bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Genomic Assessment Using a Blood-based mRNA Signature (NETest) is Cost-effective and Predicts Neuroendocrine Tumor Recurrence With 94% Accuracy
Authors: Modlin Irvin M. , Kidd Mark , Frilling Andrea , Falconi Massimo , Filosso Pier Luigi , Malczewska Anna , Kitz Alexandra
Published: June 2021

Introduction:

Identification of residual disease after neuroendocrine tumor (NET) resection is critical for management. Post-surgery imaging is insensitive, expensive, and current biomarkers ineffective. We evaluated whether the NETest, a multigene liquid biopsy blood biomarker, correlated with surgical resection and could predict recurrence.

Methods:

Multicenter evaluation of NET resections over 24 months (n = 103): 47 pancreas, 26 small bowel, 26 lung, 2 appendix, 1 duodenum, 1 stomach. Surgery: R0 (83), R1/R2 (20). One millilitre of blood was collected at D0 and posroperative day (POD) 30. Transcript quantification by polymerase chain reaction (normal: ≤20), CgA by NEOLISA (normal ≤108 ng/mL). Standard-of-care (SoC) follow-up costs were calculated and compared to POD30 NETest-stratification approach. Analyses: Wilcoxon-paired test, Chi-square test.

Results:

D0 biomarkers:

NETest: 103 of 103 (100%)-positive, whereas 23 of 103 (22%) were CgA-positive (Chi-square = 78, P < 0.0001).

In the R0 group, the NETest decreased 59 ± 28 to 26 ± 23 (P < 0.0001); 36% (30/83) remained elevated. No significant decrease was evident for CgA. In the R1/R2 group the NETest decreased but 100% remained elevated. CgA levels did not decrease.

An elevated POD30 NETest was present in R0 and 25 (83%) developed radiological recurrences. Normal score R0 s (n = 53) did not develop recurrence (Chi-square = 56, P < 0.0001). Recurrence prediction was 94% accurate with the NETest.

Cost evaluation:

Using the NETest to stratify postoperative imaging resulted in a cost-savings of 42%.

Conclusion:

NETest diagnosis is more accurate than CgA (100% vs 22%). Surgery significantly decreased NETest. An elevated POD30 NETest predicted recurrence with 94% accuracy and post-surgical POD30 NETest follow-up stratification decreased costs by 42%. CgA had no surgical utility. Further studies would define the accuracy and cost-effectiveness of the NETest in the detection of postoperative recurrent disease.
Extent of Lymphadenectomy and Long-term Survival in Esophageal Cancer
Authors: Gottlieb-Vedi Eivind , Kauppila Joonas H. , Mattsson Fredrik , Hedberg Jakob , Johansson Jan , Edholm David , Lagergren Pernilla , Nilsson Magnus ,   FINEGO group, Lagergren Jesper
Published: June 2021

Objective:

To examine the hypothesis that survival in esophageal cancer increases with more removed lymph nodes during esophagectomy up to a plateau, after which it levels out or even decreases with further lymphadenec-tomy.

Summary of Background Data:

There is uncertainty regarding the ideal extent of lymphadenectomy during esophagectomy to optimize long-term survival in esophageal cancer.

Methods:

This population-based cohort study included almost every patient who underwent esophagectomy for esophageal cancer in Sweden or Finland in 2000-2016 with follow-up through 2019. Degree of lymphadenectomy, divided into deciles, was analyzed in relation to all-cause 5-year mortality. Multivariable Cox regression provided hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for all established prognostic factors.

Results:

Among 2306 patients, the second (4–8 nodes), seventh (21–24 nodes) and eighth decile (25–30 nodes) of lymphadenectomy showed the lowest all-cause 5-year mortality compared to the first decile [hazard ratio (HR) = 0.77, 95% CI 0.61–0.97, HR = 0.76, 95% CI 0.59–0.99, and HR = 0.73, 95% CI 0.57–0.93, respectively]. In stratified analyses, the survival benefit was greatest in decile 7 for patients with pathological T-stage T3/T4 (HR = 0.56, 95% CI0.40–0.78), although it was statistically improved in all deciles except decile 10. For patients without neoadjuvant chemotherapy, survival was greatest in decile 7 (HR = 0.60, 95% CI 0.41–0.86), although survival was also statistically significantly improved in deciles 2, 6, and 8.

Conclusion:

Survival in esophageal cancer was not improved by extensive lymphadenectomy, but resection of a moderate number (20–30) of nodes was prognostically beneficial for patients with advanced T-stages (T3/T4) and those not receiving neoadjuvant therapy.
COVID-19 in Solid Organ Transplant Recipients in Spain Throughout 2020: Catching the Wave?
Authors: Coll Elisabeth , Fernández-Ruiz Mario , Padilla María , Moreso Francesc , Hernández-Vicente Ana , Yañez Iñigo , Molina María , Vázquez-Sánchez Teresa , Crespo Marta , Facundo Carme , Rodríguez-Ferrero María Luisa , Ruiz Fuentes María Carmen , Loinaz Carmelo , Bernal Gabriel , Melilli Edoardo , Bravo Carlos , Diekmann Fritz , Lladó Laura , García-Álvarez Teresa M. , Salcedo Magdalena , Beneyto Isabel , Castells Lluis , Alonso Rodrigo , Rodríguez-Benot Alberto , Díaz-Corte Carmen , Graus Javier , Ortiz-Bautista Carlos , García-Cosío María Dolores , Hinojal Rosa , Peña Lucía , Domínguez-Gil Beatriz
Published: June 2021

Background.

