bluuebunny/crossref_metadata_2025 huggingface dataset:
Capitalization of In‐Process Research and Development under SFAS 141R and Information Asymmetry
Authors: Chung Hyeesoo (Sally) H. , Hillegeist Stephen A. , Park You‐Il (Chris) , Wynn Jinyoung P.
Published: May 2019

This study examines the effect of capitalizing acquired in‐process research and development (IPR&D) on information asymmetry under Statement of Financial Accounting Standards No. 141 (R) (SFAS 141R). SFAS 141R requires acquirers to fully recognize IPR&D at fair value as an indefinite‐lived intangible asset until completion or discontinuation of the project. Prior research suggests IPR&D capitalization will result in an improvement in the information environment. In contrast, we find no evidence that capitalizing IPR&D improved the information environment for IPR&D acquirers. Instead, most of our results suggest no significant change in information asymmetry for IPR&D acquirers during the post‐SFAS 141R period, relative to the concurrent changes for non‐IPR&D acquirers. In cases in which the results suggest a statistically significant increase, the economic magnitudes are relatively small. In addition, we find no evidence that IPR&D acquirers engaged in increased classification shifting between IPR&D and goodwill during the post‐SFAS 141R period, as critics of capitalization had feared.
The Benefit of Mean Auditors: The Influence of Social Interaction and the Dark Triad on Unjustified Auditor Trust
Authors: Hobson Jessen L. , Stern Matthew T. , Zimbelman Aaron F.
Published: May 2019

Regulators and researchers have expressed concerns that social interaction leads auditors to unjustifiably trust managers, constituting a lack of sufficient professional skepticism. Using both an abstract laboratory experiment and a contextually rich experiment with practicing auditors we predict and find that higher Dark Triad auditors (those with higher levels of the shared core between psychopathy, narcissism, and Machiavellianism) are relatively more resistant to lapses in professional skepticism due to the effects of social interaction. This is likely driven by higher Dark Triad auditors' callousness, lack of empathy, and lack of response to social stimuli. In contrast, while higher social interaction initially increases lower Dark Triad auditors' unjustified trust in managers, this effect reverses in subsequent interactions when lower Dark Triad auditors observe evidence suggesting managers have reported aggressively. These findings add to research on the effect of auditor personality traits, audit‐client social interaction, and the interaction of these two variables, and suggest that practitioners and researchers account for the interplay of Dark Triad traits and social interaction and their effect on professional skepticism.
What makes a species a priority for nature conservation?
Authors: Habel J. C. , Gossner M. M. , Schmitt T.
Published: May 2019

Prioritizing species for nature conservation should follow objective ecologically and biogeographically meaningful selection criteria. In this study, we test an approach to prioritize butterfly species for nature conservation considering the following parameters: (1) geographical distribution and endemicity, (2) vulnerability and (3) ecological specialization. Following these criteria, we identified 51 species of conservation priority out of the 403 European species assessed, that is 12.7%. This list of species and those included in the annexes II and IV of the Habitats Directive (92/43/EEC) had only four species in common. The species selected by both approaches differed significantly in their traits considering their distribution and ecological specialization with the annexes of the EU Habitats Directive including many species that are neither range‐restricted nor have their core distribution within Europe, and furthermore many not threatened ecological generalists. Our results suggest that species prioritization for nature conservation should follow objective criteria, such as distribution and ecological specialization.
Modulation of CRTh2 expression on allergen‐specific T cells following peptide immunotherapy
Authors: Rudulier Christopher D. , Tonti Elena , James Eddie , Kwok William W. , Larché Mark
Published: May 2019

Background

Allergen immunotherapy using synthetic peptide T‐cell epitopes (Cat‐PAD) from the major cat allergen Fel d 1 has been shown, in allergen exposure studies, to significantly reduce symptoms of allergic rhinoconjunctivitis in cat‐allergic subjects. However, the immunological mechanisms underlying clinical benefit remain only partially understood. Since previous studies of whole allergen immunotherapy demonstrated a reduction in the frequency of allergen‐specific (MHC II tetramer+) CD4+ T cells expressing the chemokine receptor CRTh2, we assessed the impact of Cat‐PAD on the frequency and functional phenotype of Fel d 1‐specific CD4+ T cells.

Methods

Using before and after treatment samples from subjects enrolled in a randomized, double‐blind, placebo‐controlled trial of Cat‐PAD, we employed Fel d 1 MHC II tetramers and flow cytometry to analyze the expression of chemokine receptors CCR3, CCR4, CCR5, CXCR3, and CRTh2, together with markers of memory phenotype (CD27 and CCR7) on Fel d 1‐specific CD4+ T cells.

Results

No statistically significant change in the frequency of Fel d 1‐specific CD4+ T cells, nor in their expression of chemokine receptors or memory phenotype, was observed. However, a significant reduction in cell surface expression of CRTh2 was observed between the placebo and active groups (P = 0.047).

