bluuebunny/crossref_metadata_2025 huggingface dataset:
Laparoscopic‐endoscopic cooperative surgery for ileal lipoma: A case report
Authors: Nakanishi Ryota , Fukunaga Yosuke , Nagasaki Toshiya , Emoto Shin , Hirayama Kazuyoshi , Yoshioka Satoshi , Kitagawa Yusuke , Honma Satoru , Nagaoka Tomoyuki , Matsui Shimpei , Tominaga Tetsuro , Minami Hironori , Miyanari Shun , Yamaguchi Tomohiro , Akiyoshi Takashi , Konishi Tsuyoshi , Fujimoto Yoshiya , Nagayama Satoshi , Saito Shoichi , Ueno Masashi
Published: April 2019

This is the first report of laparoscopic‐endoscopic cooperative surgery (LECS) for an ileal tumor. A 50‐year‐old man was admitted to our hospital with a positive fecal occult blood test. Colonoscopy detected a submucosal tumor with intussusception located in the ileum, 10 cm oral from the Bauhin valve. On further examination, he was diagnosed with an ileal lipoma. There were no signs of malignancy. LECS was performed for the ileal tumor. After submucosal elevation by injecting saline solution, a mucosal incision was made circumferentially along the tumor. A full‐thickness incision was created endoscopically and laparoscopically on the circumferential mucosal incisional line. The tumor was withdrawn intraluminally by endoscopy. The defect of the ileal wall was closed laparoscopically in an axial direction with linear staplers. Histologically, the tumor was a 25‐mm ileal lipoma with negative resection margins and no malignancy.
Population pharmacokinetic model and Bayesian estimator for 2 tacrolimus formulations in adult liver transplant patients
Authors: Riff Camille , Debord Jean , Monchaud Caroline , Marquet Pierre , Woillard Jean‐Baptiste
Published: April 2019

Aims

Tacrolimus is a narrow therapeutic range drug that requires fine dose adjustment, for which pharmacokinetic (PK) models have been amply proposed in renal, but not in liver, transplant recipients. This study aimed to build population PK models and Bayesian estimators (BEs) in adult de novo liver transplant patients receiving either the immediate‐release (Prograf, twice daily, TD) or prolonged‐release (Advagraf, once daily, OD) forms to help PK‐guided dose individualization.

Methods

In total, 160 tacrolimus concentration–time profiles (1654 samples) were collected from 80 patients, at day 7 (D7) and week 6 (W6) post‐transplant. Four population PK models were developed using in‐parallel parametric and nonparametric approaches for each formulation and period post‐transplant. The best limited sampling strategies for estimating the area‐under‐the‐curve (AUC) were selected by comparing predicted values to an independent dataset. Finally, the doses required to reach AUC targets were estimated using each BE and compared to the doses obtained using the trapezoidal AUC.

Results

Tacrolimus PK was best described using a 1‐compartmental model with first‐order elimination and 2 γ‐distributions to describe the absorption. In the validation datasets, Bayesian AUC estimates yielded mean bias/root mean squared prediction error of −5.06%/13.43% (OD D7), 2.25%/8.51% (OD W6), −2.36%/7.27% (TD D7) and 0.87%/9.07% (TD W6) for the in‐parallel parametric approach; and 8.95%/17.84% (OD D7), −0.11%/10.13% (OD W6), 3.57%/18.40% (TD D7) and 4.48%/12.59% (TD W6) for the nonparametric approach.

Conclusion

The BEs and limited sampling strategies proposed here are able to predict accurately and precisely tacrolimus AUC in liver patients using only 3 plasma concentrations. The dosing methods are available on our ImmunoSuppressive Bayesian dose Adjustment website (www.pharmaco.chu‐limoges.fr).
Attitudes towards redistribution and the interplay between perceptions and beliefs about inequality
Authors: García‐Sánchez Efraín , Osborne Danny , Willis Guillermo B. , Rodríguez‐Bailón Rosa
Published: April 2019

Although economic inequality has increased over the last few decades, support for redistributive policies is not widely accepted by the public. In this paper, we examine whether attitudes towards redistribution are a product of both perceptions of, and beliefs about, inequality. Specifically, we argue that the association between perceived inequality and support for redistribution varies by beliefs that justify inequality. We investigated this hypothesis in a cross‐cultural/country sample (N = 56,021 from 41 countries) using two different operationalizations of support for redistribution and two distinct beliefs that justify inequality. As hypothesized, the perceived size of the income gap correlated positively with believing that it is the government's responsibility to reduce inequality among those who rejected beliefs that justify inequality, whereas there was no association for those who endorsed these beliefs. Similarly, perceived economic inequality correlated positively with support for progressive taxation, but this association was weaker among those who endorsed meritocratic and equal opportunity beliefs. Together, these results demonstrate that ideologies influence the relationship between perceived inequality and attitudes towards redistribution, and that support for redistribution varies by how the policy is framed.
The Attachment of Demonstrators to Institutional Politics: Comparing LGBTIQ Pride Marches in Argentina and Chile
Authors: SOMMA NICOLÁS M. , ROSSI FEDERICO M. , DONOSO SOFÍA
Published: April 2019