Few studies have analyzed differences in clinical presentation and outcomes in solid organ transplant (SOT) recipients with coronavirus disease 2019 (COVID-19) across different pandemic waves.

Methods.

In this multicenter, nationwide, prospective study, we compared demographics and clinical features, therapeutic management, and outcomes in SOT recipients diagnosed with COVID-19 in Spain before (first wave) or after (second wave) 13 July 2020.

Results.

Of 1634 SOT recipients, 690 (42.2%) and 944 (57.8%) were diagnosed during the first and second periods, respectively. Compared with the first wave, recipients in the second were younger (median: 63 y [interquartile range, IQR: 53–71] versus 59 y [IQR: 49–68]; P < 0.001) and less likely to receive anti-severe acute respiratory syndrome coronavirus 2 drugs (81.8% versus 8.1%; P < 0.001), with no differences in immunomodulatory therapies (46.8% versus 47.0%; P = 0.931). Adjustment of immunosuppression was less common during the second period (76.4% versus 53.6%; P < 0.001). Hospital admission (86.7% versus 58.1%; P < 0.001), occurrence of acute respiratory distress syndrome (34.1% versus 21.0%; P < 0.001), and case-fatality rate (25.8% versus 16.7%; P < 0.001) were lower in the second period. In multivariate analysis, acquiring COVID-19 during the first wave was associated with an increased risk of death (OR: 1.47; 95% confidence interval [CI], 1.12-1.93; P = 0.005), although this impact was lost in the subgroup of patients requiring hospital (OR: 0.97; 95% CI, 0.73-1.29; P = 0.873) or intensive care unit admission (OR: 0.65; 95% CI, 0.35-1.18; P = 0.157).

Conclusions.

We observed meaningful changes in demographics, therapeutic approaches, level of care, and outcomes between the first and second pandemic waves. However, outcomes have not improved in the more severe cases of posttransplant COVID-19.
Does Social Support Moderate Wound Pain and Health-Related Quality of Life in Patients With Chronic Wounds? A Multicenter Descriptive Cross-sectional Study
Authors: Ren Hui , Wang Daguang , Ding Yanming , Hu Haiyan , Qin Zeying , Fu Xiaojin , Hu Yueyang , Cao Ruilin , Liang Leilei , Li Chuanen , Mei Songli
Published: June 2021

PURPOSE:

We sought to explore the relationships among social support, health-related quality of life (HRQOL), and wound pain, and to examine whether social support would moderate the relationship between wound pain and HRQOL.

DESIGN:

A multicenter descriptive cross-sectional study.

SUBJECTS AND SETTINGS:

Individuals with chronic wounds attending wound clinics affiliated with 3 public hospitals in Beijing, China.

METHODS:

Sociodemographic and wound characteristics of 162 participants were retrieved from medical records. Participants completed questionnaires for wound-related pain intensity (Numerical Rating Scale), social support (Social Support Rating Scale), and HRQOL (Medical Outcome Study Short Form-36). The moderating effect analysis was examined using the PROCESS analytic tool developed by Hayes, based on the bias-corrected bootstrapping method.

RESULTS:

Results revealed that higher pain intensity was significantly related to lower HRQOL (P < .01), and higher social support was associated with better HRQOL (P < .01). However, there was no significant correlation between social support and wound pain (P = .55). Importantly, the moderating effect of social support on the relationship between wound pain and HRQOL was statistically significant (P = .008).

CONCLUSIONS:

We found that social support moderated the impact of wound pain on HRQOL in patients with chronic wounds. This finding suggests that support obtained from social networks may be a beneficial intervention to improve the HRQOL of patients with chronic wounds, especially those suffering from high-intensity wound pain.
An Autologous Protein-Based Topical Ointment for Hard-to-Heal Skin Wounds
Authors: Muñoz Victoria , Pino Ander , Martinez Carmen , Echevarria Begoña , Lacramioara Varlan , Anitua Eduardo
Published: June 2021

BACKGROUND:

There is increasing evidence regarding the wound healing potential of platelet-derived autologous by-products. We provide preliminary data regarding the use of a new plasma rich in growth factors–derived autologous topical ointment for the management of hard-to-heal wounds.

CASES:

Four patients suffering from difficult-to-heal wounds were treated with the autologous ointment. Within 2 to 8 weeks, all wounds healed completely with no signs of infection or functional impairment of the affected limbs. No adverse events were reported.

CONCLUSION:

Randomized and controlled trials are needed to determine the clinical efficacy of the autologous ointment. Nevertheless, results from this multiple case series indicate that this approach may be useful for accelerating the re-epithelization of difficult-to-heal wounds.
Biomarker Prediction of Postoperative Healing of Diabetic Foot Ulcers
Authors: Cheng Pu , Dong Yunxian , Hu Zhicheng , Huang Shaobin , Cao Xiaoling , Wang Peng , Xu Hailin , Zhu Jiayuan , Tang Bing
Published: June 2021

PURPOSE:

The purpose of this study was to investigate the relationship and to determine potential usefulness of serum albumin as a biomarker for predicting postoperative diabetic foot ulcer (DFU) healing.

DESIGN:

A retrospective study.

SUBJECTS AND SETTING:

The sample comprised 266 inpatients with type 2 diabetes receiving care in The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Among them, 174 had DFUs and underwent surgery for foot DFUs including amputation, skin grafting, and flap procedures. A comparison group consisted of 92 inpatients without a DFU or surgery.

METHODS:

The association between healing and preoperative albumin levels was analyzed via a logistic regression model and receiver operating characteristic (ROC) curve.

RESULTS:

The albumin value of patients with DFU grade 3 or more (3.23 ± 0.58 g/dL) was lower than that of patients with DFU grade 1-2 (3.58 ± 0.5 g/dL), and both were lower than that of the comparison group (3.89 ± 0.3 g/dL). Patients with a DFU with hypoalbuminemia (<3.5 g/dL) had a 2.5-fold higher risk of nonhealing at postoperative 28 days than patients with normal levels (odds ratio = 3.51; 95% confidence interval, 1.75-7.06; P < .001). For patients with a DFU overall, the ROC curve showed a preoperative albumin cutoff of 3.44 g/dL for DFU wound healing.

CONCLUSIONS:

For patients with a DFU undergoing surgery, preoperative serum albumin may be used as a biomarker for predicting postoperative healing.
Intervention for Alleviating Clinical Inertia in the Management of Urinary Incontinence
Authors: Artero-López Consuelo , Márquez-Hernández Verónica V. , Estevez-Morales María Teresa , Gutiérrez-Puertas Lorena , Aguilera-Manrique Gabriel , Granados-Gámez Genoveva
Published: June 2021

PURPOSE:

The purpose of this study was to determine whether clinical inertia exists in the care of patients with urinary incontinence and to test the effects of an educational intervention designed to alleviate inertia related to care of urinary incontinence.

DESIGN:

Single-group, pretest/posttest design.

SUBJECTS AND SETTING:

The sample comprised 132 participants practicing in 6 medical-surgical inpatient care units at an urban hospital in Almería, Spain; 66 (50%) were RNs, and all other participants were unlicensed assistive personnel. Most participants (87.9%) were female; their average age was 43.99 years (SD = 7.85 years).

METHODS:

An educational intervention (online course) was provided. The main objective of the course was application of evidence-based knowledge for prevention and management of urinary incontinence in hospitalized patients. The course program comprised 3 didactic units: (1) introduction and evaluation of the patient with urinary incontinence, (2) care plans, and (3) instructions and rational use of absorbent products. Data collection included demographic and professional characteristics of respondents, desired results when caring for patients with incontinence, a medical record checklist, an occupational environment and satisfaction scale, and an assessment record of knowledge/skills and training activity satisfaction.

RESULTS:

After comparing the pre- and posttest scores of knowledge on urinary incontinence, significant differences were found before and after the intervention (z = −14.113, P = .000). Specifically, analysis revealed differences in caring actions related to urinary incontinence (z = −14.248, P = .000) and differences in direct observation of urinary incontinence practice following the intervention (z = −14.326, P = .000).

CONCLUSIONS:

Our findings indicate existence of inertia in nursing care for hospitalized patients with urinary incontinence. The educational intervention improved knowledge, observable nursing care activities related to incontinence management, and improved documentation of care.
Timing HIV infection with a simple and accurate population viral dynamics model
Authors: Reeves Daniel B. , Rolland Morgane , Dearlove Bethany L. , Li Yifan , Robb Merlin L. , Schiffer Joshua T. , Gilbert Peter , Cardozo-Ojeda E. Fabian , Mayer Bryan T.
Published: June 2021

Clinical trials for HIV prevention can require knowledge of infection times to subsequently determine protective drug levels. Yet, infection timing is difficult when study visits are sparse. Using population nonlinear mixed-effects (pNLME) statistical inference and viral loads from 46 RV217 study participants, we developed a relatively simple HIV primary infection model that achieved an excellent fit to all data. We also discovered that Aptima assay values from the study strongly correlated with viral loads, enabling imputation of very early viral loads for 28/46 participants. Estimated times between infecting exposures and first positives were generally longer than prior estimates (average of two weeks) and were robust to missing viral upslope data. On simulated data, we found that tighter sampling before diagnosis improved estimation more than tighter sampling after diagnosis. Sampling weekly before and monthly after diagnosis was a pragmatic design for good timing accuracy. Our pNLME timing approach is widely applicable to other infections with existing mathematical models. The present model could be used to simulate future HIV trials and may help estimate protective thresholds from the recently completed antibody-mediated prevention trials.
Ongoing evolution of Chlamydia trachomatis lymphogranuloma venereum: exploring the genomic diversity of circulating strains
Authors: Seth-Smith Helena M. B. , Bénard Angèle , Bruisten Sylvia M. , Versteeg Bart , Herrmann Björn , Kok Jen , Carter Ian , Peuchant Olivia , Bébéar Cécile , Lewis David A. , Puerta Teresa , Keše Darja , Balla Eszter , Zákoucká Hana , Rob Filip , Morré Servaas A. , de Barbeyrac Bertille , Galán Juan Carlos , de Vries Henry J. C. , Thomson Nicholas R. , Goldenberger Daniel , Egli Adrian
Published: June 2021

