bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbial translocation and T cell activation are modified by direct‐acting antiviral therapy in HCV‐infected patients
Authors: Lattanzi Barbara , Baroncelli Silvia , De Santis Adriano , Galluzzo Clementina Maria , Mennini Gianluca , Michelini Zuleika , Lupo Marinella , Ginanni Corradini Stefano , Rossi Massimo , Palmisano Lucia , Merli Manuela
Published: October 2018

Background

Microbial translocation from the gut lumen has been involved in the pathogenesis of liver damage in hepatitis C virus (HCV) infection.

Aim

To investigate the impact of direct‐acting antiviral treatment on microbial translocation and T‐cell activation, in patients with hepatitis C‐related liver disease.

Methods

We enrolled two groups of HCV‐infected patients undergoing direct‐acting antiviral treatment: patients with fibrosis ≥F3 according to Metavir (Group ≥F3); patients with hepatitis C recurrence after liver transplantation and Metavir ≥F2 (Group Liver Transplantation + ≥F2). All patients were treated with direct‐acting antivirals based on ongoing guidelines. Surrogate biomarkers of microbial translocation (plasma concentrations of soluble‐CD14, lipopolysaccharide‐binding protein and intestinal fatty acid‐binding protein) were evaluated at baseline, at first month, at the end of treatment and 3 months later. T‐cell activation was measured by expression of CD38+ HLA‐DR at the same time points, only in Group ≥F3.

Results

There were 32 patients in Group ≥F3 and 13 in Group LT + ≥F2. At baseline, levels of soluble‐CD14 and lipopolysaccharide‐binding protein were significantly higher in both groups vs healthy controls. Baseline soluble‐CD14 correlated with glutamic‐oxalacetic transaminase (r = 0.384, P = 0.009) and glutamic‐pyruvic transaminase (r = 0.293, P = 0.05). A significant decrease in plasma levels of surrogate microbial translocation biomarkers was observed during and after treatment in the two groups although values were not normalised. In Group ≥F3, CD38+ HLADR+ T‐cell expression was significantly decreased by direct‐acting antiviral treatment. Relapsers (9%) showed higher soluble‐CD14 levels at baseline.

Conclusion

Surrogate microbial translocation markers and T cell activation are increased in HCV‐infected patients with liver fibrosis and decrease during direct‐acting antiviral treatment.
Evaluation of controlled‐release devices for providing chromium sesquioxide and zinc in Huacaya alpacas at pasture
Authors: Judson GJ , McGregor BA , Ellis KJ , Howse AM
Published: October 2018

Objective

To assess the effectiveness of controlled‐release devices (CRDs) for providing zinc and for estimating faecal output in alpacas and sheep at pasture.

Methods

The study groups of 10 alpacas and 10 sheep at pasture were paired within species and allocated at random to receive by mouth either one CRD containing chromium sesquioxide designed to function for at least 21 days or two CRDs, one containing chromium sesquioxide and the other zinc oxide designed to release over a nominal 60‐day period. Faecal concentrations of chromium, zinc and ash, blood and plasma concentrations of zinc and plasma activity of alkaline phosphatase (ALP) were measured over a period of 117 days after treatment.

Results

The mean faecal chromium excretion profiles suggested that the CRDs performed in a similar manner in both species, releasing chromium for nearly 30 days in alpacas and for slightly more than 30 days in sheep. Using a common predetermined release rate of chromium from the CRDs, the daily faecal outputs of alpacas and sheep were estimated to be 0.54 kg dry matter and 0.33 kg dry matter, respectively. The CRD containing zinc oxide provided after 1 week an estimated daily release rate of 40 mg zinc with a lifetime of between 60 and 70 days in both species. The additional zinc did not elicit a response in blood zinc concentrations or in plasma ALP activity.

Conclusion

The CRDs were retained in the gastrointestinal tracts of the alpacas and sheep and both types functioned as expected. The CRD delivering chromium sesquioxide at a known release rate provided an estimate of faecal dry matter output over a period of almost 3 weeks and the CRD formulated to deliver supplementary zinc did so at the nominal release rate over a period of approximately 60 days in both species. These data indicated that the standard sheep CRD is applicable for use in alpacas.
Using photo‐elicitation to explore the lived experience of informal caregivers of individuals living with dementia
Authors: Rayment Georgie , Swainston Katherine , Wilson Gemma
Published: October 2018

Objectives

This study aims to explore the subjective lived experience of informal caregivers supporting an individual with dementia.

Design

This study uses the interpretive phenomenological approach utilizing the method of photo‐elicitation and in‐depth semi‐structured interviews.

Methods

Six individuals were given a disposable camera to capture photographs which they felt illustrated their own lived experiences of being a caregiver of an individual living with dementia. Photographs were printed and used to form discussion within an in‐depth semi‐structured interview. The photographs provided an innovative way of capturing the lived experiences of formal dementia caregivers and allowed the interview data to be grounded in their daily living, centring around their own lived experiences.

Results

Three themes emerged from data analysis: ‘conceptualising the role of informal caregiver’, ‘support for the informal caregiver’, and ‘the caregivers own needs’.

Conclusions

Findings demonstrated the complexity of the relationship between the caregiver and the person living with dementia, and the shift in this relationship specifically due to the role of carer, with notable differences between spousal caregivers and adult‐child caregivers. The importance of social, emotional, and practical support for caregivers was highlighted, as well as significance of the caregiver's individual needs.

Statement of contribution

What is already known on this subject?

Informal caregivers of individuals living with dementia cover much of the associated health care costs.

Informal caregiving of individuals living with dementia can lead to negative health outcomes of the carer.

Health outcomes of informal caregivers living with dementia are grounded in culture and are influenced by multiple factors.

What does this study add?

The complexity of the transition from family member to informal caregiver has both a physical and emotional impact on caregivers.

The transition, and experiences of informal caregiving, is dependent on the relationship to the individual living with dementia.

Caregiver support and recognizing the caregiver's individual needs were imperative to caregiver well‐being.
Late‐Quaternary history of ‘great lakes’ on the Tibetan Plateau and palaeoclimatic implications – A review
Authors: Yu Shi‐Yong , Colman Steven M. , Lai Zhong‐Ping
Published: October 2018

Geomorphic evidence suggests that shorelines of 100–200 m above the modern lake levels were common across the Tibetan Plateau during late Marine Isotope Stage (MIS) 3. The timing of this lake‐level highstand is mainly based on radiocarbon ages. Problems surrounding the ages of lacustrine sediments at or beyond the limit of the radiocarbon‐dating method have created a need for alternative geochronometers. Chronological advances during the last decade have renewed interest in the timing of events beyond the limit of radiocarbon dating. Here, we synthesize published data for elevated lacustrine landforms of 48 lakes on the Tibetan Plateau, in order to provide a thorough perspective on the timing and pattern of lake‐level changes in this alpine area during the late Quaternary. The ages of these elevated shore features reveal a long‐term trend of relative lake‐level fall from at least MIS 5, instead of a peak in MIS 3, as previously thought. Dating lacustrine terrace sequences reveals that the rate of lake‐level fall ranged from ~1 to 3 mm a−1, comparable with that of related river downcutting across the plateau. Palaeoclimatic proxy records point to a sustained drying since the Last Interglacial, suggesting that long‐term aridification might be the culprit for this widespread and progressive lake‐level fall.
Postglacial relative sea‐level rise in the Limfjord region, northern Jutland, Denmark
Authors: Jessen Catherine , Christensen Charlie , Nielsen Bjarne H.
Published: October 2018

A new core drilled at Nørrekær Enge, Løgstør, Denmark, shows terrestrial lake and bog sediments lying beneath 10 m of marine sediments. Pollen analysis, 14C dating and sedimentary observations show that these sediments relate to an ancient lake basin that was flooded when the rising sea levels reached 8.0 m b.s.l. This new study has allowed a review of previous data relating to shoreline displacement from the Limfjord region of northern Jutland, Denmark. Here we present a new shoreline displacement curve spanning the period between c. 11 700 and 7700 cal. a BP and built upon the Nørrekær Enge data and data from seven other boreholes and excavations from the Limfjord region. A previous shoreline displacement curve for this region suggested a very rapid relative sea‐level rise of 3 to 5 m 100 a−1 whereas this new curve suggests a much slower rise of around 1 m 100 a−1, similar to global rates.
Clusterin contributes to early stage of Alzheimer's disease pathogenesis
Authors: Oh Shin‐Bi , Kim Min Sun , Park SuJi , Son HyunJu , Kim Seog‐Young , Kim Min‐Seon , Jo Dong‐Gyu , Tak Eunyoung , Lee Joo‐Yong
Published: October 2018

While clusterin is reportedly involved in Alzheimer's disease (AD) pathogenesis, how clusterin interacts with amyloid‐β (Aß) to cause Aß neurotoxicity remains unclear in vivo. Using 5×FAD transgenic mice, which develop robust AD pathology and memory deficits when very young, we detected interactions between clusterin and Aß in the mouse brains. The two proteins were concurrently upregulated and bound or colocalized with each other in the same complexes or in amyloid plaques. Neuropathology and cognitive performance were assessed in the progeny of clusterin‐null mice crossed with 5×FAD mice, yielding clu−/−;5×FAD and clu+/+;5×FAD. We found far less of the various pools of Aß proteins, most strikingly soluble Aß oligomers and amyloid plaques in clu−/−;5×FAD mice at 5 months of age. At that age, those mice also had higher levels of neuronal and synaptic proteins and better motor coordination, spatial learning and memory than age‐matched clu+/+;5×FAD mice. However, at 10 months of age, these differences disappeared, with Aß and plaque deposition, neuronal and synaptic proteins and impairment of behavioral and cognitive performance similar in both groups. These findings demonstrate that clusterin is necessarily involved in early stages of AD pathogenesis by enhancing toxic Aß pools to cause Aß‐directed neurodegeneration and behavioral and cognitive impairments, but not in late stage.
Firms’ timing of production with heterogeneous consumers
Authors: Pan Cong
Published: October 2018

I revisit endogenous timing in a quantity‐setting duopoly game. In the basic model, I show that given strong heterogeneity in consumers’ willingness to pay (WTP) and a moderately small consumer segment with low WTP, sequential moving outcomes can appear in equilibrium with the follower enjoying second‐mover advantage. Owing to consumer heterogeneity in WTP, there is a local property that a firm's aggressive behaviour may lead to a competitor responding more aggressively. Hence, the sequential moves can restrict firms’ total outputs to avoid a price collapse, and result in firms’ strategic choices that Pareto dominate those under the simultaneous move. I further generalize my results and show that although firms compete in quantity, under some conditions of the demand function, features of strategic complements can appear.
Inhibition of key enzymes in the inflammatory pathway by hybrid molecules of terpenes and synthetic drugs: In vitro and in silico studies
Authors: Theoduloz Cristina , Alzate‐Morales Jans , Jiménez‐Aspee Felipe , Isla Maria Inés , Alberto María Rosa , Pertino Mariano Walter , Schmeda‐Hirschmann Guillermo
Published: October 2018

The aim of this work was to compare the anti‐inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen. The anti‐inflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of lipoxygenases (LOX) and COX‐2, and in silico docking studies in 15‐LOX and COX‐2. The synthesized hybrids showed an inhibition of COX‐2 and LOX between 9.8%–57.4% and 0.0%–97.7%, respectively. None of the hybrids showed an improvement in the inhibitory effect toward these pro‐inflammatory enzymes, compared to the parent terpenes and non‐steroidal anti‐inflammatory drugs. The docking studies allowed us to predict the potential binding modes of hybrids 6–15 within COX‐2 and 15‐LOX active sites. The relative affinity of the compounds inside the binding sites could be explained by forming non‐covalent interactions with most important and known amino acids reported for those enzymes. A good correlation (r2 = 0.745) between docking energies and inhibition percentages against COX‐2 was found. The high inhibition obtained for compound 10 against COX‐2 was explained by hydrogen bond interactions at the enzyme binding site. New synthetic possibilities could be obtained from our in silico models, improving the potency of these hybrid compounds.
From Early Relationships to Preacademic Knowledge: A Sociocognitive Developmental Cascade to School Readiness
Authors: Bernier Annie , Beauchamp Miriam H. , Cimon‐Paquet Catherine
Published: October 2018

This study aimed to test a four‐wave sequential mediation model linking mother–child attachment to children's school readiness through child executive functioning (EF) and prosociality in toddlerhood and the preschool years. Mother–child attachment security was assessed when children (N = 255) were aged 15 months and 2 years, child EF at age 2, prosocial behavior at age 4, and finally cognitive school readiness in kindergarten (age 6). The results revealed three indirect pathways linking attachment to school readiness: one through EF only, one through prosocial behavior only, and a last pathway involving both EF and prosocial behavior serially. These findings suggest that secure attachment may equip children with both cognitive and social skills that are instrumental to their preparedness for school.
Providing oral care for adults with mental health disorders: Dental professionals’ perceptions and experiences in Perth, Western Australia
Authors: Scrine Clair , Durey Angela , Slack‐Smith Linda
Published: October 2018

Objective

To explore dental professionals’ perceptions and experiences of providing oral health care for adults with mild to moderate mental health disorders (MHD) in Perth, Western Australia.

Methods

A grounded theory approach guided this research which comprised semi‐structured interviews with oral health professionals working in private and/or public dental facilities attended by adults with MHD. An iterative analysis of transcripts identified emerging issues that were organized into categories under which key themes were noted, coded, compared, discussed, reviewed and revised independently by two researchers to ensure rigour.

Results

Sixteen interviews were conducted with six general dentists, three dental specialists, four oral health therapists (OHT) and three dental assistants. Barriers to providing oral health care for adults with MHD included limitations of the current model of care, often focused on treating advanced disease; limited inter‐professional collaboration; an over‐burdened public dental system and the financial constraints of private practice. Personal barriers included perceptions that people with MHD had limited capacity for self‐care and preventing oral disease. Factors that would enable oral health care included training and professional development for dental professionals to work effectively with people with MHD and a more flexible, inter‐professional approach that involved prevention and inviting family to consultations about oral health in primary health care settings.

Conclusions

Our study reveals structural barriers where services often appear to be inadequately prepared to meet the oral health needs of people with MHD. This suggests the need for strategies to review current models of care and encourage and support dental professionals to provide oral health care that is inclusive, inter‐professional, focused on prevention and sensitive to the social context and lived experience of people with MHD.
Rho and Rac, but not ROCK, are required for secretion of human and mouse eosinophil‐associated RNases
Authors: Shamri Revital , Young Kristen M. , Weller Peter F.
Published: October 2018

Background

Eosinophil‐associated RNases (EARs) are stored preformed in eosinophil cytoplasmic secretory granules and have a key role in eosinophil effector functions in host defence and inflammatory disorders. However, the secretion mechanisms of EARs are poorly understood.

Objective

Our study aimed to understand the involvement of cytoskeleton machinery in EAR secretion.

Methods

Fresh human and mouse eosinophils were stimulated with CCL11, and the secretion of enzymatically active EARs was detected using an RNase activity assay. The involvement of cytoskeletal elements or microtubules was probed using specific inhibitors.

Results

We found that dynamic polymerization of microtubules and cytoskeletal elements, such as Rho and Rac, is required for chemokine‐mediated EAR secretion from human and mouse eosinophils. However, inhibition of ROCK (Rho‐associated protein kinase) increased EAR secretion in human and mouse eosinophils even in the absence of chemokine stimulation, suggesting ROCK negatively regulates EAR secretion.

Conclusions

Collectively, these data suggest a cytoskeleton‐dependent mechanism of EAR secretion from eosinophils, findings that are pertinent to host defence, allergy and other eosinophil‐associated diseases.
The impact of child and parental age on protective factors against child maltreatment
Authors: Conrad‐Hiebner Aislinn , Wallio Stephanie , Schoemann Alexander , Sprague‐Jones Jessica
Published: October 2018

Although young age for both the parent and child is implicated in incidences of maltreatment, little is known about the association between parent or child age and protective factors related to child maltreatment prevention. With a sample of parents receiving child maltreatment prevention services in Kansas (N = 1993), we used regression analyses to examine whether the interaction of child and parent age influences family‐level protective factors over time. We found mixed support for each hypothesis, indicating that the age of parents and children differentially impacts family‐level protective factors. Implications for the Strengthening Families approach and child maltreatment prevention are discussed.
Urban Walkability Design Using Virtual Population Simulation
Authors: Mathew C. D. Tharindu , Knob Paulo R. , Musse Soraia Raupp , Aliaga Daniel G.
Published: October 2018

We present a system to generate a procedural environment that produces a desired crowd behaviour. Instead of altering the behavioural parameters of the crowd itself, we automatically alter the environment to yield such desired crowd behaviour. This novel inverse approach is useful both to crowd simulation in virtual environments and to urban crowd planning applications. Our approach tightly integrates and extends a space discretization crowd simulator with inverse procedural modelling. We extend crowd simulation by goal exploration (i.e. agents are initially unaware of the goal locations), variable‐appealing sign usage and several acceleration schemes. We use Markov chain Monte Carlo to quickly explore the solution space and yield interactive design. We have applied our method to a variety of virtual and real‐world locations, yielding one order of magnitude faster crowd simulation performance over related methods and several fold improvement of crowd indicators.
Rapamycin and FK506 derivative TH2849 could ameliorate neurodegenerative diseases through autophagy with low immunosuppressive effect
Authors: Ding Li , Nan Wen‐Hao , Zhu Xian‐Bing , Li Xiao‐Ming , Zhou Li‐Yan , Chen Hou‐Jie , Yu Lu , Ullah Khan Fahim , Zhong Han‐Bing , Shi Xiao‐Jun
Published: October 2018

Autophagy is an essential cellular process concern with cellular homeostasis down‐regulated by mTOR, whose activity can be modulated by rapamycin, a kind of lipophilic macrolide antibiotic, through forming a complex with immunophilin FKBP12 essential for mTOR regulation to induce autophagy. Therefore, rapamycin is normally used as a neuron protective agent. The immunophilin FKBP12 binding ligand FK506 is well known as an immunosuppressive agent by inhibiting the calcineurin expression. In this study, we synthesized a series of modified compounds based on the FKBP12 binding moiety to as same as the binding structure of rapamycin and FK506 particularly. We removed the other binding regions of the complex that has the property of immunosuppression. We found that a novel small molecule named TH2849 from these derivative compounds has a significant binding connection with mTOR by comparing to calcineurin. The effects of TH2849 on calcineurin/NFAT were not as significant as FK506, and weak effects on IL2/p34cdc2/cyclin signaling pathway were also found. Moreover, TH2849 also shows mitochondrial protective effect through stabilizing the mitochondrial structure and transmembrane potential (ΔΨm) and could rescue dopaminergic neurons in MPTP‐treated zebrafishes as well as mice models with less immunosuppressive effect. Our present study shows that TH2849 works as a neuroprotective agent possibly by inducing autophagy and low immunosuppressive effect.
Event Structures Drive Semantic Structural Priming, Not Thematic Roles: Evidence From Idioms and Light Verbs
Authors: Ziegler Jayden , Snedeker Jesse , Wittenberg Eva
Published: October 2018

What are the semantic representations that underlie language production? We use structural priming to distinguish between two competing theories. Thematic roles define semantic structure in terms of atomic units that specify event participants and are ordered with respect to each other through a hierarchy of roles. Event structures instead instantiate semantic structure as embedded sub‐predicates that impose an order on verbal arguments based on their relative positioning in these embeddings. Across two experiments, we found that priming for datives depended on the degree of overlap in event structures. Specifically, while all dative structures showed priming, due to common syntax, there was a boost for compositional datives priming other compositional datives. Here, the two syntactic forms have distinct event structures. In contrast, there was no boost in priming for dative light verbs, where the two forms map onto a single event representation. On the thematic roles hypothesis, we would have expected a similar degree of priming for the two cases. Thus, our results support event structural approaches to semantic representation and not thematic roles.
Case of endoscopic ultrasonography‐guided pancreatic duct rendezvous stenting in which initial contrast medium injection was useful for the second puncture
Authors: Omoto Shunsuke , Takenaka Mamoru , Kudo Masatoshi
Published: October 2018

Watch a video of this article
Endoscopic myotomy of Zenker's diverticulum using a novel electrosurgical knife: First reported case in the USA
Authors: Syed Aslam , Kaul Vivek , Thakkar Shyam
Published: October 2018

Watch a videos of this article
Practical tools and strategies for researchers to increase replicability
Authors: Nuijten Michèle B
Published: October 2018

A growing body of evidence indicates that the effects reported in many scientific fields may be overestimated or even false. This problem has gained a lot of attention in the field of psychology, where researchers have even started to speak of a ‘replication crisis’. Fortunately, a number of measures to rectify this problem have already been proposed and implemented, some inspired by practices in other scientific fields. In this review, I briefly examine this issue in the field of psychology and suggest some practical tools and strategies that researchers can implement to increase replicability and the overall quality of their scientific research.

What this paper adds

Researchers can implement many practical tools and strategies to improve replicability of their findings.

Strategies include improving statistical inference, pre‐registration, multisite collaboration, and sharing data.

Different scientific fields could benefit from looking at each other's best practices.
Neuromuscular correlates of motor function in cerebral palsy: towards targeted treatment
Authors: Rose Jessica
Published: October 2018

This commentary is on the original article by Noble et al. on pages 57–61 of this issue.
New clinical trial designs for establishing drug efficacy and safety in a precision medicine era
Authors: Heerspink Hiddo J. L. , List James , Perkovic Vlado
Published: October 2018

Despite advances in pharmacotherapy, diabetic kidney disease (DKD) remains associated with a high burden of micro‐ and macrovascular complications often leading to premature mortality. New therapies are highly desirable to mitigate the burden of this disease. However, there are a number of barriers that hamper drug development in DKD. These include, amongst others, the lengthy and complex clinical trials required to prove drug efficacy and safety, inefficiencies in clinical trial conduct, and the high costs associated with these development programs. In this review a number of aspects are discussed, aiming to identify opportunities to transform and innovate drug development for DKD. Many clinical trials in DKD, as well as in other areas, face difficulties in timely and efficient enrolment of participants. To address this issue a network of sites should be created that are continuously recruiting individuals with DKD and collecting crucial information that can be used to understand prognosis and prognostic factors, and more importantly to serve as a pool of participants for recruitment to randomized trials. Second, the current clinical endpoints are late events in the progression of DKD. Endpoints based on lesser declines in estimated glomerular filtration rate (eGFR) or changes in albuminuria can shorten follow‐up and/or lead to smaller and cheaper trials. Enrichment by enrolling clinical trial populations based on biomarker profiles is another approach that may facilitate clinical trial efficiency and conduct. Biomarkers can be used to individualize treatment by targeting populations more likely to respond leading to smaller and more efficient trials. Finally, using new trial design such as basket, umbrella or more broadly platform trials to assess a number of therapies simultaneously offers the potential to transform the drug development process in DKD. There are a number of opportunities to transform development approaches for new therapies for DKD. Platform trials along with appropriate biomarker‐based enrichment strategies offer the possibility to foster drug development in a precision medicine era.
Treating diabetic complications; from large randomized clinical trials to precision medicine
Authors: Heerspink Hiddo J. L. , de Zeeuw Dick
Published: October 2018

In the last decades, many large randomized controlled trials have been conducted to assess the efficacy and safety of new interventions for the treatment of diabetic kidney disease (DKD). Unfortunately, these trials failed to demonstrate additional kidney or cardiovascular protection. One of the explanations for the failure of these trials appears to be the large variation in drug response between individual patients. All trials to date tested a drug which was targeted to a large heterogeneous population assuming that every individual will show a similar beneficial respond to the drug. Post hoc analyses from the past clinical trials, however, suggest that individual patients show a marked variation in drug response. This highlights the need to personalize treatment taking proper account of the characteristics and preferences of individual patients. Transitioning to a personalized therapy approach will have implications for clinical trial designs, drug registration and its use in clinical practice. Successful implementation of personalized medicine thus requires engagement of multiple stakeholders including academic community, pharmaceutical industry, regulatory agencies, health policy makers, physicians and patients. This supplement of Diabetes Obesity and Metabolism provides a summary on the state‐of‐the‐art of personalized medicine in diabetic kidney disease from the views of various stakeholders.
Precision medicine in diabetes and diabetic kidney disease: Regulatory considerations
Authors: Mol Peter G. M. , Thompson Aliza , Heerspink Hiddo J. L. , Leufkens Hubert G. M.
Published: October 2018

Over the past 15 years, three new classes of drugs, glucagon‐like peptide‐1 (GLP‐1) receptor agonists, dipeptidyl peptidase 4 (DPP‐4) inhibitors and sodium glucose cotransporter‐2 (SGLT‐2) inhibitors have been approved to treat type 2 diabetes based on effects on glycemic control. Although large randomized controlled trials have played an important role in characterizing the efficacy and safety of these agents on a population level, questions remain about how best to individualize therapy and target the “right” medicine to the “right” patient. In contrast, few medicines have been approved to treat diabetic kidney disease and initiatives have been launched on both sides of the Atlantic to facilitate the development of effective personalized medicines for the treatment of diabetic kidney disease. Increasingly, “omics,” imaging and other biomarkers will be used to match patients with therapies to which they are likely to respond best. This review addresses regulatory considerations related to precision medicine, draws lessons learned from other therapeutic areas and discusses efforts undertaken by the European (EMA) and United States (FDA) to facilitate the development of such therapies. Moving forward, an integrated approach that makes use of predictive preclinical models, innovative trial designs, observational “real‐world” data and novel statistical methodologies will likely be needed to complement inherently smaller RCTs conducted in more selected populations. Patient involvement will also be critical. Regulatory agencies are ready to engage in such approaches.
Long‐term retention of avulsed maxillary permanent incisors replanted after prolonged non‐physiological storage
Authors: Krug Ralf , Kremeier Karin , Krastl Gabriel
Published: October 2018

Ankylosis and external replacement resorption (ERR) are two typical biological responses to delayed replantation of avulsed teeth in cases where adequate root canal treatment is performed. The patient's growth stage affects the progression of root resorption and the long‐term outcome of the affected teeth. This case report describes the long‐term outcome of an 18.5‐year‐old patient following an accident in which both of his maxillary central incisors were avulsed and replanted after four hours of non‐physiological storage.ERRand ankylosis of teeth 11 and 21 were detected clinically and radiographically during the second year of follow‐up. Sixteen years after replantation, replacement resorption was progressing very slowly, enabling functional tooth retention with favorable esthetics. Young adults, with delayed replantation of avulsed teeth, may benefit from tooth retention with slowERR.
Effect of mouthguard design on retention and potential issues arising with usability in sport
Authors: Karaganeva Raya , Pinner Susan , Tomlinson David , Burden Adrian , Taylor Rebecca , Yates Julian , Winwood Keith
Published: October 2018

Background/Aims

Mouthguard retention could potentially increase an athlete's motivation to wear the device, due to potential improvements in physical comfort. The aim of this study was to examine the retentive properties of selected customised mouthguard designs, during normal conditions (dry) and within the presence of artificial saliva (wet). Additionally, the correlation between thickness and retention was investigated.

Material and Methods

Six different custom mouthguard designs (MG1‐MG6) reported in previous studies, were pressure‐formed with 2 and 4 mm blanks accordingly. Thickness was measured 10 times at seven anatomical points and the mean (±SD) was recorded. A novel rig was fabricated to connect the mouthguards to a Hounsfield H10KS Tensometer, which was used to fully displace each device from the model at a constant rate of 50 mm/min. The test was repeated under both dry and wet conditions.

Results

Retention forces recorded at the anterior region demonstrated higher measurements under wet conditions than dry (P < 0.001). The total retention of the mouthguards was influenced by alterations in their design. Trend analysis indicated that 64% of MG retention could be explained by their thickness under dry conditions and 55% when wet.

Conclusions

Design and thickness of mouthguards are key factors in retention. Mouthguard fabrication techniques should be considered in order to minimize dislodgment of the devices as well as potentially increasing the wearability of mouthguards during sport.
Variation in pathogenicity of differentLeptographium terebrantisisolates toPinus taedaL.
Authors: Devkota Pratima , Eckhardt Lori G.
Published: October 2018

Variation in the pathogenicity of 42 isolates ofLeptographium terebrantistoPinus taedawas examined. Stems of 1‐year‐oldP. taedaseedlings were artificially inoculated with the fungal isolates. Eight weeks following inoculation,L. terebrantisisolates caused dark necrotic lesion and sapwood occlusion in the seedling stems. The fungal isolates varied in their ability to cause lesion and tissue occlusion. Lesions caused by fungal isolates were, however, significantly longer than the control. Results suggest that different isolates ofL. terebrantismay not put the health ofP. taedaat equal risk.
Measuring innovation in education: The outcomes of a national education sector innovation survey
Authors: Halász Gábor
Published: October 2018

This article presents the results of a national education sector innovation survey in Hungary. A conceptual and analytical framework for studying innovation processes in the education sector and a data collection tool were created in the framework of a research project on the emergence and spread of local/school level innovations (“Innova research”). Using this tool, data were collected from close to 5,000 educational units from all sub‐subsystems of the national education system. A composite education indicator was created, allowing for the comparison of innovation activity across various groups of educational units. The educational unit (e.g., schools, university departments) was used as the primary unit of analysis. Data show a relatively high level of innovation activity in all subsystems with significant differences between various groups (e.g., units with higher and lower organisational capacities or participating in top‐down development interventions with higher or lower intensity). Connecting the Innova database with data from the regular national pupil achievement survey also made it possible to analyse the relationship between innovation activity and performance.
E3 ubiquitin ligases LNX1 and LNX2 localize at neuronal gap junctions formed by connexin36 in rodent brain and molecularly interact with connexin36
Authors: Lynn Bruce D. , Li Xinbo , Hormuzdi Sheriar G. , Griffiths Emily K. , McGlade C. Jane , Nagy James I.
Published: October 2018

Electrical synapses in the mammalian central nervous system (CNS) are increasingly recognized as highly complex structures for mediation of neuronal communication, both with respect to their capacity for dynamic short‐ and long‐term modification in efficacy of synaptic transmission and their multimolecular regulatory and structural components. These two characteristics are inextricably linked, such that understanding of mechanisms that contribute to electrical synaptic plasticity requires knowledge of the molecular composition of electrical synapses and the functions of proteins associated with these synapses. Here, we provide evidence that the key component of gap junctions that form the majority of electrical synapses in the mammalian CNS, namely connexin36 (Cx36), directly interacts with the related E3 ubiquitin ligase proteins Ligand of NUMB protein X1 (LNX1) and Ligand of NUMB protein X2 (LNX2). This is based on immunofluorescence colocalization of LNX1 and LNX2 with Cx36‐containing gap junctions in adult mouse brain versus lack of such coassociation in LNX null mice, coimmunoprecipitation of LNX proteins with Cx36, and pull‐down of Cx36 with the second PDZ domain of LNX1 and LNX2. Furthermore, cotransfection of cultured cells with Cx36 and E3 ubiquitin ligase‐competent LNX1 and LNX2 isoforms led to loss of Cx36‐containing gap junctions between cells, whereas these junctions persisted following transfection with isoforms of these proteins that lack ligase activity. Our results suggest that a LNX protein mediates ubiquitination of Cx36 at neuronal gap junctions, with consequent Cx36 internalization, and may thereby contribute to intracellular mechanisms that govern the recently identified modifiability of synaptic transmission at electrical synapses.
Community, Context, and Coping: How Social Connections Influence Coping and Well‐Being for Military Members and Their Spouses
Authors: O'Neal Catherine Walker , Richardson Evin W. , Mancini Jay A.
Published: October 2018

Military members and their spouses (n = 223 families) were selected from an Active Duty Army installation and assessed with regard to their connections with the military community, their levels of coping with military culture demands, and their reports of individual (depression and life satisfaction) and family well‐being. Guided by the contextual model of family stress and the social organization theory of action and change, results from a structural equation model indicated that military community connections, for both military members and their civilian spouses, were related to coping with the military culture and its demands, which in turn was related to both individual and family well‐being. Unique actor and partner effects also emerged where both active duty military members' and their civilian spouses' perceptions of military community connections influenced the civilian spouses' satisfaction with military life, but only the active duty military members' community connections influenced their military‐specific coping. Additionally, the associations between military‐specific coping and individual and family well‐being only had actor effects. When examined within the context of important military culture elements, namely rank and extent of military transitions (deployment and relocation), these core findings linking communities to coping and well‐being were unchanged. Implications for theory, future research, and practice are shared.
Unequally into “Us”: Characteristics of Individuals in Asymmetrically Committed Relationships
Authors: Stanley Scott M. , Rhoades Galena K. , Kelmer Gretchen , Scott Shelby B. , Markman Howard J. , Fincham Frank D.
Published: October 2018

This study examined characteristics of individuals that are associated with being in asymmetrically committed relationships (ACRs), defined as romantic relationships in which there was a substantial difference in the commitment levels of the partners. These ACRs were studied in a national sample of unmarried, opposite‐sex romantic relationships (N = 315 couples). Perceiving oneself as having more potential alternative partners was associated with increased odds of being the less committed partner in an ACR compared to not being in an ACR, as was being more attachment avoidant, having more prior relationship partners, and having a history of extradyadic sex during the present relationship. Additionally, having parents who never married was associated with being the less committed partner in an ACR but parental divorce was not. Although fewer characteristics were associated with being the more committed partner within an ACR, more attachment anxiety was associated with increased odds of being in such a position compared to not being in an ACR. We also address how some findings change when controlling for commitment levels. Overall, the findings advance understanding of commitment in romantic relationships, particularly when there are substantial asymmetries involved. Implications for both research on asymmetrical commitment as well as practice (e.g., therapy or relationship education) are discussed.
Uneven winter snow influence on tree growth across temperate China
Authors: Wu Xiuchen , Li Xiaoyan , Liu Hongyan , Ciais Philippe , Li Yuanqiao , Xu Chongyang , Babst Flurin , Guo Weichao , Hao Bingyan , Wang Pei , Huang Yongmei , Liu Shaomin , Tian Yuhong , He Bin , Zhang Cicheng
Published: October 2018