Conclusions

Peptide immunotherapy with Cat‐PAD does not significantly alter the frequency or phenotype of Fel d 1‐CD4+ T cells, but may decrease their expression of CRTh2.
Propofol use in children with allergies to egg, peanut, soybean or other legumes
Authors: Sommerfield D. L. , Lucas M. , Schilling A. , Drake‐Brockman T. F. E. , Sommerfield A. , Arnold A. , von Ungern‐Sternberg B. S.
Published: May 2019

Propofol is the most commonly administered intravenous agent for anaesthesia in children. However, there are concerns that the emulsified preparation may not be safe in children with an allergy to egg, peanut, soybean or other legumes. We conducted a retrospective study of children with immunologically confirmed egg, peanut, soybean or legume allergy and who underwent general anaesthesia at Princess Margaret Hospital for Children between 2005 and 2015. We extracted details regarding allergy diagnosis, each anaesthetic administered and any adverse events or signs of an allergic reaction in the peri‐operative period. A convenience sample of patients without any known food allergies was identified from our prospective anaesthesia research database and acted as a control group. We identified 304 food‐allergic children and 649 procedures where propofol was administered. Of these, 201 (66%) had an egg allergy, 226 (74%) had a peanut allergy, 28 (9%) had a soybean allergy and 12 (4%) had a legume allergy. These were compared with 892 allergy‐free patients who were exposed to propofol. In 10 (3%) allergy patients and 124 (14%) allergy‐free patients, criteria for a possible allergic reaction were met. In nine of the food‐allergic children and in all the controls valid non‐allergic explanations for the clinical symptoms were found. One likely mild allergic reaction was experienced by a child with a previous history of intralipid allergy. We conclude that genuine serious allergic reaction to propofol is rare and is not reliably predicted by a history of food allergy.
One‐third of school‐aged children with cerebral palsy have neuropsychiatric impairments in a population‐based study
Authors: Påhlman Magnus , Gillberg Christopher , Himmelmann Kate
Published: May 2019

Aim

To describe motor function and associated impairments, particularly autism spectrum disorder (ASD) and attention‐deficit/hyperactivity disorder (ADHD), in school‐aged children with cerebral palsy (CP).

Methods

Population‐based study of all children with CP born 1999–2006 from the county of Västra Götaland, Sweden; 264 children (141 males, 123 females). Information was obtained from the CP Register of western Sweden (data collected at 4–8 years of age) and all medical records at 10–17 years of age.

Results

Cerebral palsy was spastic in 76%, dyskinetic in 17% and ataxic in 7% of all children. Sixty‐three per cent were independent walkers. Associated impairments were present in 75%. Vision was impaired in 19%, hearing in 8% and speech in 54%. Intellectual disability (ID) was present in 53% and epilepsy in 41%. ID had increased from 42% to 53% since preschool‐age. Neuropsychiatric impairments were present in 32% of the children; ASD in 18%; and ADHD in 21%. All impairments, except for ASD and ADHD, increased with more severe motor impairment.

Conclusion

Three in four school‐aged children with CP have associated impairments, underscoring the need to broadly assess every child. The high rate of ASD and ADHD points to the importance of in‐depth studies of such impairments in CP.
A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury
Authors: Hoff Uwe , Bubalo Gordana , Fechner Mandy , Blum Maximilian , Zhu Ye , Pohlmann Andreas , Hentschel Jan , Arakelyan Karen , Seeliger Erdmann , Flemming Bert , Gürgen Dennis , Rothe Michael , Niendorf Thoralf , Manthati Vijaya L. , Falck John R. , Haase Michael , Schunck Wolf‐Hagen , Dragun Duska
Published: May 2019

Aim

Imbalances in cytochrome P450 (CYP)‐dependent eicosanoid formation may play a central role in ischemic acute kidney injury (AKI). We reported previously that inhibition of 20‐hydroxyeicosatetraenoic acid (20‐HETE) action ameliorated ischemia/reperfusion (I/R)‐induced AKI in rats. Now we tested the hypothesis that enhancement of epoxyeicosatrienoic acid (EET) actions may counteract the detrimental effects of 20‐HETE and prevent the initiation of AKI.

Methods

Male Lewis rats underwent right nephrectomy and ischemia was induced by 45 min clamping of the left renal pedicle followed by up to 48 h of reperfusion. Circulating CYP‐eicosanoid profiles were compared in patients who underwent cardiac surgery with (n = 21) and without (n = 38) developing postoperative AKI.

Results

Ischemia induced an about eightfold increase of renal 20‐HETE levels, whereas free EETs were not accumulated. To compensate for this imbalance, a synthetic 14,15‐EET analogue was administered by intrarenal infusion before ischemia. The EET analogue improved renal reoxygenation as monitored by in vivo parametric MRI during the initial 2 h reperfusion phase. The EET analogue improved PI3K‐ as well as mTORC2‐dependent rephosphorylation of Akt, induced inactivation of GSK‐3β, reduced the development of tubular apoptosis and attenuated inflammatory cell infiltration. The EET analogue also significantly alleviated the I/R‐induced drop in creatinine clearance. Patients developing postoperative AKI featured increased preoperative 20‐HETE and 8,9‐EET levels.