Focusing on LGBTIQ demonstrations in Argentina and Chile, we study protesters' attachment to institutional politics, defined as their emotional and attitudinal connection with the political system. We show that Argentine LGBTIQ demonstrators are on average more attached to institutional politics than Chilean ones. This can be explained neither by differences between Argentines and Chileans in general, nor by demonstrators' individual characteristics. Instead, expanding the political process model, we argue that achieving a substantial part of the LGBTIQ agenda in Argentina, and limited success in Chile, contributed to build a stronger attachment to the political system among Argentine LGBTIQ demonstrators than their Chilean counterparts.
Oncometabolites in cancer aggressiveness and tumour repopulation
Authors: Dando Ilaria , Pozza Elisa Dalla , Ambrosini Giulia , Torrens‐Mas Margalida , Butera Giovanna , Mullappilly Nidula , Pacchiana Raffaella , Palmieri Marta , Donadelli Massimo
Published: April 2019

Tumour repopulation is recognized as a crucial event in tumour relapse where therapy‐sensitive dying cancer cells influence the tumour microenvironment to sustain therapy‐resistant cancer cell growth. Recent studies highlight the role of the oncometabolites succinate, fumarate, and 2‐hydroxyglutarate in the aggressiveness of cancer cells and in the worsening of the patient's clinical outcome. These oncometabolites can be produced and secreted by cancer and/or surrounding cells, modifying the tumour microenvironment and sustaining an invasive neoplastic phenotype. In this review, we report recent findings concerning the role in cancer development of succinate, fumarate, and 2‐hydroxyglutarate and the regulation of their related enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. We propose that oncometabolites are crucially involved in tumour repopulation. The study of the mechanisms underlying the relationship between oncometabolites and tumour repopulation is fundamental for identifying efficient anti‐cancer therapeutic strategies and novel serum biomarkers in order to overcome cancer relapse.
How to manage creativity time? Results from a social psychological time model lab experiment on individual creative and routine performance
Authors: Brem Alexander , Utikal Verena
Published: April 2019

Companies have long used various approaches for organizing their employees' time for creative and routine tasks in order to improve innovative performance. In this paper, we examine how work schedule autonomy affects individuals' creative and routine performance. We then evaluate non‐commissioned time models. Results of laboratory experiments with 233 participants reveal that while average routine performance is not affected by schedule autonomy, the effect of schedule autonomy on creative performance depends on the subject's impulsiveness. There is evidence of an inverse relationship between schedule autonomy and creative performance among subjects of low impulsiveness. Hence, our results indicate that the optimal management policy depends on the manager's focus on creative or routine performance and the types of employees the manager supervises. For routine performance, the creativity time model has no significant impact.
The Canadian productivity stagnation, 2002–2014
Authors: Conesa Juan Carlos , Pujolas Pau S.
Published: April 2019

Total factor productivity (TFP) growth in Canada between 2002 and 2014 has been only 0.16% per year. This figure is substantially smaller than that of the United States, or that of Canada in the past. We perform multiple counterfactual exercises to show that this small TFP growth cannot be accounted for by several compositional effects or mismeasurements of factors of production. We identify two key sectors (mostly Mining and to a lesser extent Manufacturing) that drive all of the TFP growth difference with the United States. Despite the lack of TFP growth, Canada has experienced sustained income growth due to a prolonged period of appreciation of the terms of trade (while US terms of trade have deteriorated), making real income in the two countries grow at similar rates.
Prevalence of growth hormone (GH) deficiency in previously GH‐treated young adults with Prader‐Willi syndrome
Authors: Donze Stephany H. , Damen Layla , van Alfen‐van der Velden Janiëlle A. E. M. , Bocca Gianni , Finken Martijn J. J. , Hoorweg‐Nijman Gera J. G. , Jira Petr E. , van Leeuwen Mariëtte , Hokken‐Koelega Anita C. S.
Published: April 2019

Objective

Some features of subjects with Prader‐Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin‐like growth factor (IGF‐I) axis and the prevalence of GHD in previously GH‐treated young adults with PWS.

Design

Cross‐sectional study in 60 young adults with PWS.

Measurements

Serum IGF‐I and IGFBP‐3 levels, GH peak during combined growth hormone‐releasing hormone (GHRH)‐arginine stimulation test.

Results

Serum IGF‐I was <−2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP‐3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 μg/L (12.2; 29.7) [~53.4 mU/L] and below 9 μg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 μg/L and IGF‐I < −2 SDS), also when BMI‐dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD).

Conclusions

In a large group of previously GH‐treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 μg/L during a GHRH‐arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD.
Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases
Authors: Birtel Johannes , Gliem Martin , Oishi Akio , Müller Philipp L. , Herrmann Philipp , Holz Frank G. , Mangold Elisabeth , Knapp Michael , Bolz Hanno J. , Charbel Issa Peter
Published: April 2019

Importance

Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next‐generation sequencing may be increased by a reasonable preselection of RP‐patients.

Background

To systematically evaluate and compare features of genetically solved and unsolved RP‐patients.

Design

Retrospective, observational study.

Participants

One‐hundred and twelve consecutive RP‐patients who underwent extensive molecular genetic analysis.

Methods

Characterization of patients based on multimodal imaging and medical history.

