bluuebunny/crossref_metadata_2025 huggingface dataset:
Opening up the black box of a Gateway to Medicine programme: a realist evaluation
Authors: Gibson Smith Kathrine , Alexander Kirsty , Cleland Jennifer
Published: July 2021

Objectives

A Gateway to Medicine programme, developed in partnership between a further and higher education setting and implemented to increase the socioeconomic diversity of medicine, was examined to identify precisely what works within the programme and why.

Design

This study employed realist evaluation principles and was undertaken in three phases: document analysis and qualitative focus groups with widening access (WA) programme architects; focus groups and interviews with staff and students; generation of an idea of what works.

Setting

Participants were recruited from a further/higher education setting and were either enrolled or involved in the delivery of a Gateway to Medicine programme.

Participants

Twelve staff were interviewed either individually (n=3) or in one of three group interviews. Nine focus groups (ranging from 5 to 18 participants in each focus group) were carried out with Gateway students from three consecutive cohorts at 2–3 points in their Gateway programme year.

Results

Data were generated to determine what ‘works’ in the Gateway programme. Turning a realist lens on the data identified six inter-relating mechanisms which helped students see medicine as attainable and achievable and prepared them for the transition to medical school. These were academic confidence (M1); developing professional identity (M2); financial support/security (M3); supportive relationships with staff (M4) and peers (M5); and establishing a sense of belonging as a university student (M6).

Conclusions

By unpacking the ‘black box’ of a Gateway programme through realist evaluation, we have shown that such programmes are not solely about providing knowledge and skills but are rather much more complex in respect to how they work. Further work is needed to further test the mechanisms identified in our study in other contexts for theory development and to identify predictors of effectiveness in terms of students’ preparedness to transition.
Gender disparity between authors in leading medical journals during the COVID-19 pandemic: a cross-sectional review
Authors: Misra Vaidehi , Safi Frozan , Brewerton Kathryn A , Wu Wei , Mason Robin , Chan An-Wen , Rochon Paula A , Lega Iliana C , Abdel-Qadir Husam
Published: July 2021

Objectives

Evaluate gender differences in authorship of COVID-19 articles in high-impact medical journals compared with other topics.

Design

Cross-sectional review.

Data sources

Medline database.

Eligibility criteria

Articles published from 1 January to 31 December 2020 in the seven leading general medical journals by impact factor. Article types included primary research, reviews, editorials and commentaries.

Data extraction

Key data elements were whether the study topic was related to COVID-19 and names of the principal and the senior authors. A hierarchical approach was used to determine the likely gender of authors. Logistic regression assessed the association of study characteristics, including COVID-19 status, with authors’ likely gender; this was quantified using adjusted ORs (aORs).

Results

We included 2252 articles, of which 748 (33.2%) were COVID-19-related and 1504 (66.8%) covered other topics. A likely gender was determined for 2138 (94.9%) principal authors and 1890 (83.9%) senior authors. Men were significantly more likely to be both principal (1364 men; 63.8%) and senior (1332 men; 70.5%) authors. COVID-19-related articles were not associated with the odds of men being principal (aOR 0.99; 95% CI 0.81 to 1.21; p=0.89) or senior authors (aOR 0.96; 95% CI 0.78 to 1.19; p=0.71) relative to other topics. Articles with men as senior authors were more likely to have men as principal authors (aOR 1.49; 95% CI 1.21 to 1.83; p<0.001). Men were more likely to author articles reporting original research and those with corresponding authors based outside the USA and Europe.

Conclusions

Women were substantially under-represented as authors among articles in leading medical journals; this was not significantly different for COVID-19-related articles. Study limitations include potential for misclassification bias due to the name-based analysis. Results suggest that barriers to women’s authorship in high-impact journals during COVID-19 are not significantly larger than barriers that preceded the pandemic and that are likely to continue beyond it.

PROSPERO registration number

CRD42020186702.
Heart failure medication dosage and survival in women and men seen at outpatient clinics
Authors: Bots Sophie Heleen , Onland-Moret N Charlotte , Tulevski Igor I , van der Harst Pim , Cramer Maarten J M , Asselbergs Folkert W , Somsen G Aernout , den Ruijter Hester M
Published: July 2021

Objective

Women with heart failure with reduced ejection fraction (HFrEF) may reach optimal treatment effect at half of the guideline-recommended medication dose. This study investigates prescription practice and its relation with survival of patients with HF in daily care.

Methods

Electronic health record data from 13 Dutch outpatient cardiology clinics were extracted for HF receiving at least one guideline-recommended HF medication. Dose changes over consecutive prescriptions were modelled using natural cubic splines. Inverse probability-weighted Cox regression was used to assess the relationship between dose (reference≥50% target dose) and all-cause mortality.