Conclusions

Pharmacological interventions targeting the CYP‐eicosanoid pathway could offer promising new options for AKI prevention. Individual differences in CYP‐eicosanoid formation may contribute to the risk of developing AKI in clinical settings.
Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype‐guided doses in renal transplantation patients
Authors: Anutrakulchai Sirirat , Pongskul Cholatip , Kritmetapak Kittrawee , Limwattananon Chulaporn , Vannaprasaht Suda
Published: May 2019

Aims

Although cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype‐guided tacrolimus doses.

Methods

This randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype‐guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations.

Results

The genotype‐guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P = .048). A lower proportion of over‐therapeutic concentration patients was noted in the genotype‐guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype‐guided group (41.9 vs 22.2%, P = .018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37‐month follow‐up period.

Conclusions

Determination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses.
Comparison of pharmacokinetics and the exposure–response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus
Authors: Busse David , Tang Weifeng , Scheerer Markus , Danne Thomas , Biester Torben , Sokolov Viktor , Boulton David , Parkinson Joanna
Published: May 2019

Aims

To quantitatively compare pharmacokinetics (PK) and the exposure–response (ER) relationship of the sodium‐glucose cotransporter‐2 inhibitor, dapagliflozin, between adolescents/young adults and adults with type 1 diabetes mellitus (T1DM).

Methods

Data from 2 clinical studies for dapagliflozin were analysed using a non‐linear mixed‐effects approach. The PK and the relationship between dapagliflozin exposure and response (24‐hour urinary glucose excretion) were characterized. PK was evaluated using a 2‐compartment model with first‐order absorption while the exposure response‐relationship was analysed using a sigmoidal maximal‐effect model. The 24‐hour median blood glucose, estimated glomerular filtration rate (eGFR), sex, age and body weight were evaluated as covariates.

Results

A 2‐compartment model with first order absorption provided a reasonable fit to the dapagliflozin PK data. Body weight was found to be a significant covariate on dapagliflozin exposure. The ER relationship was best described by a sigmoidal maximal effect model with 24‐hour median blood glucose and eGFR as significant covariates on maximal effect. In accordance with the observed data, model‐predicted urinary glucose excretion response following 10 mg dapagliflozin dose was higher in the study in adolescents/young adults (138.0 g/24 h) compared to adults (70.5 g/24 h) with T1DM. This is linked to higher eGFR and 24‐hour median blood glucose in this trial.

Conclusions

Dapagliflozin PK and ER relationship were similar in the 2 analysed studies after accounting for covariate effects. These results suggest that no dose adjustment is required for adolescent patients with T1DM.
Pharmacotherapies for co‐occurring substance use and bipolar disorders: A systematic review
Authors: Coles Alexandria S. , Sasiadek Julia , George Tony P.
Published: May 2019

Objectives

Substance use disorders (SUDs), including those for alcohol, stimulants, tobacco, opioids and cannabis, in patients with bipolar disorder are a major clinical and public health problem, and are present in the majority of these patients. Nonetheless, the development of effective pharmacological treatments for co‐occurring SUDs in bipolar illness have not been well‐developed and may be an important practical reason for the reduced effectiveness of these medications in community practice.

Methods

We conducted a systematic review of the literature (PubMed, Medline, Google Scholar), and identified N = 29 clinical studies, which evaluated both mental health and SUD outcomes in patients with co‐occurring bipolar disorders and SUDs.

Results

Our findings suggest the potential of valproate sodium and lamotrigine as preferred pharmacological agents for the treatment of co‐occurring psychiatric and substance use outcomes in these patients. However, many of the reviewed studies are of open‐label designs and of modest sample sizes.

Conclusions

Thus, given the gaps in our knowledge, recommendations for treatment of this common and important co‐morbidity are preliminary. Accordingly, the conduct of larger, randomized controlled trials for this co‐morbidity is clearly needed.
Health‐related quality of life around the time of diagnosis in patients with bladder cancer
Authors: Yu Evan Yi‐Wen , Nekeman Duncan , Billingham Lucinda J. , James Nicholas D. , Cheng KK , Bryan Richard T. , Wesselius Anke , Zeegers Maurice P.
Published: May 2019

Objectives

To quantify the health‐related quality of life (HRQoL) of patients with bladder cancer around the time of diagnosis and to test the hypotheses of a two‐factor model for the HRQoL questionnaire QLQ‐C30.

Methods

From participants in the Bladder Cancer Prognoses Programme, a multicentre cohort study, sociodemographic data were collected using semi‐structured face‐to‐face interviews. Answers to the QLQ‐C30 were transformed into a scale from 0 to 100. HRQoL data were analysed in multivariate analyses. The hypothesized two‐factor (Physical and Mental Health) domain structure of the QLQ‐C30 was also tested with confirmatory factor analyses (CFA).

Results

A total of 1160 participants (78%) completed the questionnaire after initial visual diagnosis and before pathological confirmation. Despite non‐muscle‐invasive bladder cancer (NMIBC) being associated with a higher HRQoL than carcinoma invading bladder muscle, only the domain Role Functioning was clinically significantly better in patients with NMIBC. Age, gender, bladder cancer stage and comorbidity all had a significant influence on QLQ‐C30 scores. The CFA showed an overall good fit of the hypothesized two‐factor model.

