalanced by a high prevalence of IBP among referred patients, demonstrating the effective usage of IBP in primary care as selection parameter for referral to rheumatology. Notably, this study illustrates potential shifts in specificity and LR+ of diagnostic tests if these tests are used to select patients for referral.
Basement membrane and blood–brain barrier
Authors: Xu Lingling , Nirwane Abhijit , Yao Yao
Published: December 2018

The blood–brain barrier (BBB) is a highly complex and dynamic structure, mainly composed of brain microvascular endothelial cells, pericytes, astrocytes and the basement membrane (BM). The vast majority of BBB research focuses on its cellular constituents. Its non-cellular component, the BM, on the other hand, is largely understudied due to its intrinsic complexity and the lack of research tools. In this review, we focus on the role of the BM in BBB integrity. We first briefly introduce the biochemical composition and structure of the BM. Next, the biological functions of major components of the BM in BBB formation and maintenance are discussed. Our goal is to provide a concise overview on how the BM contributes to BBB integrity.
Comparative efficacy of two parenteral iron‐containing preparations, iron gleptoferron and iron dextran, for the prevention of anaemia in suckling piglets
Authors: Sperling Daniel , Freudenschuss Barbara , Shrestha Aruna , Hinney Barbara , Karembe Hamadi , Joachim Anja
Published: December 2018

Iron‐deficiency anaemia (IDA) is a serious health problem in neonatal piglets and is controlled by routine application of iron in various formulations. The efficacy and safety of two iron‐containing products for the prevention of IDA in suckling piglets were compared in a randomised, parallel study. Newborn piglets were treated with 200 mg iron supplied by intramuscular injection in the neck as either Forceris (gleptoferron; n=13) or Uniferon 200 (iron dextran; n=12) 24–48 hours after birth. Blood samples were collected before and after treatment (2nd, 18th and 31st day of life) for complete haematology. The treatments were well tolerated with only mild transient swelling observed in two piglets (Forceris group). Piglets treated with Forceris had significantly higher haemoglobin, haematocrit, mean corpuscular volume and haemoglobin concentration values, as well as significantly higher plasma iron and transferritin saturation and a lower total iron binding capacity than those treated with Uniferon. No animals in the Forceris group but 17 per cent of piglets in the Uniferon group had haemoglobin levels <9 g/dl after treatment, indicating anaemia. These results suggest that both products were safe and effective in the prophylaxis of IDA in piglets, and that Forceris was superior to Uniferon in preventing IDA in piglets.
Hemodynamic responses to an exercise stress test in Parkinson’s disease patients without orthostatic hypotension
Authors: Roberson Kirk B. , Signorile Joseph F. , Singer Carlos , Jacobs Kevin A. , Eltoukhy Moataz , Ruta Nicolette , Mazzei Nicolle , Buskard Andrew N.L.
Published: December 2018

The presence of postganglionic sympathetic denervation is well established in Parkinson’s disease (PD). Denervation at cardiac and blood vessel sites may lead to abnormal cardiovascular and hemodynamic responses to exercise. The aim of the present investigation was to examine how heart rate (HR) and hemodynamics are affected by an exercise test in PD patients without orthostatic hypotension. Thirty individuals without orthostatic hypotension, 14 individuals with PD, and 16 age-matched healthy controls performed an exercise test on a cycle ergometer. Heart rate, blood pressure, and other hemodynamic variables were measured in a fasted state during supine rest, active standing, exercise, and supine recovery. Peak HR and percent of age-predicted maximum HR (HRmax) achieved were significantly blunted in PD (p < 0.05, p < 0.01). HR remained significantly elevated in PD during recovery compared with controls (p = 0.03, p < 0.05). Systolic, diastolic, and mean arterial pressures were significantly lower at multiple time-points during active standing in PD compared with controls. Systemic vascular resistance index (SVRI) decreased significantly at the onset of exercise in PD, and remained significantly lower during exercise and the first minute of supine recovery. End diastolic volume index (EDVI) was significantly lower in PD during supine rest and recovery. Our results indicate for the first time that normal hemodynamics are disrupted during orthostatic stress and exercise in PD. Despite significant differences in EDVI at rest and during recovery, and SVRI during exercise, cardiac index was unaffected. Our finding of significantly blunted HRmax and HR recovery in PD patients has substantial implications for exercise prescription and recovery guidelines.
Ultimate seismic bearing capacities and failure mechanisms for strip footings placed adjacent to slopes
Authors: Zhou Haizuo , Zheng Gang , Yang Xinyu , Li Tao , Yang Pengbo
Published: December 2018