Lymphogranuloma venereum (LGV), the invasive infection of the sexually transmissible infection (STI)

Chlamydia trachomatis

, is caused by strains from the LGV biovar, most commonly represented by ompA-genotypes L2b and L2. We investigated the diversity in LGV samples across an international collection over seven years using typing and genome sequencing. LGV-positive samples (n=321) from eight countries collected between 2011 and 2017 (Spain n=97, Netherlands n=67, Switzerland n=64, Australia n=53, Sweden n=37, Hungary n=31, Czechia n=30, Slovenia n=10) were genotyped for pmpH and ompA variants. All were found to contain the 9 bp insertion in the pmpH gene, previously associated with ompA-genotype L2b. However, analysis of the ompA gene shows ompA-genotype L2b (n=83), ompA-genotype L2 (n=180) and several variants of these (n=52; 12 variant types), as well as other/mixed ompA-genotypes (n=6). To elucidate the genomic diversity, whole genome sequencing (WGS) was performed from selected samples using SureSelect target enrichment, resulting in 42 genomes, covering a diversity of ompA-genotypes and representing most of the countries sampled. A phylogeny of these data clearly shows that these ompA-genotypes derive from an ompA-genotype L2b ancestor, carrying up to eight SNPs per isolate. SNPs within ompA are overrepresented among genomic changes in these samples, each of which results in an amino acid change in the variable domains of OmpA (major outer membrane protein, MOMP). A reversion to ompA-genotype L2 with the L2b genomic backbone is commonly seen. The wide diversity of ompA-genotypes found in these recent LGV samples indicates that this gene is under immunological selection. Our results suggest that the ompA-genotype L2b genomic backbone is the dominant strain circulating and evolving particularly in men who have sex with men (MSM) populations.
A thematic analysis of Prison and Probation Ombudsman fatal incident reports involving prisoners on palliative/end-of-life care pathways in the long-term high security estate in England and Wales
Authors: Kirkham Joanne
Published: June 2021

Objectives

In this study, the clinical and non-clinical factors that may influence the provision of palliative/end of life care in long-term high security prisons in England and Wales are identified through the lens of Prison and Probation Ombudsman (PPO) fatal incident reports.

Methods

This work extends that of McParland and Johnston (2019) and contemporary literature published in the subsequent period to 2020 through a thematic analysis of fatal incident reports published by the PPO in the period 2014-2020. The results are discussed in context of the ‘Dying Well in Custody Charter’ and positioned within the extant literature.

Conclusions

The results suggest that prisoners in long-term high security prisons who are receiving palliative care are more likely than not to receive care that is comparable to that in the community. Directions for further research are also identified.
Loss-of-function of MFGE8 and protection against coronary atherosclerosis
Authors: Ruotsalainen Sanni E. , Surakka Ida , Mars Nina , Karjalainen Juha , Kurki Mitja , Kanai Masahiro , Krebs Kristi , Mishra Pashupati P. , Mishra Binisha H. , Sinisalo Juha , Palta Priit , Lehtimäki Terho , Raitakari Olli ,   Estonian Biobank research team, Milani Lili ,   The Biobank Japan Project, Okada Yukinori ,   FinnGen, Palotie Aarno , Widen Elisabeth , Daly Mark J. , Ripatti Samuli
Published: June 2021

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland’s population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere.

In FinnGen, a large Finnish biobank study, we identified an inframe insertion rs534125149 in MFGE8 to have protective effect against coronary atherosclerosis (OR = 0.75, p = 2.63×10-16) and related endpoints. This variant is highly enriched in Finland (70-fold compared to Non-Finnish Europeans) with allele frequency of 3% in Finland. The protective association was replicated in meta-analysis of biobanks of Japan and Estonian (OR = 0.75, p = 5.41×10-7).

Additionally, we identified a splice acceptor variant rs201988637 in MFGE8, independent of the rs534125149 and similarly protective in relation to coronary atherosclerosis (OR = 0.72, p = 7.94×10-06) and related endpoints, with no significant risk-increasing associations. The protein-truncating variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial stiffness and aging also in humans in addition to previous evidence in mice. In conclusion, our results show that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.
Development of a digitally-obtainable 10-year all-cause mortality risk score based on data from 497,712 UK Biobank participants
Authors: Colombo Michele , Dolezalova Nikola , Despotovic Aleksa , Reed Angus B. , Morelli Davide , Aral Mert , Plans David
Published: June 2021

Background

All-cause mortality (ACM) scores are a useful tool for identifying individuals with decreased life expectancy. An interpretable score consisting of smartphone-obtainable variables could allow for long-term management of individual health and support the next generation of healthcare monitoring and preventative practices. The aim of this study was to develop a 10-year ACM risk score using the UK Biobank dataset, using only digitally-obtainable variables.

Methods

The models were developed using the full UK Biobank cohort comprising nearly 500,000 individuals. We extracted 399 features from the dataset and, through a data-driven feature selection process with subsequent clinical review, identified 34 features for the final model. As part of the study, we compared two survival analysis approaches: Cox proportional hazards model and DeepSurv, a deep learning-based survival analysis algorithm.

