bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide analysis of focal DNA hypermethylation inIDH-mutant AML samples
Authors: Wilson Elisabeth R. , Helton Nichole M. , Heath Sharon E. , Fulton Robert S. , Payton Jacqueline E. , Welch John S. , Walter Matthew J. , Westervelt Peter , DiPersio John F. , Link Daniel C. , Miller Christopher A. , Ley Timothy J. , Spencer David H.
Published: March 2021

Recurrent mutations inIDH1orIDH2in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples withIDH1orIDH2mutations, which identified ~4,000 focal regions that were uniquely hypermethylated vs. normal CD34+ cells. These regions had modest, but significant, hypermethylation in AMLs with biallelicTET2mutations, and 5-hydroxymethylation levels that were dependent on functional TET2, indicating that hypermethylation in these regions is caused by inhibition of TET-mediated demethylation. Focal hypermethylation inIDHmutAMLs occurred in regions with low methylation in normal CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containingIDHandDNMT3AR882mutations were significantly less hypermethylated, suggesting that methylation in these regions is mediated by DNMT3A.IDHmut-specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, includingMYCandETV6. These results suggest that focal hypermethylation inIDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.
High-frequency screening combined with diagnostic testing for control of SARS-CoV-2 in high-density settings: an economic evaluation of resources allocation for public health benefit
Authors: Rogers Will , Ruiz-Aravena Manuel , Hansen Dale , Madden Wyatt , Kessler Maureen , Fields Matthew W. , Ferrari Matthew J. , Chang Connie B. , Morrow Jayne , Hoegh Andrew , Plowright Raina K.
Published: March 2021

SARS-CoV-2 spreads quickly in dense populations, with serious implications for universities, workplaces, and other settings where exposure reduction practices are difficult to implement. Rapid screening has been proposed as a tool to slow the spread of the virus; however, many commonly used diagnostic tests (e.g., RT-qPCR) are expensive, difficult to deploy (e.g., require a nasopharyngeal specimen), and have extended turn-around times. We evaluated testing regimes that combined diagnostic testing using qPCR with high-frequency screening using a novel reverse-transcription loop-mediated isothermal amplification (RT-LAMP, herein LAMP) assay. We used a compartmental susceptible-exposed-infectious-recovered (SEIR) model to simulate screening of a university population. We also developed a Shiny application to allow administrators and public health professionals to develop optimal testing strategies given site-specific assumptions about testing investment, target population, and cost. The frequency of screening, especially when pooling samples, was more important for minimizing epidemic size than test sensitivity, behavioral compliance, contact tracing capacity, and time between testing and results. Our results suggest that when testing budgets are limited, it is safer and more cost-effective to allocate the majority of funds to screening. Rapid, cost-effective, and scalable screening tests, like LAMP, should be viewed as critical components of SARS-CoV-2 testing in high-density populations.
High seroprevalence of anti-SARS-CoV-2 antibodies after the first wave of the COVID-19 pandemic in a vulnerable population in Perpignan, France
Authors: Beaumont Adeline , Durand Cécile , Ledrans Martine , Schwoebel Valérie , Noel Harold , Le Strat Yann , Diulius Donatien , Colombain Léa , Médus Marie , Gueudet Philippe , Mouly Damien , Aumaître Hugues
Published: March 2021

Background

In March 2020, many cases of COVID-19 were reported in three socially deprived neighbourhoods of the city of Perpignan, in the south of France, where large sedentary gypsy communities live. A study to measure seroprevalence was conducted in July 2020 to assess the level of contamination in these neighbourhoods after the first wave of the pandemic, and to identify factors associated with seropositivity.

Methods

SCoPe is a cross-sectional survey conducted in selected persons aged six years old and over living in three neighbourhoods in Perpignan. Households were selected by systematic sampling and participants by random sampling. Collected blood samples were tested for SARS-CoV-2 IgG and IgM antibodies using the EIecsys® immunoassay to target the coronavirus’s spike protein. Antibody seroprevalence was estimated from weighted data and associated factors were investigated using multivariate logistic regression.

Results

The seroprevalence of anti-SARS-CoV-2 antibodies was 35.4% (95% CI: 30.2-41.0). Over a fifth of seropositive individuals (21.7% ([14.1-31.8]) did not report any COVID-19 symptom. People aged 15-64 years old were at greater risk of seropositivity than those aged 65 years or over. Obesity prevalence was 40.7% (35.8-45.8) and obese people were more likely to be seropositive (aOR=2.0 [1.1-3.8]). The risk of being seropositive was higher in households with clinical COVID-19 cases (One case: aOR=2.5 [1.3-5.0]). In the neighbourhood with the highest measured seroprevalence, people living in a dwelling with 1-2 rooms had a higher risk of being seropositive than those living in a 4-room house (aOR=2.8 [1.2-6.3]). Working during the lockdown was associated with a lower risk of seropositivity (aOR=0.2 [0.03-1.0]).