Results

The study population comprised 561 women (29% HFrEF (ejection fraction (EF)<40%), 49% heart failure with preserved ejection fraction (EF≥50%); HFpEF and 615 men (47% and 25%, respectively). During a median follow-up of 3.7 years, 252 patients died (48% women; 167 HFrEF, 84 HFpEF). Nine hundred thirty-four patients (46% women) received ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), 795 (48% women) beta blockers and 178 (42% women) mineralocorticoid receptor antagonists (MRAs). In both sexes, the mean target dose across prescriptions was 50% for ACEI/ARBs and beta blockers, and 100% for MRAs. ACEI/ARB dose of <50% was associated with lower mortality in women but not in men with HFrEF. This was not seen in patients with HFpEF. Beta-blocker dose was not associated with all-cause mortality.

Conclusion

Patients with HF seen in outpatient cardiology clinics receive half of the guideline-recommended medication dose. Lower ACEI/ARB dose was associated with improved survival in women with HFrEF. These results underscore the importance of (re)defining optimal medical therapy for women with HFrEF.
Aspirin versus P2Y12inhibitors with anticoagulation therapy for atrial fibrillation
Authors: Fukaya Hidehira , Ako Junya , Yasuda Satoshi , Kaikita Koichi , Akao Masaharu , Matoba Tetsuya , Nakamra Masato , Miyauchi Katsumi , Hagiwara Nobuhisa , Kimura Kazuo , Hirayama Atsushi , Matsui Kunihiko , Ogawa Hisao
Published: July 2021

Objective

Patients with coronary artery disease (CAD) and atrial fibrillation (AF) can be treated with multiple antithrombotic therapies including antiplatelet and anticoagulant therapies; however, this has the potential to increase bleeding risk. Here, we aimed to evaluate the efficacy and safety of P2Y12inhibitors and aspirin in patients also receiving anticoagulant therapy.

Methods

We evaluated patients from the Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial who received rivaroxaban plus an antiplatelet agent; the choice of antiplatelet agent was left to the physician’s discretion. The primary efficacy and safety end points, consistent with those of the AFIRE trial, were compared between P2Y12inhibitors and aspirin groups. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation or death from any cause. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria.

Results

A total of 1075 patients were included (P2Y12inhibitor group, n=297; aspirin group, n=778). Approximately 60% of patients were administered proton pump inhibitors (PPIs) and there was no significant difference in PPI use in the groups. There were no significant differences in the primary end points between the groups (efficacy: HR 1.31; 95% CI 0.88 to 1.94; p=0.178; safety: HR 0.79; 95% CI 0.43 to 1.47; p=0.456).

Conclusions

There were no significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with P2Y12inhibitors or aspirin in the chronic phase.

Trial registration number

UMIN000016612;NCT02642419.
TASK-WARRANTED GRADUATE JOBS AND MISMATCH
Authors: GREEN FRANCIS , HENSEKE GOLO
Published: July 2021

We distinguish between “task-warranted” and “task-unwarranted” graduate jobs. For both types, a degree is required but task-warranted graduate jobs involve carrying out typical graduate-level tasks. We operationalize the distinction, using representative surveys of resident Singapore workers. We find that the ongoing fast expansion of higher attainment between 2013 and 2017 was met by a similarly-strong growth in task-warranted graduate jobs. Compared with the matched graduates, the graduates in task-unwarranted graduate jobs and in non-graduate jobs both perceive lower skills utilization. There is a negative wage gap of 18% for graduates in task-unwarranted graduate jobs, and of 31% for underemployed graduates.
Dynamics of dissipative self-gravitating source in Rastall gravity
Authors: Tahir M. , Abbas G. , Bamba Kazuharu , Shahzad M. R.
Published: July 2021

The dynamics of dissipative gravitational collapse of a source is explored in Rastall gravity. The field equations are derived for the geometry and collapsing matter. The dynamical equations are formulated for the heat flux and diffusion approximation. The heat transportation equation is derived by using Müller–Israel–Stewart approach to investigate the effects of heat flux on the collapsing source. Moreover, an equation is found by combining the dynamical and heat transport equation, the consequences of this equation are discussed in detail. Furthermore, the Rastall parameter [Formula: see text] effect is analyzed for the collapse of sphere.
Three pairs of congruences concerning sums of central binomial coefficients
Authors: Mao Guo-Shuai , Tauraso Roberto
Published: July 2021

Recently the first author proved a congruence proposed in 2006 by Adamchuk: [Formula: see text] for any prime [Formula: see text]. In this paper, we provide more examples (with proofs) of congruences of the same kind [Formula: see text] where [Formula: see text] is a prime such that [Formula: see text], [Formula: see text] is a fraction in [Formula: see text] and [Formula: see text] is a [Formula: see text]-adic integer. The key ingredients are the [Formula: see text]-adic Gamma function [Formula: see text] and a special class of computer-discovered hypergeometric identities.
Periodicity of the solutions of general system of rational difference equations related to fibonacci numbers
Authors: Talha Ibtissam , Badidja Salim
Published: July 2021