Results

Before feature selection, Cox performed similarly to DeepSurv, achieving a c-index of 0.771 (95% CI 0.770–0.772) and 0.774 (95% CI 0.772–0.775) on the test dataset, respectively. Using the selected 34 features, the c-index of Cox decreased slightly to 0.770 (95% CI 0.769–0.770) and DeepSurv to 0.758 (95% CI 0.755–0.762). The models show excellent calibration at 10 years.

Conclusions

This study improves on a previous smartphone-compatible score, C-Score, by incorporating non-modifiable factors in addition to variables which can be actively modified to reduce risk. This score is comprehensive, easily interpretable and actionable, and as such, could provide a powerful tool for preventative healthcare.
Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of the matricellular protein Mindin
Authors: Badarinath Krithika , Dam Binita , Kataria Sunny , Zirmire Ravindra K. , Dey Rakesh , Singh Randhir , Masudi Tafheem A. , Sambath Janani , Kumar Prashanth , Gulyani Akash , He You-Wen , Krishna Sudhir , Jamora Colin
Published: June 2021

Intratumoral heterogeneity poses a major challenge in designing effective anti-cancer strategies. Accumulating evidence suggests that this heterogeneity arises from cancer stem cells (CSCs) that also drives tumor aggressiveness and drug resistance. The stemness of CSCs are preserved by an ill-defined combination of intrinsic and external factors and is particularly intriguing since they exist within a sea of similar cells at various degrees of differentiation. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-EMT function for the transcription factor Snail in maintaining stemness of keratinocytes. This is accomplished by the secretion of the matricellular protein Mindin from Snail expressing cells, which creates a protective niche that impedes differentiation. In an autocrine fashion, extracellular Mindin activates a Src –STAT3 pathway to reinforce the stem/progenitor phenotype and disruption of this signalling module in human cSCC attenuates tumorigenesis. The expression of Mindin in multiple carcinomas, and its critical role in cancer progression suggests that it would be a promising target for therapeutic intervention.
A comprehensive approach to artifact-free sample preparation and the assessment of mitochondrial morphology in tissue and cultured cells
Authors: Hinton Antentor , Katti Prasanna , Christensen Trace A. , Mungai Margaret , Shao Jianqiang , Zhang Liang , Trushin Sergey , Alghanem Ahmad , Jaspersen Adam , Geroux Rachel E. , Neikirk Kit , Biete Michelle , Lopez Edgar Garza , Vue Zer , Beasley Heather K. , Marshall Andrea G. , Ponce Jessica , Bleck Christopher K. E. , Hicsasmaz Innes , Murray Sandra A. , Edmonds Ranthony A.C. , Dajles Andres , Koo Young Do , Bacevac Serif , Salisbury Jeffrey L. , Pereira Renata O. , Glancy Brian , Trushina Eugenia , Abel E. Dale
Published: June 2021

Mitochondrial dynamics (fission, fusion, and the formation of nanotunnels) and morphology are very sensitive to the cellular environment. Mitochondria may be adversely affected by oxidative stress, changes in calcium levels, and hypoxia. Investigating the precise relationship between organelle structure and function requires methods that can adequately preserve mitochondria while providing accurate, quantitative measurements of morphological attributes. Here, we demonstrate a practical approach for preserving and measuring fine structural changes using two-dimensional, high-resolution electron micrographs. This approach is further applicable for three-dimensional volume renderings, obtained using serial block-face and focused ion beam-scanning electron microscopy, highlighting the specific advantages of these techniques. Additionally, this study defines a set of quantifiable metrics that can be applied to measure mitochondrial architecture and other organellar structures. Finally, we validated specimen preparation methods that avoid the introduction of morphological artifacts that may interfere with mitochondrial appearance and do not require whole-animal perfusion.
Implicit agency is related to gamma power changes in an automatic imitation task
Authors: Ulloa José Luis , Vastano Roberta , Jensen Ole , Brass Marcel
Published: June 2021

Often we have a feeling that we can control effects in the external world through our actions. The role of action processing associated with this implicit form of agency is still not clear. In this study, we used automatic imitation and electroencephalography to investigate neural oscillations associated with action processing and its possible contribution to implicit agency. Brain activity was recorded while participants performed actions (congruent or incongruent with a displayed finger movement) which subsequently triggered an outcome (a tone). We used a time estimation task to measure intentional binding (an index of implicit agency). We observed a decrease of alpha, beta and gamma power for congruent compared to incongruent actions and increased theta power for incongruent compared to congruent actions. Crucially, participants who showed greater intentional binding for congruent versus incongruent actions also presented greater gamma power differences. Alpha, beta and theta power were modulated by congruency but were unrelated to intentional binding. Our study suggests that an increased implicit agency for facilitated actions is associated with changes in gamma power. Our study also contributes to a characterization of neural oscillations in automatic imitation.
Integrative analyses of convergent adaptation in sympatric extremophile fishes
Authors: Greenway Ryan , De-Kayne Rishi , Brown Anthony P. , Camarillo Henry , Delich Cassandra , McGowan Kerry L. , Nelson Joel , Arias-Rodriguez Lenin , Kelley Joanna L. , Tobler Michael
Published: June 2021

