bluuebunny/crossref_metadata_2025 huggingface dataset:
Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De‐novo heart transplant recipients: Design of the randomized controlled EVOLVD trial
Authors: Broch Kaspar , Gude Einar , Karason Kristjan , Dellgren Göran , Rådegran Göran , Gjesdal Grunde , Gustafsson Finn , Eiskjær Hans , Lommi Jyri , Pentikäinen Markku , Lemström Karl B. , Andreassen Arne K. , Gullestad Lars
Published: May 2020

Background

Cardiac allograft vasculopathy (CAV) is characterized by diffuse thickening of the arterial intima. Statins reduce the incidence of CAV, but despite the use of statins, CAV remains one of the leading causes of long‐term death after heart transplant. Inhibitors of proprotein convertase subtilisin‐kexin type 9 (PCSK9) substantially reduce cholesterol levels but have not been tested in heart transplant recipients.

Methods

The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De‐novo heart transplant recipients (EVOLVD) trial (ClinicalTrials.gov Identifier: NCT03734211) is a randomized, double‐blind trial designed to test the effect of the PCSK9 inhibitor evolocumab on coronary intima thickness in heart transplant recipients. Adults who have received a cardiac transplant within the past 4‐8 weeks are eligible. Exclusion criteria include an estimated glomerular filtration rate < 20 mL/min/1.73 m2, renal replacement therapy, or contraindications to coronary angiography with intravascular ultrasound. 130 patients will be randomized (1:1) to 12‐month treatment with evolocumab or matching placebo. The primary endpoint is the coronary artery intima thickness as measured by intravascular ultrasound.

Conclusion

The EVOLVD trial is a randomized clinical trial designed to show whether treatment with the PCSK9 inhibitor evolocumab can ameliorate CAV over the first year after heart transplant.
What solid organ transplant healthcare providers should know about renin‐angiotensin‐aldosterone system inhibitors and COVID‐19
Authors: Wong Sunnie Y. , Brubaker Aleah L. , Wang Aileen X. , Taiwo Adetokunbo A. , Melcher Marc L.
Published: May 2020

The data on the outcomes of solid organ transplant recipients who have contracted coronavirus disease 2019 (COVID‐19) are still emerging. Kidney transplant recipients are commonly prescribed renin‐angiotensin‐aldosterone system (AAS) inhibitors given the prevalence of hypertension, diabetes, and cardiovascular disease. As the angiotensin‐converting enzyme 2 (ACE2) facilitates the entry of coronaviruses into target cells, there have been hypotheses that preexisting use of renin‐angiotensin‐aldosterone system (RAAS) inhibitors may increase the risk of developing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Given the common use of RAAS inhibitors among solid organ transplant recipients, we sought to review the RAAS cascade, the mechanism of SARS‐CoV‐2 entry, and pertinent data related to the effect of RAAS inhibitors on ACE2 to guide management of solid organ transplant recipients during the COVID‐19 pandemic. At present, there is no clear evidence to support the discontinuation of RAAS inhibitors in solid organ transplant recipients during the COVID‐19 pandemic.
Technical Note: Mean Lead‐Time as a Real‐Time Key Performance Indicator
Authors: Niemi Tapio , Gallay Olivier , Hameri Ari‐Pekka
Published: May 2020

Measuring the average time that a process takes from start to finish, using observation time windows (OTWs) of different length, is required for numerous operational monitoring and control processes. We refer to this measure as the Mean Lead‐Time (MLT). This study is based on the fact that computing the MLT in an operational context is often misleading for two reasons: (1) the computed value directly depends on the length of the used OTW; and (2) some jobs are usually still running at the end of the OTW, and thus their final lead‐time is not known yet. To overcome these issues, we revisit the definition of the MLT as well as the way to measure it. We develop a method to take these two aspects into account and apply this method to four real‐life cases in different business contexts. Using these practical cases, we show that the proposed methodology makes it possible to compute a standardized measure of the MLT, allowing for a meaningful comparison when different OTW lengths are considered. These new results open the door for an efficient use of the MLT as a commensurable performance indicator and allow near real‐time monitoring and comparison across different process steps, departments, and factories.
The moment‐to‐moment pitch dynamics of child‐directed speech shape toddlers’ attention and learning
Authors: Nencheva Mira L. , Piazza Elise A. , Lew‐Williams Casey
Published: May 2020

Young children have an overall preference for child‐directed speech (CDS) over adult‐directed speech (ADS), and its structural features are thought to facilitate language learning. Many studies have supported these findings, but less is known about processing of CDS at short, sub‐second timescales. How do the moment‐to‐moment dynamics of CDS influence young children's attention and learning? In Study 1, we used hierarchical clustering to characterize patterns of pitch variability in a natural CDS corpus, which uncovered four main word‐level contour shapes: ‘fall’, ‘rise’, ‘hill’, and ‘valley’. In Study 2, we adapted a measure from adult attention research—pupil size synchrony—to quantify real‐time attention to speech across participants, and found that toddlers showed higher synchrony to the dynamics of CDS than to ADS. Importantly, there were consistent differences in toddlers’ attention when listening to the four word‐level contour types. In Study 3, we found that pupil size synchrony during exposure to novel words predicted toddlers’ learning at test. This suggests that the dynamics of pitch in CDS not only shape toddlers’ attention but guide their learning of new words. By revealing a physiological response to the real‐time dynamics of CDS, this investigation yields a new sub‐second framework for understanding young children's engagement with one of the most important signals in their environment.
Martin Luther and Philip Melanchthon on the care and feeding of [future] Pastors
Authors: Wengert Timothy J.
Published: May 2020