Conclusion

Transmission prevalence of the SARS-COV-2 virus in this vulnerable population was very high during the COVID-19 pandemic’s first wave. Our results highlight the need to strengthen and adapt preventive measures by taking into account all social determinants of health, especially housing conditions.
Predicting functional consequences of mutations using molecular interaction network features
Authors: Ozturk Kivilcim , Carter Hannah
Published: March 2021

Variant interpretation remains a central challenge for precision medicine. Missense variants are particularly difficult to understand as they change only a single amino acid in protein sequence yet can have large and varied effects on protein activity. Numerous tools have been developed to identify missense variants with putative disease consequences from protein sequence and structure. However, biological function arises through higher order interactions among proteins and molecules within cells. We therefore sought to capture information about the potential of missense mutations to perturb protein interaction networks by integrating protein structure and interaction data. We developed 16 network-based annotations for missense mutations that provide orthogonal information to features classically used to prioritize variants. We then evaluated them in the context of a proven machine-learning framework for variant effect prediction across multiple benchmark datasets to demonstrate their potential to improve variant classification. Interestingly, network features resulted in larger performance gains for classifying somatic mutations than for germline variants, possibly due to different constraints on what mutations are tolerated at the cellular versus organismal level. Our results suggest that modeling variant potential to perturb context-specific interactome networks is a fruitful strategy to advancein silicovariant effect prediction.
Evotuning protocols for Transformer-based variant effect prediction on multi-domain proteins
Authors: Yamaguchi Hideki , Saito Yutaka
Published: March 2021

Accurate variant effect prediction has broad impacts on protein engineering. Recent machine learning approaches toward this end are based on representation learning, by which feature vectors are learned and generated from unlabeled sequences. However, it is unclear how to effectively learn evolutionary properties of an engineering target protein from homologous sequences, taking into account the protein’s sequence-level structure called domain architecture (DA). Additionally, no optimal protocols are established for incorporating such properties into Transformer, the neural network well-known to perform the best in natural language processing research. This article proposes DA-aware evolutionary fine-tuning, or “evotuning”, protocols for Transformer-based variant effect prediction, considering various combinations of homology search, fine-tuning, and sequence vectorization strategies. We exhaustively evaluated our protocols on diverse proteins with different functions and DAs. The results indicated that our protocols achieved significantly better performances than previous DA-unaware ones. The visualizations of attention maps suggested that the structural information was incorporated by evotuning without direct supervision, possibly leading to better prediction accuracy.

Availability

https://github.com/dlnp2/evotuning_protocols_for_transformers

Supplementary information

Supplementary data are available atBriefings in Bioinformaticsonline.
Sleep deprivation exacerbates seizures and diminishes GABAergic tonic inhibition
Authors: Konduru Sai Surthi , Pan Yuzhen , Wallace Eli , Pfammatter Jesse A , Jones Mathew V. , Maganti Rama K.
Published: March 2021

Patients with epilepsy report that sleep deprivation is a common trigger for breakthrough seizures. The basic mechanism of this phenomenon is unknown. In the Kv1.1-/-mouse model of epilepsy, daily sleep deprivation indeed exacerbated seizures though these effects were lost after the 3rdday. Sleep deprivation also accelerated mortality in ~52% of Kv1.1-/-mice, not observed in controls. Voltage-clamp experiments on the day after recovery from sleep deprivation showed reductions in GABAergic tonic inhibition in dentate granule cells both in Kv1.1-/-and wild-type mice. Our results suggest that sleep deprivation is detrimental to seizures and survival, possibly due to reductions in GABAergic tonic inhibition.
Regulation of coordinated muscular relaxation by a pattern-generating intersegmental circuit
Authors: Hiramoto Atsuki , Jonaitis Julius , Niki Sawako , Kohsaka Hiroshi , Fetter Richard , Cardona Albert , Pulver Stefan , Nose Akinao
Published: March 2021

Typical patterned movements in animals are achieved through combinations of contraction and delayed relaxation of groups of muscles. However, how intersegmentally coordinated patterns of muscular relaxation are regulated by the neural circuits remain poorly understood. Here, we identify Canon, a class of higher-order premotor interneurons, that regulates muscular relaxation during backward locomotion ofDrosophilalarvae. Canon neurons are cholinergic interneurons present in each abdominal neuromere and show wave-like activity during fictive backward locomotion. Optogenetic activation of Canon neurons induces relaxation of body wall muscles, whereas inhibition of these neurons disrupts timely muscle relaxation. Canon neurons provide excitatory outputs to inhibitory premotor interneurons. Canon neurons also connect with each other to form an intersegmental circuit and regulate their own wave-like activities. Thus, our results demonstrate how coordinated muscle relaxation can be realized by an intersegmental circuit that regulates its own patterned activity and sequentially terminates motor activities along the anterior-posterior axis.
Wearable sensing devices acceptance behavior in construction safety and health: assessing existing models and developing a hybrid conceptual model
Authors: Okpala Ifeanyi , Nnaji Chukwuma , Awolusi Ibukun
Published: March 2021

Purpose

This study aims to examine relationships between several key technology acceptance variables that predict workers’ wearable sensing devices (WSDs) acceptance in the construction industry by using technology acceptance model, theory of planned behavior and unified theory of acceptance and use of technology (UTAUT) model. The study proposes a hybrid conceptual model to measure construction field workers’ intentions to use WSDs and their usage behaviors. The study introduces variables that are instrumental in understanding and improving WSD acceptance in construction.