In this paper, we deal with the periodicity of solutions of the following general system rational of difference equations: [Formula: see text] where [Formula: see text] [Formula: see text] and the initial conditions are arbitrary nonzero real numbers.
TAMIZHİ: Historical Tamil-Brahmi Script Recognition Using CNN and MobileNet
Authors: S Dhivya , Devi G Usha
Published: July 2021

Computational epigraphy is the study of an ancient script where the computer science and mathematical model is relatively built for epigraphy. The Tamil-Brahmi inscriptions are the most ancient of the extant written of the Tamil. The inscriptions furnish valuable information on many aspects of life in the ancient Tamil country from a period anterior to the literary age of Sangam. The recognition of the script and systematic analysis of the script is required. The recognition of this script is complex, containing various curves for a single character and the style of writing overlap with curves and lines. Generating corpus of the script is necessary, since it is the initial step for computational epigraphy. The archaeological department has supported the raw data that helped to develop a corpus of Tamizhi. In this article, we have implemented a convolution neural network in various ways, i.e., (i) Training the CNN model from scratch a Softmax classifier in a sequential model (ii) using MobileNet: Transfer learning paradigm from a pre-trained model on a Tamizhi dataset (iii) Building Model with CNN and SVM (iv) SVM for evaluation of best accuracy to recognize handwritten Brahmi characters. To train the CNN Model an extensive TAMIZHİ handwritten Brahmi Dataset of 1lakh and 90,000 isolated samples for the character has been created and deployed. The designed dataset consists of 9 vowels and 18 consonants and 209 class so researchers can use machine learning. MobileNet outperformed among all the models implemented with the accuracy of 68.3%, whereas other algorithm ranges from 58% to 67% with respect to the Tamizhi dataset. MobileNet model is trained and tested for the dataset of vowels (8 class), consonants (18 class), and consonants vowels (26 class) with the accuracy of 98.1%, 97.7%, 97.5%, respectively.
Deep Structured Learning for Natural Language Processing
Authors: Li Yong , Yang Xiaojun , Zuo Min , Jin Qingyu , Li Haisheng , Cao Qian
Published: July 2021

The real-time and dissemination characteristics of network information make net-mediated public opinion become more and more important food safety early warning resources, but the data of petabyte (PB) scale growth also bring great difficulties to the research and judgment of network public opinion, especially how to extract the event role of network public opinion from these data and analyze the sentiment tendency of public opinion comment. First, this article takes the public opinion of food safety network as the research point, and a BLSTM-CRF model for automatically marking the role of event is proposed by combining BLSTM and conditional random field organically. Second, the Attention mechanism based on vocabulary in the field of food safety is introduced, the distance-related sequence semantic features are extracted by BLSTM, and the emotional classification of sequence semantic features is realized by using CNN. A kind of Att-BLSTM-CNN model for the analysis of public opinion and emotional tendency in the field of food safety is proposed. Finally, based on the time series, this article combines the role extraction of food safety events and the analysis of emotional tendency and constructs a net-mediated public opinion early warning model in the field of food safety according to the heat of the event and the emotional intensity of the public to food safety public opinion events.
Compressing RNNs to Kilobyte Budget for IoT Devices Using Kronecker Products
Authors: Thakker Urmish , Fedorov Igor , Zhou Chu , Gope Dibakar , Mattina Matthew , Dasika Ganesh , Beu Jesse
Published: July 2021

Micro-controllers (MCUs) make up most of the processors in the world with widespread applicability from automobile to medical devices. The Internet of Things promises to enable these resource-constrained MCUs with machine learning algorithms to provide always-on intelligence. Many Internet of Things applications consume time-series data that are naturally suitable for recurrent neural networks (RNNs) like LSTMs and GRUs. However, RNNs can be large and difficult to deploy on these devices, as they have few kilobytes of memory. As a result, there is a need for compression techniques that can significantly compress RNNs without negatively impacting task accuracy. This article introduces a method to compress RNNs for resource-constrained environments using the Kronecker product (KP). KPs can compress RNN layers by 16× to 38× with minimal accuracy loss. By quantizing the resulting models to 8 bits, we further push the compression factor to 50×. We compare KP with other state-of-the-art compression techniques across seven benchmarks spanning five different applications and show that KP can beat the task accuracy achieved by other techniques by a large margin while simultaneously improving the inference runtime. Sometimes the KP compression mechanism can introduce an accuracy loss. We develop a hybrid KP approach to mitigate this. Our hybrid KP algorithm provides fine-grained control over the compression ratio, enabling us to regain accuracy lost during compression by adding a small number of model parameters.
Emerging Roles for Social Robots in Rehabilitation
Authors: Langer Allison , Levy-Tzedek Shelly
Published: July 2021