This article argues that humanist training was all‐encompassing, not just for Philip Melanchthon but also for Martin Luther. By reexamining the relationship between the two reformers in this area, the article shows how their substantial, overarching agreements, especially in matters of pedagogy, led to a single‐minded reform of Wittenberg's curriculum. Finally, it argues that their revolutionary approach to seminary training also addresses its collapse in our own day.
Oral antidiabetes agents for the management of inpatient hyperglycaemia: so far, yet so close
Authors: Koufakis T. , Mustafa O. G. , Zebekakis P. , Kotsa K.
Published: May 2020

Background

Hyperglycaemia is an ongoing challenge in hospital settings and is associated with poor outcomes. Current recommendations for the management of inpatient hyperglycaemia suggest insulin as the main glucose‐lowering treatment choice and limit the administration of oral antidiabetes agents to a small proportion of cases because of safety concerns.

Aim

To present and critically appraise the available evidence on the use of oral antidiabetes agents in the hospital setting and the risk–benefit balance of such an approach in the era of cardiovascular outcomes trials.

Methods

PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the efficacy and the safety profile of oral agents in the context of their use in hospitalized individuals are summarized and discussed in this narrative review.

Results

There is no robust evidence to suggest the use of metformin, thiazolidinediones, sulfonylureas and sodium‐glucose co‐transporter‐2 inhibitors in the hospital setting, although some of their effects on acute outcomes deserve further evaluation in future studies. However, the use of dipeptidyl peptidase‐4 inhibitors in inpatients with type 2 diabetes is supported by a few, well‐designed, randomized controlled trials. These trials have demonstrated good safety and tolerability profiles, comparable to insulin glucose‐lowering efficacy, and a reduction in insulin dose when dipeptidyl peptidase‐4 inhibitors are co‐administered with insulin, in individuals with mild to moderate hyperglycaemia and a stable clinical condition.

Conclusion

The administration of dipeptidyl peptidase‐4 inhibitors to specific groups of inpatients might be a safe and effective alternative to insulin.
Higher levels of bodily pain in people with long‐term type 1 diabetes: associations with quality of life, depressive symptoms, fatigue and glycaemic control – the Dialong study
Authors: Molvær A. K. , Iversen M. M. , Igland J. , Peyrot M. , Tell G. S. , Holte K. B. , Berg T. J.
Published: May 2020

Aims

To compare reported level of bodily pain, overall and health‐related quality of life (QoL), depression and fatigue in people with long‐term type 1 diabetes vs. a comparison group without diabetes. Further, to examine the associations of total bodily pain with QoL, depression, fatigue and glycaemic control in the diabetes group.

Methods

Cross‐sectional study of 104 (76% of eligible) people with type 1 diabetes of ≥ 45 years’ duration attending the Norwegian Diabetes Centre and 75 persons without diabetes who completed questionnaires measuring bodily pain (RAND‐36 bodily pain domain), shoulder pain (Shoulder Pain and Disability Index), hand pain (Australian/Canadian Osteoarthritis Hand Index), overall QoL (World Health Organization Quality of Life – BREF), health‐related QoL (RAND‐36), diabetes‐specific QoL (Audit of Diabetes‐Dependent Quality of Life; only diabetes group), depression (Patient Health Questionnaire) and fatigue (Fatigue questionnaire). For people with type 1 diabetes, possible associations between the bodily pain domain (lower scores indicate higher levels of bodily pain) and other questionnaire scores, were measured with regression coefficients (B) per 10‐unit increase in bodily pain score from linear regression.

Results

The diabetes group reported higher levels of bodily (P = 0.003), shoulder and hand pain (P < 0.001) than the comparison group. In the diabetes group, bodily pain was associated with lower overall and diabetes‐specific QoL [B (95% confidence intervals)]: 0.2 (0.1, 0.2) and 0.2 (0.1, 0.3); higher levels of depression −1.0 (−1.3, −0.7) and total fatigue −1.5 (−1.9, −1.2); and worse glycaemic control HbA1c (mmol/mol; %) −0.8 (−1.5, −0.1); −0.1 (−0.1, −0.01).

Conclusions

People with long‐term type 1 diabetes experience a high level of bodily pain compared with a comparison group. Total bodily pain was associated with worse QoL and glycaemic control.
Prevalence of diabetes and impaired fasting glucose in Poland in 2005–2014: results of the WOBASZ surveys
Authors: Rutkowski M. , Wojciechowska A. , Śmigielski W. , Drygas W. , Piwońska A. , Pająk A. , Tykarski A. , Kozakiewicz K. , Waśniewska M. K , Zdrojewski T.
Published: May 2020

Aims

To evaluate the prevalence of diabetes and impaired fasting glucose in Poland in 2013–2014 and to determine the temporal trends between 2003–2005 and 2013–2014.