Assessment of the ultimate bearing capacity of foundations adjacent to slopes is complex as it is highly dependent on the slope geometry and soil properties. Seismic loading may impact both the critical failure mechanism and its associated bearing capacity. The existing approaches for analyzing the seismic bearing capacity of footings near slopes typically employ coefficients developed to fit the conventions of Terzaghi’s bearing capacity equation, herein referred to as the “superposition method.” In this study, a rigorous assessment of the seismic bearing capacity is performed using an upper-bound limit state plasticity framework known as discontinuity layout optimization (DLO), which makes few prior assumptions concerning the failure geometry. Results show that soil properties, slope configuration, and pseudostatic seismic loading all influence the realized failure mechanism and associated bearing capacity. The use of bearing capacity coefficients that fit within the conventional superposition method may underestimate limit loads when the underlying soil provides a relative increase in resistance, but may greatly overestimate bearing capacity when the self-weight of the soil is destabilizing in nature. A set of design charts using direct computational methods for a variety of geometric, geotechnical, and seismic conditions is provided.
Two-photon decay of P-wave positronium: a tutorial
Authors: Sen Abhijit , Silagadze Zurab K.
Published: December 2018

A detailed exposition of two-photon decays of P-wave positronium is given to fill an existing gap in the pedagogical literature. Annihilation decay rates of P-wave positronium are negligible compared to the rates of radiative electric dipole transitions to the lower energy S-states. This circumstance makes such decays experimentally inaccessible. However, the situation is different for quarkonium and the experimental and theoretical research of two-photon and two-gluon decays of P-wave quarkonia is a still a flourishing field.
Factors affecting the permeability of road mitigation measures to the movement of small mammals
Authors: Ford Adam T. , Clevenger Anthony P.
Published: December 2018

Mitigation measures, such as wildlife-exclusion fencing and crossing structures (overpasses, underpasses, culverts), have been widely demonstrated to reduce the negative effects of roads on medium-sized and large animals. It is unclear how these mitigation measures influence the movement of small mammals (<5 kg). Our study has three objectives: (1) to test whether culverts improve highway permeability; (2) to determine factors associated with culvert use, such as culvert obstruction by snow; (3) to evaluate factors contributing towards fence permeability, such as the presence of a culvert, snow depth, and fence mesh size. We used snow tracking to assess the movement for four small-mammal taxa along the Trans-Canada Highway corridor in Banff National Park, Alberta, Canada. We found that the presence of a culvert within 100 m of transects significantly improved fence and highway permeability. Obstruction of the culvert entrance by snow was negatively correlated with the probability of use, and therefore, of highway permeability. Furthermore, the mesh size of the fencing did not affect fence or highway permeability. We recommend that culvert entrances be located on the outside of fenced right-of-ways to reduce obstruction by highway maintenance activities such as snowplowing.
M2C Polarization by Baicalin Enhances Efferocytosis via Upregulation of MERTK Receptor
Authors: Lai Yin-Siew , Putra Renanda Baghaz Dzulhamdhani Surya , Aui Shin-Peir , Chang Ko-Tung
Published: December 2018

Baicalin is the main active ingredient primary isolated from the Chinese herb, Scutellaria baicalensis Georgi. Although baicalin can induce M2 macrophage polarization, we still do not know the subtype of macrophages polarized by baicalin. In this study, we characterized that murine bone marrow derived macrophages induced by M-CSF can be further polarized into M2C phenotype by baicalin. The signatures of M2C macrophages for mRNA expression like interferon regulatory factor 4 (IRF4), interleukin-10 (IL-10), MERTK and PTX3 were up-regulated. Moreover, we observed the concomitantly decreasing of tumor necrosis factor alpha (TNF-[Formula: see text]), interferon regulatory factor 5 (IRF5), IL-6. In contrast, M2 macrophages polarized by IL-4 increased gene transcript of arginase-1 (Arg-1) and surface marker of CD206 indicates that their identity as M2A rather than M2C subtypes. Interestingly, the phagocytosis as well as efferocytosis activity were significantly enhanced in M2C macrophage polarized by baicalin and these capacities were associated with the expression of MERTK receptor. Finally, we conclude that baicalin induced M2C macrophages polarization with both elevations of efferocytosis and anti-inflammatory activity.
Statistical Inference of Second-Order Cone Programming
Authors: Wang Jiani , Zhang Liwei
Published: December 2018

The randomness of the second-order cone programming problems is mainly reflected in the objective function and the constraints both having random vectors. In this paper, we discuss the statistical properties of estimates of the respective optimal value and optimal solutions when the random vectors are estimated by their sample both in the objective function and the constraints, which are based on perturbation analysis theory of second-order cone programming. As an example we consider the problem of minimizing a sum of norms with weights.
EVALUATION OF THE TUBERCULOSIS TRANSMISSION OF DRUG-RESISTANT STRAINS IN MAINLAND CHINA
Authors: YANG JUNYUAN , KUNIYA TOSHIKAZU , XU FEI , CHEN YUMING
Published: December 2018