The evolution of independent lineages along replicated environmental gradients frequently results in convergent adaptation, yet the degree to which convergence is present across multiple levels of biological organization is often unclear. Additionally, inherent biases associated with shared ancestry and variation in selective regimes across geographic replicates often pose challenges for confidently identifying patterns of convergence. We investigated a system in which three species of poeciliid fishes sympatrically occur in a toxic spring rich in hydrogen sulfide (H2S) and an adjacent nonsulfidic stream to examine patterns of adaptive evolution across levels of biological organization. We found convergence in morphological and physiological traits and genome-wide patterns of gene expression among all three species. In addition, there were shared signatures of selection on genes encoding H2S toxicity targets in the mitochondrial genomes of each species. However, analyses of nuclear genomes revealed neither evidence for substantial genomic islands of divergence around genes involved in H2S toxicity and detoxification nor substantial congruence of strongly differentiated regions across population pairs. These non-convergent, heterogenous patterns of genomic divergence may indicate that sulfide tolerance is highly polygenic, with shared allele frequency shifts present at many loci with small effects along the genome. Alternatively, H2S tolerance may involve substantial genetic redundancy, with non-convergent lineage-specific variation at multiple loci along the genome underpinning similar changes in phenotypes and gene expression. Overall, we demonstrate variability in the extent of convergence across organizational levels and highlight the challenges of linking patterns of convergence across scales.
A novel live cell imaging assay reveals regulation of endosome maturation
Authors: Podinovskaia Maria , Prescianotto-Baschong Cristina , Buser Dominik P. , Spang Anne
Published: June 2021

Cell-cell communication is an essential process in life, with endosomes acting as key organelles for regulating uptake and secretion of signaling molecules. Endocytosed material is accepted by the sorting endosome where it either is sorted for recycling or remains in the endosome as it matures to be degraded in the lysosome. Investigation of the endosome maturation process has been hampered by the small size and rapid movement of endosomes in most cellular systems. Here, we report an easy versatile live-cell imaging assay to monitor endosome maturation kinetics, which can be applied to a variety of mammalian cell types. Acute ionophore treatment led to enlarged early endosomal compartments that matured into late endosomes and fused with lysosomes to form endolysosomes. Rab5-to-Rab7 conversion and PI(3)P formation and turn over were recapitulated with this assay and could be observed with a standard widefield microscope. We used this approach to show that Snx1- and Rab11-dependent endosomal recycling occurred throughout endosome maturation and was uncoupled from Rab conversion. In contrast, efficient endosomal acidification was dependent on Rab conversion. The assay provides a powerful tool to further unravel various aspects of endosome maturation.
A prosocial character of head-gaze aversion in common marmosets
Authors: Spadacenta S. , Dicke P.W. , Thier P.
Published: June 2021

Gaze aversion is a behavior adopted by several mammalian and non-mammalian species in response to eye contact and usually interpreted as reaction to perceived threat. Unlike many other primates, common marmosets (Callithrix jacchus) are thought to have high tolerance for direct gaze, barely exhibiting gaze avoidance towards conspecifics and humans. Here we show that this does not hold for marmosets interacting with a familiar experimenter who suddenly establishes eye contact in a playful interaction (“peek-a-boo”). In video footage synchronously recorded from the two agents, we found that our monkeys consistently alternated between eye contact and head-gaze aversion. The striking similarity with the gaze aversion’s dynamics exhibited by human infants interacting with their caregivers suggests a shared behavioral strategy to disengage temporarily from overwhelming social stimulation, in order to prepare for a new round of rewarding, affiliative face-to-face interaction. The potential of our finding for a marmoset model of autism is discussed.
N4-hydroxycytidine and inhibitors of dihydroorotate dehydrogenase synergistically suppress SARS-CoV-2 replication
Authors: Stegmann Kim M. , Dickmanns Antje , Heinen Natalie , Groß Uwe , Görlich Dirk , Pfaender Stephanie , Dobbelstein Matthias
Published: June 2021

Effective therapeutics to inhibit the replication of SARS-CoV-2 in infected individuals are still under development. The nucleoside analogue N4-hydroxycytidine (NHC), also known as EIDD-1931, interferes with SARS-CoV-2 replication in cell culture. It is the active metabolite of the prodrug Molnupiravir (MK-4482), which is currently being evaluated for the treatment of COVID-19 in advanced clinical studies. Meanwhile, inhibitors of dihydroorotate dehydrogenase (DHODH), by reducing the cellular synthesis of pyrimidines, counteract virus replication and are also being clinically evaluated for COVID-19 therapy. Here we show that the combination of NHC and DHODH inhibitors such as teriflunomide, IMU-838/vidofludimus, and BAY2402234, strongly synergizes to inhibit SARS-CoV-2 replication. While single drug treatment only mildly impaired virus replication, combination treatments reduced virus yields by at least two orders of magnitude. We determined this by RT-PCR, TCID50, immunoblot and immunofluorescence assays in Vero E6 and Calu-3 cells infected with wildtype and the Alpha and Beta variants of SARS-CoV-2. We propose that the lack of available pyrimidine nucleotides upon DHODH inhibition increases the incorporation of NHC in nascent viral RNA, thus precluding the correct synthesis of the viral genome in subsequent rounds of replication, thereby inhibiting the production of replication competent virus particles. This concept was further supported by the rescue of replicating virus after addition of pyrimidine nucleosides to the media. Based on our results, we suggest combining these drug candidates, which are currently both tested in clinical studies, to counteract the replication of SARS-CoV-2, the progression of COVID-19, and the transmission of the disease within the population.