Methods

A questionnaire survey was conducted in a representative sample of Polish adults, complemented by anthropometric and fasting plasma glucose measurements. The research was part of the national cross‐sectional WOBASZ study. Diabetes was assessed as self‐reported or screened (fasting plasma glucose level ≥ 7 mmol/l, based on one blood sample).

Results

In the years 2013–2014 among 5694 participants aged 20–74 years, 6.0% (95% CI 5.4–6.6) reported a previous diagnosis of diabetes (5.8% in women and 6.2% in men). In addition, 2.4% of the participants (95% CI 2.0–2.8) without a previous diagnosis of diabetes (1.8% of women and 3.1% of men) had a fasting blood glucose level ≥7.0 mmol/l in a single measurement. In a single measurement, 18.4% of the participants (95% CI 17.4–19.4; 13.2% of women and 23.8% of men) had impaired fasting glucose. The prevalence of dysglycaemia in the WOBASZ II study was significantly higher compared to the WOBASZ I study findings from 2003–2005, increased from 6.6% to 8.4% for diabetes and from 9.3% to 18.4% for impaired fasting glucose (after age and sex standardization to the 2013 Polish population).

Conclusions

The prevalence of diabetes in Poland is similar to that observed in other European populations and has increased significantly over the last decade.
Implementation of the Endocrine Society clinical practice guidelines for gestational diabetes mellitus to a knowledge tool
Authors: Korvesi Vasiliki M. , Chouvarda Ioanna , Mastorakos George , Goulis Dimitrios G.
Published: May 2020

Background

Despite the production of clinical practice guidelines (CPGs) in many medical areas, their use is not sufficiently adopted in clinical practice. Incorporation of CPGs in knowledge tools (KnowT) or decision support systems (DSS) for routine use can improve healthcare providers' compliance to CPGs.

Materials and methods

Clinical practice guidelines for gestational diabetes mellitus (GDM) were searched for, collected and compared. The CPG that met pre‐specified criteria ([a] published by a European or American organization between 2010 and 2018, [b] being developed a systematic way and [c] having statements of “level of evidence” and “strength of recommendation”) was chosen for implementation (Endocrine Society, 2013). Its recommendations were deconstructed, re‐organized and reconstructed as an algorithm (in the form of a flowchart), which was integrated into a KnowT. Content completeness and evaluation of CPG by the Guideline Implementability Appraisal tool (GLIA) were performed as well. The primary objective was the development of a clinical algorithm in the field of GDM and its integration into a KnowT. The secondary objective was to demonstrate the completeness of the CPG content and evaluate its implementability in the KnowT.

Results

Endocrine Society 2013 CPG was restructured as a flowchart, and a KnowT was constructed with the use of the “Openlabyrinth” software. The completeness of the content was confirmed, and GLIA appraisal demonstrated its implementability.

Conclusion

Endocrine Society 2013 CPG for GDM is a complete set of recommendations. Its structure makes possible the design of a clinical algorithm and its implementation into a KnowT.
Natural variation of root lesion nematode antagonism in the biocontrol fungus Clonostachys rosea and identification of biocontrol factors through genome‐wide association mapping
Authors: Iqbal Mudassir , Broberg Martin , Haarith Deepak , Broberg Anders , Bushley Kathryn E. , Brandström Durling Mikael , Viketoft Maria , Funck Jensen Dan , Dubey Mukesh , Karlsson Magnus
Published: May 2020

Biological control is a promising approach to reduce plant diseases caused by nematodes to ensure high productivity in agricultural production. Large‐scale analyses of genetic variation in fungal species used for biocontrol can generate knowledge regarding interaction mechanisms that can improve efficacy of biocontrol applications. In this study, we performed a genome‐wide association study (GWAS) for in vitro antagonism against the root lesion nematode Pratylenchus penetrans in 53 previously genome re‐sequenced strains of the biocontrol fungus Clonostachys rosea. Nematode mortality in C. rosea potato dextrose broth (PDB) culture filtrates was highly variable and showed continuous variation (p < .001) between strains, indicating a polygenic inheritance. Twenty‐one strains produced culture filtrates with higher (p ≤ .05) nematode mortality compared with the PDB control treatment, while ten strains lowered (p ≤ .05) the mortality. The difference in in vitro antagonism against P. penetrans correlated with antagonism against the soybean cyst nematode Heterodera glycines, indicating lack of host specificity in C. rosea. An empirical Bayesian multiple hypothesis testing approach identified 279 single nucleotide polymorphism markers significantly (local false sign rate < 10–10) associated with the trait. Genes present in the genomic regions associated with nematicidal activity included several membrane transporters, a chitinase and genes encoding proteins predicted to biosynthesize secondary metabolites. Gene deletion strains of the predicted nonribosomal peptide synthetase genes nps4 and nps5 were generated and showed increased (p ≤ .001) fungal growth and conidiation rates compared to the wild type. Deletion strains also exhibited reduced (p < .001) nematicidal activity and reduced (p ≤ .05) biocontrol efficacy against nematode root disease and against fusarium foot rot on wheat. In summary, we show that the GWAS approach can be used to identify biocontrol factors in C. rosea, specifically the putative nonribosomal peptide synthetases NPS4 and NPS5.
Abemaciclib sensitizes HPV‐negative cervical cancer to chemotherapy via specifically suppressing CDK4/6‐Rb‐E2F and mTOR pathways
Authors: Liu Yuan , Zhao Runsheng , Fang Shanshan , Li Quan , Jin Yiqiang , Liu Bo
Published: May 2020