Conclusion

This study identified a baseline reference value for HRQoL for patients with bladder cancer, which allows better evaluation of any changes in HRQoL as disease progresses or after treatment. In addition, a two‐factor (Physical and Mental Health) model was developed for the QLQ‐C30.
New‐onset metabolic risk factors and the incidence of kidney stones: a prospective cohort study
Authors: Ping Hao , Lu Na , Wang Mingshuai , Lu Jiapeng , Liu Yuexin , Qiao Ludong , Wang Yun , Jiang Lixin , Zhang Xiaodong
Published: May 2019

Objective

To examine the association of kidney stones with new‐onset hypertension, diabetes and obesity.

Participants and Methods

This prospective cohort study included participants in the Qingdao Port Cardiovascular Health Study who were aged ≥18 years and had abdominal ultrasonography results in 2013 that were negative for kidney stones. Multivariable Cox regression models with time‐dependent covariates were used to estimate the effects of new‐onset hypertension, diabetes and obesity on the incidence of kidney stones.

Results

There were 9667 participants without kidney stones in 2013 (mean age 46.2 years; 75.6% men). During a mean (range) follow‐up of 33.5 (6–42) months, 676 (7.0%) incident cases of kidney stones were identified. Kidney stones were more frequent among those who had new‐onset of a metabolic factor vs those who did not (hypertension: 7.7 vs 6.0%; diabetes: 8.4 vs 6.6%; obesity: 7.4 vs 6.8%). Adjusted Cox models identified that increased risk of kidney stones was associated with new‐onset hypertension (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.25–2.27), new‐onset diabetes (HR 1.78, 95% CI 1.07–2.96), and new‐onset obesity (HR 1.78, 95% CI 1.15–2.74).

Conclusions

New‐onset of hypertension, diabetes and obesity were all strongly associated with an increased risk of kidney stones in this prospective cohort study. Results suggest that a substantial proportion of kidney stones are potentially preventable by appropriate control of these metabolic risk factors.
Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions
Authors: Desai Radha , Campanella Michelangelo
Published: May 2019

The pharmacological targeting of cholesterol levels continues to generate interest due to the undoubted success of therapeutic agents, such as statins, in extending life expectancy by modifying the prognosis of diseases associated with the impairment of lipid metabolism. Advances in our understanding of mitochondrial dysfunction in chronic age‐related diseases of the brain have disclosed an emerging role for mitochondrial cholesterol in their pathophysiology, thus delineating an opportunity to provide mechanistic insights and explore strategies of intervention. This review draws attention to novel signalling mechanisms in conditions linked with impaired metabolism associated with impaired handling of cholesterol and its oxidized forms (oxysterols) by mitochondria. By emphasizing the role of mitochondrial cholesterol in neurological diseases, we here call for novel approaches and new means of assessment.

Linked Articles

This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc
Spermidine‐enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway
Authors: Yan Jing , Yan Jian‐Yun , Wang Yu‐Xi , Ling Yuan‐Na , Song Xu‐Dong , Wang Si‐Yi , Liu Hai‐Qiong , Liu Qi‐Cai , Zhang Ya , Yang Ping‐Zhen , Wang Xian‐Bao , Chen Ai‐Hua
Published: May 2019

Background and Purpose

Spermidine, a natural polyamine, is abundant in mammalian cells and is involved in cell growth, proliferation, and regeneration. Recently, oral spermidine supplements were cardioprotective in age‐related cardiac dysfunction, through enhancing autophagic flux. However, the effect of spermidine on myocardial injury and cardiac dysfunction following myocardial infarction (MI) remains unknown.

Experimental Approach

We determined the effects of spermidine in a model of MI, Sprague–Dawley rats with permanent ligation of the left anterior descending artery, and in cultured neonatal rat cardiomyocytes (NRCs) exposed to angiotensin II (Ang II). Cardiac function in vivo was assessed with echocardiography. In vivo and in vitro studies used histological and immunohistochemical techniques, along with western blots.

Key Results

Spermidine improved cardiomyocyte viability and decreased cell necrosis in NRCs treated with angiotensin II. In rats post‐MI, spermidine reduced infarct size, improved cardiac function, and attenuated myocardial hypertrophy. Spermidine also suppressed the oxidative damage and inflammatory cytokines induced by MI. Moreover, spermidine enhanced autophagic flux and decreased apoptosis both in vitro and in vivo. The protective effects of spermidine on cardiomyocyte apoptosis and cardiac dysfunction were abolished by the autophagy inhibitor chloroquine, indicating that spermidine exerted cardioprotective effects at least partly through promoting autophagic flux, by activating the AMPK/mTOR signalling pathway.