Main Outcome Measures

Differences between genetically solved and unsolved RP‐patients.

Results

Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease‐onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years‐of‐age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing.

Conclusions and Relevance

The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP‐patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease‐causing mutations and may impact patient counselling.
A call to action to inform patient‐centred approaches to obesity management: Development of a disease‐illness model
Authors: Fastenau John , Kolotkin Ronette L. , Fujioka Ken , Alba Maria , Canovatchel William , Traina Shana
Published: April 2019

Patient‐centred care is an essential component of high‐quality health care, shown to improve clinical outcomes and patient satisfaction, and reduce costs. While there are several authoritative models of obesity pathophysiology and treatment algorithms, a truly patient‐centred model is lacking. We describe the development of a patient‐centric obesity model. A disease‐illness framework was selected because it emphasizes each patient's unique experience while capturing biomedical aspects of the disease. Model input was obtained from an accumulation of research including contributions from experts in obesity and patient‐reported outcomes, qualitative research with adults living in the United States, and two targeted literature searches. The model places the patient with obesity at its core and links pathologic imbalances of energy intake and expenditure to environmental, sociodemographic, psychological, behavioural, physiological and medical health determinants. It highlights relationships between obesity signs and symptoms, comorbid conditions, impacts on health‐related quality of life, and some barriers to obesity management that must be considered to attain better outcomes. Providers need to evaluate patients holistically, understand what changes each patient is motivated to make, and recognize what challenges might impede weight reduction, improvements in comorbid conditions, signs and symptoms, and health‐related quality of life before pursuing individualized treatment goals. Patients living with obesity who do lose weight perceive benefits beyond weight loss. Ideally, this model will increase awareness of the complex, heterogeneous impacts of obesity on patients' well‐being and recognition of obesity as a chronic disease, and prompt a call to action among stakeholders to improve quality of care.
ROUNDTABLE DISCUSSION ON IMMIGRATION
Authors: Ashenfelter Orley , McFadden Daniel L. , Payne Abigail , Potts Jason , Gregory Robert , Martin Wade E.
Published: April 2019

This article is based upon presentations at the closing session of the 14th International Conference of the Western Economic Association International (WEAI), hosted by the Newcastle Business School, University of Newcastle, Australia, January 11–14, 2018. The panellists are: Orley Ashenfelter, Daniel L. McFadden, Abigail Payne, Jason Potts, Robert Gregory, and Wade Martin. (JEL J6)
Easement or public land? An economic analysis of different ownership modes for nature conservation measures in California
Authors: Schöttker Oliver , Santos Maria João
Published: April 2019

Biodiversity conservation requires space where conservation measures are implemented for a desired purpose. Setting land aside for conservation has been widely applied, while novel conservation modes (private–public partnerships, private multipurpose land management) may be fundamental to achieve conservation goals. We perform an economic analysis of the cost development for two conservation options in California, in‐fee and easements, from 1970 to today. We find that in‐fee options have lower costs than easements in the long run. While there are high costs of purchase for in‐fee, ultimately they even‐out or generate profits. Costs of easements continue growing exponentially overtaking costs of purchase. Sensitivity analysis shows increases in purchasing prices and opportunity costs positively influencing conservation costs, while increasing interest rates negatively influence them. The results suggest that easements are not yet an economically viable alternative for in‐fee conservation purchases. Our analysis is a first step to assess economic viability of choosing easements.
Integrating spatially realistic infrastructure impacts into conservation planning to inform strategic environmental assessment
Authors: Tulloch Ayesha I.T. , Gordon Ascelin , Runge Claire A. , Rhodes Jonathan R.
Published: April 2019

Infrastructures such as roads and pipelines have environmental impacts that diffuse far beyond the local development footprint, including fragmenting habitat or changing hydrology. Broad‐scale diffuse impacts are challenging to incorporate into conservation planning and strategic environmental assessment due to difficulties in determining how impacts spread across landscapes. We built curves representing expert‐elicited magnitudes and spatial extents of direct and diffuse impacts of infrastructure on biodiversity groups, to incorporate these impacts into a spatial conservation prioritization. We demonstrate how different prioritization outputs inform different steps of the impact assessment mitigation hierarchy. In southern Australia we find the diffuse‐impact footprint to be four times higher than direct (i.e., local) infrastructure impacts, with >75,000 km2 of spatial priority areas for mitigation and >37,000 km2 of spatial priority areas for offsets potentially missed if diffuse impacts are ignored. Understanding both direct and diffuse infrastructure impacts will avoid inefficient spatial allocation of environmental mitigation, restoration, and offsetting efforts.
Spatiotemporal bycatch analysis of the Atlantic halibut (Hippoglossus hippoglossus) longline fishery survey indicates hotspots for species of conservation concern
Authors: Hurley Isabelle , Wringe Brendan F. , den Heyer Cornelia E. , Shackell Nancy L. , Lotze Heike K.
Published: April 2019