SIGNIFICANCE

The strong synergy displayed by DHODH inhibitors and the active compound of Molnupiravir might enable lower concentrations of each drug to antagonize virus replication, with less toxicity.

Both Molnupiravir and DHODH inhibitors are currently being tested in advanced clinical trials or are FDA-approved for different purposes, raising the perspective of rapidly testing their combinatory efficacy in clinical studies.

Molnupiravir is currently a promising candidate for treating early stages of COVID-19, under phase II/III clinical evaluation. However, like Remdesivir, it appears only moderately useful in treating severe COVID-19. Since the combination inhibits virus replication far more strongly, and since DHODH inhibitors may also suppress excessive immune responses, the combined clinical application bears the potential of alleviating the disease burden even at later stages.
Disease modeling by efficient genome editing using a near PAM-less base editorin vivo
Authors: Rosello Marion , Serafini Malo , Mione Marina C , Concordet Jean-Paul , Del Bene Filippo
Published: June 2021

Base Editors are emerging as an innovative technology to introduce point mutations in complex genomes. So far, the requirement of an NGG Protospacer Adjacent Motif (PAM) at a suitable position often limits the editing possibility to model human pathological mutations in animals. Here we show that, using the CBE4max-SpRY variant recognizing the NRN PAM sequence, we could introduce point mutations for the first time in an animal model and achieved up to 100% efficiency, thus drastically increasing the base editing possibilities. With this near PAM-less base editor we could simultaneously mutate several genes and developed a co-selection method to identify the most edited embryos based on a simple visual screening. Finally, we applied our method to create a new zebrafish model for melanoma predisposition based on the simultaneous editing of multiple genes. Altogether, our results considerably expand the Base Editor application to introduce human disease-causing mutations in zebrafish.
Enhanced fitness of SARS-CoV-2 variant of concern B.1.1.7, but not B.1.351, in animal models
Authors: Ulrich Lorenz , Halwe Nico Joel , Taddeo Adriano , Ebert Nadine , Schön Jacob , Devisme Christelle , Trüeb Bettina Salome , Hoffmann Bernd , Wider Manon , Bekliz Meriem , Essaidi-Laziosi Manel , Schmidt Marie Luisa , Niemeyer Daniela , Corman Victor Max , Kraft Anna , Godel Aurélie , Laloli Laura , Kelly Jenna N. , Breithaupt Angele , Wylezich Claudia , Veiga Inês Berenguer , Gultom Mitra , Adea Kenneth , Meyer Benjamin , Eberhardt Christiane , Thomann Lisa , Gsell-Albert Monika , Labroussaa Fabien , Jores Jörg , Summerfield Artur , Drosten Christian , Eckerle Isabella Anne , Dijkman Ronald , Hoffmann Donata , Thiel Volker , Beer Martin , Benarafa Charaf
Published: June 2021

Emerging variants of concern (VOCs) drive the SARS-CoV-2 pandemic. We assessed VOC B.1.1.7, now prevalent in several countries, and VOC B.1.351, representing the greatest threat to populations with immunity to the early SARS-CoV-2 progenitors. B.1.1.7 showed a clear fitness advantage over the progenitor variant (wt-S614G) in ferrets and two mouse models, where the substitutions in the spike glycoprotein were major drivers for fitness advantage. In the “superspreader” hamster model, B.1.1.7 and wt-S614G had comparable fitness, whereas B.1.351 was outcompeted. The VOCs had similar replication kinetics as compared to wt-S614G in human airway epithelial cultures. Our study highlights the importance of using multiple models for complete fitness characterization of VOCs and demonstrates adaptation of B.1.1.7 towards increased upper respiratory tract replication and enhanced transmission in vivo.

Summary sentence

B.1.1.7 VOC outcompetes progenitor SARS-CoV-2 in upper respiratory tract replication competition in vivo.
A SARS-CoV-2 mini-genome assay based on negative-sense RNA to study replication inhibitors and emerging mutations
Authors: Vial Thomas , Oade Michael S. , Russell Colin A. , Eggink Dirk , te Velthuis Aartjan J.W.
Published: June 2021

Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus and the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Efforts to identify inhibitors of SARS-CoV-2 replication enzymes and better understand the mechanisms underlying viral RNA synthesis have largely relied on biosafety level 3 (BSL3) laboratories, limiting throughput and accessibility. Recently, replicon systems have been proposed that involve~30 kb RNA-based replicons or large plasmids that express the viral structural and non-structural proteins (nsp) in addition to a positive-sense reporter RNA. Unfortunately, these assays are not user-friendly due to plasmid instability or a poor signal to background ratio. We here present a simple mini-genome assay consisting of a~2.5 kb-long negative-sense, nanoluciferase-encoding sub-genomic reporter RNA that is expressed from a plasmid, and amplified and transcribed by the SARS-CoV-2 RNA polymerase core proteins nsp7, nsp8 and nsp12. We show that expression of nsp7, 8 and 12 is sufficient to obtain robust positive- and negative-sense RNA synthesis in cell culture, that addition of other nsps modulates expression levels, and that replication of the reporter RNA can be inhibited by active site mutations in nsp12 or the SARS-CoV-2 replication inhibitor remdesivir. The mini-genome assay provides a signal that is 170-fold above background on average, providing excellent sensitivity for high-throughput screens, while the use of small plasmids facilitates site-directed mutagenesis for fundamental analyses of SARS-CoV-2 RNA synthesis.