Conclusions and Implications

Our findings suggest that spermidine improved MI‐induced cardiac dysfunction by promoting AMPK/mTOR‐mediated autophagic flux.
Second M3 muscarinic receptor binding site contributes to bronchoprotection by tiotropium
Authors: Kistemaker Loes E.M. , Elzinga Carolina R.S. , Tautermann Christofer S. , Pieper Michael P. , Seeliger Daniel , Alikhil Suraya , Schmidt Martina , Meurs Herman , Gosens Reinoud
Published: May 2019

Background and Purpose

The bronchodilator tiotropium binds not only to its main binding site on the M3 muscarinic receptor but also to an allosteric site. Here, we have investigated the functional relevance of this allosteric binding and the potential contribution of this behaviour to interactions with long‐acting β‐adrenoceptor agonists, as combination therapy with anticholinergic agents and β‐adrenoceptor agonists improves lung function in chronic obstructive pulmonary disease.

Experimental Approach

ACh, tiotropium, and atropine binding to M3 receptors were modelled using molecular dynamics simulations. Contractions of bovine and human tracheal smooth muscle strips were studied.

Key Results

Molecular dynamics simulation revealed extracellular vestibule binding of tiotropium, and not atropine, to M3 receptors as a secondary low affinity binding site, preventing ACh entry into the orthosteric binding pocket. This resulted in a low (allosteric binding) and high (orthosteric binding) functional affinity of tiotropium in protecting against methacholine‐induced contractions of airway smooth muscle, which was not observed for atropine and glycopyrrolate. Moreover, antagonism by tiotropium was insurmountable in nature. This behaviour facilitated functional interactions of tiotropium with the β‐agonist olodaterol, which synergistically enhanced bronchoprotective effects of tiotropium. This was not seen for glycopyrrolate and olodaterol or indacaterol but was mimicked by the interaction of tiotropium and forskolin, indicating no direct β‐adrenoceptor–M3 receptor crosstalk in this effect.

Conclusions and Implications

We propose that tiotropium has two binding sites at the M3 receptor that prevent ACh action, which, together with slow dissociation kinetics, may contribute to insurmountable antagonism and enhanced functional interactions with β‐adrenoceptor agonists.
Growth hormone treatment and health‐related quality of life in children and adolescents: A national, prospective, one‐year controlled study
Authors: Butler Gary , Turlejski Tymoteusz , Wales Gillian , Bailey Linda , Wright Neil
Published: May 2019

Background

Health‐related quality of life (HRQOL) may improve as an additional benefit of the growth hormone treatment (GHT) in children with short stature, but this effect has not been conclusively proven.

Objectives

To explore the direct effect of GHT on HRQOL in children starting GHT due to isolated or multiple GH deficiency (IGHD), acquired GH deficiency (AGHD) and Turner syndrome (TS), in comparison with untreated short stature controls in 18 UK centres.

Methods

We used recognized measures of HRQOL, the PedsQL, the Strengths and Difficulties Questionnaire and Youth Life Optimism Test scales to investigate the effect of GHT at 0, 6 and 12 months in children and adolescents 6‐16 years with IGHD (n = 73) and AGHD (n = 45), and 22 girls with TS. 49 children with non‐GHD short stature served as the controls.

Results

Children rated their HRQOL better than their parents. Those with IGHD and TS rated their overall HRQOL lower than the controls at baseline, psychosocial scores significantly lower in IGHD. After 12 months, the control and TS groups scored higher than UK norms. Those with AGHD had lowest HRQOL scores at all time points, due to poorer physical functioning. The controls showed the greatest improvement in the strength and difficulties scale. All measures evaluated, whether from child, parent or teacher showed an equal improvement over the year of GHT with no discernible direct treatment effect, despite reduced numbers in some patient groups.

Conclusions

Children with short stature resulting from GHD have lower functioning than controls but HRQOL appears to improve with GHT, most likely on account of greater attention and as a result of the retest phenomenon. We were not able to demonstrate an absolute and independent effect of GHT in itself. HRQOL should not be used as a primary measure, as in adults, to determine whether children should receive GHT.
Biofilm formation on dental implants with different surface micro‐topography: An in vitro study
Authors: Bermejo Patricia , Sánchez María Carmen , Llama‐Palacios Arancha , Figuero Elena , Herrera David , Sanz Alonso Mariano
Published: May 2019

Objectives

To compare biofilm formation on whole dental titanium implants with different surface micro‐topography.

Methods

A multispecies in vitro biofilm model consisting of initial (Streptococcus oralis and Actinomyces naeslundii), early (Veillonella parvula), secondary (Fusobacterium nucleatum) and late colonizers (Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans) was grown for 96 hr on sterile titanium dental implants with either minimal (Sa: 0.5–1.0 mm) or moderate‐roughness titanium surfaces (Sa: 1.1–2.0 mm). The resulting biofilms were studied with Confocal Laser Scanning Microscopy (CLSM) and Scanning Electron Microscope. Concentrations (colony‐forming units per mL [CFU/ml]) of each bacterium were measured by quantitative Polymerase Chain Reaction (qPCR) and compared by Student t tests.