The Atlantic halibut (Hippoglossus hippoglossus) longline fishery is the second most valuable groundfish fishery in Atlantic Canada and received Marine Stewardship Council certification in 2013. The bottom longline fishery accounts for most halibut landings but incidentally catches nontargeted species (bycatch). Since 1998, Fisheries and Oceans Canada and the halibut fishing industry performed annual longline surveys across the Scotian Shelf and Southern Grand Banks stock management area to monitor halibut abundance, and at‐sea observers also recorded bycatch information. We examined the species composition and proportion of the survey bycatch and analyzed temporal and spatial trends in standardized weight of (a) halibut catch, (b) total bycatch, and (c) bycatch of species of conservation concern. From 1998 to 2016, 70% of the total catch by weight and 85% by number of individuals were bycatch. Over 100 identified species of finfish, sharks, skates, benthic invertebrates, marine mammals, and seabirds were caught as bycatch in the survey. This included four species listed under the Species at Risk Act (Northern wolffish, Anarhichas denticulatus; spotted wolffish, A. minor; Atlantic wolffish, A. lupus; Atlantic cod, Gadus morhua), and another 14 species awaiting a listing decision based on assessments by the Committee on the Status of Endangered Wildlife in Canada. Generally, the standardized weight of halibut and barndoor skate (Dipturus laevis) increased over time, while Atlantic cod, spiny dogfish (Squalus acanthias), white hake (Urophycis tenuis), and thorny skate (Amblyraja radiata) decreased. Spatial patterns indicated high bycatch levels on the southern Scotian Shelf and southern edge of the Southern Grand Banks, with hotspots for certain species of conservation concern. Our results identify temporal trends in threatened species and areas where they are susceptible to the Atlantic halibut longline fishery which can inform recovery strategies, bycatch levels and spatial zoning in fisheries management and marine conservation.
Detecting and protecting the threatened Kangaroo Island dunnart (Sminthopsis fuliginosus aitkeni)
Authors: Hohnen Rosemary , P. Murphy Brett , A. Gates Jody , Legge Sarah , R. Dickman Chris , C. Z. Woinarski John
Published: April 2019

Reliable and cost‐effective monitoring methods are a critical component of conservation management practices that work to prevent the extinction of threatened species. We evaluated the best means of monitoring the threatened Kangaroo Island dunnart (Sminthopsis fuliginosus aitkeni, hereafter KI dunnart). Variation in detection probability and cost was examined between four trapping methods. We then compared the occupancy of the KI dunnart in a 2017–2018 survey to a survey from 1999 to 2001. Across the 2017–2018 survey, the KI dunnart was detected at only five sites and was detected most frequently using camera traps on drift fence lines. The taxon was estimated to occupy 27% (95% confidence interval: 7–65%) of sites in the eucalypt woodlands of western KI. Of the methods that have successfully detected KI dunnarts, cameras on fence lines were the most cost‐effective. Power analysis suggests that future monitoring surveys in spring and autumn must survey at least 55 sites to be capable of detecting a 60% decline in the KI dunnart population, and 26 sites to detect an 80% decline. Ongoing intensive monitoring is required to assess the population trajectory of the taxon and support its persistence on the island in the long term.
Model for improved undergraduate training in translational conservation science
Authors: Kelley Patricia H. , Dietl Gregory P. , Visaggi Christy C.
Published: April 2019

The “Research Experiences for Undergraduates (REU) in Biodiversity Conservation” project models transdisciplinary training in conservation science, and particularly in the emerging field of conservation paleobiology (CPB), which applies geohistorical records (e.g., sediments, fossils) and approaches to solve conservation problems. We analyzed recent funding patterns in the National Science Foundation REU program (Biological Sciences and Geosciences directorates) and found that, at most REU sites, undergraduates conduct individual projects supervised by a mentor. In contrast, at the REU in Biodiversity Conservation Site, students from geology, biology, archaeology, and environmental sciences worked in transdisciplinary teams on conservation‐related research using fossil, archaeological, and modern samples. The project successfully incorporated CPB approaches and taught research and soft skills useful in conservation; 85% of students subsequently pursued STEM graduate study or employment. However, because translational science partnerships with conservation practitioners were not sought, the research‐implementation gap remained. We propose a new model for REU sites involving conservation practitioners and stakeholders as partners in research that includes the human dimension and meets community needs, resulting in transdisciplinary, team‐focused training that yields actionable results. We recommend that the National Science Foundation encourage researchers to think beyond typical one‐on‐one mentorship when planning an REU, especially for conservation science projects.
Neuropsychiatric profile of paediatric hypothalamic hamartoma: systematic review and case series
Authors: Corbet Burcher Georgina , Liang Holan , Lancaster Rebecca , Cross J Helen , Tisdall Martin , Varadkar Sophia , Spoudeas Helen A , Caredda Elisabetta , Bennett Sophie , Heyman Isobel
Published: April 2019

Aim

To evaluate neuropsychiatric comorbidities in children and adolescents with hypothalamic hamartoma.

Method

We retrospectively analysed case notes for all individuals with hypothalamic hamartoma referred to Great Ormond Street Hospital, London, between 2000 and 2016. In addition, a systematic review aiming to identify all previous paediatric case series was performed. Psychiatric symptoms, demographics, physical comorbidities, and cognitive functioning were recorded for all cases where possible. Analyses were performed to determine which factors were associated with psychopathology and potential mechanisms investigated.