Insights from social and cognitive neuroscience should inform the design of socially assistive robots for neurorehabilitation as novel roles emerge for them in human-human interactions.
Identification of variants of ISL1 gene promoter and cellular functions in isolated ventricular septal defects
Authors: Zheng Si-Qiang , Chen Huan-Xin , Liu Xiao-Cheng , Yang Qin , He Guo-Wei
Published: July 2021

Ventricular septal defects (VSDs) are the most common congenital heart defects (CHDs). Studies have documented that ISL1 has a crucial impact on cardiac growth, but the role of variants in the ISL1 gene promoter in patients with VSD has not been explored. In 400 subjects (200 patients with isolated and sporadic VSDs: 200 healthy controls), we investigated the ISL1 gene promoter variant and performed cellular functional experiments by using the dual-luciferase reporter assay to verify the impact on gene expression. In the ISL1 promoter, five variants were found only in patients with VSD by sequencing. Cellular functional experiments demonstrated that three variants decreased the transcriptional activity of the ISL1 promoter ( P < 0.05). Further analysis with the online JASPAR database demonstrated that a cluster of putative binding sites for transcription factors may be altered by these variants, possibly resulting in change of ISL1 protein expression and VSD formation. Our study has, for the first time, identified novel variants in the ISL1 gene promoter region in the Han Chinese patients with isolated and sporadic VSD. In addition, the cellular functional experiments, electrophoretic mobility shift assay, and bioinformatic analysis have demonstrated that these variants significantly alter the expression of the ISL1 gene and affect the binding of transcription factors, likely resulting in VSD. Therefore, this study may provide new insights into the role of the gene promoter region for a better understanding of genetic basis of the formation of CHDs and may promote further investigations on mechanism of the formation of CHDs.
LRG1 facilitates corneal fibrotic response by inducing neutrophil chemotaxis via Stat3 signaling in alkali-burned mouse corneas
Authors: Yu Bingjie , Yang Lingling , Song Shan , Li Weina , Wang Huifeng , Cheng Jun
Published: July 2021

Leucine-rich α-2-glycoprotein-1 (LRG1) is a novel profibrotic factor that modulates transforming growth factor-β (TGF-β) signaling. However, its role in the corneal fibrotic response remains unknown. In the present study, we found that the LRG1 level increased in alkali-burned mouse corneas. In the LRG1-treated alkali-burned corneas, there were higher fibrogenic protein expression and neutrophil infiltration. LRG1 promoted neutrophil chemotaxis and CXCL-1 secretion. Conversely, LRG1-specific siRNA reduced fibrogenic protein expression and neutrophil infiltration in the alkali-burned corneas. The clearance of neutrophils effectively attenuated the LRG1-enhanced corneal fibrotic response, whereas the presence of neutrophils enhanced the effect of LRG1 on the fibrotic response in cultured TKE2 cells. In addition, the topical application of LRG1 elevated interleukin-6 (IL-6) and p-Stat3 levels in the corneal epithelium and in isolated neutrophils. The clearance of neutrophils inhibited the expression of p-Stat3 and IL-6 promoted by LRG1 in alkali-burned corneas. Moreover, neutrophils significantly increased the production of IL-6 and p-Stat3 promoted by LRG1 in TKE2 cells. Furthermore, the inhibition of Stat3 signaling by S3I-201 decreased neutrophil infiltration and alleviated the LRG1-enhanced corneal fibrotic response in the alkali-burned corneas. S3I-201 also reduced LRG1 or neutrophil-induced fibrotic response in TKE2 cells. In conclusion, LRG1 promotes the corneal fibrotic response by stimulating neutrophil infiltration via the modulation of the IL-6/Stat3 signaling pathway. Therefore, LRG1 could be targeted as a promising therapeutic strategy for patients with corneal fibrosis.
Elephant seal muscle cells adapt to sustained glucocorticoid exposure by shifting their metabolic phenotype
Authors: Torres-Velarde Julia María , Kolora Sree Rohit Raj , Khudyakov Jane I. , Crocker Daniel E. , Sudmant Peter H. , Vázquez-Medina José Pablo
Published: July 2021