Results

A biofilm, located mainly at the peak and lateral areas of the implant threads, was observed on both implant surfaces, with a greater biomass and a greater live/dead ratio in moderate‐ compared to minimal‐roughness surface implants. Statistically significant higher values of total bacteria (mean difference = 2.61 × 107 CFU/ml; 95% confidence interval — CI [1.91 × 106; 5.02 × 107]; p = 0.036), F. Nucleatum (mean difference = 4.43 × 106 CFU/ml; 95% CI [1.06 × 106; 7.80 × 106]; p = 0.013) and A. actinomycetemcomitans (mean difference = 2.55 × 107 CFU/ml; 95% CI [1.07 × 107; 4.04 × 107]; p = 0.002), were found in the moderate‐ compared to minimal‐roughness surface dental implants.

Conclusions

Implants with moderate‐roughness surfaces accumulated more bacterial biomass and significant higher number of pathogenic bacteria (F. nucleatum and A. actinomycetemcomitans), when compared to implants with minimal‐roughness surfaces, within a similar biofilm structure.
Prognostic value of fluorodeoxyglucose positron emission tomography/computed tomography and inguinal sentinel lymph node biopsy in patients with anal cancer
Authors: De Nardi P. , Guarneri G. , Canevari C. , Tamburini A. , Slim N. , Passoni P. , Rosati R.
Published: May 2019

Aim

The aim of this study was to assess the value of positron emission tomography (PET)/CT and sentinel lymph node (SLN) biopsy in staging inguinal lymph nodes in anal cancer patients and to determine if the results of the two methods could be of prognostic value.

Method

Sixty‐three patients with anal cancer and clinically negative inguinal lymph nodes underwent lymphoscintigraphy and inguinal SLN biopsy and/or fluorodeoxyglucose (FDG) PET/CT scan. All patients were treated with radiotherapy combined with 5‐fluorouracil and mitomycin‐C.

Results

Overall (OS) and disease‐free survival (DFS) were 43 months (range 5–211) and 43 months (range 4–142) respectively. PET/CT examination showed high FDG uptake in the inguinal lymph nodes in 25% of patients. Thirty‐five patients with inguinal uptake at lymphoscintigraphy underwent inguinal SLN biopsy and metastatic nodes were found in 31.4%. There was no statistical difference in OS (55 vs 41 months; P = 0.652) and DFS (48 vs 38 months; P = 0.992) between the group which showed inguinal uptake on PET/CT and the group which did not, while a positive inguinal SLN was associated with a worse OS (28 vs 59 months; P = 0.028) and DFS (56 vs 21 months; P = 0.046). When the two examinations were compared PET/CT showed a sensitivity, specificity, positive predictive value and negative predictive value of 22%, 82%, 33% and 73% respectively.

Conclusion

The technique of SLN biopsy had a better diagnostic accuracy than total body FDG‐PET/CT for the staging of inguinal lymph nodes in anal cancer patients; moreover it was a stronger predictor of OS and DFS than PET/CT.
Comparing statistical learning across perceptual modalities in infancy: An investigation of underlying learning mechanism(s)
Authors: Emberson Lauren L. , Misyak Jennifer B. , Schwade Jennifer A. , Christiansen Morten H. , Goldstein Michael H.
Published: May 2019

Statistical learning (SL), sensitivity to probabilistic regularities in sensory input, has been widely implicated in cognitive and perceptual development. Little is known, however, about the underlying mechanisms of SL and whether they undergo developmental change. One way to approach these questions is to compare SL across perceptual modalities. While a decade of research has compared auditory and visual SL in adults, we present the first direct comparison of visual and auditory SL in infants (8–10 months). Learning was evidenced in both perceptual modalities but with opposite directions of preference: Infants in the auditory condition displayed a novelty preference, while infants in the visual condition showed a familiarity preference. Interpreting these results within the Hunter and Ames model (1988), where familiarity preferences reflect a weaker stage of encoding than novelty preferences, we conclude that there is weaker learning in the visual modality than the auditory modality for this age. In addition, we found evidence of different developmental trajectories across modalities: Auditory SL increased while visual SL did not change for this age range. The results suggest that SL is not an abstract, amodal ability; for the types of stimuli and statistics tested, we find that auditory SL precedes the development of visual SL and is consistent with recent work comparing SL across modalities in older children.
Impact of severe diabetic kidney disease on the clinical outcome of autologous cell therapy in people with diabetes and critical limb ischaemia
Authors: Dubský M. , Jirkovská A. , Bem R. , Němcová A. , Fejfarová V. , Hazdrová J. , Sutoris K. , Chlupáč J. , Skibová J. , Jude E. B.
Published: May 2019

Aim

To assess the impact of autologous cell therapy on critical limb ischaemia in people with diabetes and diabetic kidney disease.

Methods

A total of 59 people with diabetes (type 1 or type 2) and critical limb ischaemia, persisting after standard revascularization, were treated with cell therapy in our foot clinic over 7 years; this group comprised 17 people with and 42 without severe diabetic kidney disease. The control group had the same inclusion criteria, but was treated conservatively and comprised 21 people with and 23 without severe diabetic kidney disease. Severe diabetic kidney disease was defined as chronic kidney disease stages 4–5 (GFR <30 ml/min/1.73 m²). Death and amputation‐free survival were assessed during the 18‐month follow‐up; changes in transcutaneous oxygen pressure were evaluated at 6 and 12 months after cell therapy.