Results

Forty‐six cases were included in the case series (28 males, 18 females; mean age at assessment 11y 8mo [1y 11mo–16y 11mo,SD4y 0mo]). Twenty‐nine papers representing data from 264 cases met inclusion criteria for the systematic review. Overall, at least 50% of cases presented with psychopathology. Epilepsy, intellectual disability, and male sex were associated with externalizing disorders (attention‐deficit/hyperactivity disorder, conduct and oppositional defiance disorders, and rage attacks). Intellectual disability mediated the effects of epilepsy on externalizing psychopathology. No factors were associated with internalizing disorders (anxiety and depressive disorders), although these were not well reported.

Interpretation

Psychiatric comorbidities are highly prevalent in the presentation of paediatric hypothalamic hamartoma. The aetiology of psychopathology comprises a range of interacting biological and psychosocial factors with particular influence from epilepsy. Further research is required to achieve an evidence base for treatment.

What this paper adds

Over half of children with hypothalamic hamartoma present with psychiatric comorbidity.

Externalizing and internalizing disorders are present in approximately 60% and 30% of children with hypothalamic hamartomas respectively.

Epilepsy and male sex are associated with externalizing psychopathology.

Intellectual disability mediates the association between epilepsy and externalizing symptoms.

No clear associations are evident for internalizing disorders or precocious puberty.
Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors and cancer: A meta‐analysis of randomized controlled trials
Authors: Dicembrini Ilaria , Nreu Besmir , Mannucci Edoardo , Monami Matteo
Published: April 2019

Aim

The aim of this meta‐analysis of randomized trials was to assess the effects of SGLT‐2i on the overall incidence of malignancies and on different types of cancer, summerizing the results of trials with a duration of at least 1 year. This was done in light of the effect of SGLT‐2 inhibitors (SGLT‐2is) that has been highlighted by some studies, showing an increased incidence of bladder cancer, particularly with use of empagliflozin.

Materials and methods

A Medline and Embase search for “Canaglifozin”, “Dapaglifozin”, “Empaglifozin”, “Ertuglifozin”, “Ipraglifozin”, Tofoglifozin” or “Luseoglifozin” was performed, identifying randomized trials with a duration of more than 52 weeks up to 1 December 2018 that compared SGLT‐2is with placebo or active comparators. The outcomes considered were all types of cancer and several site‐specific cancers (ie, breast, pulmonary, gastrointestinal, hepatic, pancreatic, skin, prostate and bladder). Mantel–Haenszel odds ratios with 95% Confidence Intervals (MH‐OR, 95% CI) were calculated for all outcomes.

Results

A total of 27 trials fulfilled the inclusion criteria. Retrieved trials had enrolled 27 744 and 20 441 patients in SGLT‐2 inhibitor and comparator groups, respectively. No difference was observed in the incidence of all malignancies between patients allocated to SGLT‐2i and comparators (MH‐OR 0.98[0.77–1.24]). The incidence of bladder cancer, and of any other type of cancer, was not significantly increased by treatment with any SGLT‐2i.

Conclusions

Available data from randomized trials do not suggest a detrimental effect of SGLT‐2is on the incidence of malignancies in general, or in bladder cancer in particular.
Early cardiovascular risk and all‐cause mortality following an incident of severe hypoglycaemia: A population‐based cohort study
Authors: Lo Shih‐Chang , Yang Yi‐Sun , Kornelius Edy , Huang Jing‐Yang , Lai Yung‐Rung , Huang Chien‐Ning , Chiou Jeng‐Yuan
Published: April 2019

Aims

Severe hypoglycaemia is associated with a high risk of cardiovascular events in patient with diabetes. The aim of this study was to clarify the temporal relationship between hypoglycaemia and cardiovascular events.

Materials and methods

This observational cohort study was conducted using Taiwan's Longitudinal Cohort of Diabetes Patients Database, which included 360 000 patients with newly diagnosed diabetes during the period 1999 to 2001. Patients with the first severe hypoglycaemia after 2002 served as the study cohort. Each patient in the study cohort was matched with two control patients without severe hypoglycaemia, based on a propensity score. A joinpoint regression model was used to determine trends in all‐cause mortality and incidence of cardiovascular disease (CVD) events in both cohorts.

Results

A total of 10 157 patients with severe hypoglycaemia and 20 314 matched controls were recruited. Patients with severe hypoglycaemia had a significantly higher risk of CVD (HR, 7.28; 95% CI, 5.19–10.20) and all‐cause mortality (HR, 19.92; 95% CI, 13.42–29.56) during the first month compared with those without. In patients with severe hypoglycaemia, the incidence of CVDs dropped by 17.29% monthly during the first 4 months and slowly decreased (−0.67%) during subsequent months. All‐cause mortality decreased by 16.55% and 3.24% monthly during months 0–6 and months 6–17, respectively.

Conclusions

Severe hypoglycaemia is associated with a greater risk of cardiovascular events and death, especially during the first month following a hypoglycaemic episode. Patients prone to severe hypoglycaemia should be made aware of the elevated risk of subsequent cardiovascular events.
More than 10 years of speckle tracking echocardiography: Still a novel technique or a definite tool for clinical practice?
Authors: Cameli Matteo , Mandoli Giulia E. , Sciaccaluga Carlotta , Mondillo Sergio
Published: April 2019

Speckle tracking echocardiography (STE) cannot be considered a recent technique anymore. Its application has gained growing importance over the last decade in several clinical settings, and the deformation analysis has fully entered in diagnostic algorithms and guidelines of various pathologies. STE allows to track the displacement of “speckles” in two‐dimensional (2D) echocardiographic images in an angle‐independent way and to assess their movement (strain) during the cardiac cycle. Its high feasibility, reproducibility, and accuracy have been widely demonstrated. In this review, we describe how STE has been applied to different aspects of the daily clinical practice, including ischemic heart diseases, heart valve disease, heart failure, and prognostication, highlighting the possible added value that strain parameters have shown over the years.
What if they take it all? Heterogeneous impact of sickness absence reform
Authors: Pertold Filip
Published: April 2019

I investigate the effect of sickness absence reform in the Czech Republic, which reduced benefits paid during the first three days of sickness absence to zero. I find a substantial decrease in the incidence of sickness absence, which is about 15 percent of the pre‐reform mean. I find that workers in occupations with high flexibility and fewer routine tasks are more likely to reduce their sickness absences.
Immunosuppressive therapy (IST) in adult patients with acquired aplastic anemia (AA): A single‐center experience over the past 15 years
Authors: Alashkar Ferras , Oelmüller Maren , Herich‐Terhürne Dörte , Turki Amin T. , Schmitz Christine , Vance Colin , Dührsen Ulrich , Röth Alexander
Published: April 2019

Objective

Immunosuppressive therapy (IST) with horse anti‐thymocyte globulin (hATG) and cyclosporine (CsA) is considered one of the first‐line therapies in patients (pts) with acquired aplastic anemia (AA).

Methods

In our single‐center, retrospective analysis response rates (RRs) to ATG/CsA at a minimum of 6 mo were evaluated in 67 treatment‐naïve (TN) AA pts (52.2% (35/67) females; median age 45 y (range 18‐89 y)) being treated at the West German Cancer Center at the Department of Hematology at the University Hospital of Essen between April 2000 and December 2015.

Results

Overall 6 mo RRs in TN pts following ATG/CsA were 67.2% (45/67) (5‐year OS: 79.5%). In TN hATG‐treated pts 6 mo RRs were 75.5% (37/49) (5‐year OS: 81%) compared to 44.4% (8/18) (5‐year OS 73.5%) following rabbit ATG (rATG). Response to ATG/CsA was dependent of age, absolute reticulocyte count (ARC), and disease severity. Six mo RRs to salvage ATG/CsA in relapsed/refractory (R/R) pts were 37.5% (6/16).

Conclusion

Our data independently confirm the findings of previous studies that hATG/CsA is superior to rATG/CsA in TN pts. The lack of hATG availability should not result in abstaining it from an indicated ATG therapy, even though ATGAM® is not registered in Germany.
Genomic data provide new insights on the demographic history and the extent of recent material transfers in Norway spruce
Authors: Chen Jun , Li Lili , Milesi Pascal , Jansson Gunnar , Berlin Mats , Karlsson Bo , Aleksic Jelena , Vendramin Giovanni G. , Lascoux Martin
Published: April 2019

Primeval forests are today exceedingly rare in Europe, and transfer of forest reproductive material for afforestation and improvement has been very common, especially over the last two centuries. This can be a serious impediment when inferring past population movements in response to past climate changes such as the last glacial maximum (LGM), some 18,000 years ago. In the present study, we genotyped 1,672 individuals from three Picea species (P. abies, P. obovata, and P. omorika) at 400K SNPs using exome capture to infer the past demographic history of Norway spruce (P. abies) and estimate the amount of recent introduction used to establish the Norway spruce breeding program in southern Sweden. Most of these trees belong to P. abies and originate from the base populations of the Swedish breeding program. Others originate from populations across the natural ranges of the three species. Of the 1,499 individuals stemming from the breeding program, a large proportion corresponds to recent introductions from mainland Europe. The split of P. omorika occurred 23 million years ago (mya), while the divergence between P. obovata and P. abies began 17.6 mya. Demographic inferences retrieved the same main clusters within P. abies than previous studies, that is, a vast northern domain ranging from Norway to central Russia, where the species is progressively replaced by Siberian spruce (P. obovata) and two smaller domains, an Alpine domain and a Carpathian one, but also revealed further subdivision and gene flow among clusters. The three main domains divergence was ancient (15 mya), and all three went through a bottleneck corresponding to the LGM. Approximately 17% of P. abies Nordic domain migrated from P. obovata ~103K years ago, when both species had much larger effective population sizes. Our analysis of genomewide polymorphism data thus revealed the complex demographic history of Picea genus in Western Europe and highlighted the importance of material transfer in Swedish breeding program.
Salicylic acid treats acne vulgaris by suppressing AMPK/SREBP1 pathway in sebocytes
Authors: Lu Jin , Cong Tianxin , Wen Xiang , Li Xiaoxue , Du Dan , He Gu , Jiang Xian
Published: April 2019

Acne vulgaris is a prevalent cutaneous disease characterized by a multifactorial pathogenic process including hyperseborrhea, inflammation, over‐keratinization of follicular keratinocytes and Propionibacterium acnes (P acnes) overgrowth. Salicylic acid (SA), a beta‐hydroxy acid, is frequently used in the treatment of acne. SA has been found to decrease skin lipids and to possess anti‐inflammatory properties. However, few studies have elucidated the mechanisms and pathways involved in such treatment of acne. In this study, we initially investigated the anti‐acne properties of SA in human SEB‐1 sebocytes. Treatment with SA decreased sebocyte lipogenesis by downregulating the adenosine monophosphate‐activated protein kinase (AMPK)/sterol response element‐binding protein‐1 (SREBP‐1) pathway and reduced inflammation by suppressing the NF‐κB pathway in these cells. Salicylic acid also decreased the cell viability of SEB‐1 by increasing apoptosis via the death signal receptor pathway. Subsequently, histopathological analysis of a rabbit ear acne model after application of SA for three weeks confirmed that SA suppressed the levels of cytokines and major pathogenic proteins around acne lesions, which supports the mechanisms suggested by our in vitro experiments. These results initially clarified that therapeutic activities of SA in acne vulgaris treatment could be associated with the regulation of SREBP‐1 pathway and NF‐κB pathway in human SEB‐1 sebocytes.
Characterizing lysine acetylation of Escherichia coli type II citrate synthase
Authors: Venkat Sumana , Chen Hao , McGuire Paige , Stahman Alleigh , Gan Qinglei , Fan Chenguang
Published: April 2019

The citrate synthase (CS) catalyzes the first reaction of the tricarboxylic acid cycle, playing an important role in central metabolism. The acetylation of lysine residues in the Escherichia coli Type II CS has been identified at multiple sites by proteomic studies, but their effects remain unknown. In this study, we applied the genetic code expansion strategy to generate 10 site‐specifically acetylated CS variants which have been identified in nature. Enzyme assays and kinetic analyses showed that lysine acetylation could decrease the overall CS enzyme activity, largely due to the acetylation of K295 which impaired the binding of acetyl‐coenzyme A. Further genetic studies as well as in vitro acetylation and deacetylation assays were performed to explore the acetylation and deacetylation processes of the CS, which indicated that the CS could be acetylated by acetyl‐phosphate chemically, and be deacetylated by the CobB deacetylase.
Airports and cities in the context of globalisation: A multidimensional symbiosis in Adolfo Suárez‐Madrid Barajas Airport
Authors: Díez‐Pisonero Roberto
Published: April 2019

The interpretation of airports as places where landings and take‐offs occur is obsolete. Globalisation, the “mobility era” and a so‐called “culture‐cognitive capitalism,” favour the reconceptualisation of airports and may turn them into necessary infrastructures for every city that aspires to be “global.” An airport–city symbiosis is analysed and is defined from a multidimensional perspective (operative, economic, and symbolic). These perspectives have led to important works of expansion and renovation of airport facilities and a multiplication of the services that may be developed within them. The results show this multidimensional symbiosis in general, although it is analysed in detail for the Spanish case study of the Adolfo Suarez‐Madrid Barajas Airport, which is the main air gateway of Spain to the rest of the world and the most important European hub connecting Latin America with Europe. Its global exposure is reflected in its ability to stimulate the economic and residential development of its surroundings and to strengthen the modern image of Madrid, thanks to morphological changes and increases in non‐aeronautical uses, which are viewed as city marketing initiatives that help to promote Madrid in the world urban hierarchy.
Grazing intensity affects forage accumulation and persistence of Marandu palisadegrass in the Brazilian savannah
Authors: Euclides Valéria P. B. , Montagner Denise B. , Macedo Manuel Cláudio M. , de Araújo Alexandre R. , Difante Gelson S. , Barbosa Rodrigo A.
Published: April 2019

This 3‐year study evaluated the effects of grazing intensity on herbage and steer responses in continuously stocked Brachiaria brizantha cv. Marandu pasture in the Brazilian savanna. Treatments consisted of three grazing intensity levels, characterized by canopy heights of 15, 30 and 45 cm, measured twice per week. Responses variables included tiller population density (TPD), herbage accumulation rate (HAR) and body weight gain per area (WGA). A decline in TPD (1,237 vs. 767 tillers/m2) was observed from the first to the third grazing years, which influenced the HAR from the first to the third years (90.1 vs. 52.4 kg ha−1 day−1). A marked decline in body WGA (541 vs. 276 kg ha−1 year−1) was observed along the three years in pastures managed at a height of 15 cm, indicating that this is an unstable condition for Marandu palisadegrass pasture. HAR was similar for pastures managed at 30 or 45 cm and was relatively stable during the experimental period, averaging 91.8 and 99.1 kg ha−1 day−1 respectively. Body WGA was similar and constant throughout the experimental period for pastures managed at 30 (596 kg ha−1 year−1) and 45 cm (566 kg ha−1 year−1). Maintaining continuously stocked Marandu palisadegrass pastures at a 15 cm canopy height should be avoided due to long‐term decreases in plant persistence and animal body WGA, particularly when soil P is below critical levels at pasture establishment and during pasture utilization.
Safety and Tolerability of Fremanezumab for the Prevention of Migraine: A Pooled Analysis of Phases 2b and 3 Clinical Trials
Authors: Silberstein Stephen D. , McAllister Peter , Ning Xiaoping , Faulhaber Nicola , Lang Nicole , Yeung Paul , Schiemann Jimmy , Aycardi Ernesto , Cohen Joshua M. , Janka Lindsay , Yang Ronghua
Published: April 2019

Objective

Presentation of pooled analysis of safety data for fremanezumab in patients with chronic (CM) or episodic migraine (EM) from 4 placebo‐controlled phase 2b and phase 3 studies.