Elephant seals experience natural periods of prolonged food deprivation while breeding, molting, and undergoing postnatal development. Prolonged food deprivation in elephant seals increases circulating glucocorticoids without inducing muscle atrophy, but the cellular mechanisms that allow elephant seals to cope with such conditions remain elusive. We generated a cellular model and conducted transcriptomic, metabolic, and morphological analyses to study how seal cells adapt to sustained glucocorticoid exposure. Seal muscle progenitor cells differentiate into contractile myotubes with a distinctive morphology, gene expression profile, and metabolic phenotype. Exposure to dexamethasone at three ascending concentrations for 48 h modulated the expression of six clusters of genes related to structural constituents of muscle and pathways associated with energy metabolism and cell survival. Knockdown of the glucocorticoid receptor (GR) and downstream expression analyses corroborated that GR mediates the observed effects. Dexamethasone also decreased cellular respiration, shifted the metabolic phenotype toward glycolysis, and induced mitochondrial fission and dissociation of mitochondria-endoplasmic reticulum (ER) interactions without decreasing cell viability. Knockdown of DNA damage-inducible transcript 4 (DDIT4), a GR target involved in the dissociation of mitochondria-ER membranes, recovered respiration and modulated antioxidant gene expression in myotubes treated with dexamethasone. These results show that adaptation to sustained glucocorticoid exposure in elephant seal myotubes involves a metabolic shift toward glycolysis, which is supported by alterations in mitochondrial morphology and a reduction in mitochondria-ER interactions, resulting in decreased respiration without compromising cell survival.
Fetal growth, high altitude, and evolutionary adaptation: a new perspective
Authors: Wilsterman Kathryn , Cheviron Zachary A.
Published: July 2021

Residence at high altitude is consistently associated with low birthweight among placental mammals. This reduction in birthweight influences long-term health trajectories for both the offspring and mother. However, the physiological processes that contribute to fetal growth restriction at altitude are still poorly understood, and thus our ability to safely intervene remains limited. One approach to identify the factors that mitigate altitude-dependent fetal growth restriction is to study populations that are protected from fetal growth restriction through evolutionary adaptations (e.g., high altitude-adapted populations). Here, we examine human gestational physiology at high altitude from a novel evolutionary perspective that focuses on patterns of physiological plasticity, allowing us to identify 1) the contribution of specific physiological systems to fetal growth restriction and 2) the mechanisms that confer protection in highland-adapted populations. Using this perspective, our review highlights two general findings: first, that the beneficial value of plasticity in maternal physiology is often dependent on factors more proximate to the fetus; and second, that our ability to understand the contributions of these proximate factors is currently limited by thin data from altitude-adapted populations. Expanding the comparative scope of studies on gestational physiology at high altitude and integrating studies of both maternal and fetal physiology are needed to clarify the mechanisms by which physiological responses to altitude contribute to fetal growth outcomes. The relevance of these questions to clinical, agricultural, and basic research combined with the breadth of the unknown highlight gestational physiology at high altitude as an exciting niche for continued work.
Transient antibiotic-induced changes in the neonatal swine intestinal microbiota impact islet expression profiles reducing subsequent function
Authors: Sosa Alvarado Carla , Yang Kaiyuan , Qiu Hongbo , Mills Erinn , Fouhse Janelle M. , Ju Tingting , Buteau Jean , Field Catherine J. , Willing Benjamin P. , Chan Catherine B.
Published: July 2021

Neonatal antibiotics administered to human infants initiate gut microbiota dysbiosis that may have long-term effects on body weight and metabolism. We examined antibiotic-induced adaptations in pancreatic islets of the piglet, a well-accepted model of human infant microbiota and pancreas development. Neonatal piglets randomized to amoxicillin [30 mg/kg body wt/day; n = 7, antibiotic (ANTI)] or placebo [vehicle control; n = 7, control (CON)] from postnatal day ( PND) 0– 13 were euthanized at PND7, 14, and 49. The metabolic phenotype along with functional, immunohistological, and transcriptional phenotypes of the pancreatic islets were studied. The gut microbiome was characterized by 16S rRNA gene sequencing, and microbial metabolites and microbiome-sensitive host molecules were measured. Compared with CON, ANTI PND7 piglets had elevated transcripts of genes involved in glucagon-like peptide 1 ((GLP-1) synthesis or signaling in islets ( P < 0.05) coinciding with higher plasma GLP-1 ( P = 0.11), along with increased tumor necrosis factor α ( Tnf) ( P < 0.05) and protegrin 1 ( Npg1) ( P < 0.05). Antibiotic-induced relative increases in Escherichia, Coprococcus, Ruminococcus, Dehalobacterium, and Oscillospira of the ileal microbiome at PND7 normalized after antibiotic withdrawal. In ANTI islets at PND14, the expression of key regulators pancreatic and duodenal homeobox 1 ( Pdx1), insulin-like growth factor-2 ( Igf2), and transcription factor 7-like 2 ( Tcf7l2) was downregulated, preceding a 40% reduction of β-cell area ( P < 0.01) and islet insulin content at PND49 ( P < 0.05). At PND49, a twofold elevated plasma insulin concentration ( P = 0.07) was observed in ANTI compared with CON. We conclude that antibiotic treatment of neonatal piglets elicited gut microbial changes accompanied by phasic alterations in key regulatory genes in pancreatic islets at PND7 and 14. By PND49, reduced β-cell area and islet insulin content were accompanied by elevated nonfasted insulin despite normoglycemia, indicative of islet stress.
Metabolism- and sex-dependent critical WBGT limits at rest and during exercise in the heat
Authors: Wolf S. Tony , Folkerts Mireille A. , Cottle Rachel M. , Daanen Hein A. M. , Kenney W. Larry
Published: July 2021

Critical environmental limits are environmental thresholds above which heat gain exceeds heat loss and body core temperature (Tc) cannot be maintained at equilibrium. Those limits can be represented as critical wet-bulb globe temperature (WBGTcrit), a validated index that represents the overall thermal environment. Little is known about WBGTcrit at rest and during low-to-moderate intensity exercise, or sex differences in WBGTcrit, in unacclimated young adults. The following hypotheses were tested: 1) WBGTcrit progressively decreases as metabolic heat production (Mnet) increases, 2) no sex differences in WBGTcrit occur at rest, and 3) WBGTcrit is lower during absolute-intensity exercise but higher at relative intensities in women than in men. Thirty-six participants [19 men (M)/17 women (W); 23 ± 4 yr] were tested at rest, during light, absolute-intensity exercise (10 W), or during moderate, relative-intensity exercise [30% maximal oxygen consumption (V̇o2max)] in an environmental chamber. Dry-bulb temperature was clamped as relative humidity or ambient water vapor pressure was increased until an upward inflection was observed in Tc (rectal or esophageal temperature). Sex-aggregated WBGTcrit was lower during 10 W (32.9°C ± 1.7°C, P < 0.0001) and 30% V̇o2max (31.6°C ± 1.1°C, P < 0.0001) exercise versus at rest (35.3°C ± 0.8°C), and lower at 30% V̇o2max versus 10 W ( P = 0.01). WBGTcrit was similar between sexes at rest (35.6°C ± 0.8°C vs. 35.0°C ± 0.8°C, P = 0.83), but lower during 10 W (31.9°C ± 1.7°C vs. 34.1°C ± 0.3°C, P < 0.01) and higher during 30% V̇o2max (32.4°C ± 0.8°C vs. 30.8°C ± 0.9°C, P = 0.03) exercise in women versus men. These findings suggest that WBGTcrit decreases as Mnet increases, no sex differences occur in WBGTcrit at rest, and sex differences in WBGTcrit during exercise depend on absolute versus relative intensities.
Chronic ablation of TRPV1-sensitive skeletal muscle afferents attenuates the muscle metaboreflex
Authors: Mannozzi Joseph , Al-Hassan Mohamed-Hussein , Lessanework Beruk , Alvarez Alberto , Senador Danielle , O'Leary Donal S.
Published: July 2021

Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex-induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express transient receptor potential vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultrapotent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1-sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4–L6) of RTX (2 µg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex-induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min), and stroke work (2.27 ± 0.2 L·mmHg vs. 1.01 ± 0.2 L·mmHg). Effects were maintained until 78 ± 14 days post-RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 µg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre-RTX vs. +19.7 ± 3.1 mmHg post-RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.
The 2021 Carl Ludwig Lecture. Unsympathetic autonomic regulation in heart failure: patient-inspired insights
Authors: Floras John S.
Published: July 2021

Defined as a structural or functional cardiac abnormality accompanied by symptoms, signs, or biomarkers of altered ventricular pressures or volumes, heart failure also is a state of autonomic disequilibrium. A large body of evidence affirms that autonomic disturbances are intrinsic to heart failure; basal or stimulated sympathetic nerve firing or neural norepinephrine (NE) release more often than not exceed homeostatic need, such that an initially adaptive adrenergic or vagal reflex response becomes maladaptive. The magnitude of such maladaptation predicts prognosis. This Ludwig lecture develops two theses: the elucidation and judiciously targeted amelioration of maladaptive autonomic disturbances offers opportunities to complement contemporary guideline-based heart failure therapy, and serendipitous single-participant insights, acquired in the course of experimental protocols with entirely different intent, can generate novel insight, inform mechanisms, and launch entirely new research directions. I précis six elements of our current synthesis of the causes and consequences of maladaptive sympathetic disequilibrium in heart failure, shaped by patient-inspired epiphanies: arterial baroreceptor reflex modulation, excitation stimulated by increased cardiac filling pressure, paradoxical muscle sympathetic activation as a peripheral neurogenic constraint on exercise capacity, renal sympathetic restraint of natriuresis, coexisting sleep apnea, and augmented chemoreceptor reflex sensitivity and then conclude by envisaging translational therapeutic opportunities.
Daily acute intermittent hypoxia enhances phrenic motor output and stimulus-evoked phrenic responses in rats
Authors: Perim Raphael R. , Sunshine Michael D. , Welch Joseph F. , Santiago Juliet , Holland Ashley , Ross Ashley , Mitchell Gordon S. , Gonzalez-Rothi Elisa J.
Published: July 2021