In this paper, we propose a mathematical model to evaluate the transmission of Tuberculosis with drug-resistant strains and with drug-sensitive strains. Based on the epidemic data from Chinese Center for Disease Control and Prevention, we first estimate the values of parameters in the model. Then the basic reproduction number of TB infection in the mainland China is calculated to be [Formula: see text] Since the basic reproduction number is greater than [Formula: see text] Tuberculosis spreads as an endemic in mainland China. Through our investigations, the basic reproduction number associated with drug-sensitive strains is less than 1, but the number of individuals infected by drug-resistant strains will still increase quickly, thus the epidemic is not under control. Moreover, increasing the vaccination coverage rate for newborns is not always beneficial for controlling TB prevalence in China. Whether vaccination effect is positive or negative depends on the relapse rate from the recovered state to the infected state. In summary, improving sanitation conditions, introducing efficient measures to detect the disease, and keeping the public informed about how to lower the chance of being infected and the current epidemic situation are essential in slowing down or eliminating Tuberculosis transmission.
Cyclic AMP-dependent protein kinase A and EPAC mediate VIP and secretin stimulation of PAK4 and activation of Na+,K+-ATPase in pancreatic acinar cells
Authors: Ramos-Alvarez Irene , Lee Lingaku , Jensen R. T.
Published: December 2018

Rat pancreatic acinar cells possess only the p21-activated kinase (PAKs), PAK4 of the group II PAK, and it is activated by gastrointestinal hormones/neurotransmitters stimulating PLC and by a number of growth factors. However, little is known generally of cAMP agents causing PAK4 activation, and there are no studies with gastrointestinal hormones/neurotransmitters activating cAMP cascades. In the present study, we examined the ability of VIP and secretin, which stimulate cAMP generation in pancreatic acini, to stimulate PAK4 activation, the signaling cascades involved, and their possible role in activating sodium-potassium adenosine triphosphatase (Na+,K+-ATPase). PAK4 activation was compared with activation of the well-established cAMP target, cyclic AMP response element binding protein (CREB). Secretin-stimulated PAK4 activation was inhibited by KT-5720 and PKA Type II inhibitor (PKI), protein kinase A (PKA) inhibitors, whereas VIP activation was inhibited by ESI-09 and HJC0197, exchange protein directly activated by cAMP (EPAC) inhibitors. In contrast, both VIP/secretin-stimulated phosphorylation of CREB (pCREB) via EPAC activation; however, it was inhibited by the p44/42 inhibitor PD98059 and the p38 inhibitor SB202190. The specific EPAC agonist 8-CPT-2- O-Me-cAMP as well 8-Br-cAMP and forskolin stimulated PAK4 activation. Secretin/VIP activation of Na+,K+-ATPase, was inhibited by PAK4 inhibitors (PF-3758309, LCH-7749944). These results demonstrate PAK4 is activated in pancreatic acini by stimulation of both VIP-/secretin-preferring receptors, as is CREB. However, they differ in their signaling cascades. Furthermore, PAK4 activation is needed for Na+,K+ATPase activation, which mediates pancreatic fluid secretion. These results, coupled with recent studies reporting PAKs are involved in both pancreatitis/pancreatic cancer growth/enzyme secretion, show that PAK4, similar to PAK2, likely plays an important role in both pancreatic physiological/pathological responses.

NEW & NOTEWORTHY Pancreatic acini possess only the group II p21-activated kinase, PAK4, which is activated by PLC-stimulating agents/growth factors and is important in enzyme-secretion/growth/pancreatitis. Little information exists on cAMP-activating agents stimulating group II PAKs. We studied ability/effect of cyclic AMP-stimulating agents [vasoactive intestinal polypeptide (VIP), secretin] on PAK4 activity in rat pancreatic-acini. Both VIP/secretin activated PAK4/CREB, but the cAMP signaling cascades differed for EPAC, MAPK, and PKA pathways. Both hormones require PAK4 activation to stimulate sodium-potassium adenosine triphosphatase activity. This study shows PAK4 plays an important role in VIP-/secretin-stimulated pancreatic fluid secretion and suggests it plays important roles in pancreatic acinar physiological/pathophysiological responses mediated by cAMP-activating agents.
Impaired hypoxic pulmonary vasoconstriction in a mouse model of Leigh syndrome
Authors: Schleifer Grigorij , Marutani Eizo , Ferrari Michele , Sharma Rohit , Skinner Owen , Goldberger Olga , Grange Robert Matthew Henry , Peneyra Kathryn , Malhotra Rajeev , Wepler Martin , Ichinose Fumito , Bloch Donald B. , Mootha Vamsi K. , Zapol Warren M.
Published: December 2018

Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 ( Ndufs4−/−) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4−/− mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen during LMBO was lower in Ndufs4−/− and in piericidin A-treated Ndufs4+/+ mice than in respective controls. Impairment of HPV in Ndufs4−/− mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4-deficient mice, 3 wk of breathing 11% O2 restored HPV in response to LMBO. When compared with Ndufs4−/− mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV.