bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulsed food resources, but not forest cover, determine lifetime reproductive success in a forest‐dwelling rodent
Authors: Hoset Katrine S. , Villers Alexandre , Wistbacka Ralf , Selonen Vesa
Published: June 2017

The relative contributions of habitat and food availability on fitness may provide evidence for key habitat features needed to safeguard population persistence. However, defining habitat quality for a species can be a complex task, especially if knowledge on the relationship between individual performance and habitat quality is lacking.

Here, we determined the relative importance of the availability of suitable forest habitat, body mass and food from masting tree species on female lifetime reproductive success (LRS) of Siberian flying squirrels (Pteromys volans).

We calculated LRS of 500 female flying squirrels based on a 22‐year‐long longitudinal dataset of two populations from western Finland. We assessed with generalised additive models the potential effects of availability of suitable habitat and cumulative lifetime availability of food from masting tree species on female LRS, longevity and fecundity. On a reduced dataset, we evaluated the importance of female winter body mass and conducted a piecewise path analysis to determine how variables were connected.

According to generalised additive models female longevity, fecundity and LRS were mainly determined by variation in cumulative lifetime availability of food from masting alder and birch. Instead, habitat and body mass had a smaller role. The path analysis indicated that lifetime food availability had a direct effect on longevity and fecundity, and these had an equal effect on LRS at both study sites.

Our results on LRS show that the occurrence of tree masting events during a female flying squirrel's lifetime has a profoundly larger effect on LRS than the cover of suitable forest habitat. Furthermore, this study emphasises the importance of both fecundity and longevity, and the indirect effects of food availability via those components, as determinants of lifetime fitness in female flying squirrels.
Diffusion of Corporate Risk‐Management Characteristics: Perspectives of Chief Audit Executives through a Survey Approach
Authors: Christopher Joe , Sarens Gerrit
Published: June 2017

This study examines how corporate risk‐management characteristics in Australian public universities have diffused under an environment of conflicting management cultures. The findings reveal that corporate risk‐management characteristics have diffused in a pluralist form to satisfy stakeholders of different management approaches across its governance levels as opposed to a unilateral form aligned to the corporate approach. The accepted practice of this adapted version challenges the existing notion that the adoption of corporate control processes in the public sector is problematic, and provides insights into the emergence of a hybrid control process to address the needs of multiple stakeholders. These findings have policy implications for defining a new hybrid governance‐control paradigm for the public sector as an alternative to the corporate‐influenced control paradigm, and provide avenues for further research to confirm the phenomenon with other corporate control processes, public‐sector entities, and if so its impact on effective governance.
Dynamics and origin of cytokinins involved in plant manipulation by a leaf‐mining insect
Authors: Zhang Hui , Guiguet Antoine , Dubreuil Géraldine , Kisiala Anna , Andreas Peter , Emery R. J. Neil , Huguet Elisabeth , Body Mélanie , Giron David
Published: June 2017

Several herbivorous insects and plant‐associated microorganisms control the phytohormonal balance, thus enabling them to successfully exploit the plant by inhibiting plant defenses and withdrawing plant resources for their own benefit. The leaf‐mining moth Phyllonorycter blancardella modifies the cytokinin (CK) profile of mined leaf‐tissues, and the insect symbiotic bacteria Wolbachia is involved in the plant manipulation to the benefit of the insect host. To gain a deeper understanding into the possible origin and dynamics of CKs, we conducted an extensive characterization of CKs in larvae and in infected apple leaves. Our results show the enhanced CK levels in mines, both on green and yellow leaves, allowing insects to control their nutritional supply under fluctuating environmental conditions. The spatial distribution of CKs within the mined leaves shows that hormone manipulation is strictly limited to the mine suggesting the absence of CK translocation from distant leaf areas toward the insect feeding site. Mass spectrometry analyses reveal that major CK types accumulating in mines and larvae are similar to what is observed for most gall‐inducers, suggesting that strategies underlying the plant manipulation may be shared between herbivorous insects with distinct life histories. Results further show that CKs are detected in the highest levels in larvae, reinforcing our hypothesis that CKs accumulating in the mines originate from the insect itself. Presence of bacteria‐specific methylthio‐CKs is consistent with previous results suggesting that insect bacterial symbionts contribute to the observed phenotype. Our study provides key findings toward the understanding of molecular mechanisms underlying this intricate plant–insect–microbe interaction.
The effect of CT scanners in the trauma room – an observational study
Authors: Wulffeld S. , Rasmussen L. S. , Højlund Bech B. , Steinmetz J.
Published: June 2017

Background

A CT scanner incorporated in the trauma resuscitation bay may benefit trauma patients by fastening work‐up times; however, evidence in the area is still sparse. We assessed if time from admission to first CT scan was lower after incorporation of a CT scanner in the resuscitation bay.

Methods

We included trauma patients admitted in two 1‐year periods, before and after a major rebuilding of the trauma room. Beforehand, one CT scanner was located in an adjacent room. After the rebuilding, two mobile CT scanners were placed in the resuscitation bays, where a moving gantry was combined with a trauma resuscitation table. Subgroup analyses were performed on severely injured and patients with traumatic brain injury.

Results

We included 784 patients before and 742 patients after the reconstruction. Case‐mix differed between study periods as there was a higher proportion of severe injuries, traumatic brain injury and penetrating trauma in the after period. We found a minor increase in time to CT in the after period (20 vs. 21 min, P = 0.008). In a multivariate regression analysis adjusted for differences in case‐mix and with time to CT as outcome, period was an insignificant explanatory variable [β (before vs. after): 0.96 min 95% CI: 0.9–1.02, P = 0.3]. In both subgroups, we found no significant difference in time to CT.

Conclusion

We found no reduction in time to CT scan, when comparing a period with mobile CT scanners incorporated in the resuscitation bay to an earlier period with a CT scanner next to the trauma room.
Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption
Authors: Kallupi Marsida , Shen Qianwei , de Guglielmo Giordano , Yasuda Dennis , Journigan V. Blair , Zaveri Nurulain T. , Ciccocioppo Roberto
Published: June 2017

Buprenorphine's clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ‐opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self‐administer cocaine for 2 hours daily. Buprenorphine (0.3, 1.0 and 3.0 mg/kg) given intraperitoneally 90 minutes before access to cocaine significantly and dose dependently reduced its intake. Pre‐treatment with naltrexone or with the selective nociceptin/orphanin FQ peptide (NOP) antagonist SB‐612111 did not prevent buprenorphine‐induced reduction of cocaine intake. However, when naltrexone and SB‐612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co‐activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT‐034, AT‐201 and AT‐202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa‐opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine's effects, results demonstrated that AT‐034 and AT‐201, which co‐activate MOP and NOP receptors, reduced cocaine self‐administration like buprenorphine. AT‐202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co‐activation of MOP and NOP receptors is essential to reduce cocaine consumption. These results open new vistas on the treatment of cocaine addiction by developing compounds with mixed MOP/NOP agonist properties.
Genetics‐based methods for agricultural insect pest management
Authors: Alphey Nina , Bonsall Michael B.
Published: June 2017

The sterile insect technique is an area‐wide pest control method that reduces agricultural pest populations by releasing mass‐reared sterile insects, which then compete for mates with wild insects. Contemporary genetics‐based technologies use insects that are homozygous for a repressible dominant lethal genetic construct rather than being sterilized by irradiation.

Engineered strains of agricultural pest species, including moths such as the diamondback moth Plutella xylostella and fruit flies such as the Mediterranean fruit fly Ceratitis capitata, have been developed with lethality that only operates on females.

Transgenic crops expressing insecticidal toxins are widely used; the economic benefits of these crops would be lost if toxin resistance spread through the pest population. The primary resistance management method is a high‐dose/refuge strategy, requiring toxin‐free crops as refuges near the insecticidal crops, as well as toxin doses sufficiently high to kill wild‐type insects and insects heterozygous for a resistance allele.

Mass‐release of toxin‐sensitive engineered males (carrying female‐lethal genes), as well as suppressing populations, could substantially delay or reverse the spread of resistance. These transgenic insect technologies could form an effective resistance management strategy.

We outline some policy considerations for taking genetic insect control systems through to field implementation.
Characteristics of corneal biomechanical responses detected by a non‐contact scheimpflug‐based tonometer in eyes with glaucoma
Authors: Jung Younhea , Park Hae‐Young L. , Yang Hee Jung , Park Chan Kee
Published: June 2017

Purpose

To determine the corneal biomechanical properties in eyes with glaucoma using a non‐contact Scheimpflug‐based tonometer.

Methods

Corneal biomechanical responses were examined using a non‐contact Scheimpflug‐based tonometer. The tonometer parameters of the normal control group (n = 75) were compared with those of the glaucoma group (n = 136), including an analysis of glaucoma subgroups categorized by visual field loss.

Results

After adjusting for potential confounding factors, including the intraocular pressure (IOP), central corneal thickness (CCT), age and axial length, the deformation amplitude was smaller in the glaucoma group (1.09 ± 0.02 mm) than in the normal control group (1.12 ± 0.02 mm; p value = 0.031). The deformation amplitude and the deflection amplitude of the severe glaucoma group (1.12 ± 0.02 mm and 0.92 ± 0.01 mm) were significantly greater than that of the early glaucoma group (1.07 ± 0.01 mm and 0.88 ± 0.11 mm, p = 0.006 and p = 0.031), whereas that of the moderate glaucoma group (1.09 ± 0.02 mm and 0.90 ± 0.02 mm) was greater than that of the early glaucoma group, but this difference was not statistically significant. The deformation amplitude showed a negative correlation with the CCT in the normal control group (r = −0.235), with a weaker negative relationship observed in the early glaucoma group (r = −0.099). However, in the moderate and severe glaucoma groups, the deformation amplitude showed a positive relationship with the CCT, showing an inverse relationship. The duration and number of antiglaucomatous eyedrops used had negative correlations with the CCT in eyes with moderate and severe glaucoma.

Conclusion

Overall, the glaucoma group showed significantly less deformable corneas than did the normal controls, even after adjusting for the IOP, CCT, age and axial length. However, there were also differences according to the severity of glaucoma, where the corneal deformation amplitude was greater in the severe glaucoma group compared to the early glaucoma group. The combined effects of stiffening due to glaucoma and increased viscoelastic properties caused by the chronic use of antiglaucomatous eyedrops may have resulted in the present findings.
Bilateral diffuse uveal melanocytic proliferation: Case report and literature review
Authors: Klemp Kristian , Kiilgaard Jens Folke , Heegaard Steffen , Nørgaard Tove , Andersen Mette Klarskov , Prause Jan Ulrik
Published: June 2017

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular disease that causes progressive visual loss in patients driven by an IgG factor associated with an underlying malignancy. Characteristic ocular findings include exudative retinal detachment, rapid cataract formation and uveal melanocytic tumours. The awareness and documentation of BDUMP has increased during the past decade, and the increasing amount of data collected demonstrates the effect of treatment with plasmapheresis and the value of diagnostic tools in BDUMP such as genetic and immunologic investigations. The literature of BDUMP has not been reviewed since 2003, and there is a growing need for an updated review on diagnosis and management of BDUMP. We review the literature and report a case of BDUMP with a white ciliary body tumour, iris rubeosis, increased iris pigmentation and cataract.
C‐Reactive protein and progression of vision loss in retinitis pigmentosa
Authors: Murakami Yusuke , Ikeda Yasuhiro , Nakatake Shunji , Fujiwara Kohta , Tachibana Takashi , Yoshida Noriko , Notomi Shoji , Hisatomi Toshio , Yoshida Shigeo , Ishibashi Tatsuro , Sonoda Koh‐Hei
Published: June 2017

Purpose

Chronic inflammation is involved in retinitis pigmentosa (RP). We demonstrated previously that intraocular inflammatory levels, as measured by slit‐lamp ophthalmoscopy or laser flare photometry, are inversely correlated with central visual function in patients with RP. Here, we investigated the relationship between serum high‐sensitivity C‐reactive protein (hs‐CRP) and visual parameters in RP.

Methods

We studied 58 consecutive typical patients with RP <40 years old and 29 age‐ and gender‐matched controls. High‐sensitivity C‐reactive protein (hs‐CRP) was detected by immunoturbidimetry. The relationships between hs‐CRP and visual parameters including best‐corrected visual acuity (BCVA), mean deviation (MD) of static perimetry tests (Humphrey Field Analyzer, the central 10‐2 programme) and VA changes over the prior 5 years and MD changes over the prior 3 years were analysed in the patients with RP.

Results

The serum hs‐CRP levels of the patients with RP were significantly higher than those of the controls (0.06 ± 0.08 versus 0.03 ± 0.04 mg/dl, p = 0.0119). In the patients with RP, there was no correlation of hs‐CRP with cross‐sectionally assessed VA or MD, but the baseline hs‐CRP was significantly correlated with the MD deterioration (r = −0.4073, p = 0.0314).

Conclusion

The average serum hs‐CRP was significantly increased in the patients with RP, and higher hs‐CRP was associated with faster deterioration of central visual function. These results suggest that the systemic inflammatory profile is altered and may be associated with disease progression in RP.
Comparative study shows differences in screen exposure, sleep patterns and sleep disturbances between Jewish and Muslim children in Israel
Authors: Tzischinsky Orna , Haimov Iris
Published: June 2017

Aim

This study determined the differences in screen exposure, sleep patterns and sleep disturbances, and the associations between these factors, among Jewish and Muslim children in Israel.

Methods

The participants were 1049 school children – 499 Jewish and 550 Muslim – with a mean age of 9.2 ± 0.7 years, who attended public schools in both urban and rural residential settings in 2014. They all completed the Sleep Self‐Report questionnaire and the Screen Exposure Questionnaire.

Results

Muslim children reported increased screen time, despite having fewer televisions and computers in their bedroom than Jewish children. Muslim children also reported earlier bedtimes and longer sleep duration, but greater sleep disturbances. Having screens in bedrooms and non‐school days were related to later bedtimes and later wake‐up times for all children. Children who spent four or more hours watching television or using a computer on school days reported significantly more sleep disturbances than children with lower usage.

Conclusion

Muslim children with a mean age of nine years reported longer screen exposure, earlier bedtimes and longer sleep duration, but more sleep disturbances, than Jewish children. Cultural sleep practices may contribute to the differences in sleep patterns and sleep disturbances of Jewish and Muslim children in Israel.
Comparison of effect sizes between enriched and nonenriched trials of analgesics for chronic musculoskeletal pain: a systematic review
Authors: Yamato Tie P. , Maher Chris G. , Saragiotto Bruno T. , Shaheed Christina Abdel , Moseley Anne M. , Lin Chung‐Wei Christine , Koes Bart , McLachlan Andrew J.
Published: June 2017

AIMS

To investigate the use of an enriched study design on the estimates of treatment effect in analgesic trials for chronic musculoskeletal pain.

Methods

Database searches were conducted from 2004 to 2014. We included randomized placebo‐controlled trials evaluating pain medications for chronic musculoskeletal pain. Methodological quality was assessed using the PEDro scale. The estimates of treatment effect on pain and adverse events were compared between enriched and nonenriched designs. Metaregression was used to assess the association between the effect size estimate and the study design controlling for analgesic dose and methodological quality.

Results

We included 108 trials, of which 99 were included in the meta‐analysis (n = 44 171). There were no overall differences in effect sizes between enriched and nonenriched designs for pain intensity. There was a significant difference for a reduction in any adverse events favouring enriched designs for opioids, but not for other analgesics or the outcome serious adverse events. There was an association between effect size and methodological quality, with failure to blind the outcome assessor and failure to use intention‐to‐treat analysis being associated with larger effect sizes.

Conclusions

There is no evidence that the use of an enriched study design changes the treatment effect size estimate for pain. There is some evidence that clinical trials that employ enriched designs report a reduced risk of adverse events in trials for chronic musculoskeletal pain, but it is unclear whether enriched designs influence estimates of serious adverse events. Features of trial design and study quality were associated with treatment effect estimates.
Molecular regulation and pharmacological targeting of the β‐catenin destruction complex
Authors: van Kappel Eline C , Maurice Madelon M
Published: June 2017

The β‐catenin destruction complex is a dynamic cytosolic multiprotein assembly that provides a key node in Wnt signalling regulation. The core components of the destruction complex comprise the scaffold proteins axin and adenomatous polyposis coli and the Ser/Thr kinases casein kinase 1 and glycogen synthase kinase 3. In unstimulated cells, the destruction complex efficiently drives degradation of the transcriptional coactivator β‐catenin, thereby preventing the activation of the Wnt/β‐catenin pathway. Mutational inactivation of the destruction complex is a major pathway in the pathogenesis of cancer. Here, we review recent insights in the regulation of the β‐catenin destruction complex, including newly identified interaction interfaces, regulatory elements and post‐translationally controlled mechanisms. In addition, we discuss how mutations in core destruction complex components deregulate Wnt signalling via distinct mechanisms and how these findings open up potential therapeutic approaches to restore destruction complex activity in cancer cells.

Linked Articles

This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc
Neuroadaptations of presynaptic and postsynaptic GABAB receptor function in the paraventricular nucleus in response to chronic unpredictable stress
Authors: Gao Yonggang , Zhou Jing‐Jing , Zhu Yun , Wang Li , Kosten Therese A , Zhang Xiangjian , Li De‐Pei
Published: June 2017

Background and purpose

Chronic stress impairs GABAA (GABA type A) receptor‐mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABAB receptor function is also altered. We hypothesize that chronic stress alters GABAB receptor function in PVN corticotrophin‐releasing hormone (CRH) neurons to control hypothalamus‐pituitary–adrenal axis activity.

Experimental Approach

Whole‐cell patch clamp recordings were made of PVN‐CRH neurons expressing eGFP driven by CRH promoter in brain slices from unstressed rats and rats exposed to chronic unpredictable mild stress (CUMS).

Key Results

CUMS elevated the basal circulating corticosterone levels and increased the basal firing activity of PVN‐CRH neurons. Microinjection of GABAB receptor agonist baclofen into the PVN suppressed the increased corticosterone levels in CUMS rats compared with unstressed rats. CUMS blunted the baclofen‐induced inhibition on PVN‐CRH neurons and outward currents in these neurons. Furthermore, CUMS reduced expression of GABAB1 (GABABR1) protein in the PVN. Blocking NMDA receptors with AP5 restored the reduced baclofen‐induced currents in CUMS rats but had no effect on GABAB1 expression. Furthermore, CUMS treatment augmented the baclofen‐induced decrease in the frequency of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitor postsynaptic currents in PVN‐CRH neurons. The GABAB receptor antagonist CGP55845 increased the firing activity of PVN‐CRH neurons only in CUMS‐treated rats and not in unstressed rats.

Conclusions and Implications

These findings suggest that chronic stress impairs postsynaptic GABAB receptor function but augments presynaptic GABAB receptor function in controlling glutamatergic and GABAergic synaptic inputs in PVN‐CRH neurons.
Diversity and stability of egg‐bacterial assemblages: The role of paternal care in the glassfrog Hyalinobatrachium colymbiphyllum
Authors: Hughey Myra C. , Delia Jesse , Belden Lisa K.
Published: June 2017

Embryos of oviparous organisms must cope with harsh environments and are especially susceptible to disease, considering that many immune mechanisms do not develop until later in life. Parents may transmit symbiotic microflora to eggs, which can contribute to embryo immune defense. Despite the importance of symbiotic microbes for immune function and survival of adult amphibians, vertical transfer of symbionts in amphibians has received less attention than in other taxa. Here, we test the role of male‐only parental care in establishing and maintaining the diversity of egg‐bacterial assemblages in a Neotropical glassfrog (Centrolenidae). Previous research suggests that father Hyalinobatrachium colymbiphyllum may transfer bacterial symbionts to their eggs. We combined a male‐removal experiment in situ with 16S rRNA gene amplicon sequencing to determine whether egg attendance by father H. colymbiphyllum influences the bacterial community and survival of eggs. We found that eggs harbor a diverse and stable bacterial assemblage. Despite different host environments, we found that adult skin and eggs supported very similar bacterial assemblages—even after removing fathers. While we found overlap in the bacteria present on eggs and their fathers, our experiment reveals that extended male care does not contribute to the maintenance of egg‐bacterial communities, so there may be other potential routes of transfer. This study contributes to our understanding of the diversity and maintenance of egg microbiomes, and motivates further research on how initial bacteria are acquired and the ontogenetic development of host–symbiont communities.
Kinetic parameters for the reaction of 1,2,4‐trioxolanes and artemisinin with iron(II): New evidence for the source of antimalarial activity
Authors: Lopes Nicolas S. , Ciscato Luiz Francisco M. L.
Published: June 2017

The Fenton‐like reductive cleavage of antimalarial peroxides like artemisinin by iron(II) species is a chemical reaction whose mechanistic pathway has not been yet fully understood; it is, however, known that there is considerable production of radical species centered at both the oxygen and carbon, which are important to the therapeutical effects of those compounds. This article reports kinetic data for the reaction of artemisinin and two model 1,2,4‐trioxolanes with iron(II) species and also a mechanistic interpretation of this reductive cleavage from transition state thermodynamics. The suggestion of the presence of an enhancing specific factor inside the plasmodium is made.
Revisiting the weighting function for lightness in the CIEDE2000 colour‐difference formula
Authors: Melgosa Manuel , Cui Guihua , Oleari Claudio , Pardo Pedro J. , Huang Min , Li Changjun , Luo Ming Ronnier
Published: June 2017

We have used 13 experimental datasets (7420 colour pairs) to study the performance of the weighting function for lightness proposed by the CIEDE2000 colour‐difference formula, because it has been suggested that this function can be improved by using the weighting function for lightness SL = 1 adopted by the CIE94 colour‐difference formula. Using the standardised residual sum of squares (STRESS) index, it was found that: (i) replacing the SL in CIEDE2000 with SL = 1 improved the results for 7/13 datasets considered, but the improvement was statistically significant only for 1/13 datasets; (ii) a Whittle‐type lightness‐difference formula can be used to replace the term ∆L*/SL in CIEDE2000, which led to a new colour‐difference formula with no statistically significant difference with respect to CIEDE2000 for any of the 13 experimental datasets. A modification of the CIEDE2000 formula using a Whittle‐type lightness formula is proposed.
Annual direct medical costs associated with diabetes‐related complications in the event year and in subsequent years in Hong Kong
Authors: Jiao F. , Wong C. K. H. , Tang S. C. W. , Fung C. S. C. , Tan K. C. B. , McGhee S. , Gangwani R. , Lam C. L. K.
Published: June 2017

Aim

To develop models to estimate the direct medical costs associated with diabetes‐related complications in the event year and in subsequent years.

Methods

The public direct medical costs associated with 13 diabetes‐related complications were estimated among a cohort of 128 353 people with diabetes over 5 years. Private direct medical costs were estimated from a cross‐sectional survey among 1825 people with diabetes. We used panel data regression with fixed effects to investigate the impact of each complication on direct medical costs in the event year and subsequent years, adjusting for age and co‐existing complications.

Results

The expected annual public direct medical cost for the baseline case was US$1,521 (95% CI 1,518 to 1,525) or a 65‐year‐old person with diabetes without complications. A new lower limb ulcer was associated with the biggest increase, with a multiplier of 9.38 (95% CI 8.49 to 10.37). New end‐stage renal disease and stroke increased the annual medical cost by 5.23 (95% CI 4.70 to 5.82) and 5.94 (95% CI 5.79 to 6.10) times, respectively. History of acute myocardial infarction, congestive heart failure, stroke, end‐stage renal disease and lower limb ulcer increased the cost by 2–3 times. The expected annual private direct medical cost of the baseline case was US$187 (95% CI 135 to 258) for a 65‐year‐old man without complications. Heart disease, stroke, sight‐threatening diabetic retinopathy and end‐stage renal disease increased the private medical costs by 1.5 to 2.5 times.

Conclusions

Wide variations in direct medical cost in event year and subsequent years across different major complications were observed. Input of these data would be essential for economic evaluations of diabetes management programmes.
Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA‐T2D trial
Authors: Groop Per‐Henrik , Cooper Mark E. , Perkovic Vlado , Hocher Berthold , Kanasaki Keizo , Haneda Masakazu , Schernthaner Guntram , Sharma Kumar , Stanton Robert C. , Toto Robert , Cescutti Jessica , Gordat Maud , Meinicke Thomas , Koitka‐Weber Audrey , Thiemann Sandra , von Eynatten Maximilian
Published: June 2017

Aims

The MARLINA‐T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard‐of‐care in individuals with type 2 diabetes and albuminuria.

Methods

A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48–86 mmol/mol), estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and urinary albumin‐to‐creatinine ratio (UACR) 30–3000 mg/g despite single agent renin‐angiotensin‐system blockade were randomized to double‐blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time‐weighted average of percentage change from baseline in UACR over 24 weeks, respectively.

Results

Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo‐adjusted mean change in HbA1c from baseline was −0.60% (−6.6 mmol/mol) (95% confidence interval [CI], −0.78 to −0.43 [−8.5 to −4.7 mmol/mol]; P < .0001). The placebo‐adjusted gMean for time‐weighted average of percentage change in UACR from baseline was −6.0% (95% CI, −15.0 to 3.0; P = .1954). The adverse‐event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups.

Conclusions

In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo‐adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.
COLLEGE CHOICE AS A COLLECTIVE DECISION
Authors: Huntington‐Klein Nick
Published: June 2017

Although the choice between colleges can be thought of as being made collectively by a family, models of educational choice almost universally portray the decision as made by the student alone. Using a novel experimental method for identifying collective decision functions, I find that students have more influence than parents over the decision, but not exclusive control. Students care more than parents about classroom experience and future earnings. Ignoring the dual‐agent nature of the decision can weaken predictions and lead to poorly targeted policy designs. (JEL I21, J24, D13)
Dietary map of Nile tilapia using stable isotopes in three tropical lakes, Ethiopia
Authors: Fetahi Tadesse , Rothhaupt Karl‐Otto , Peeters Frank
Published: June 2017

Comprehensive analysis of food webs requires identifying dietary sources that support the production of all major organisms within the food web/food chain. Here, we use stable isotope ratios (δ13C, δ34S and δ15N) to assess the relative contribution of different basal carbon sources to the diet of Nile tilapia (Oreochromis niloticusL.) in three tropical lakes Hawassa (also Awasa in literature), Ziway and Koka (Ethiopia). Computations were carried out with Stable Isotope Analysis in R (SIAR) model to quantify the dietary proportion of each prey for the tilapia fish. Basal food sources were distinguishable based on their δ13C, δ34S and δ15N values. In Lake Ziway, macrophytes (64%) were the dominant assimilated diet of tilapia while particulate organic matter (POM) and zooplankton contributed only 20% and 16%, respectively. In parallel, Nile tilapia in Lake Hawassa assimilated macrophytes (35%),POM(33%) and zooplankton (32%) at comparatively equal proportion. The dietary sources of the fish in Lake Koka werePOM(49%) and zooplankton (51%). In contrast with earlier studies based on gut content analysis, the present results reveal that macrophytes contributed more and phytoplankton less than previously reported especially in macrophyte‐dominated lakes Ziway and Hawassa. The ecological condition of the lakes might have been predominantly accountable for the diet change of the tilapia. As dietary data are prerequisite for food web/food chain analysis and aquaculture industry, re‐evaluating the diet of aquatic organisms appear relevant.
A small molecule activator of Nav1.1 channels increases fast‐spiking interneuron excitability and GABAergic transmission in vitro and has anti‐convulsive effects in vivo
Authors: Frederiksen Kristen , Lu Dunguo , Yang Jinhui , Jensen Henrik Sindal , Bastlund Jesper Frank , Larsen Peter Hjørringgaard , Liu Henry , Crestey François , Dekermendjian Kim , Badolo Lassina , Laursen Morten , Hougaard Charlotte , Yang Charles , Svenstrup Niels , Grunnet Morten
Published: June 2017

Nav1.1 (SCN1A) channels primarily located in gamma‐aminobutyric acid (GABA)ergic fast‐spiking interneurons are pivotal for action potential generation and propagation in these neurons. Inappropriate function of fast‐spiking interneurons, leading to disinhibition of pyramidal cells and network desynchronization, correlates with decreased cognitive capability. Further, reduced functionality of Nav1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of Nav1.1 channels available for studying pharmacological modulation of interneuron function. In the current study, we identified a small molecule Nav1.1 activator, 3‐amino‐5‐(4‐methoxyphenyl)thiophene‐2‐carboxamide, named AA43279, and provided an in vitro to in vivo characterization of the compound. In HEK‐293 cells expressing human Nav1.1 channels, AA43279 increased the Nav1.1‐mediated current in a concentration‐dependent manner mainly by impairing the fast inactivation kinetics of the channels. In rat hippocampal brain slices, AA43279 increased the firing activity of parvalbumin‐expressing, fast‐spiking GABAergic interneurons and increased the spontaneous inhibitory post‐synaptic currents (sIPSCs) recorded from pyramidal neurons. When tested in vivo, AA43279 had anti‐convulsive properties in the maximal electroshock seizure threshold test. AA43279 was tested for off‐target effects on 72 different proteins, including Nav1.2, Nav1.4, Nav1.5, Nav1.6 and Nav1.7 and exhibited reasonable selectivity. Taken together, AA43279 might constitute a valuable tool compound for revealing biological functions of Nav1.1 channels.
E‐cadherin mediates ultraviolet radiation‐ and calcium‐induced melanin transfer in human skin cells
Authors: Singh Suman K. , Baker Richard , Sikkink Stephen K. , Nizard Carine , Schnebert Sylvianne , Kurfurst Robin , Tobin Desmond J.
Published: June 2017

Skin pigmentation is directed by epidermal melanin units, characterized by long‐lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously, we reported that MC:KC contact is required for melanosome transfer that can be enhanced by filopodi, and by UVR/UVA irradiation, which can upregulate melanosome transfer via Myosin X‐mediated control of MC filopodia. Both MC and KC express Ca2+‐dependent E‐cadherins. These homophilic adhesion contacts induce transient increases in intra‐KC Ca2+, while ultraviolet radiation (UVR) raises intra‐MC Ca2+ via calcium‐selective ORAI1 ion channels; both are associated with regulating melanogenesis. However, how Ca2+ triggers melanin transfer remains unclear. Here we evaluated the role of E‐cadherin in UVR‐mediated melanin transfer in human skin cells. MC and KC in human epidermis variably express filopodia‐associated E‐cadherin, Cdc42, VASP and β‐catenin, all of which were upregulated by UVR in human MC in vitro. Knockdown of E‐cadherin revealed that this cadherin is essential for UVR‐induced MC filopodia formation and melanin transfer. Moreover, Ca2+ induced a dose‐dependent increase in filopodia formation and melanin transfer, as well as increased β‐catenin, Cdc42, Myosin X and E‐cadherin expression in these skin cells. Together, these data suggest that filopodial proteins and E‐cadherin, which are upregulated by intracellular (UVR‐stimulated) and extracellular Ca2+ availability, are required for filopodia formation and melanin transfer. This may open new avenues to explore how Ca2+ signalling influences human pigmentation.
The Sox2: GFP+/− knock‐in mouse model does not faithfully recapitulate Sox2 expression in skin
Authors: Salz Lucia , Driskell Ryan R.
Published: June 2017

Hair follicle heterogeneity may be regulated by distinct dermal papillae (DP) that represent mesenchymal lineages, which can be defined by Sox2 expression. However, it was recently shown that GFP expression in the Sox2: GFP+/− mouse model occurs in the DPs of all hair follicle types, challenging the idea that hair follicle heterogeneity can be defined by DP heterogeneity. Here, we investigated whether the knock‐in mouse model faithfully expresses GFP when compared to endogenous Sox2 expression. The results reveal that GFP expression is aberrant in both the infundibulum of hair follicles and in the DPs. Consequently, we provide an explanation for the aberrant expression of the knock‐in gene based on the original cloning strategy for the mouse model in the context of a newly identified regulatory element associated within the coding region of Sox2.
Recent climatic drying leads to age‐independent growth reductions of white spruce stands in western Canada
Authors: Hogg Edward H. , Michaelian Michael , Hook Trisha I. , Undershultz Michael E.
Published: June 2017

Since 2001, climatic conditions have been notably drier than normal across large areas of the western Canadian interior, leading to widespread impacts on the forests of this region. This poses a major concern for the future, given climate change projections for continued warming and drying. We conducted tree‐ring analysis in 75 pure stands of white spruce (Picea glauca) across Alberta and west‐central Saskatchewan to examine the effects of recent climatic drying on the growth of this important boreal tree species. Allometric equations were used to calculate annual growth in aboveground tree biomass (GBM) from ring width measurements. Results showed an increasing trend in GBM from the 1960s to the 1990s, followed by a sharp decline during the severe drought of 2001–2002. Of the 75 stands, only 18 recovered sufficiently to cause an increase in mean GBM from the predrought decade of 1991–2000 to the subsequent decade of 2001–2010. The remaining 57 stands exhibited a decline in mean GBM between these decades. Climatic drying was a major cause of the growth decline, as shown by the significant stand‐level relationship between percentage change in decadal mean GBM and the change in decadal mean values of a climate moisture index from 1991–2000 to 2001–2010. Subsequent analyses of boreal stands sampled across Alberta during 2015 revealed that white spruce growth had declined even further as drought conditions intensified during 2014–2015. Overall, there was a 38% decrease in mean GBM between 1997 and 2015, but surprisingly, the percentage decrease was not significantly different for young, productive stands compared with older, less productive stands. Thus, stand ageing cannot explain the observed decline in white spruce growth during the past quarter century, suggesting that these forests are at risk if the trend towards more frequent, severe drought continues in the region.
Potential drug–drug interactions in older adults: A population‐based study
Authors: Santos Thalyta Renata Araújo , Silveira Erika Aparecida , Pereira Lílian Varanda , Provin Mércia Pandolfo , Lima Dione Marçal , Amaral Rita Goreti
Published: June 2017

Aim

To evaluate the potential drug–drug interactions (PDDI) between drugs used by older adults, any associated factors and recommended clinical management.

Methods

A cross‐sectional, population‐based study was carried out through a home survey of 934 older adults (from December 2009 to April 2010). A questionnaire was applied, and the participants were asked to show all the drugs used and their respective prescriptions, thus providing data to identify polypharmacy, self‐medication and PDDI. PDDI, their consequences, severity and clinical management were identified using Micromedex.

Results

Overall, 2846 drugs and 665 PDDI were identified, 71.0% of which were moderate and 22.4% serious. The prevalence of PDDI was 36.9%. Drugs with a narrow therapeutic index were involved in 17.0% of the PDDI. The variables female sex (PR = 1.11, 95% CI 1.02–1.20), age ≥80 years (PR = 1.15, 95% CI 1.03–1.28), no polypharmacy (PR = 0.72, 95% CI 0.67–0.78) and no hospitalization in the past year (PR = 0.90, 95% CI 0.82–0.97) remained associated with the presence of three or more PDDI in the final multivariate analysis model.

Conclusions

Most PDDI were related to routinely used drugs (enalapril, hydrochlorothiazide, calcium, captopril, levothyroxine and simvastatin), and more than one‐third of the older adults were exposed to PDDI with the possible risk of serious health consequences. Drugs with a narrow therapeutic index were involved in several PDDI, with increased risk of toxicity. The clinical management procedures most recommended are dose adjustment and dosing changes, control of the drugs’ serum levels, and monitoring of the clinical conditions.Geriatr Gerontol Int 2017; 17: 2336–2346.
Prevalence and impact of obesity in people with haemophilia: Review of literature and expert discussion around implementing weight management guidelines
Authors: Kahan S. , Cuker A. , Kushner R. F. , Maahs J. , Recht M. , Wadden T. , Willis T. , Majumdar S. , Ungar D. , Cooper D.
Published: June 2017

Obesity affects more than 35% of Americans, increasing the risk of more than 200 comorbid conditions, impaired quality of life and premature mortality. This review aimed to summarize literature published over the past 15 years regarding the prevalence and impact of obesity in people with haemophilia (PWH) and to discuss implementing general guidelines for weight management in the context of the haemophilia comprehensive care team. Although few studies have assessed the effects of obesity on haemophilia‐specific outcomes, existing evidence indicates an important impact of weight status on lower extremity joint range of motion and functional disability, with potentially important effects on overall quality of life. Data regarding bleeding tendency in PWH with coexisting obesity are largely inconclusive; however, some individuals may experience reduced joint bleeds following moderate weight loss. Additionally, conventional weight‐based dosing of factor replacement therapy leads to increased treatment costs for PWH with obesity or overweight, suggesting pharmacoeconomic benefits of weight loss. Evidence‐based recommendations for weight loss include behavioural strategies to reduce caloric intake and increase physical activity, pharmacotherapy and surgical therapy in appropriate patients. Unique considerations in PWH include bleed‐related risks with physical activity; thus, healthcare professionals should advise patients on types and intensities of, and approaches to, physical activity, how to adjust treatment to accommodate exercise and how to manage potential activity‐related bleeding. Increasing awareness of these issues may improve identification of PWH with coexisting obesity and referral to appropriate specialists, with potentially wide‐ranging benefits in overall health and well‐being.
Co‐morbidities and bleeding in elderly patients with haemophilia—A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH)
Authors: Miesbach W. , Reitter‐Pfoertner S.‐E. , Klamroth R. , Langer F. , Wolf H.‐H. , Tiede A. , Siegmund B. , Scholz U. , Müller P. R. , Eichler H. , Pabinger I.
Published: June 2017

Background

Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co‐morbidities and co‐medication in elderly patients.

Objectives

To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co‐morbidities, co‐medication, bleeding sites and patient mortality.

Methods

A retrospective multi‐centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry.

Results

A total of 185 haemophilia patients (mean age, 69.0±7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co‐morbidity, but it occurred significantly less frequently than in an age‐matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs.

Conclusions

The most common co‐morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs.