bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitric oxide added to the sweep gas of the oxygenator during cardiopulmonary bypass in infants: A pilot randomized controlled trial
Authors: Niebler Robert A. , Chiang‐Ching Huang , Daley Kevin , Janecke Rae , Jobe Shawn M. , Mitchell Michael E. , Varner Caleb , Woods Katherine , Scott John P.
Published: August 2020

Our objective was to assess the effect of nitric oxide added to the sweep gas of the oxygenator during cardiopulmonary bypass (CPB) in infants on platelet count, platelet function, clinical outcomes, and safety. A randomized, double‐blinded, placebo‐controlled clinical trial in infants less than a year of age undergoing cardiac surgery requiring CPB was undertaken. Nitric oxide at a dose of 20 ppm was added to the sweep gas in the treatment group. Blood was collected at baseline and prior to separation from CPB to measure platelet count and function as determined by responsiveness to specific agonists. Clinical outcomes were observed through hospital discharge. Methemoglobin levels were measured preoperatively, at the conclusion of CPB, and upon admission to the ICU. Forty patients consented and were randomized in the trial. Eighteen patients were randomized to the treatment group and 22 were included in the placebo group. The groups were similar in terms of age, weight, gender, and surgical complexity. No significant differences were found in measures of platelet count, platelet response to agonist, or clinical outcomes. Patients in the treatment group had higher methemoglobin levels after receiving nitric oxide, but no levels approached toxicity (maximum 2.4%). Nitric oxide added to the sweep gas of the oxygenator during CPB in infants did not have an appreciable effect on the preservation of platelet count, platelet responsiveness to agonist, or clinical outcomes. Methemoglobin levels were increased after receiving nitric oxide but were far below a toxic level of 15%.
Drug–drug and drug–food interactions in an infant with early‐onset SCN2A epilepsy treated with carbamazepine, phenytoin and a ketogenic diet
Authors: Welzel Tatjana , Ziesenitz Victoria C. , Weber Peter , Datta Alexandre N. , van den Anker Johannes N. , Gotta Verena
Published: August 2020

Sodium channel 2 subunit α (SCN2A) mutations cause difficult‐to‐treat early‐onset epilepsy. Effective treatment includes high‐dose phenytoin or carbamazepine ± ketogenic diet (KD). We describe an infant with early‐onset SCN2A‐epilepsy with subtherapeutic carbamazepine concentration during transition from phenytoin treatment to avoid long‐term neurotoxicity. The transition from high‐dose phenytoin (20 mg kg−1 d−1, concentration: ≥20 mg/L) with KD, to carbamazepine (50–75 mg kg−1 d−1, concentration: 9–12 mg/L) lasted 85 days, which we suspected was due to significant drug–drug and/or drug–food interactions. Model‐based analysis of carbamazepine pharmacokinetics quantified significant time‐ and dose‐dependent phenytoin‐mediated CYP3A4 induction and carbamazepine concentration‐dependent auto‐induction (apparent clearance increased up to 2.5/3‐fold). Lower carbamazepine concentrations under KD were modelled as decreased relative bioavailability (44%), potentially related to decreased fraction absorbed (unexpected for this lipophilic drug), increased intestinal/hepatic metabolism and/or decreased protein‐binding with KD. This suggests importance of carbamazepine‐concentration monitoring during KD‐introduction/removal and necessity of high carbamazepine doses to achieve therapeutic concentrations, especially in infants treated with high‐dose phenytoin.
Using pharmacy dispensing data to predict falls in older individuals
Authors: Gemmeke Marle , Koster Ellen S. , Pajouheshnia Romin , Kruijtbosch Martine , Taxis Katja , Bouvy Marcel L.
Published: August 2020

Aims

Associations between individual medication use and falling in older individuals are well‐documented. However, a comprehensive risk score that takes into account overall medication use and that can be used in daily pharmacy practice is lacking. We, therefore, aimed to determine whether pharmacy dispensing records can be used to predict falls.

Methods

A retrospective cohort study was conducted using pharmacy dispensing data and self‐reported falls among 3454 Dutch individuals aged ≥65 years. Two different methods were used to classify medication exposure for each person: the drug burden index (DBI) for cumulative anticholinergic and sedative medication exposure as well as exposure to fall risk‐increasing drugs (FRIDs). Multinomial regression analyses, adjusted for age and sex, were conducted to investigate the association between medication exposure and falling classified as nonfalling, single falling and recurrent falling. The predictive performances of the DBI and FRIDs exposure were estimated by the polytomous discrimination index (PDI).

Results

There were 521 single fallers (15%) and 485 recurrent fallers (14%). We found significant associations between a DBI ≥1 and single falling (adjusted odds ratio: 1.30 [95% confidence interval {CI}: 1.02–1.66]) and recurrent falling (adjusted odds ratio: 1.60 [95%CI: 1.25–2.04]). The PDI of the DBI model was 0.41 (95%CI: 0.39–0.42) and the PDI of the FRIDs model was 0.45 (95%CI: 0.43–0.47), indicating poor discrimination between fallers and nonfallers.

Conclusion

The study shows significant associations between medication use and falling. However, the medication‐based models were insufficient and other factors should be included to develop a risk score for pharmacy practice.
Antidopaminergic antiemetics and trauma‐related hospitalization: A population‐based self‐controlled case series study
Authors: Bezin Julien , Noize Pernelle , Mansiaux Yohann , Jarne Ana , Pariente Antoine
Published: August 2020

Aims

The aim of this study was to evaluate the risk of trauma associated with the use of antidopaminergic antiemetics in a real‐world setting.

Methods

A self‐controlled case series analysis was performed using the EGB database, the representative sample of the French national healthcare insurance system database. All subjects aged 18 years and over who presented with at least 1 trauma‐related hospitalization and 1 supply for domperidone, metoclopramide or metopimazine between 2009 and 2014 were included in the study. Associations were evaluated by incidence rate ratios.

Results

Included exposed cases were 7610 for domperidone cohort, 2189 for metoclopramide and 3911 for metopimazine. Incidence rate ratio for trauma‐related hospitalization during the first 7 days of exposure period compared to unexposed period was 1.53 (95% confidence interval 1.29–1.80) for domperidone, 2.00 (1.37–2.91) for metoclopramide and 2.30 (1.71–3.09) for metopimazine.

Conclusion

We found an increased risk of hospitalizations for traumatic injuries for the main marketed antidopaminergic antiemetics during the first days of use. The highest risk was observed for metopimazine, which could relate to its pharmacological profile and central effects.
Protein kinase inhibitors for amyotrophic lateral sclerosis therapy
Authors: Palomo Valle , Nozal Vanesa , Rojas‐Prats Elisa , Gil Carmen , Martinez Ana
Published: August 2020

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes the progressive loss of motoneurons and, unfortunately, there is no effective treatment for this disease. Interconnecting multiple pathological mechanisms are involved in the neuropathology of this disease, including abnormal aggregation of proteins, neuroinflammation and dysregulation of the ubiquitin proteasome system. Such complex mechanisms, together with the lack of reliable animal models of the disease have hampered the development of drugs for this disease. Protein kinases, a key pharmacological target in several diseases, have been linked to ALS as they play a central role in the pathology of many diseases. Therefore several inhibitors are being currently trailed for clinical proof of concept in ALS patients. In this review, we examine the recent literature on protein kinase inhibitors currently in pharmaceutical development for this diseaseas future therapy for AS together with their involvement in the pathobiology of ALS.

LINKED ARTICLES

This article is part of a themed issue on Recent advances in ALS pathogenesis and therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc
NKp30 ‐ A prospective target for new cancer immunotherapy strategies
Authors: Pinheiro Pedro F. , Justino Gonçalo C. , Marques M. Matilde
Published: August 2020

Natural killer (NK) cells are an important arm of the innate immune system. They constitutively express the NKp30 receptor. NKp30‐mediated responses are triggered by the binding of specific ligands e.g. tumour cell‐derived B7‐H6 and involve the secretion of cytotoxic mediators including TNF‐α, IFN‐γ, perforins and granzymes. The latter two constitute a target cell‐directed response that is critical in the process of immunosurveillance. The structure of NKp30 is presented, focusing on the ligand‐binding site, on the ligand‐induced structural changes and on the experimental data available correlating structure and binding affinity. The translation of NKp30 structural changes to disease progression is also reviewed. NKp30 role in immunotherapy has been explored in chimeric antigen receptor T‐cell (CAR‐T) therapy. However, antibodies or small ligands targeting NKp30 have not yet been developed. The data reviewed herein unveil the key structural aspects that must be considered for drug design in order to develop novel immunotherapy approaches.
Child Effects on Parental Negativity: The Role of Heritable and Prenatal Factors
Authors: Liu Chang , Ji Linying , Chow Sy‐Miin , Kang Boyoung , Leve Leslie D. , Shaw Daniel S. , Ganiban Jody M. , Natsuaki Misaki N. , Reiss David , Neiderhiser Jenae M.
Published: August 2020

This study examined two possible mechanisms, evocative gene–environment correlation and prenatal factors, in accounting for child effects on parental negativity. Participants included 561 children adopted at birth, and their adoptive parents and birth parents within a prospective longitudinal adoption study. Findings indicated child effects on parental negativity, such that toddlers’ negative reactivity at 18 months was positively associated with adoptive parents’ over‐reactive and hostile parenting at 27 months. Furthermore, we found that child effects on parental negativity were partially due to heritable (e.g., birth mother [BM] internalizing problems and substance use) and prenatal factors (e.g., BM illicit drug use during pregnancy) that influence children’s negative reactivity at 18 months. This study provides critical evidence for “child on parent” effects.
Explaining Individual Differences in Trajectories of Simultaneous Bilingual Development: Contributions of Child and Environmental Factors
Authors: Lauro Justin , Core Cynthia , Hoff Erika
Published: August 2020

Effects of child and environmental factors in moderating the course of bilingual development were investigated using longitudinal data, from age 2.5 to 5 years, on 126 U.S.‐born children with early exposure to Spanish and English. Multilevel models of Spanish and English expressive vocabulary identified children’s phonological memory ability as a significant predictor of both outcomes, while also replicating the effect of the relative amount of language exposure. In addition, nonverbal IQ was a significant predictor of English vocabulary; birth order and maternal education in Spanish were significant predictors of Spanish vocabulary. These findings expand our understanding of the sources of the wide heterogeneity in bilingual development and of the requirements that language acquisition makes of learners and their environments.
Prevalence of latent and overt polyautoimmunity in autoimmune thyroid disease: A systematic review and meta‐analysis
Authors: Botello Alejandro , Herrán María , Salcedo Valentina , Rodríguez Yhojan , Anaya Juan‐Manuel , Rojas Manuel
Published: August 2020

Background

Thyroid autoimmunity is the most frequent condition involved in polyautoimmunity (PolyA). However, the frequency of latent and overt PolyA in patients with autoimmune thyroid disease (AITD) as the index condition is unknown. Therefore, the purpose of this study was to determine the prevalence of these types of PolyA in patients with AITD as the index condition.

Methods

This study adhered to the relevant sections of the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guideline. Searches through MEDLINE, Embase and LILACS were done to find articles in Spanish and English. Relevant vocabulary terms and key terms related to AITD and other autoimmune diseases were used. Two investigators independently screened the eligible studies, extracted data and assessed the quality and risk of bias. Fixed and random effect models were used accordingly. Cluster analysis was used to determine similarities among diseases in the articles included (based on Jaccard index).

Results

A total of 56 articles fulfilled the inclusion criteria. Of these, 25 were case‐controls, 17 were cohorts, and 14 were cross‐sectional studies. These studies included a total of 47 509 patients. Female was the predominant gender and included 38 950 patients (81.23%, 95% CI: 80.85‐81.60). Graves’ disease (GD) was the most common type of thyroid autoimmunity (69.16%, 95% CI: 68.23‐70.07). Globally, overt PolyA was found in 13.46% of the patients with AITD. This type of PolyA was represented mainly by type 1 diabetes and autoimmune gastritis. Latent PolyA was presented in 17.45% of the patients, and anti‐proinsulin, anti‐parietal cells and dsDNA antibodies were the most common. HT had the highest frequency of overt PolyA in Europe (15.60%, 95% CI: 14.72‐16.53), whereas latent PolyA was most common in patients with GD in Asia (21.03%, 95% CI: 17.76‐24.71). Overt and latent PolyA were associated with gastrointestinal and endocrinological ADs in most of cases and clustered with rheumatological, dermatological and neurological ADs.

Conclusions

Latent and overt PolyA are common in patients with AITD. These results provide insightful information for early diagnosis and management of concurrent ADs in patients with AITD. Aggregation of ADs in different clusters may help to define different phenotypes associated with thyroid autoimmunity that are critically relevant in clinical settings.
Trends in tonsillectomy surgery in children in Scotland 2000‐2018
Authors: Kubba Haytham , Downie Laura S.
Published: August 2020

Background

Tonsillectomy is one of the most common surgical procedures in children but indications and surgical practice change over time.

Objectives

We aimed to identify trends in tonsillectomy procedures in children, in particular the number of procedures performed, the age of child undergoing tonsillectomy and the type of hospital in which the surgery was performed.

Design

Review of Scottish Morbidity Records data (SMR01) which are routinely collected after everyday case procedure or overnight stay in all Scottish NHS hospitals.

Setting

All NHS hospitals in all 14 Scottish health boards.

Participants

All children (0‐16 years) undergoing tonsillectomy, 2000‐2018.

Main outcome measures

Number of tonsillectomy procedures; rate of tonsillectomy per 1000 children in the population; number of children aged 0‐2 years and 3‐4 years undergoing tonsillectomy; health board in which the surgery occurred; diagnostic coding for these episodes; length of stay and readmission within 30 days of surgery.

Results

During 2000‐2018, there were 50,208 tonsillectomies performed in children in Scotland (mean 2642/year). The number of tonsillectomies per year remained constant (R = 0.322, P = .178) but tonsillectomies performed in children 0‐2 years rose from 0.41 to 1.56 per 1000 (R = 0.912, P < .001), and 3‐4 years from 3.06 to 6.93 per 1000 (R = 0.864, P < .001). The proportion of all children's tonsillectomies performed up to age 4 rose from 20.6% to 35.9% and up to age 2 from 2.4% to 8.1%. All specialist children's hospitals showed a significant increase in surgery in very young children.

Conclusions

Tonsillectomy rates remained static between 2000 and 2018, despite a falling population. More tonsillectomies are now performed for obstructive sleep apnoea, at a young age and in regional children's hospitals. This has important implications for the workload of these specialist hospitals.
Quality‐of‐life changes following three‐dimensional printing of prosthesis for large nasal septal perforations—Our experience of 13 patients
Authors: Medikeri Gaurav S. , Khong Grace C. , Fleming Sarah , Malhotra Taran , Leong Samuel C.
Published: August 2020

Nasal septal perforations can be caused by a number of aetiology including intra‐nasal drug abuse, trauma and iatrogenic causes.
Improvement of the experience of colorectal cancer patients in Sweden with a regional cancer plan
Authors: Sjövall A. , Söderqvist L. , Martling A. , Buchli C.
Published: August 2020

Aim

The Stockholm‐Gotland Regional Cancer Plan was launched in 2012 to improve cancer care. A personal contact nurse (CN), an individual written care plan (IWCP) and a standardized care pathway (SCP) were introduced. The aim of the current study was to evaluate whether these efforts have resulted in an improved experience for patients treated for colorectal cancer.

Method

Patients treated with bowel resection for colorectal cancer in the Stockholm‐Gotland region between 1 January 2013 and 31 December 2017 were identified through the Swedish Colorectal Cancer Registry. Six to eight months postoperatively, the patients received a patient‐reported experience questionnaire. Patients were classified as ‘satisfied’ or ‘not satisfied’.

Results

The questionnaire was sent to 4465 patients, and 3154 (70.64%) responded. The proportion of patients assigned a CN increased over time (79.84%–88.44%) and so did the proportion of patients receiving an IWCP (39.36%–70.00%). The waiting times were significantly shortened during the study period. In multivariable analysis, access to a CN and an IWCP was independently associated with increased patient satisfaction (OR 3.03, 95% CI 2.28–4.02 and OR 1.64, 95% CI 1.38–1.94). Patients with a long waiting time were significantly less satisfied than patients with a short waiting time (OR 0.72, 95% CI 0.60–0.88).

Conclusion

Implementation of a CN, IWCP and SCP has been successful, measured by a higher proportion of patients gaining access to these assets and shortened waiting times. This has led to an improved patient experience in patients treated for colorectal cancer in the Stockholm‐Gotland region.
CEO outside directorships and managerial efficiency: The role of host board capital
Authors: Mutlu Canan C. , Mutlu Sunay , Sauerwald Steve
Published: August 2020

Research Question/Issue

Do CEO outside board directorships improve or reduce CEO managerial efficiency? What is the role of host board capital in this relationship?

Research Findings/Insights

We explore the value of CEO outside directorships on managerial efficiency by identifying a unique empirical setting where a CEO's number of outside board seats is exogenously decreased by a merger that eliminates the board of a host firm the CEO is serving on. Using this event as our empirical instrument, we find that outside directorships decrease a CEO's managerial efficiency while host board capital reduces this effect.

Theoretical/Academic Implications

Proponents view outside board service as a valuable leadership development tool to mentor the CEO while others promulgating an agency view argue that outside board service detracts from the CEO's ability to improve the efficiency of the home firm as it leads to busyness of the CEO. We shed light on this debate by arguing that CEO outside directorships might reduce CEO's managerial efficiency; however, this effect might be contingent on the characteristics of the host board.

Practitioner/Policy Implications

Our findings offer insights to practitioners about the value of multiple directorships and the importance of the host board capital while informing policy makers about the potential restrictions on outside board assignments.
Physician and patient acceptance of policies to reduce kidney discard
Authors: Mehrotra Sanjay , Schantz Karolina , Friedewald John J. , Ladner Daniela P. , Becker Yolanda , Formica Richard , Barah Masoud , Gu Jiayi , Gordon Elisa J.
Published: August 2020

Despite the shortage of kidneys for transplantation in the United States, approximately 18%‐20% of deceased donor kidneys are discarded each year. These discarded kidneys can offer a survival benefit to suitable patients. Revisions to the current kidney allocation policy may be needed to reduce deceased donor kidney discard. We surveyed transplant physicians and patients to assess their perceived acceptability of policy proposals to reduce the discard of deceased donor kidneys. Members of professional societies (AST, ASTS) and a patient organization (AAKP) were invited to complete the survey. Responses were obtained from 97 physicians and 107 patients. The majority of physicians (73.4%) and patients (73.8%) "somewhat" or "completely" accepted a policy for fast‐tracking kidneys at risk of discard. Physicians and patients also supported returning a proportion of waiting time to patients who accept KDPI >85 kidneys and experience graft failure within the first 12 months, with 36% of physicians and 50% of patients electing to return 100% of the waiting time. The majority of physicians (75%) "somewhat or completely" accepted a policy to skip less aggressive centers for KDPI 90 + offers. Physicians and patients provided insights into factors researchers, and policymakers should consider in the design and implementation of these policies.
Environmental drivers of movement in a threatened seabird: insights from a mechanistic model and implications for conservation
Authors: Frankish Caitlin K. , Phillips Richard A. , Clay Thomas A. , Somveille Marius , Manica Andrea
Published: August 2020

Aim

Determining the drivers of movement of different life‐history stages is crucial for understanding age‐related changes in survival rates and, for marine top predators, the link between fisheries overlap and incidental mortality (bycatch), which is driving population declines in many taxa. Here, we combine individual tracking data and a movement model to investigate the environmental drivers and conservation implications of divergent movement patterns in juveniles (fledglings) and adults of a threatened seabird, the white‐chinned petrel (Procellaria aequinoctialis).

Location

South‐west Atlantic Ocean.

Methods

We compare the spatial distributions and movement characteristics of juvenile, breeding and non‐breeding adult petrels, and apply a mechanistic movement model to investigate the extent to which chlorophyll a concentrations (a proxy for food resources) and ocean surface winds drive their divergent distribution patterns. We also consider the conservation implications by determining the relative overlap of each life‐history stage with fishing intensity and reported fishing effort (proxies for bycatch risk).

Results

Naïve individuals fledged with similar flight capabilities (based on distances travelled, flight speeds and track sinuosity) to adults but differed in their trajectories. Comparison of simulations from the mechanistic model with real tracks showed that juvenile movements are best predicted by prevailing wind patterns, whereas adults are attracted to food resources on the Patagonian Shelf. The juveniles initially dispersed to less productive oceanic waters than those used by adults, and overlapped less with fishing activity; however, as they moved westwards towards South America, bycatch risk increased substantially.

Main conclusions

The use of a mechanistic framework provided insights into the ontogeny of movement strategies within the context of learned versus innate behaviour and demonstrated that divergent movement patterns of adults and juveniles can have important implications for the conservation of threatened seabirds.
Metabolic syndrome in type 1 diabetes and its association with diabetes complications
Authors: Lee Angela S. , Twigg S. M. , Flack J. R.
Published: August 2020

Aim

To assess the prevalence of metabolic syndrome in type 1 diabetes, and its age‐related association with diabetes complications.

Methods

Australian National Diabetes Information Audit and Benchmarking (ANDIAB) was a well‐established quality audit programme. It provided cross‐sectional data on people attending specialist diabetes services across Australia. We determined the prevalence of metabolic syndrome (WHO criteria) in adults with type 1 diabetes and its associations with diabetes complications across age groups.

Results

Metabolic syndrome prevalence was 30% in 2120 adults with type 1 diabetes. Prevalence increased with age: 21% in those aged <40 years, 35% in those aged 40–60 years, and 44% in those aged >60 years (P<0.001), which was driven by an increase in hypertension rate. Metabolic syndrome was associated with a higher prevalence of microvascular, macrovascular and foot complications, with the greatest impact at a younger age. The odds ratio for macrovascular complications with metabolic syndrome, compared with without, was 5.9 (95% CI 2.1–16.4) in people aged <40 years, 2.7 (95% CI 1.7–4.2) in those aged 40–60 years, and 1.7 (95% CI 1.1–2.7) in those aged >60 years (all P < 0.05). Metformin use was higher in those with metabolic syndrome (16% vs 4%; P<0.001).

Conclusions

In this large Australian cohort, metabolic syndrome was common in type 1 diabetes and identified people at increased risk of the spectrum of diabetes complications, particularly in young to middle‐aged adults. Potential clinical implications are that therapies targeting insulin resistance in this high‐risk group may reduce diabetes complications and should be explored.
Aggrecan modulates the expression and phosphorylation of tau in a novel bigenic TauP301L ‐ Acan mouse model
Authors: Schmidt Sophie , Stapf Caroline , Schmutzler Sandra , Lachmann Ingolf , Arendt Thomas , Holzer Max , Sonntag Mandy , Morawski Markus
Published: August 2020

Selected types of neurons in the central nervous system are associated with a specialized form of extracellular matrix. These so‐called perineuronal nets (PNs) are supramolecular structures surrounding neuronal somata, proximal dendrites and axon initial segments. PNs are involved in the regulation of plasticity and synaptic physiology. In addition, PNs were proposed to carry neuroprotective functions as PN‐ensheathed neurons are mostly spared of tau pathology in brains of Alzheimer patients. Recently, the neuroprotective action of PNs was confirmed experimentally, demonstrating (i) that mainly aggrecan mediates the neuroprotective function of PNs and (ii) that aggrecan seems to generate an external shielding preventing the internalization of pathological forms of tau. In the present study, we aimed at extending these findings and hypothesized that aggrecan further provides an intracellular protection by preventing mutation‐triggered formation of pathological forms of tau. We used crossbreds of TauP301L mice and heterozygous aggrecan mice which are characterized by spontaneous deletion of the aggrecan allele. We analysed the extent of tau pathology in dependence of aggrecan protein amount by applying immunohistochemistry, Western blotting and ELISA. The results clearly indicate that aggrecan has no significant impact on tau aggregation in the brainstem of our mouse model. Still, reduced aggrecan levels were accompanied by increased levels of tau protein and reduced number of Tau‐1‐positive neurons, which indicate an increase in phosphorylation of tau. In conclusion, these data demonstrate a correlation between aggrecan and P301L mutation‐triggered tau expression and phosphorylation in our bigenic mouse model.
Influence of proanthocyanidins combined with ethanol‐wet bonding on the bonding quality of fibre posts to root dentine
Authors: Shen Lipei , Xiong Jie , Jiang Qingsong
Published: August 2020

This study evaluated the influence of a bonding approach using proanthocyanidins (PAs) combined with ethanol‐wet bonding (EWB) and a hydrophobic adhesive on the bonding quality of fibre posts. After endodontic treatment and post‐space preparation, 72 single‐rooted extracted human teeth were etched, thoroughly rinsed, and then treated using the following procedures (n = 24 teeth per group): group 1, no pretreatment; group 2, pretreatment with absolute ethanol three times, for 30 s each time; or group 3, pretreatment with absolute ethanol solution containing 5% PAs three times, for 30 s each time. Six teeth per group were dried according to a dry and a wet drying protocol and then observed using field emission‐scanning electron microscopy. The remaining 18 teeth in each group were cemented with fibre posts: All‐Bond 3 and Duo‐Link cement were used for group 1; and hydrophobic adhesive and Duo‐Link cement were used for groups 2 and 3. Push‐out bond strength, failure mode, and nanoleakage were evaluated immediately and after collagenase treatment. Higher push‐out bond strength and less nanoleakage were observed in the two ethanol‐pretreatment groups, regardless of storage conditions. Teeth pretreated with PAs + ethanol exhibited significantly higher push‐out bond strength after collagenase treatment than did teeth pretreated with ethanol alone. Within the limits of this study, the bonding approach of PAs combined with EWB and a hydrophobic adhesive synergistically improved the durability of fibre post bonds.
Cues for seizure timing
Authors: Rao Vikram R. , G. Leguia Marc , Tcheng Thomas K. , Baud Maxime O.
Published: August 2020

The cyclical organization of seizures in epilepsy has been described since antiquity. However, historical explanations for seizure cycles—based on celestial, hormonal, and environmental factors—have only recently become testable with the advent of chronic electroencephalography (cEEG) and modern statistical techniques. Here, factors purported over millennia to influence seizure timing are viewed through a contemporary lens. We discuss the emerging concept that seizures are organized over multiple timescales, each involving differential influences of external and endogenous rhythm generators. Leveraging large cEEG datasets and circular statistics appropriate for cyclical phenomena, we present new evidence for circadian (day‐night), multidien (multi‐day), and circannual (about‐yearly) variation in seizure activity. Modulation of seizure timing by multiscale temporal variables has implications for diagnosis and therapy in clinical epilepsy. Uncovering the mechanistic basis for seizure cycles, particularly the factors that govern multidien periodicity, will be a major focus of future work.
Host plants and Wolbachia shape the population genetics of sympatric herbivore populations
Authors: Fu Zhen , Meier Amanda R. , Epstein Brendan , Bergland Alan O. , Castillo Carrillo Carmen I. , Cooper William R. , Cruzado Regina K. , Horton David R. , Jensen Andrew S. , Kelley Joanna L. , Rashed Arash , Reitz Stuart R. , Rondon Silvia I. , Thinakaran Jenita , Wenninger Erik J. , Wohleb Carrie H. , Crowder David W. , Snyder William E.
Published: August 2020

Changing climate and land‐use practices have the potential to bring previously isolated populations of pest insects into new sympatry. This heightens the need to better understand how differing patterns of host–plant association, and unique endosymbionts, serve to promote genetic isolation or integration. We addressed these factors in populations of potato psyllid, Bactericera cockerelli (Šulc), a generalist herbivore that vectors a bacterial pathogen (Candidatus Liberibacter solanacearum, causal pathogen of zebra chip disease) of potato (Solanum tuberosum L.). Genome‐wide SNP data revealed two major genetic clusters—psyllids collected from potato crops were genetically similar to psyllids found on a common weed, Lycium spp., but dissimilar from those found on another common non‐crop host, Solanum dulcamara L. Most psyllids found on Lycium spp. and potato represented a single mitochondrial cytochrome oxidase I (COI) haplotype that has been suggested to not be native to the region, and whose arrival may have been concurrent with zebra chip disease first emerging. The putatively introduced COI haplotype usually co‐occurred with endosymbiotic Wolbachia, while the putatively resident COI haplotype generally did not. Genetic intermediates between the two genetic populations of insects were rare, consistent with recent sympatry or reproductive isolation, although admixture patterns of apparent hybrids were consistent with introgression of genes from introduced into resident populations. Our results suggest that both host–plant associations and endosymbionts are shaping the population genetic structure of sympatric psyllid populations associated with different non‐crop hosts. It is of future interest to explicitly examine vectorial capacity of the two populations and their potential hybrids, as population structure and hybridization might alter regional vector capacity and disease outbreaks.
Development and characterization of a human Th17‐driven ex vivo skin inflammation model
Authors: Jardet Claire , David Anthony , Braun Emilie , Descargues Pascal , Grolleau Jean‐Louis , Hebsgaard Josephine , Norsgaard Hanne , Lovato Paola
Published: August 2020

Skin models mimicking features of psoriasis‐related inflammation are needed to support the development of new drugs in dermatology. Reconstructed skin models lack tissue complexity, including a fully competent skin barrier, and presence and/or diversity of immune cells. Here, we describe InflammaSkin®, a novel human Th17‐driven ex vivo skin inflammation model. In this model, skin‐resident T cells are in situ activated by intradermal injection of anti‐CD3 and anti‐CD28 antibodies and Th17 cell polarization is sustained by culture in a chemically defined medium supplemented with IL‐1β, IL‐23 and TGF‐β for seven days. The acquired Th17 signature is demonstrated by the sustained secretion of IL‐17A, IL‐17AF, IL‐17F, IL‐22, IFN‐γ, and to some degree IL‐15 and TNF‐α observed in the activated ex vivo skin inflammation model compared with the non‐activated skin model control. Furthermore, expression of S100A7 and Keratin‐16 by keratinocytes and loss of epidermal structure integrity occur subsequently to in situ Th17cell activation, demonstrating cellular crosstalk between Th17 cells and keratinocytes. Finally, we demonstrate the use of this model to investigate the modulation of the IL‐23/IL‐17 immune axis by topically applied anti‐inflammatory compounds. Taken together, we show that by in situ activation of skin‐resident Th17 cells, the InflammaSkin® model reproduces aspects of inflammatory responses observed in psoriatic lesions and could be used as a translational tool to assess efficacy of test compounds.
Tumor markers as an entry for SARS‐CoV‐2 infection?
Authors: Xia Pu , Dubrovska Anna
Published: August 2020

Coronavirus disease 2019 (COVID‐19), the highly contagious illness caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has spread across the globe, becoming one of the most challenging public health crisis of our times. SARS‐CoV‐2 can cause severe disease associated with multiple organ damage. Cancer patients have a higher risk of SARS‐CoV‐2 infection and death. While the virus uses angiotensin‐converting enzyme 2 (ACE2) as the primary entry receptor, the recent experimental and clinical findings suggest that some tumor markers, including CD147 (basigin), can provide an additional entry for SARS‐CoV‐2 infection through binding to the viral spike (S) protein. In the absence of specific viral drugs, blocking of CD147 might be a way to prevent virus invasion. Identifying other target proteins is of high importance as targeting the alternative receptors for SARS‐CoV‐2 might open up a promising avenue for the treatment of COVID‐19 patients, including those who have cancer.
Agricultural residues bioenergy potential that sustain soil carbon depends on energy conversion pathways
Authors: Hansen Julie H. , Hamelin Lorie , Taghizadeh‐Toosi Arezoo , Olesen Jørgen E. , Wenzel Henrik
Published: August 2020

Agricultural crop residues represent a significant part of the biomass potentially available for renewable energy systems. Sustaining soil organic carbon (C) is a common limiting factor applied to the biophysically available resource to determine crop residues potential for bioenergy. Studies quantifying this potential have so far largely considered crop biomass to produce renewable energy as being independent from the energy conversion pathway. However, the conversion method has great influence on how much C in crop residues can be returned back and retained in soils. Here, we applied the C‐TOOL soil C model for two extreme conversion pathways of agricultural straw management in terms of C returned back to soils, using Denmark as a case study. Those were anaerobic digestion, involving the return of recalcitrant C to fields, and combustion, involving no C returns to agricultural fields. Danish agriculture was represented by six different soil‐cropping schemes units on which our two extreme bioenergy pathways were modelled. We applied a premise that for a given geographical unit, the same long‐term soil C level needs to be achieved under these extreme bioenergy scenarios; therefore, we identified how much straw could be removed from agricultural fields in each case while maintaining equal soil organic carbon (SOC) levels. We found that at the scale of the whole country, only 26% of the straw potential can be harvested for use in combustion to maintain in average long‐term SOC at the same level as it would have been with the anaerobic digestion scenario. Thus, consideration for the biomass conversion pathway is important when identifying agricultural residue potentials for energy conversion while ensuring that SOC level is not compromised.
Geographical Analysis at Midlife
Authors: Franklin Rachel S.
Published: August 2020

In this commentary, I reflect on geographical analysis as it enters middle age, focusing on what I perceive to be central elements—for both field and journal—of past growth and development, as well as future robustness and potential. My particular interest lies in evaluating “geographical analysis” as it stands today, taking the journal as one proxy for the larger field, and placing this within a wider context of quantitative human geography. As with any set of perspectives, mine are idiosyncratic and the product of a particular experience at a particular time. To make my case, I draw on manuscript citation histories from Geographical Analysis, my interpretation of recent developments in the discipline, and of course the insights of others who have plowed these pastures before me. I close by offering some thoughts about the future directions of our field and our journal.
Screening siRNAs against host glycosylation pathways to develop novel antiviral agents against hepatitis B virus
Authors: Ito Kiyoaki , Angata Kiyohiko , Kuno Atsushi , Okumura Akinori , Sakamoto Kazumasa , Inoue Rieko , Morita Naoko , Watashi Koichi , Wakita Takaji , Tanaka Yasuhito , Sugiyama Masaya , Mizokami Masashi , Yoneda Masashi , Narimatsu Hisashi
Published: August 2020

Aim

Hepatitis B virus (HBV) relies on glycosylation for crucial functions, such as entry into host cells, proteolytic processing and protein trafficking. The aim of this study was to identify candidate molecules for the development of novel antiviral agents against HBV using an siRNA screening system targeting the host glycosylation pathway.

Methods

HepG2.2.15.7 cells that consistently produce HBV were employed for our in vitro study. We investigated the effects of siRNAs that target 88 different host glycogenes on hepatitis B surface antigen (HBsAg) and HBV DNA secretion using the siRNA screening system.

Results

We identified four glycogenes that reduced HBsAg and/or HBV DNA secretion; however, the observed results for two of them may be due to siRNA off‐target effects. Knocking down ST8SIA3, a member of the sialyltransferase family, significantly reduced both HBsAg and HBV DNA secretion. Knocking down GALNT7, which transfers N‐acetylgalactosamine to initiate O‐linked glycosylation in the Golgi apparatus, also significantly reduced both HBsAg and HBV DNA levels.

Conclusions

These results showed that knocking down the ST8SIA3 and GALNT7 glycogenes inhibited HBsAg and HBV DNA secretion in HepG2.2.15.7 cells, indicating that the host glycosylation pathway is important for the HBV life cycle and could be a potential target for the development of novel anti‐HBV agents.
Adaptation and qualitative evaluation of Ask 3 Questions — a simple and generic intervention to foster patient empowerment
Authors: Lindig Anja , Hahlweg Pola , Frerichs Wiebke , Topf Cheyenne , Reemts Martin , Scholl Isabelle
Published: August 2020

Background

Patients are often not actively engaged in medical encounters. Short interventions like Ask 3 Questions (Ask3Q) can increase patient participation in decision‐making. Up to now, Ask3Q was not available in German.

Objective

To translate Ask3Q and evaluate its acceptability and feasibility.

Methods

We translated and adapted several English versions of Ask3Q using a team translation protocol and cognitive interviews. Acceptability and feasibility of the final German Ask3Q version were assessed via focus groups and interviews with patients and healthcare professionals (HCPs). Data were analysed via qualitative content analysis.

Results

Translation and adaptation were successful. Participants of focus groups and interviews perceived Ask3Q as a tool to empower patients to ask more questions. Moreover, it was seen as a guideline for physicians not to forget conveying important information. Several characteristics of patients, HCPs, the clinical setting and the intervention were identified as facilitators and barriers for an effective implementation of Ask3Q.

Conclusion

We provide the German version of Ask3Q. According to participants, implementation of Ask3Q in the German healthcare system is feasible. Future studies should evaluate if positive effects of Ask3Q can be replicated for patient participation and communication behaviour of HCPs in Germany.
Dendritic cells in Th2 immune responses and allergic sensitization
Authors: Lamiable Olivier , Mayer Johannes U , Munoz‐Erazo Luis , Ronchese Franca
Published: August 2020

Allergic responses are characterized by the activation of a specific subset of effector CD4+ T cells, the T‐helper type 2 (Th2) cells, that respond to harmless environmental antigens causing inflammation and pathology. Th2 cells are also found in the context of parasite infections, where they can mediate parasite clearance and expulsion, and support tissue repair. The process that leads to the activation of Th2 cells in vivo is incompletely understood: while it has become clear that “conventional” dendritic cells are essential antigen‐presenting cells for the initiation of Th2 immune responses, the molecules that are expressed by dendritic cells exposed to allergens, and the mediators that are produced as a consequence and signal to naïve CD4+ T cells to promote their development into effector Th2, remain to be defined. Here we summarize recent developments in the identification of the dendritic cell subsets involved in Th2 responses, review potential mechanisms proposed to explain the generation of these immune responses, and discuss the direct and indirect signals that condition dendritic cells to drive the development of Th2 responses during allergen or parasite exposure.
p38 MAPK signaling mediates retinoic acid‐induced CD103 expression in human dendritic cells
Authors: Roe Mandi M. , Hashimi Marziah , Swain Steve , Woo Krista M. , Bimczok Diane
Published: August 2020

Retinoic acid (RA) is an active derivative of vitamin A and a key regulator of immune cell function. In dendritic cells (DCs), RA drives the expression of CD103 (integrin αE), a functionally relevant DC subset marker. In this study, we analyzed the cell type specificity and the molecular mechanisms involved in RA‐induced CD103 expression. We show that RA treatment caused a significant up‐regulation of CD103 in differentiated monocyte‐derived DCs and blood DCs, but not in differentiated monocyte‐derived macrophages or T cells. DC treatment with an RA receptor α (RARα) agonist led to an increase in CD103 expression similar to that in RA treatment, whereas RARA gene silencing with small interfering RNA blocked RA‐induced up‐regulation of CD103, pointing to a major role of RARα in the regulation of CD103 expression. To elucidate RA‐induced signaling downstream of RARα, we used Western blot analysis of RA‐treated DCs and showed a significant increase of p38 mitogen‐activated protein kinase (MAPK) phosphorylation. In addition, DCs cultured with RA and a p38 MAPK inhibitor had a significantly reduced expression of CD103 compared with DCs cultured with RA only, indicating that p38 MAPK is involved in CD103 regulation. In summary, these findings suggest that the RA‐induced expression of CD103 is specific to DCs, is mediated primarily through RARα and involves p38 MAPK signaling.
Pyroptotic and non‐pyroptotic effector functions of caspase‐11
Authors: Abu Khweek Arwa , Amer Amal O.
Published: August 2020

Innate immune cells, epithelial cells, and many other cell types are capable of detecting infection or tissue injury, thus mounting regulated immune response. Inflammasomes are highly sophisticated and effective orchestrators of innate immunity. These oligomerized multiprotein complexes are at the center of various innate immune pathways, including modulation of the cytoskeleton, production and maturation of cytokines, and control of bacterial growth and cell death. Inflammasome assembly often results in caspase‐1 activation, which is an inflammatory caspase that is involved in pyroptotic cell death and release of inflammatory cytokines in response to pathogen patterns and endogenous danger stimuli. However, the nature of stimuli and inflammasome components are diverse. Caspase‐1 activation mediated release of mature IL‐1β and IL‐18 in response to canonical stimuli initiated by NOD‐like receptor (NLR), and apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC). On the other hand, caspase‐11 delineates a non‐canonical inflammasome that promotes pyroptotic cell death and non‐pyroptotic functions in response to non‐canonical stimuli. Caspase‐11 in mice and its homologues in humans (caspase‐4/5) belong to caspase‐1 family of cysteine proteases, and play a role in inflammation. Knockout mice provided new genetic tools to study inflammatory caspases and revealed the role of caspase‐11 in mediating septic shock in response to lethal doses of lipopolysaccharide (LPS). Recognition of LPS mediates caspase‐11 activation, which promotes a myriad of downstream effects that include pyroptotic and non‐pyroptotic effector functions. Therefore, the physiological functions of caspase‐11 are much broader than its previously established roles in apoptosis and cytokine maturation. Inflammation induced by exogenous or endogenous agents can be detrimental and, if excessive, can result in organ and tissue damage. Consequently, the existence of sophisticated mechanisms that tightly regulate the specificity and sensitivity of inflammasome pathways provides a fine‐tuning balance between adequate immune response and minimal tissue damage. In this review, we summarize effector functions of caspase‐11.
Placental Transfer of Phenylalanine in Macaca mulatta and Macaca fascicularis
Authors: Pueschel Siegfried M. , Boylan Joan M. , Jackson Benjamin T. , Piasecki George J.
Published: August 2020

We investigated placental transport mechanisms of phenylalanine in Macaca mulatta and Macaca fascicularis. In the beginning of the third trimester we administered i.v. phenylalanine and p‐chlorophenylalaninc to pregnant animals. Initial higher phenylalanine concentrations were observed followed by a rapid decrease in both rhesus mothers and fetuses when compared with phenylalanine levels in fascicularis mothers and fetuses. In general, however, placental transfer mechanisms of phenylalanine did not differ significantly between the two species.