Cervical cancer is the second most common malignancy in women, and the novel therapeutic treatment is needed. Abemaciclib is a FDA‐approved drug for breast cancer treatment. In this work, we identified that abemaciclib has potent anti‐cervical cancer activity. We demonstrate that abemaciclib is the most effective drug against human papillomavirus (HPV)‐negative cervical cancer cells compared to ribociclib and palbociclib, with its IC50 at nanomolar concentration range. This is achieved by the inhibition of proliferation and induction of apoptosis, through specifically suppressing CDK4/6‐Rb‐E2F and mTOR pathways by abemaciclib in HPV‐negative cervical cancer cells. Of note, the combination of abemaciclib with paclitaxel and cisplatin at sublethal concentration results in much greater efficacy than chemotherapy alone. In addition, we confirm the efficacy of abemaciclib and its combination with paclitaxel or cisplatin at the doses that are not toxic to mice in HPV‐negative cervical cancer xenograft mouse model. Interestingly, we show that abemaciclib and other CDK4/6 inhibitors are not effective in targeting HPV‐positive cervical cancer cells, and this is likely to be associated with the high p16 and low Rb expression in HPV‐positive cervical cancer cells. Our work is the first to provide the preclinical evidence to demonstrate the potential of abemaciclib for the treatment of HPV‐negative cervical cancer. The mechanism analysis highlights the therapeutic value of inhibiting CDK4/6 in HPV‐negative but not HPV‐positive cervical cancer.
Peptidomimetic‐based identification of FDA‐approved compounds inhibiting IRE1 activity
Authors: Doultsinos Dimitrios , Carlesso Antonio , Chintha Chetan , Paton James C. , Paton Adrienne W. , Samali Afshin , Chevet Eric , Eriksson Leif A.
Published: May 2020

Inositol‐requiring enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease that is a major mediator of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Tumour cells experience ER stress due to adverse environmental cues such as hypoxia or nutrient shortage and high metabolic/protein‐folding demand. To cope with those stresses, cancer cells utilise IRE1 signalling as an adaptive mechanism. Here, we report the discovery of the FDA‐approved compounds methotrexate, cefoperazone, folinic acid and fludarabine phosphate as IRE1 inhibitors. These were identified through a structural exploration of the IRE1 kinase domain using IRE1 peptide fragment docking and further optimisation and pharmacophore development. The inhibitors were verified to have an impact on IRE1 activity in vitro and were tested for their ability to sensitise human cell models of glioblastoma multiforme (GBM) to chemotherapy. We show that all molecules identified sensitise glioblastoma cells to the standard‐of‐care chemotherapy temozolomide (TMZ).
Mouse model systems of autism spectrum disorder: Replicability and informatics signature
Authors: Kabitzke Patricia , Morales Diana , He Dansha , Cox Kimberly , Sutphen Jane , Thiede Lucinda , Sabath Emily , Hanania Taleen , Biemans Barbara , Brunner Daniela
Published: May 2020

Phenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter‐ and intra‐laboratory replicability, particularly in behavioral domains such as social and cognitive function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies of five genetic mouse model systems of ASD. To assess the intra‐laboratory robustness of previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three‐yearlong effort using informatics techniques to assess commonalities and differences. Our results showed high intra‐laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle but pivotal differences in testing conditions, housing enrichment, or background strains and less so on the variability of the behavioral phenotypes. The overall informatics analysis suggests that in our behavioral assays we can separate the set of tested mouse model system into two main classes that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.
Effect of Fremanezumab Monthly and Quarterly Doses on Efficacy Responses
Authors: Fiedler‐Kelly Jill , Passarell Julie , Ludwig Elizabeth , Levi Micha , Cohen‐Barak Orit
Published: May 2020

Objective

Exposure‐response (E‐R) models were developed to provide a description of the time‐course of treatment effect for monthly and quarterly dosing regimens of fremanezumab.

Background

Fremanezumab is a monoclonal antibody for preventive treatment of episodic migraine (EM) and chronic migraine (CM). In phase 2b and 3 clinical studies of fremanezumab, significant reductions in migraine and headache days and other clinical endpoints were observed for patients with EM and patients with CM. Development of E‐R models relating individual‐specific measures of drug exposure to clinical endpoints provides a more granular understanding of the expected effects of different doses on therapeutic outcomes by accounting for variability in pharmacokinetic (PK) properties.

Methods

Data from 2 phase 2b and 2 phase 3 studies of adults with EM or CM were used. Individual exposures were calculated from a population PK model and related to monthly migraine days in EM and moderate‐severe (M/S) headache days in CM. Model‐based stochastic simulations were performed to compare predicted responses for the various treatment regimens.

Results

The effect of average fremanezumab concentration compared to placebo on the reduction in migraine days and M/S headache days was predicted by the models to be similar for 225 mg monthly and 675 mg once quarterly over time for both EM and CM patients. Both regimens were associated with better response than placebo. A similar percent of EM and CM responders was predicted across the range of observed body weights.