Results

Transcutaneous oxygen pressure increased significantly in both groups receiving cell therapy compared to baseline (both P<0.01); no significant change in either of the control groups was observed. The cell therapy severe diabetic kidney disease group had a significantly longer amputation‐free survival time compared to the severe diabetic kidney disease control group (hazard ratio 0.36, 95% CI 0.14–0.91; P=0.042); there was no difference in the non‐severe diabetic kidney disease groups. The severe diabetic kidney disease control group had a tendency to have higher mortality (hazard ratio 2.82, 95% CI 0.81–9.80; P=0.062) than the non‐severe diabetic kidney disease control group, but there was no difference between the severe diabetic kidney disease and non‐severe diabetic kidney disease cell therapy groups.

Conclusions

The present study shows that autologous cell therapy in people with severe diabetic kidney disease significantly improved critical limb ischaemia and lengthened amputation‐free survival in comparison with conservative treatment; however, the treatment did not influence overall survival.
Value‐Added Tax, Input–Output Linkages and Informality
Authors: Hoseini Mohammad
Published: May 2019

This paper analyses the impact of adopting a value‐added tax (VAT) on the size of the informal sector across different activities. Under VAT, formal traders desire to purchase their inputs from formal suppliers for a deduction in their tax bill. I model this ‘self‐enforcement’ feature of VAT on an input–output economy and quantify it among different activities using a forward linkage index. The administration can reduce the size of the informal economy by reallocating the audits to activities with higher backward linkages and final consumption. Empirical evidence from the Indian services sector justifies the theoretical results and shows a significant increase in the tax compliance of forwardly linked activities following the VAT adoption in 2003.
Superior colliculus encodes visual saliency during smooth pursuit eye movements
Authors: White Brian J. , Itti Laurent , Munoz Douglas P.
Published: May 2019

The saliency map has played a long‐standing role in models and theories of visual attention, and it is now supported by neurobiological evidence from several cortical and subcortical brain areas. While visual saliency is computed during moments of active fixation, it is not known whether the same is true while engaged in smooth pursuit of a moving stimulus, which is very common in real‐world vision. Here, we examined extrafoveal saliency coding in the superior colliculus, a midbrain area associated with attention and gaze, during smooth pursuit eye movements. We found that SC neurons from the superficial visual layers showed a robust representation of peripheral saliency evoked by a conspicuous stimulus embedded in a wide‐field array of goal‐irrelevant stimuli. In contrast, visuomotor neurons from the intermediate saccade‐related layers showed a poor saliency representation, even though most of these neurons were visually responsive during smooth pursuit. These results confirm and extend previous findings that place the SCs in a unique role as a saliency map that monitors peripheral vision during foveation of stationary and now moving objects.
Parental mosaicism in epilepsies due to alleged de novo variants
Authors: Møller Rikke S. , Liebmann Nora , Larsen Line H. G. , Stiller Mathias , Hentschel Julia , Kako Nahrain , Abdin Dalia , Di Donato Nataliya , Pal Deb K. , Zacher Pia , Syrbe Steffen , Dahl Hans A. , Lemke Johannes R.
Published: May 2019

Severe early onset epilepsies are often caused by de novo pathogenic variants. Few studies have reported the frequency of somatic mosaicism in parents of children with severe epileptic encephalopathies. Here we aim to investigate the frequency of mosaicism in the parents of children with epilepsy caused by alleged de novo variants. We tested parental genomic DNA derived from different tissues for 75 cases using targeted next‐generation sequencing. Five parents (6.6%) showed mosaicism at minor allele frequencies of 0.8%‐29% for the pathogenic variant detected in their offspring. Parental mosaicism was observed in the following genes: SCN1A, SCN2A, SCN8A, and STXBP1. One of the identified parents had epilepsy himself. Our results show that de novo events can occur already in parental tissue and in some cases can be detected in peripheral blood. Consequently, parents affected by low‐grade mosaicism are faced with an increased recurrence risk for transmitting the pathogenic variant, compared to the overall recurrence risk for a second affected child estimated at approximately 1%. However, testing for parental somatic mosaicism will help identifying those parents who truly are at higher risk and will significantly improve genetic counseling in the respective families.
Can Cognitive‐Behavioral Therapy Be Optimized With Parent Psychoeducation? A Randomized Effectiveness Trial of Adolescents With Major Depression in Puerto Rico
Authors: Bernal Guillermo , Rivera‐Medina Carmen L. , Cumba‐Avilés Eduardo , Reyes‐Rodríguez Mae Lynn , Sáez‐Santiago Emily , Duarté‐Vélez Yovanska , Nazario Lelis , Rodríguez‐Quintana Natalie , Rosselló Jeannette
Published: May 2019