Design/methodology/approach

The study was carried out using a structured literature review, online survey and structural equation modeling. A total of 195 field workers across the USA, with experience in using WSDs, participated in the study.

Findings

Results indicate that all three theories predict WSD acceptance with variables explaining at least 89% of the variance in actual use, with the UTAUT outperforming other models (91%). However, the differences between the predictive power of these models were not statistically significant. A hybrid conceptual model is proposed using findings from the present study.

Practical implications

The study contributes to knowledge and practice by highlighting key variables that influence WSD acceptance. Findings from this study should provide stakeholders with critical insights needed to successfully drive WSD acceptance in the construction industry.

Originality/value

To the best of the authors’ knowledge, this is the first study that evaluates the predictive strength of multiple technology acceptance theories and models within the construction worker safety technology domain. Additionally, the study proposes a hybrid conceptual model which could provide practitioners and researchers with information pertinent to enhancing WSD acceptance.
A deployment framework for BIM localization
Authors: Wang Jing , Lu Weisheng
Published: March 2021

Purpose

Over the past two decades, building information modeling (BIM) has been promoted as one of the most disruptive innovations across the global architecture, engineering and construction (AEC) community. Nevertheless, despite its widely propagated benefits, BIM adoption in various localities is not progressing excitingly. BIM as an innovation developed from a presumed, general context may not fit well with the specific regulatory, social and cultural settings of a locality. This study aims to tackle the lukewarm local BIM adoption by developing a deployment framework for BIM localization.

Design/methodology/approach

Drawing upon the diffusion of innovation (DoI) theory, a longitudinal case study is designed and conducted by engaging closely with a top cost consultancy company in Hong Kong for forty-one months.

Findings

The findings refuted the “one-size-fits-for-all” view to use a standardized BIM for international users. Rather, an organization needs to undergo a series of localization works to integrate global BIM in its specific local context. The deployment framework outlines the BIM dimensions (i.e. technology, process and protocol) and the mechanisms (i.e. configuration, coupling and reinterpretation) of BIM localization that go through the three “A”s (i.e. analysis, adaption and assimilation) process under a firm's network and contextual factors.

Originality/value

This study improves our understanding of sluggish BIM adoption by attributing it to the gap between general BIM development and the local, unique BIM use context. Proposing the deployment framework, the study also offers a handy tool for prospective executives to localize BIM and harness its power in their respective organizations and localities.
Context counts: a qualitative study exploring the interplay between context and implementation success
Authors: Rogers Lisa , De Brún Aoife , Birken Sarah A. , Davies Carmel , McAuliffe Eilish
Published: March 2021

Purpose

Implementing change in healthcare is difficult to accomplish due to the unpredictability associated with challenging the status quo. Adapting the intervention/practice/program being implemented to better fit the complex context is an important aspect of implementation success. Despite the acknowledged influence of context, the concept continues to receive insufficient attention at the team-level within implementation research. Using two heterogeneous multidisciplinary healthcare teams as implementation case studies, this study evaluates the interplay between context and implementation and highlights the ways in which context influences the introduction of a collective leadership intervention in routine practice.

Design/methodology/approach

The multiple case study design adopted, employed a triangulation of qualitative research methods which involved observation (Case A = 16 h, Case B = 15 h) and interview data (Case A = 13 participants, Case B = 12 participants). Using an inductive approach, an in-depth thematic analysis of the data outlined the relationship between team-level contextual factors and implementation success.

Findings

Themes are presented under the headings: (1) adapting to the everyday realities, a key determinant for implementation success and (2) implementation stimulating change in context. The findings demonstrate a dynamic relationship between context and implementation. The challenges of engaging busy healthcare professionals emphasised that mapping the contextual complexity of a site and adapting implementation accordingly is essential to enhance the likelihood of successful implementation. However, implementation also altered the surrounding context, stimulating changes within both teams.

Originality/value

By exposing the reciprocal relationship between team-level contextual factors and implementation, this research supports the improved design of implementation strategies through better understanding the interplay and mutual evolution of evidence-based healthcare interventions within different contexts.
Examining the extent of and drivers for materiality assessment disclosures in sustainability reports
Authors: Farooq Muhammad Bilal , Zaman Rashid , Sarraj Dania , Khalid Fahad
Published: March 2021

Purpose

This paper aims to evaluate the extent of materiality assessment disclosures in sustainability reports and their determinants. The study examines the disclosure practices of listed companies based in the member states of the Cooperation Council for the Arab States of the Gulf, colloquially referred to as the Gulf Cooperation Council (GCC).

Design/methodology/approach

First, the materiality assessment disclosures were scored through a content analysis of sustainability reports published by listed GCC companies during a five-year period from 2013 to 2017. Second, a fixed effect ordered logic regression was used to examine the determinants of materiality assessment disclosures.