Winter snow is an important driver of tree growth in regions where growing‐season precipitation is limited. However, observational evidence of this influence at larger spatial scales and across diverse bioclimatic regions is lacking. Here, we investigated the interannual effects of winter (here defined as previous October to current February) snow depth on tree growth across temperate China over the period of 1961–2015, using a regional network of tree ring records, in situ daily snow depth observations, and gridded climate data. We report uneven effects of winter snow depth on subsequent growing‐season tree growth across temperate China. There shows little effect on tree growth in drier regions that we attribute mainly to limited snow accumulation during winter. By contrast, winter snow exerts important positive influence on tree growth in stands with high winter snow accumulation (e.g., in parts of cold arid regions). The magnitude of this effect depends on the proportion of winter snow to pre‐growing‐season (previous October to current April) precipitation. We further observed that tree growth in drier regions tends to be increasingly limited by warmer growing‐season temperature and early growing‐season water availability. No compensatory effect of winter snow on the intensifying drought limitation of tree growth was observed across temperate China. Our findings point toward an increase in drought vulnerability of temperate forests in a warming climate.
The response of boreal peatland community composition and NDVI to hydrologic change, warming, and elevated carbon dioxide
Authors: McPartland Mara Y. , Kane Evan S. , Falkowski Michael J. , Kolka Randy , Turetsky Merritt R. , Palik Brian , Montgomery Rebecca A.
Published: October 2018

Widespread changes in arctic and boreal Normalized Difference Vegetation Index (NDVI) values captured by satellite platforms indicate that northern ecosystems are experiencing rapid ecological change in response to climate warming. Increasing temperatures and altered hydrology are driving shifts in ecosystem biophysical properties that, observed by satellites, manifest as long‐term changes in regional NDVI. In an effort to examine the underlying ecological drivers of these changes, we used field‐scale remote sensing of NDVI to track peatland vegetation in experiments that manipulated hydrology, temperature, and carbon dioxide (CO2) levels. In addition to NDVI, we measured percent cover by species and leaf area index (LAI). We monitored two peatland types broadly representative of the boreal region. One site was a rich fen located near Fairbanks, Alaska, at the Alaska Peatland Experiment (APEX), and the second site was a nutrient‐poor bog located in Northern Minnesota within the Spruce and Peatland Responses Under Changing Environments (SPRUCE) experiment. We found that NDVI decreased with long‐term reductions in soil moisture at the APEX site, coincident with a decrease in photosynthetic leaf area and the relative abundance of sedges. We observed increasing NDVI with elevated temperature at the SPRUCE site, associated with an increase in the relative abundance of shrubs and a decrease in forb cover. Warming treatments at the SPRUCE site also led to increases in the LAI of the shrub layer. We found no strong effects of elevated CO2 on community composition. Our findings support recent studies suggesting that changes in NDVI observed from satellite platforms may be the result of changes in community composition and ecosystem structure in response to climate warming.
Ocean acidification increases iodine accumulation in kelp‐based coastal food webs
Authors: Xu Dong , Brennan Georgina , Xu Le , Zhang Xiao W. , Fan Xiao , Han Wen T. , Mock Thomas , McMinn Andrew , Hutchins David A. , Ye Naihao
Published: October 2018

Kelp are main iodine accumulators in the ocean, and their growth and photosynthesis are likely to benefit from elevated seawater CO2 levels due to ocean acidification. However, there are currently no data on the effects of ocean acidification on iodine metabolism in kelp. As key primary producers in coastal ecosystems worldwide, any change in their iodine metabolism caused by climate change will potentially have important consequences for global geochemical cycles of iodine, including iodine levels of coastal food webs that underpin the nutrition of billions of humans around the world. Here, we found that elevated pCO2 enhanced growth and increased iodine accumulation not only in the model kelp Saccharina japonica using both short‐term laboratory experiment and long‐term in situ mesocosms, but also in several other edible and ecologically significant seaweeds using long‐term in situ mesocosms. Transcriptomic and proteomic analysis of S. japonica revealed that most vanadium‐dependent haloperoxidase genes involved in iodine efflux during oxidative stress are down‐regulated under increasing pCO2, suggesting that ocean acidification alleviates oxidative stress in kelp, which might contribute to their enhanced growth. When consumed by abalone (Haliotis discus), elevated iodine concentrations in S. japonica caused increased iodine accumulation in abalone, accompanied by reduced synthesis of thyroid hormones. Thus, our results suggest that kelp will benefit from ocean acidification by a reduction in environmental stress however; iodine levels, in kelp‐based coastal food webs will increase, with potential impacts on biogeochemical cycles of iodine in coastal ecosystems.