This is a longitudinal randomized control trial on the impact of adding a parent psychoeducation intervention (TEPSI) as part of cognitive‐behavioral therapy (CBT) for adolescents with Major Depressive Disorder (MDD) in a Puerto Rican sample. We tested the efficacy of adding 8 group sessions of TEPSI to 12 sessions of individual CBT on reducing depressive symptoms, MDD diagnosis, and improving family functioning. Participants (n = 121) were randomized to individual CBT with or without TEPSI. No main group effects were found for most patient domains including depression symptoms, as well as presence of adolescent's MDD diagnosis at posttreatment. Results did show a main effect of CBT over time for depression symptoms, suicide ideation, family criticism, and the presence of MDD diagnosis decreasing from pre‐ to postintervention. A year post treatment, almost 70% of adolescents in both conditions (CBT and CBT + TEPSI) remained in remission. A main effect was obtained for treatment in the adolescent's perception of familism and family emotional involvement. The primary hypothesis that family psychoeducation would optimize CBT for depression in adolescents was not supported. Both conditions yielded similar clinical end points. The culturally adapted CBT was found effective with Latino/a adolescents showing clinically significant improvements from pretreatment to posttreatment and remained stable at a 1‐year follow‐up. Regarding family outcomes, adolescents in CBT + TEPSI remained stable from pretreatment to posttreatment on family emotional involvement, while adolescents in CBT‐alone showed an increase. The implication of these findings is discussed.
The relationship between wealth and biodiversity: A test of the Luxury Effect on bird species richness in the developing world
Authors: Chamberlain Dan E. , Henry Dominic A. W. , Reynolds Chevonne , Caprio Enrico , Amar Arjun
Published: May 2019

The Luxury Effect hypothesizes a positive relationship between wealth and biodiversity within urban areas. Understanding how urban development, both in terms of socio‐economic status and the built environment, affects biodiversity can contribute to the sustainable development of cities, and may be especially important in the developing world where current growth in urban populations is most rapid. We tested the Luxury Effect by analysing bird species richness in relation to income levels, as well as human population density and urban cover, in landscapes along an urbanization gradient in South Africa. The Luxury Effect was supported in landscapes with lower urbanization levels in that species richness was positively correlated with income level where urban cover was relatively low. However, the effect was reversed in highly urbanized landscapes, where species richness was negatively associated with income level. Tree cover was also positively correlated with species richness, although it could not explain the Luxury Effect. Species richness was negatively related to urban cover, but there was no association with human population density. Our model suggests that maintaining green space in at least an equal proportion to the built environment is likely to provide a development strategy that will enhance urban biodiversity, and with it, the positive benefits that are manifest for urban dwellers. Our findings can form a key contribution to a wider strategy to expand urban settlements in a sustainable way to provide for the growing urban population in South Africa, including addressing imbalances in environmental justice across income levels and racial groups.
Microbial assemblages reflect environmental heterogeneity in alpine streams
Authors: Hotaling Scott , Foley Mary E. , Zeglin Lydia H. , Finn Debra S. , Tronstad Lusha M. , Giersch J. Joseph , Muhlfeld Clint C. , Weisrock David W.
Published: May 2019

Alpine streams are dynamic habitats harboring substantial biodiversity across small spatial extents. The diversity of alpine stream biota is largely reflective of environmental heterogeneity stemming from varying hydrological sources. Globally, alpine stream diversity is under threat as meltwater sources recede and stream conditions become increasingly homogeneous. Much attention has been devoted to macroinvertebrate diversity in alpine headwaters, yet to fully understand the breadth of climate change threats, a more thorough accounting of microbial diversity is needed. We characterized microbial diversity (specifically Bacteria and Archaea) of 13 streams in two disjunct Rocky Mountain subranges through 16S rRNA gene sequencing. Our study encompassed the spectrum of alpine stream sources (glaciers, snowfields, subterranean ice, and groundwater) and three microhabitats (ice, biofilms, and streamwater). We observed no difference in regional (γ) diversity between subranges but substantial differences in diversity among (β) stream types and microhabitats. Within‐stream (α) diversity was highest in groundwater‐fed springs, lowest in glacier‐fed streams, and positively correlated with water temperature for both streamwater and biofilm assemblages. We identified an underappreciated alpine stream type—the icy seep—that are fed by subterranean ice, exhibit cold temperatures (summer mean <2°C), moderate bed stability, and relatively high conductivity. Icy seeps will likely be important for combatting biodiversity losses as they contain similar microbial assemblages to streams fed by surface ice yet may be buffered against climate change by insulating debris cover. Our results show that the patterns of microbial diversity support an ominous trend for alpine stream biodiversity; as meltwater sources decline, stream communities will become more diverse locally, but regional diversity will be lost. Icy seeps, however, represent a source of optimism for the future of biodiversity in these imperiled ecosystems.
Efficacy and safety of ribavirin therapy for chronic hepatitis E after kidney transplantation
Authors: Yoshida Tomoaki , Takamura Masaaki , Goto Ryo , Takeuchi Suguru , Tsuchiya Atsunori , Kamimura Kenya , Tasaki Masayuki , Nakagawa Yuki , Saito Kazuhide , Tomita Yoshihiko , Terai Shuji
Published: May 2019

Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid‐organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy.

Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV‐RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.