Findings

While sustainability reporting rates improved across the sample period, a significant majority of listed GCC companies do not engage in sustainability reporting. The use of internationally recognised standards has also declined. While reporters provide more information on their materiality assessment, the number of sustainability reports that offer information on how the reporter identifies material issues has declined. These trends potentially indicate the existence of managerial capture. Materiality assessment disclosure scores are positively influenced by higher financial performance (Return on Assets), lower leverage and better corporate governance. However, company size and market-to-book ratio do not influence materiality assessment disclosures.

Practical implications

The findings may prove useful to managers responsible for preparing sustainability reports who can benefit from the examples of materiality assessment disclosures. An evaluation of the materiality assessment should be included in the scope of assurance engagements and practitioners can use the examples of best practice when evaluating sustainability reports. Stock exchanges may consider developing improved corporate governance guidelines as these will lead to materiality assessment disclosures.

Social implications

The findings may assist in improving sustainability reporting quality, through better materiality assessment disclosures. This will allow corporate stakeholders to evaluate the reporting entities underlying processes, which leads to transparency and corporate accountability. Improved corporate sustainability reporting supports the GCC commitment to implement the United Nations Sustainable Development Goals and transition to sustainable development.

Originality/value

This study addresses the call for greater research examining materiality within a sustainability reporting context. This is the first paper to examine sustainability reporting quality in the GCC region, focussing particularly on materiality assessment disclosures.
Does knowledge hiding undermine buyer-supplier relationship performance in supply chains? A dyadic perspective
Authors: Butt Atif Saleem , Shah Syed Hamad Hassan , Ahmad Ahmad Bayiz
Published: March 2021

Purpose

The purpose of this paper is to explore how knowledge hiding affects buyer-supplier relationship performance in the supply chain.

Design/methodology/approach

This study uses a multiple case study methodology. Overall, 26 semi-structured interviews (13 dyadic interviews) with managers of buying and supplying firms (who have been a victim of knowledge hiding) were undertaken.

Findings

Based on comprehensive data analysis, results reveal seven factors that adversely affect buyer-supplier relationship performance (lack of trust, lack of cooperation and lack of commitment). In addition, results reveal that such factors reduced the firm’s business performance in terms of low-quality products, increased lead time and higher costs.

Research limitations/implications

This study has some limitations. First, the results of this study are not generalizable to a broader population. Second, this study explores behavioral patterns with respect to United Arab Emirates culture only.

Practical implications

Firms can use the findings from this study to understand how knowledge hiding in a buyer-supplier relationship adversely affects a buyer-supplier relationship performance.

Originality/value

A considerable weakness in buyer-supplier relationship literature is a need for a study examining how knowledge hiding harms buyer-supplier relationship performance in the supply chain. This paper addresses this gap.
Influence of information and communication technologies on customer satisfaction and increase in the number of customers
Authors: Acosta-Prado Julio César , Tafur-Mendoza Arnold Alejandro
Published: March 2021

Purpose

Information and communication technologies (ICT) play an important role in business management today. However, there is little information on how the uses of ICT within firms create positive results regarding service. The purpose of the study is to know the degree of influence of ICT on customer satisfaction and increase in the number of customers.

Design/methodology/approach

The sample consisted of 102 Colombian new technology-based firms (NTBFs) located in business incubators and technology parks, selected through a non-probabilistic, purposeful sampling. To perform the statistical analysis, structural equation modeling was used.

Findings

The results indicated a good fit of the proposed model, where ICT have a positive and significant influence with a medium effect on customer satisfaction and a large effect on increase in the number of customers. The findings showed that the implementation of ICT in the different internal processes of NTBFs favors external processes, to improve and innovate the quality of their service, reflecting in a positive perception of customers.

Originality/value

Influence of ICT on the performance of firms has not been widely studied in non-economic results. The internal processes of the firms are the use of internet technologies, collaboration, management, decision-making support, search and data management. Meanwhile, external processes involve services directly visible to customers. Previous research does not consider the impact of ICT on internal processes that have repercussions on external processes.
Population risk factors for nulliparous, term, singleton, vertex caesarean birth: a national cross‐sectional study
Authors: Andrikopoulou M , Wen T , Sheen J‐J , Krenitsky N , Baptiste CD , Goffman D , Staniczenko AP , D’Alton ME , Friedman AM
Published: March 2021

Objective

To characterise medical, obstetric and demographic risk factors associated with nulliparous, term, singleton, vertex (NTSV) caesarean birth.

Study design

Cross‐sectional study.

Setting

United States delivery hospitalisations.

Population

NTSV births in 2016–18 US natality data.

Methods

This study analysed a national sample of natality data generated by the United States National Vital Statistics System. NTSV deliveries were identified. The primary outcome was caesarean birth. Risk factors including maternal age, body mass index (BMI) and pregestational diabetes were analysed. Multivariable log‐linear regression models analysed factors associated with NTSV caesarean with adjusted risk ratios (aRR) as measures of effect.