Conclusions

Exposure‐response evaluations showed that both monthly (225 mg) and quarterly (675 mg) fremanezumab dosing regimens were appropriate in achieving clinical benefit in adult patients with EM or CM.
Multiple methods of assessing nectar foraging conditions indicate peak foraging difficulty in late season
Authors: Garbuzov Mihail , Balfour Nicholas J. , Shackleton Kyle , Al Toufailia Hasan , Scandian Luciano , Ratnieks Francis L. W.
Published: May 2020

One of the major challenges faced by pollinators worldwide is the reduction in their food supply, nectar, and pollen. Given the considerable seasonal variation in the abundance of both floral resources and flower‐visiting insects, conservation initiatives aiming to help pollinators through floral resource supplementation could increase their impacts by targeting periods when the foraging conditions are most difficult. Direct assessment of foraging conditions, however, is extremely labour‐intensive.

Here, we compared eight practical measures expected to reflect the foraging difficulty for nectar in the environment. Five measures involved Apis mellifera – an indicator species for the flower‐visitor guild due to its generalist, energetically optimal, and long‐distance foraging habit. These included (i) visitation at feeders with a range of sucrose concentrations, (ii) guarding and (iii) fighting levels at hive entrances, (iv) rates of hive weight changes, and (v) foraging distances encoded in waggle dances. The other measures were (vi–viii) counts of flower‐visiting insects in relation to the rate of nectar sugar secretion in three plant species attractive to flower‐visiting insects.

There was considerable, although not complete agreement among the eight measures. Eleven of 28 pairwise correlations were statistically significant. Guarding and fighting correlated with most (five) other measures. We conclude that seven of the eight measures could be potentially useful in gauging seasonal patterns in local foraging conditions, which could help guide targeted conservation initiatives. Assessment of guarding and fighting levels at A. mellifera hive entrances is recommended, as these correlated significantly with most other measures and are easy to obtain in practice.
Mutational landscape of severe combined immunodeficiency patients from Turkey
Authors: Firtina Sinem , Yin Ng Yuk , Hatirnaz Ng Ozden , Kiykim Ayca , Aydiner Elif , Nepesov Serdar , Camcioglu Yildiz , Sayar Esra H. , Reisli Ismail , Torun Selda H. , Cogurlu Tuba , Uygun Dilara , Simsek Isil E. , Kaya Aysenur , Cipe Funda , Cagdas Deniz , Yucel Esra , Cekic Sukru , Uygun Vedat , Baris Safa , Ozen Ahmet , Ozbek Ugur , Sayitoglu Muge
Published: May 2020

Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next‐generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon‐based targeted NGS panel, which contained 18 most common SCID‐related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease‐causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom‐made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK− SCID). Incidence of autosomal‐recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom‐made sequencing panel was able to identify and confirm the previously known and novel disease‐causing variants with high accuracy.
New Venture Survival: A Review and Extension
Authors: Soto‐Simeone Aracely , Sirén Charlotta , Antretter Torben
Published: May 2020

This paper provides an evaluative overview of the new venture survival literature. Since Stinchcombe's primary attempt to explain the mortality rates of new ventures, different research fields, including entrepreneurship, management and sociology, have devoted considerable attention to the antecedents of new venture survival. Despite this lively research commitment, a comprehensive review of the literature on new venture survival – as one of the most essential performance measures for new ventures – is missing. Covering 54 years of research, this paper provides an overview of the factors affecting new venture survival and highlights important methodological aspects in this research field. The review concludes by discussing opportunities for future research.
Resisting Bare Life: Civil Solidarity and the Hunt for Illegalized Migrants
Authors: Vandevoordt Robin
Published: May 2020

While European governments have pursued illegalized migrants for decades, the techniques through which they do so have taken a more radical turn since 2015. Focusing on the particular case of Belgium, this paper documents how its Federal government has increasingly tried to “police” migrants into the European refugee regime, while migrants and citizens have continued to resist these efforts through a series of “political” actions. Drawing on ethnographic work with the Brussels‐based Citizen Platform for the Support of Refugees, I pursue two aims: first, I demonstrate how the Belgian state has consciously produced a humanitarian crisis as part of a broader “politics of exhaustion”; and second, I explore the specific forms and types of humanitarian action that emerge from citizens’ response to these policies. I do so by describing three moments in which these opposing logics of policing and politicization conjure.
Hallmarks of NLRP3 inflammasome activation are observed in organotypic hippocampal slice culture
Authors: Hoyle Christopher , Redondo‐Castro Elena , Cook James , Tzeng Te‐Chen , Allan Stuart M. , Brough David , Lemarchand Eloise
Published: May 2020