Importance statement

The impact of the COVID-19 pandemic has made it essential to better understand the basic biology of SARS-CoV-2, and to search for compounds that can block the activity of key SARS-CoV-2 replication enzymes. However, studies with live SARS-CoV-2 require biosafety level 3 facilities, while existing replicon systems depend on long positive-sense subgenomes that are often difficult to manipulate or produce a high background signal, limiting drug-screens and a rapid analysis of emerging SARS-CoV-2 mutations during the COVID-19 pandemic. To make it easier to study emerging SARS-CoV-2 mutants and screen for inhibitors, we developed a simple mini-replicon that produces a minimal background signal, that can be used in any tissue culture lab, and that only requires four small plasmids to work.
A dual process on shopping well-being across shopping contexts: the role of shopping values and impulse buying
Authors: Nghia Ho Trong , Olsen Svein Ottar , Trang Nguyen Thi Mai
Published: June 2021

Purpose

Adopting the duality approach, this study aims to examine cognitive and affective associations between shopping values, impulse buying tendencies and consumer shopping well-being. In addition, the study also aims to test the moderating role of self-control and compare the proposed relationships across the offline and online shopping contexts.

Design/methodology/approach

A survey dataset was collected from a sample of 529 offline and online consumers in Vietnam. Structural equation modelling (SEM) was employed to test the proposed relationships among the studied constructs.

Findings

The consequence of impulse buying is positive and affect-based. In addition, the positive associations between shopping values and impulse buying via dual process are validated and moderated by self-control. In addition, the association between cognitive impulse buying and shopping well-being is stronger in the online shopping context, whereas hedonic value has more influence on affective impulse buying in the offline shopping context. All other relationships are not statistically different across the two shopping contexts.

Originality/value

This study introduces an appropriate theoretical framework for studying impulse buying—the duality approach. Second, the research validates the dual process and positive consequence of impulse buying. Third, self-control's moderating role is validated, whereas the studied associations are initially compared across shopping contexts.
Discovery of factors affecting tourists' fine dining experiences at five-star hotel restaurants in Istanbul
Authors: Aktas-Polat Semra , Polat Serkan
Published: June 2021

Purpose

The purpose of this study is to discover the factors affecting customer delight, satisfaction and dissatisfaction in fine dining experiences (FDEs).

Design/methodology/approach

Online user generated 2,585 reviews on TripAdvisor for 46 five-star hotel restaurants operating in Istanbul were analyzed with the latent Dirichlet allocation (LDA) algorithm.

Findings

LDA created nine, eight and seven topics for delight, satisfaction and dissatisfaction, respectively. The most salient topics for customer delight, satisfaction and dissatisfaction in FDEs are staff (17.3%), view (19%), and food quality (23%), respectively.

Originality/value

This study is one of the few studies investigating customer delight and satisfaction together. The study shows that FDEs can be analyzed with text mining techniques. Moreover, the study contributes to the literature on customer delight by adding staff topic as an antecedent.
The driving process of technological innovation in construction: a firm-level CDM analysis
Authors: Gong Zheng , Wang Nannan
Published: June 2021

Purpose

Innovation has been acknowledged as the key for modern industries. However, the construction industry is criticised for being poor in innovation performance compared to other industry sectors. Large construction firms are the main contributor to technological innovation in the construction industry, but the driving process of their technological innovation has not yet been fully investigated in previous studies. The purpose of this paper is to provide quantitative analysis of the technological innovation driving process of large construction firms.

Design/methodology/approach

An extended crépon, duguet and mairesse (CDM) model has been developed to analyse the key influencing factors for technological innovation in construction firms. The sample data are selected from the world’s largest construction market, China, and include 129 listed construction firms.

Findings

The results show significant positive correlation between R&D investment and innovation output and also between innovation output and performance. The effect of influencing factors on the R&D investment, innovation output and performance are also revealed by the empirical study. The underlying reasons are discussed and suggestions are given for the construction industry to improve the technological innovation capacity of construction firms.

Originality/value

This research contributes to the literature of construction innovation and benefits practitioners by providing a quantitative approach to demonstrate the driving process of innovation in construction firms.
The relationship between CRM and customer loyalty: the moderating role of customer trust
Authors: Alam Mirza Mohammad Didarul , Karim Rashed Al , Habiba Wardha
Published: June 2021

Purpose

The present study investigates the moderating role of customer trust in customer relationship management (CRM) components and customer loyalty relationships in the context of the baking sector in Bangladesh.

Design/methodology/approach

Data were collected through a survey using a structured questionnaire from 350 customers of commercial banks in Bangladesh.

Findings

The key finding is that all CRM components (customer orientation, customer advocacy and customer knowledge) except customer engagement have positive impact on customer loyalty. Moreover, customer trust only moderates the relationship between customer knowledge and customer loyalty, whereas other CRM components and customer loyalty do not moderate by trust.

Originality/value

The findings of the study add to the substantial pool of knowledge on CRM components, customer trust and customer loyalty literature. More specifically, the moderating role of customer trust between customer knowledge and customer loyalty is the novel contribution of this research which will enrich the existing CRM literature particularly in the banking sector of Bangladesh.