Results

Of 11 622 400 deliveries, 3 764 707 met NTSV criteria, and their caesarean section rate was 25.9%. Maternal age 35–39 years (aRR 1.51, 95% CI 1.50–1.52) and 40–54 years (aRR 2.03, 95% 2.00–2.05) compared with age 19–34 years; BMI 25 to <30 kg/m2 (aRR 1.32, 95% CI 1.31–1.33), 30 to <35 kg/m2 (aRR 1.57 95% CI 1.56–1.58), 35 to <40 kg/m2 (aRR 1.82, 95% CI 1.80–1.83) and ≥40 kg/m2 (aRR 2.17, 95% CI 2.15–2.19) compared with BMI 18.5–24.9 kg/m2; and pregestational diabetes (aRR 1.54, 95% CI 1.51–1.57) were all associated with increased risk. Risk factors allowed stratification of patients into high‐risk versus low‐risk groups. The NTSV caesarean rate was 37.9% in women who had one or more of the following characteristics: age ≥35 years, BMI ≥30 kg/m2 or pregestational diabetes. In comparison, the NTSV caesarean rate was 20.8% among women without any of these three risk factors (P < 0.01).

Conclusion

Among NTSV births, BMI, maternal age and medical conditions are important risk factors for caesarean delivery.
Comparing footwear impressions that are close non‐matches using correlation‐based approaches
Authors: Venkatasubramanian Gautham , Hegde Vighnesh , Padi Sarala , Iyer Hari , Herman Martin
Published: March 2021

Forensic activities related to footwear evidence may be broadly classified into the following two categories: (1) intelligence gathering and (2) evidential value assessment. Intelligence gathering provides additional leads for investigators. Assessment of evidential value, as practiced in the United States, involves a trained footwear examiner evaluating the degree of similarity between a known shoe of interest (together with its test impressions) and footwear impressions obtained from a crime scene, by performing side‐by‐side visual comparisons. However, the need for developing quantitative approaches for expressing similarities during such comparisons is being increasingly recognized by the forensic science community. In this paper, we explore the ability of similarity metrics to discriminate between impressions made by a shoe of interest and impressions made by close non‐matching shoes. Close non‐matching shoes largely share the same design and size. Therefore, the ability to effectively discriminate between them requires considering, either explicitly or implicitly, not only design and size, but also wear patterns and, to some extent, individual characteristics. This type of discrimination is necessary for assessment of evidential value. The similarity metrics examined in this paper are correlation‐based metrics, including normalized cross‐correlation, phase‐only correlation, AvNCC, and AvPOC. The latter two metrics are based on features obtained from a convolutional neural network. Experiments are performed using Everspry impressions, FBI boot impressions, and the West Virginia University footwear impression collection. The results show that phase‐only correlation performs as well as or better than the other metrics in all cases for the datasets we considered.
Redesign of ultrasensitive and robust RecA gene circuit to sense DNA damage
Authors: Chen Jack X. , Lim Boon , Steel Harrison , Song Yizhi , Ji Mengmeng , Huang Wei E.
Published: March 2021

SOS box of the recA promoter, PVRecA from Vibrio natriegens was characterized, cloned and expressed in a probiotic strain E. coli Nissle 1917. This promoter was then rationally engineered according to predicted interactions between LexA repressor and PVRecA. The redesigned PVRecA‐AT promoter showed a sensitive and robust response to DNA damage induced by UV and genotoxic compounds. Rational design of PVRecA coupled to an amplification gene circuit increased circuit output amplitude 4.3‐fold in response to a DNA damaging compound mitomycin C. A TetR‐based negative feedback loop was added to the PVRecA‐AT amplifier to achieve a robust SOS system, resistant to environmental fluctuations in parameters including pH, temperature, oxygen and nutrient conditions. We found that E. coli Nissle 1917 with optimized PVRecA‐AT adapted to UV exposure and increased SOS response 128‐fold over 40 h cultivation in turbidostat mini‐reactor. We also showed the potential of this PVRecA‐AT system as an optogenetic actuator, which can be controlled spatially through UV radiation. We demonstrated that the optimized SOS responding gene circuits were able to detect carcinogenic biomarker molecules with clinically relevant concentrations. The ultrasensitive SOS gene circuits in probiotic E. coli Nissle 1917 would be potentially useful for bacterial diagnosis.
The role of EGFR‐TKIs as adjuvant therapy in EGFR mutation‐positive early‐stage NSCLC: A meta‐analysis
Authors: Lin Chutong , Hu Fengling , Chu Hongling , Ren Peng , Ma Shanwu , Wang Jingdi , Bai Jie , Han Xuan , Ma Shaohua
Published: March 2021

Background

The role of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) is not clear in early‐stage nonsmall‐cell lung cancer (NSCLC) patients. This meta‐analysis aims to compare the efficacy and safety of EGFR‐TKIs as adjuvant therapy with chemotherapy or placebo in NSCLC patients harboring EGFR mutations.

Patients and Methods

Pubmed, Embase, and Cochrane databases were searched for randomized controlled trials. The hazard ratio (HR) of disease‐free survival (DFS) and overall survival (OS) as well as the risk ratio (RR) of severe adverse events were merged.