Background

There is a need for an effective, safe, and well‐tolerated preventive therapy that specifically targets the pathophysiology of migraine to reduce the frequency and severity of migraine attacks in patients with CM or EM who experience 4 or more migraine days per month. Fremanezumab is a fully humanized monoclonal antibody that targets calcitonin gene‐related peptide, a neuropeptide involved in the pathophysiology of migraine.

Design/Methods

The 4 placebo‐controlled phases 2b and 3 studies included in this analysis were 16‐week, multicenter, randomized, double‐blind, placebo‐controlled, and parallel‐group studies consisting of a screening visit, a 28‐day pretreatment baseline period, and a 12‐week treatment period with a final evaluation 4 weeks after the final dose of the study drug. Safety endpoints included adverse events (AEs) and immunogenicity.

Results

A total of 2566 patients were randomized across all studies (fremanezumab, n = 1704; placebo, n = 862), and 2563 patients were treated. Common reasons for study discontinuation were withdrawal by patient (n = 78), patient lost to follow‐up (n = 60), and AE (n = 50). The mean (standard deviation) duration of exposure was 83.8 (13.6) days for the patients who received fremanezumab, with a total exposure of 390.4 patient years and maximum exposure of 181 days. AEs were mostly mild to moderate in severity and were reported among 48‐69% of patients in all treatment groups, and most were injection site reactions (pain, induration, and erythema). Two deaths occurred (chronic obstructive pulmonary disease and intentional overdose of diphenhydramine), both of which were deemed unrelated to study drug by the investigators and sponsor. Cardiovascular adverse events, abnormal liver function tests, and hypersensitivity were uncommon and occurred at similar rates between the placebo and fremanezumab groups.

Conclusions

Fremanezumab is a generally safe and well‐tolerated preventive therapy for migraine in adults.
A Critical Plot Twist: Changing Characters and Foreshadowing the Future of Organizational Storytelling
Authors: Beigi Mina , Callahan Jamie , Michaelson Christopher
Published: April 2019

This review explores the evolution of scholarly research about organizational storytelling over the past 40 years in a sample of 165 papers published between 1975 and 2015. The authors contend that organizational storytelling has established a conventional foothold beside the dominant, scientific narrative of organization studies. Meanwhile, the voice of critical storytelling in organizations has emerged, confirming (and extending) five organizational storytelling themes identified by Rhodes and Brown: sensemaking (and subverting); communicating (and manipulating); change, learning (and challenge); power (and dissent); and identity and identification (and alienation). This review reveals the growing influence of critical management studies, emphasizing the role stories play in disrupting conventional narratives, enriching understanding of present and future storytelling in organizations, and of organizations in general.
Concepts of GPCR‐controlled navigation in the immune system
Authors: Lämmermann Tim , Kastenmüller Wolfgang
Published: April 2019

G‐protein–coupled receptor (GPCR) signaling is essential for the spatiotemporal control of leukocyte dynamics during immune responses. For efficient navigation through mammalian tissues, most leukocyte types express more than one GPCR on their surface and sense a wide range of chemokines and chemoattractants, leading to basic forms of leukocyte movement (chemokinesis, haptokinesis, chemotaxis, haptotaxis, and chemorepulsion). How leukocytes integrate multiple GPCR signals and make directional decisions in lymphoid and inflamed tissues is still subject of intense research. Many of our concepts on GPCR‐controlled leukocyte navigation in the presence of multiple GPCR signals derive from in vitro chemotaxis studies and lower vertebrates. In this review, we refer to these concepts and critically contemplate their relevance for the directional movement of several leukocyte subsets (neutrophils, T cells, and dendritic cells) in the complexity of mouse tissues. We discuss how leukocyte navigation can be regulated at the level of only a single GPCR (surface expression, competitive antagonism, oligomerization, homologous desensitization, and receptor internalization) or multiple GPCRs (synergy, hierarchical and non‐hierarchical competition, sequential signaling, heterologous desensitization, and agonist scavenging). In particular, we will highlight recent advances in understanding GPCR‐controlled leukocyte navigation by intravital microscopy of immune cells in mice.
T cell and dendritic cell interactions in lymphoid organs: More than just being in the right place at the right time
Authors: Ugur Milas , Mueller Scott N.
Published: April 2019

The initiation of T lymphocyte responses within secondary lymphoid organs involves interactions with different subsets of dendritic cells (DCs). Recent studies have revealed the complexity of microanatomical organization within lymphoid organs. Exactly how T cells and DCs locate each other and the type of cellular interactions required for optimal priming of effector and memory T cell responses are beginning to be unraveled. Here we review advances in our understanding of how T cell priming is choreographed during infections, highlight the importance of cell positioning in this process and discuss how a spectrum of cellular interactions shapes T cell activation and differentiation.