Two weeks of daily acute intermittent hypoxia (dAIH) preconditioning enhanced stimulus-evoked phrenic responses to lateral funiculus stimulation (targeting respiratory bulbospinal projection to phrenic motor neurons). Furthermore, dAIH preconditioning enhanced baseline phrenic motor output responses to maximal chemoreflex activation in intact rats.
Visual pursuit biases tactile velocity perception
Authors: Scotto Cécile R. , Moscatelli Alessandro , Pfeiffer Thies , Ernst Marc O.
Published: July 2021

The study showed that smooth pursuit eye movement produces a bias in tactile motion perception. This phenomenon is modulated by the reliability of the tactile estimate and by the presence of a visual background, in line with the predictions of the Bayesian framework of motion perception. Overall, these results support the hypothesis of shared representations for motion perception.
Diurnal properties of tonic and synaptic GABAA receptor-mediated currents in suprachiasmatic nucleus neurons
Authors: Moldavan Michael , Cravetchi Olga , Allen Charles N.
Published: July 2021

A tonic current ( Itonic) mediated by GABAA receptors (GABAARs) containing α4-, α5- and δ-subunits was observed in the suprachiasmatic nucleus. The Itonic amplitude strongly depended on the action potential-mediated synaptic release of GABA. The equilibrium potential for Itonic corresponds to that for GABAA currents. The frequency of GABAA postsynaptic currents and Itonic amplitude increased during the day, with peak in the middle of the day, and then gradually declined with a nadir at night, thus showing a diurnal rhythm.
Hypocalcemia as a Cause of Complex Febrile Seizures in a Toddler
Authors: Meesters Kevin , Wassenberg Tessa , Vanbesien Jesse
Published: July 2021

A 13-month-old boy had suffered three episodes of complex febrile seizures. At this admission, there were signs of hyperexcitability, such as Trousseau sign and QTc prolongation. A point of care blood gas analysis revealed severe hypocalcemia. Therefore, prior to administering intravenous calcium gluconate, we took blood samples to investigate the etiology of this hypocalcemia: magnesium, parathormone, and 25-hydroxyvitamin D. Since both parathormone and phosphate were significantly elevated and 25-hydroxyvitamin D was within the normal range, pseudohypoparathyroidism was diagnosed. After two years of follow-up, serum calcium had normalized in our patient under supplementation of vitamin D and calcium. He had been free of convulsions, although different febrile episodes had occurred.
The Vertex-Edge Resolvability of Some Wheel-Related Graphs
Authors: Xing Bao-Hua , Sharma Sunny Kumar , Bhat Vijay Kumar , Raza Hassan , Liu Jia-Bao
Published: July 2021

A vertex

w
∈
V

H

distinguishes (or resolves) two elements (edges or vertices)

a
,
z
∈
V

H

∪
E

H

if

d

w
,
a

≠
d

w
,
z

. A set

W

m

of vertices in a nontrivial connected graph

H

is said to be a mixed resolving set for

H

if every two different elements (edges and vertices) of

H

are distinguished by at least one vertex of

W

m

. The mixed resolving set with minimum cardinality in

H

is called the mixed metric dimension (vertex-edge resolvability) of

H

and denoted by

m
 dim

H

. The aim of this research is to determine the mixed metric dimension of some wheel graph subdivisions. We specifically analyze and compare the mixed metric, edge metric, and metric dimensions of the graphs obtained after the wheel graphs’ spoke, cycle, and barycentric subdivisions. We also prove that the mixed resolving sets for some of these graphs are independent.
Two Consecutive Runs of Veno-Venous Extracorporeal Membrane Oxygenation in a Peripartum Patient with COVID-19 Acute Respiratory Distress Syndrome
Authors: Sella Nicolò , Pettenuzzo Tommaso , Della Paolera Michele , Andreatta Giulio , Boscolo Annalisa , De Cassai Alessandro , Muraro Luisa , Peralta Arianna , Persona Paolo , Petranzan Enrico , Zarantonello Francesco , Serra Eugenio , Navalesi Paolo
Published: July 2021