Results

Seven articles from five studies from 1843 records, a total of 1227 patients, were included in the analysis. The HR for DFS was 0.38 (95% confidence interval [CI] 0.22–0.63), in favor of EGFR‐TKIs. However, no significant benefit of OS was seen (HR = 0.61, 95% CI 0.31–1.22). Treatment benefit was more pronounced in patients with advanced disease stage and longer duration of medication, EGFR exon 19 deletion mutation, and treatment with third‐generation EGFR‐TKIs. Adjuvant targeted therapy may cause few adverse events compared with chemotherapy (RR = 0.28, 95% CI 0.09–0.94). The possibility of severe adverse events for the first‐generation drugs was significantly lower than for third‐generation drugs.

Conclusion

In EGFR mutation‐positive patients with stage IB–IIIA NSCLC, compared with adjuvant chemotherapy or placebo, adjuvant EGFR‐TKIs should effectively improve the patient's DFS, but not effectively improve OS. Disease stage, treatment duration, mutation types, and therapeutic drugs could affect the degree of benefit. Adjuvant EGFR‐TKIs had more favorable tolerability than chemotherapy, especially with the usage of first‐generation drugs.
Short‐Termist CEO Compensation in Speculative Markets: A Controlled Experiment*
Authors: Chang Yen‐Cheng , Huang Minjie , Su Yu‐Siang , Tseng Kevin
Published: March 2021

Bolton, Scheinkman, and Xiong (2006) model a setting where investors disagree and short‐sales constraints cause pessimistic views of stock prices to be less influential, which leads to speculative stock prices. A theoretical implication of the model is that existing shareholders can exploit the speculative stock prices by (i) designing managerial compensation contracts that encourage short‐term performance, and (ii) subsequently selling their shares to more optimistic investors. We document empirical support for this theory by finding that an exogenous removal (Regulation SHO) of short‐sales constraints curbs the provision of short‐term incentives, an effect reflected in longer CEO compensation duration. The effect is concentrated among stocks with high investor disagreement and short‐term‐oriented institutional ownership. Consistent with prior work, we also find that longer CEO compensation duration leads to longer CEO investment horizons, less overinvestment, and less earnings management. Collectively, our results speak to the contributing role of speculative stock prices in corporate short‐termism. Finally, our study implies that effective policies to curb corporate short‐termism should address stock market speculation and promote mechanisms that tie executive compensation to longer‐term stock price performance.
Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease
Authors: Wang Jiangong , Liu Bin , Xu Yong , Yang Meizi , Wang Chaoyun , Song Mengmeng , Liu Jing , Wang Wentao , You Jingjing , Sun Fengjiao , Wang Dan , Liu Dunjiang , Yan Haijing
Published: March 2021

Alzheimer's disease (AD) is an age‐related neurodegenerative disease, and the imbalance between production and clearance of β‐amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up‐regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up‐regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ‐induced injury. The neuroprotection by thioperamide against AD was reversed by 3‐MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic‐related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic‐lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB‐dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB‐mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD.
Efficacy and safety of treatment with biologicals for severe chronic rhinosinusitis with nasal polyps: A systematic review for the EAACI guidelines
Authors: Agache Ioana , Song Yang , Alonso‐Coello Pablo , Vogel Yasmin , Rocha Claudio , Solà Ivan , Santero Marilina , Akdis Cezmi A. , Akdis Mubeccel , Canonica Giorgio Walter , Chivato Tomas , del Giacco Stefano , Eiwegger Thomas , Fokkens Wytske , Georgalas Christos , Gevaert Philippe , Hopkins Claire , Klimek Ludger , Lund Valerie , Naclerio Robert , O'Mahony Liam , Palkonen Susanna , Pfaar Oliver , Schwarze Jürgen , Soyka Michael B. , Wang De Yun , Zhang Luo , Canelo‐Aybar Carlos , Palomares Oscar , Jutel Marek
Published: March 2021

This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared with the standard of care. PubMed, Embase, and Cochrane Library were searched for RCTs. Critical and important CRSwNP‐related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab‐2, omalizumab‐4, mepolizumab‐2, and reslizumab‐1) included 1236 adults, with follow‐up of 20–64 weeks. Dupilumab reduces the need for surgery (NFS) or oral corticosteroid (OCS) use (RR 0.28; 95% CI 0.20–0.39, moderate certainty) and improves with high certainty smell evaluated with UPSIT score (mean difference (MD) +10.54; 95% CI +9.24 to +11.84) and quality of life (QoL) evaluated with SNOT‐22 (MD −19.14; 95% CI −22.80 to −15.47), with fewer treatment‐related adverse events (TAEs) (RR 0.95; 95% CI 0.89–1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95% CI 0.78–0.92, high certainty), decreases OCS use (RR 0.38; 95% CI 0.10–1.38, moderate certainty), and improves high certainty smell (MD +3.84; 95% CI +3.64 to +4.04) and QoL (MD −15.65; 95% CI −16.16 to −15.13), with increased TAE (RR 1.73; 95% CI 0.60–5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95% CI 0.64–0.94) and improving QoL (MD −13.3; 95% CI −23.93 to −2.67) and smell (MD +0.7; 95% CI −0.48 to +1.88), with increased TAEs (RR 1.64; 95% CI 0.41–6.50). The evidence for reslizumab is very uncertain.
Objective measures of adenomyosis on MRI and their diagnostic accuracy—a systematic review & meta‐analysis
Authors: Rees Connie O. , Nederend Joost , Mischi Massimo , van Vliet Huib A. A. M. , Schoot Benedictus C.
Published: March 2021