Microglial inflammation driven by the NACHT, LRR and PYD domain‐containing protein 3 (NLRP3) inflammasome contributes to brain disease and is a therapeutic target. Most mechanistic studies on NLRP3 activation use two‐dimensional pure microglial cell culture systems. Here we studied the activation of the NLRP3 inflammasome in organotypic hippocampal slices, which allowed us to investigate microglial NLRP3 activation in a three‐dimensional, complex tissue architecture. Toll‐like receptor 2 and 4 activation primed microglial inflammasome responses in hippocampal slices by increasing NLRP3 and interleukin‐1β expression. Nigericin‐induced NLRP3 inflammasome activation was dynamically visualized in microglia through ASC speck formation. Downstream caspase‐1 activation, gasdermin D cleavage, pyroptotic cell death and interleukin‐1β release were also detected, and these findings were consistent when using different NLRP3 stimuli such as ATP and imiquimod. NLRP3 inflammasome pathway inhibitors were effective in organotypic hippocampal slices. Hence, we have highlighted organotypic hippocampal slice culture as a valuable ex vivo tool to allow the future study of NLRP3 inflammasomes in a representative tissue section, aiding the discovery of further mechanistic insights and drug development.
The association between thrombotic and inflammatory biomarkers and lower‐extremity peripheral artery disease
Authors: Celebi Savas , Berkalp Berkten , Amasyali Basri
Published: May 2020

Lower‐extremity peripheral artery disease (LEAD) is associated with increased rates of mortality and morbidity. The aim of this study was to evaluate the associations among inflammatory and thrombotic markers and lower‐extremity peripheral disease. A total of 280 patients were enrolled in this study. Of these patients, 152 patients had LEAD on peripheral angiography that was performed because of suspected lower‐extremity peripheral disease based on history, physical examination, and non‐invasive tests. The control group consisted of 128 patients without LEAD on peripheral angiography. Patients with LEAD were classified according to trans‐atlantic inter‐society consensus (TASC) II classification. Subsequently, patients in TASC A to B were defined as having mild to moderate peripheral artery disease, and those in TASC C to D were defined as having advanced peripheral artery disease. Thrombotic and inflammatory markers, such as the neutrophil‐to‐lymphocyte ratio (NLR), the high‐sensitivity C (hs‐C) reactive protein level, the monocyte‐to‐high‐density lipoprotein‐cholesterol ratio, the fibrinogen to albumin ratio (FAR), and whole‐blood viscosity at high shear rate (HSR) and low shear rate (LSR), were evaluated in this population. The NLR, the monocyte‐to‐high‐density lipoprotein‐cholesterol ratio, the FAR, and whole‐blood viscosity, both at a LSR and a HSR, were significantly higher in patients with lower‐extremity peripheral disease compared with patients without lower‐extremity peripheral disease. We determined that lower‐extremity peripheral disease severity was correlated with the NLR, monocyte‐to‐high‐density lipoprotein‐cholesterol ratio, FAR, whole‐blood viscosity at LSR, and whole‐blood viscosity at HSR (r = 0.719, P = .004; r = 0.25, P = .008; r = 0.691, P = .002; r = 0.546, P < .001; and r = 0.448, P = .001, respectively). However hs‐C reactive protein levels were similar between patients with or without LEAD (2.47 ± 1.32 1.61 ± 0.91 P = .685). In addition, there was no correlation between the severity of LEAD and hs‐C reactive levels. In this study, we determined that the levels of inflammatory and thrombotic biomarkers are elevated in peripheral artery disease, and these levels predict disease severity.
High‐pressure structural stability, equation of state, and thermal expansion behavior of cubic HfO2
Authors: Irshad K. A. , Srihari Velaga , Kumar D. Sanjay , Ananthasivan K. , Jena Hrudananda
Published: May 2020

The structural stability, equation of state, and thermal expansion behavior of nanocrystalline cubic HfO2, an ultra‐high‐temperature ceramic, have been investigated using X‐ray diffraction at extreme conditions of pressures and temperatures. High‐pressure studies show that the cubic structure is stable up to 26.2 GPa, while the high‐temperature studies show the stability of the cubic structure up to 600°C. The Rietveld structure refinement of the high‐pressure data reveals the progressive transition of secondary monoclinic phase to the cubic phase at higher pressures. The phase progression is accompanied by incompressibility along the b axis and a large compressibility along the c axis of the monoclinic structure. The second‐order Birch‐Murnaghan equation of state fit to the unit cell volume data yielded a bulk modulus of 242(16) GPa for the cubic structure. A linear thermal expansion value of αa(c) = 8.80(15) × 10−6°C−1 and a volume thermal expansion value of αv = 26.5(4) × 10−6°C−1 have been determined from the in situ high‐temperature X‐ray diffraction studies. The results are discussed by comparing with the high‐pressure and high‐temperature behavior of isostructural ZrO2. To the best of our knowledge, this is the first experimental report on the structural stability of cubic HfO2 at high pressures.
Left atrial diverticula: Innocent bystanders or wolves in sheep's clothing?
Authors: Veen Danny , Bruning Tobias A. , de Groot Natasja M. S.
Published: May 2020

Introduction

The finding of left atria diverticula (LAD) on cardiac computed tomography images obtained from patients with atrial fibrillation (AF) referred for pulmonary vein isolation is not uncommon. Prior studies reporting on LAD do not always provide definitions of LAD resulting in confusion with other anatomical structures such as left atrial accessory appendages (LAAA) and atrial aneurysms. The aim of this review is to identify an accurate definition of LAD and to describe distinctive properties between LAD and other left atrial structures, such as LAAA and aneurysms. Also, the relation between LAD and development of atrial tachyarrhythmias is discussed.

Methods

PubMed was searched for studies reporting on atrial aneurysms, left atrial diverticula, left atrial accessory appendages and atrial congenital aneurysms, resulting in 36 papers.

Results

LAD can be distinguished from LAAA by taking into account embryologic origins of the left atrium and their locations, resulting in the following definitions: (a) LAAA are contractile, trabeculated structures with circumscriptive ostia and narrow necks, originating from the primitive atria, (b) LAD are contractile, sac like structures with either smooth or trabeculated inner surfaces, circumscriptive ostia, narrow necks, and variable morphologies, originating from the embryologic common pulmonary vein, that incorporates into the LA, and (c) atrial aneurysms are non‐contractile structures with wide necks and sac like bodies. There are no differences in prevalences of LAD between patients with sinus rhythm and AF.

Conclusion

The pathophysiology of LAD is not yet fully understood. It is unlikely, that LAD are related to the development of atrial tachycardia's and AF by either being a source of ectopic activity or being part of an arrhythmogenic substrate. No differences in LAD prevalences between patients with sinus rhythm and AF have been found. Thus, it is unlikely that LAD could potentially be wolves in sheep's clothing.
Slow whole left atrial conduction velocity after pulmonary vein isolation predicts atrial fibrillation recurrence
Authors: Kurata Naoya , Masuda Masaharu , Kanda Takashi , Asai Mitsutoshi , Iida Osamu , Okamoto Shin , Ishihara Takayuki , Nanto Kiyonori , Tsujimura Takuya , Matsuda Yasuhiro , Hata Yousuke , Mano Toshiaki
Published: May 2020

Background

Atrial conduction velocity may represent atrial fibrillation (AF) substrate after pulmonary vein isolation (PVI). To elucidate the association between whole left atrial conduction velocity (LACV) and AF recurrence after PVI.

Methods and Results

This observational study enrolled 279 patients (147 paroxysmal and 132 persistent AF) who underwent PVI alone as an initial AF ablation procedure. After PVI, the left atrium was mapped with a 20‐pole multielectrode in conjunction with the CARTO3 system during 100‐ppm right atrial pacing. Left atrial conduction distance and conduction time were calculated from the start to the end of the propagation wave front in the left atrium. LACVs on the anterior and posterior routes were calculated as conduction distance divided by conduction time. Anterior and posterior LACVs were slower in patients with AF recurrence than in those without (anterior, 0.79 [0.71, 0.86] vs 0.96 [0.90, 1.06] m/s, P < .001; posterior, 0.99 [0.89, 1.14] vs 1.10 [1.00, 1.29] m/s, P < .001). AF recurrence was best predicted by anterior LACV with a cut‐off value of 0.87 m/s (sensitivity 87%, specificity 81%, and predictive accuracy 84%). Multivariate analysis demonstrated that a slow anterior LACV <0.87 m/s was an independent predictor of AF recurrence with an adjusted hazard ratio of 11.8 (6.36‐22.0). Patients with anterior low‐voltage areas demonstrated slower anterior LACV than those without low‐voltage areas (0.89 [0.71, 1.00] vs 0.94 [0.87, 1.05] m/s, P < .001).

Conclusion

A slow anterior LACV was an excellent predictor of AF recurrence after PVI.
ARRB1 ameliorates liver ischaemia/reperfusion injury via antagonizing TRAF6‐mediated Lysine 6‐linked polyubiquitination of ASK1 in hepatocytes
Authors: Xu Xiaoliang , Zhang Zechuan , Lu Yijun , Sun Qikai , Liu Yang , Liu Qiaoyu , Tian Wenfang , Yin Yin , Yu Hailong , Sun Beicheng
Published: May 2020

Hepatic ischaemia/reperfusion (I/R) injury is a major clinical problem during liver surgical procedures, which usually lead to early transplantation failure and higher organ rejection rate, and current effective therapeutic strategies are still limited. Therefore, in‐depth exploring of the molecular mechanisms underlying liver I/R injury is key to the development of new therapeutic methods. β‐arrestins are multifunctional proteins serving as important signalling scaffolds in numerous physiopathological processes, including liver‐specific diseases. However, the role and underlying mechanism of β‐arrestins in hepatic I/R injury remain largely unknown. Here, we showed that only ARRB1, but not ARRB2, was down‐regulated during liver I/R injury. Hepatocyte‐specific overexpression of ARRB1 significantly ameliorated liver damage, as demonstrated by decreases in serum aminotransferases, hepatocellular necrosis and apoptosis, infiltrating inflammatory cells and secretion of pro‐inflammatory cytokines relative to control mice, whereas experiments with ARRB1 knockout mice gotten opposite effects. Mechanistically, ARRB1 directly interacts with ASK1 in hepatocytes and inhibits its TRAF6‐mediated Lysine 6‐linked polyubiquitination, which then prevents the activation of ASK1 and its downstream signalling pathway during hepatic I/R injury. In addition, inhibition of ASK1 remarkably abolished the disruptive effect result from ARRB1 deficiency in liver I/R injury in vivo, indicating that ASK1 was required for ARRB1 function in hepatic I/R injury. In conclusion, we proposed that ARRB1 is a novel protective regulator during liver I/R injury, and modulation of the regulatory axis between ARRB1 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.
Evidence‐based practice guideline on integrative medicine for stroke 2019
Authors: Ni Xiaojia , Lin Hao , Li Hui , Liao Wenjing , Luo Xufei , Wu Darong , Chen Yaolong , Cai Yefeng ,   Evidence‐based Practice Guideline on Integrative Medicine for Stroke working team, Neurology Chapter of China Association of Chinese Medicine, Neurology Committee of Guangdong Provincial Association of Chinese Medicine, and Stroke Committee of Guangdong Provincial Association of Chinese Integrative Medicine
Published: May 2020

Objective

Stroke is the leading cause of death and disability in China. Chinese medicine integrated with conventional medicine is now widely used in the prevention and treatment of stroke. A clinical practice guideline for the application of integrative medicine in stroke is urgently needed.

Methods

This guideline was developed following the methodology and procedures recommended in the World Health Organization Handbook for Guideline Development and the Guideline Development Handbook for Diagnosis and Therapy of Integrative Medicine. The quality of evidence and strength of recommendations were evaluated using the GRADE approach. The guideline followed the RIGHT statement and AGREE II was consulted to ensure its quality.

Results

A multidisciplinary working team was established. Eleven research questions from 15 clinical questions were identified by questionnaire surveys, face‐to‐face meetings, and analyzed by the working team. Fourteen recommendations regarding integrative medicine for ischemic stroke, hemorrhagic stroke, and complications of stroke were formulated from systematic reviews of the benefits, harms, cost‐effectiveness, quality of evidence, the values and preferences of patients and their family members, feedback on proposed recommendations from medical practitioners from a variety of disciplines, and a face‐to‐face consensus meeting.

Conclusions

This guideline focuses on clinical treatments that are specific to integrative medicine for stroke and can be used at all levels in medical institutions and rehabilitation facilities. The end‐users of the guideline are most likely to be medical practitioners, including Chinese herbal medicine specialists, acupuncturists, integrative medicine practitioners, physicians, physical therapists, and clinical pharmacists.
Effect of phytosphingosine on staining resistance and microhardness of tooth enamel
Authors: Amorim Ayodele Alves , de Arruda Carolina Noronha Ferraz , Vivanco Rocio Geng , Bikker Floris , de Pires‐de‐Souza Fernanda Carvalho Panzeri
Published: May 2020

Objective

To evaluate the protective effect of phytosphingosine (PHS) against staining on dental enamel.

Materials and Methods

Ninety‐six specimens of bovine teeth (6 mm × 6 mm × 2 mm) were cut, and initial color (Easyshade, VITA), microhardness (HMV‐2, Shimadzu) and fluorescence (Matlabs software, Matworks) measurements were performed. Specimens were separated into four groups according to the treatments: Distilled water (control); Human saliva (HS); PHS; PHS + HS. Specimens (n = 6) were submitted to staining procedures: Distilled water (immersion for 30 days—control); Coffee (15 minutes, twice a day/for 15 days); Black tea (as described for Coffee) and cigarette smoke (20 cigarettes/sample). Final measurements were performed, and data were analyzed (Color—CIEDE2000, fluorescence—2‐way ANOVA, Tukey, and microhardness—Kruskal‐Wallis Dunn, P < .05).

Results

Coffee caused the highest color change (ΔE00), followed by black tea, regardless of the treatment employed. Distilled water and cigarette smoke produced similar color changes (P > .05) for the groups control (water = 1.0 + − 0.5/ cigarette = 2.3 0.3) and PHS (water = 0.8 0.4/ cigarette = 2.3 0.4). PHS + HS demonstrated intermediate means than PHS and HS when stained with coffee and tea. After treatments, the least fluorescence alterations occurred for the groups treated with distilled water and cigarette, regardless of the treatment, with no difference (P > .05) between them. There was a significant difference (P < .05) on microhardness between all the groups, as PHS + HS > PHS > HS > Distilled water.

Conclusions

It was concluded that PHS treatment did not protect the staining of the enamel by coffee and tea, but increased the microhardness, both in the presence and absence of a salivary pellicle.

Practical Implications

Phytoshingosine is a novel agent and considered a promising component for anti‐biofilm and anti‐erosion properties by the formation of a diffusion barrier on the dental enamel. In line, PHS might be considered for anti‐staining purposes.
ACTIVITY STRATEGIES, AGENCY PROBLEMS, AND BANK RISK
Authors: Tran Dung V. , Hassan M. Kabir , Girerd‐Potin Isabelle , Louvet Pascal
Published: May 2020

We investigate whether diversification affects bank risk taking in the U.S. banking industry, and whether this relation is partially explained by agency theory. Our results show that U.S. banks with a relatively high share of noninterest income become riskier when moving toward non‐interest‐income‐generating activities, especially activities from investment banking, proprietary trading, and so on. Diversification not only affects conditional average risk, but also the dispersion of risk. Moreover, diversified banks that received assistance from the Troubled Asset Relief Program (TARP) become riskier than diversified nonrecipients after TARP capital injections. Our main findings are robust to a battery of robustness tests. The results are partially explained under agency frameworks related to poor corporate governance.