Introduction

Magnetic resonance imaging (MRI) diagnosis of adenomyosis is considered the most accurate non‐invasive technique, but remains subjective, with no consensus on which diagnostic parameters are most accurate. We aimed to systematically review the literature on how adenomyosis can be objectively quantified on MRI in a scoping manner, to review the diagnostic performance of these characteristics compared with histopathological diagnosis, and to summarize correlations between measures of adenomyosis on MRI and clinical outcomes.

Material and methods

We searched databases Pubmed, Embase, and Cochrane for relevant literature up to April 2020 according to PRISMA guidelines. We included studies that objectively assessed adenomyosis on MRI, and separately assessed studies investigating the diagnostic performance of MRI vs histopathology for inclusion in a meta‐analysis. The QUADAS‐2 tool was used for risk of bias, with many studies showing an unclear or high risk of bias.

Results

Eighty studies were included, of which 14 assessed the diagnostic performance of individual MRI parameters, with four included in the meta‐analysis of diagnostic accuracy. Common MRI parameters were: junctional zone (JZ) characteristics, such as maximum JZ thickness—pooled sensitivity 71.6% (95% CI 46.0%–88.2%), specificity 85.5% (52.3%–97.0%); JZ differential—pooled sensitivity 58.9% (95% CI 44.3%–72.1%), specificity 83.2% (95% CI 71.3%–90.8%); and JZ to myometrial ratio—pooled sensitivity 63.3% (95% CI 51.9%–73.4%), specificity 79.4% (95% CI 42.0%–95.4%); adenomyosis lesion size, uterine morphology (pooled sensitivity 42.9% (95% CI 15.9%–74.9%), specificity 87.7%, (95% CI 37.9–98.8) and changes in signal intensity—eg, presence of myometrium cysts; pooled 59.6% (95% CI 41.6%–75.4%) and specificity of 96.1% (95% CI 80.7%–99.3%). Other MRI parameters have been used for adenomyosis diagnosis, but their diagnostic performance is unknown. Few studies attempted to correlate adenomyosis MRI phenotype to clinical outcomes.

Conclusions

A wide range of objective parameters for adenomyosis exist on MRI; however, in many cases their individual diagnostic performance remains uncertain. JZ characteristics remain the most widely used and investigated with acceptable diagnostic accuracy. Specific research is needed into how these objective measures of adenomyosis can be correlated to clinical outcomes.
Local cyclic adenosine monophosphate signalling cascades—Roles and targets in chronic kidney disease
Authors: Sholokh Anastasiia , Klussmann Enno
Published: March 2021

The molecular mechanisms underlying chronic kidney disease (CKD) are poorly understood and treatment options are limited, a situation underpinning the need for elucidating the causative molecular mechanisms and for identifying innovative treatment options. It is emerging that cyclic 3′,5′‐adenosine monophosphate (cAMP) signalling occurs in defined cellular compartments within nanometre dimensions in processes whose dysregulation is associated with CKD. cAMP compartmentalization is tightly controlled by a specific set of proteins, including A‐kinase anchoring proteins (AKAPs) and phosphodiesterases (PDEs). AKAPs such as AKAP18, AKAP220, AKAP‐Lbc and STUB1, and PDE4 coordinate arginine‐vasopressin (AVP)‐induced water reabsorption by collecting duct principal cells. However, hyperactivation of the AVP system is associated with kidney damage and CKD. Podocyte injury involves aberrant AKAP signalling. cAMP signalling in immune cells can be local and slow the progression of inflammatory processes typical for CKD. A major risk factor of CKD is hypertension. cAMP directs the release of the blood pressure regulator, renin, from juxtaglomerular cells, and plays a role in Na+ reabsorption through ENaC, NKCC2 and NCC in the kidney. Mutations in the cAMP hydrolysing PDE3A that cause lowering of cAMP lead to hypertension. Another major risk factor of CKD is diabetes mellitus. AKAP18 and AKAP150 and several PDEs are involved in insulin release. Despite the increasing amount of data, an understanding of functions of compartmentalized cAMP signalling with relevance for CKD is fragmentary. Uncovering functions will improve the understanding of physiological processes and identification of disease‐relevant aberrations may guide towards new therapeutic concepts for the treatment of CKD.
Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ
Authors: Xiang Jiaqing , Yang Guangyan , Ma Chuanrui , Wei Lingling , Wu Han , Zhang Wei , Tao Xiuhua , Jiang Lingyun , Liang Zhen , Kang Lin , Yang Shu
Published: March 2021

Background and Purpose

Increasing evidence suggests that human cholestasis is closely associated with the accumulation and activation of hepatic macrophages. Research indicates that activation of PPARγ exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that prevent their clinical application in the treatment of CLD. In this study, we found that tectorigenin alleviates intrahepatic cholestasis in mice by activating PPARγ.

Experimental Approach

Wild‐type mice were intragastrically administered α‐naphthylisothiocyanate (ANIT) or fed a diet containing 0.1% 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) to simultaneously establish an experimental model of intrahepatic cholestasis and tectorigenin intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ‐deficient mice were administered ANIT and/or tectorigenin to determine whether tectorigenin exerts its liver protective effect by activating PPARγ.

Key Results

Treatment with tectorigenin alleviated intrahepatic cholestasis by inhibiting the recruitment and activation of hepatic macrophages and by promoting the expression of bile transporters via activation of PPARγ. Furthermore, tectorigenin increased expression of the bile salt export pump (BSEP) through enhanced PPARγ binding to the BSEP promoter. In PPARγ‐deficient mice, the hepatoprotective effect of tectorigenin during cholestasis was blocked.

Conclusion and Implications

In conclusion, tectorigenin reduced the recruitment and activation of hepatic macrophages and enhanced the export of bile acids by activating PPARγ. Taken together, our results suggest that tectorigenin is a candidate compound for cholestasis treatment.
UK Head and neck cancer surgical capacity during the second wave of the COVID—19 pandemic: Have we learned the lessons? COVIDSurg collaborative
Authors: Shaw Richard ,   COVIDSurg Collaborative
Published: March 2021

Objectives

The aim of this study was to evaluate the differences in surgical capacity for head and neck cancer in the UK between the first wave (March‐June 2020) and the current wave (Jan‐Feb 2021) of the COVID‐19 pandemic.

Design

REDcap online‐based survey of hospital capacity.

Setting

UK secondary and tertiary hospitals providing head and neck cancer surgery.

Participants

One representative per hospital was asked to report the capacity for head and neck cancer surgery in that institution.

Main outcome measures

The principal measures of interests were new patient referrals, capacity in outpatients, theatres and critical care; therapeutic compromises constituting delay to surgery, de‐escalated surgery and therapeutic migration to non‐surgical primary modality.

Results

Data were returned from approximately 95% of UK hospitals with a head and neck cancer surgery specialist service. 50% of UK head and neck cancer patients requiring surgery have significantly compromised treatments during the second wave: 28% delayed, 10% have received radiotherapy‐based treatment instead of surgery, and 12% have received de‐escalated surgery. Surgical capacity has been more severely constrained in the second wave (58% of pre‐pandemic level) compared with the first wave (62%) despite the time to prepare.

Conclusions

Some hospitals are overwhelmed by COVID‐19 and unable to offer essential cancer surgery, but all have neighbouring hospitals in their region retaining good (or even normal) capacity. It is noteworthy that very few patients have been appropriately redirected away from the hospitals most constrained by their burden of COVID‐19. The paucity of an effective central or regional strategic response to this evident mismatch between demand and surgical capacity is to the detriment of our head and neck cancer patients.
Validation of the Alternative International Prognostic Score‐E (AIPS‐E): Analysis of Binet stage A chronic lymphocytic leukemia patients enrolled into the O‐CLL1‐GISL protocol
Authors: Morabito Fortunato , Tripepi Giovanni , Vigna Ernesto , Bossio Sabrina , D’Arrigo Graziella , Martino Enrica Antonia , Storino Francesca , Recchia Anna Grazia , Fronza Gilberto , Di Raimondo Francesco , Colombo Monica , Fais Franco , Neri Antonino , Cutrona Giovanna , Ferrarini Manlio , Gentile Massimo
Published: March 2021

Objectives

To validate the predictive value on time to first treatment (TTFT) of AIPS‐E and IPS‐E evaluated in an independent cohort of newly diagnosed and non‐referred Binet stage A CLL patients enrolled in the O‐CLL1‐GISL protocol (clinicaltrial.gov identifier: NCT00917540).

Methods

A cohort of 292 newly diagnosed Binet A CLL cases has been enrolled in the study. Patients from several Italian Institutions were prospectively enrolled within 12 months of diagnosis into the O‐CLL1‐GISL protocol.

Results

The majority of patients were male (62%); median age was 60.4 years, 102 cases (34.9%) showed unmutated IGHV genes, 8 cases (2.8) the presence of del(11q)/del(17p), 142 cases (48.6%) the presence of palpable lymph nodes and 146 cases (50%) and ALC > 15 × 109/l. After a median follow‐up of 7.2 years, 130 patients underwent treatment. According to the AIPS‐E, 96 patients were classified as low‐risk, 128 as intermediate‐risk, and 68 as high‐risk. These groups showed significant differences in terms of TTFT. The C‐statistic was 0.71 (P < .0001) for predicting TTFT. According to IPS‐E, 77 patients were classified as low‐risk, 135 as intermediate‐risk, and 80 as high‐risk. These groups showed significant differences in terms of TTFT. The C‐statistic was 0.705 (P < .0001) for predicting TTFT.

Conclusions

Our data confirm an accurate prognostic utility of both AIPS‐E and IPS‐E at the individual patient level. These data may be useful for a precise stratification of early‐stage patients.