Veno-venous extracorporeal membrane oxygenation (V-V ECMO) may be required to treat critically ill patients with COVID-19-associated severe acute respiratory distress syndrome (ARDS). We report the case of a 43-year-old peripartum patient, who underwent two sequential V-V ECMO runs. The first extracorporeal support was established for COVID-19 ARDS, as characterized by severe hypoxemia and hypercapnia (arterial partial pressure of oxygen to inspired oxygen fraction ratio 85 mmHg and arterial partial pressure of carbon dioxide 95 mmHg) and reduction of respiratory system static compliance to 25 mL/cmH2O, unresponsive to mechanical ventilation and prone positioning. After 22 days of lung rest, V-V ECMO was successfully removed and ventilator weaning initiated. A second V-V ECMO was required 7 days later, because of newly onset ARDS due to Pseudomonas aeruginosa ventilator-associated pneumonia. The second V-V ECMO run lasted 12 days. During both V-V ECMO runs, anticoagulation and ventilator settings were titrated through bedside thromboelastometry and electrical impedance tomography, respectively, without major complications. The patient was successfully decannulated, weaned from mechanical ventilation, and finally discharged home without oxygen therapy. At one-month follow-up, she showed good general conditions and no sign of respiratory failure.
Metformin Inhibits the Development of Hypopharyngeal Squamous Cell Carcinoma through Circ_0003214-Mediated MiR-489-3p-ADAM10 Pathway
Authors: Chen Xiaoqiang , Li Chen , Chen Wei , Lin Shuchun , Yi Xuehan , Lin Qin , Xu Hao , Wang Desheng
Published: July 2021

Purpose. This study aims to explore the function of metformin in hypopharyngeal squamous cell carcinoma (HSCC) and the underlying mechanism. Methods. Cell viability, colony formation, cell apoptosis, and cell cycle were investigated using cell counting kit-8 assay, colony formation, and flow cytometry assay. Gene expression was detected by quantitative real-time polymerase chain reaction and western blot. The target relationship was validated by dual-luciferase reporter assay or RNA immunoprecipitation assay. An animal study was implemented to clarify the effect of metformin in vivo. Results. Metformin suppressed HSCC cell viability and colony formation ability and induced cell cycle arrest and apoptosis, and circ_0003214 overexpression weakened these effects. Circ_0003214 regulated A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) expression via targeting miR-489-3p. Besides, miR-489-3p restoration reversed the role of circ_0003214, and ADAM10 knockdown reversed miR-489-3p inhibition-mediated effect. Moreover, metformin blocked tumor growth via the circ_0003214-miR-489-3p-ADAM10 axis in vivo. Conclusion. Metformin inhibits HSCC progression through the circ_0003214/miR-489-3p/ADAM10 pathway.
High-Density Lipoprotein Cholesterol in Young Nondiabetic Coronary Heart Disease Patients
Authors: Hu Ziyang , Cui Jingle , Li Xueshan , Zhou Yaohui , Cai Lu , Zhang Shibin
Published: July 2021

Objective. To investigate the association between the lipid profiles and coronary heart disease (CHD) in nondiabetic patients younger than 65 years of age. Method. 424 patients were enrolled in this study from January 2019 to December 2020. All the patients were screened for clinically indicated coronary angiography. They were divided into two groups according to the coronary angiography results: 340 patients with the presence of CHD (at least one coronary artery stenosis ≥50%) were classified as the CHD group, and the rest with the absence of CHD comprised the normal group. The demographic data and lipid profiles were compared. Result. CHD was higher in males than females (84.5% vs. 62.2%,

P
<
0.001

). In the CHD group, the level of high‐density lipoprotein cholesterol (HDL-C) was lower

P
<
0.001

, while the triglyceride (TG)/HDL-C ratio was higher

P
=
0.022

. No significant differences were shown between the two groups in terms of age, family history of CHD, hypertension, and the levels of TC, TG, and LDL-C. Gender differences were further explored. In men, except for the level of HDL-C which was significantly lower in the CHD group than that in the normal group

P
=
0.017

, parameters were comparable. A binary logistic regression model further indicated that HDL-C was associated with CHD (OR = 0.137, 95%CI: 0.031–0.594,

P
=
0.008

). Also, with the increase of the number of coronary artery with lesions, the levels of HDL-C decreased significantly in men. In women, no differences were observed between the CHD group and normal group. Conclusion. HDL-C may be inversely associated with the risk of CHD in young nondiabetes patients, especially in men. More research is needed to confirm it.
Construction of Adaptive Consensus Gains for Multiagent Systems with Multiplicative Noise
Authors: Jin Shoubo , Yu Qiuju
Published: July 2021

The leader‐following consensus of linear multiagent systems with multiplicative noise and adaptive gains is investigated under the fixed directed graph. Because of multiplicative noise, the agents interacting with the leader can only obtain the inaccurate information. Firstly, this paper designs the adaptive gains of multiagent systems, which can converge to some fixed values and force the states to synchronize. Different from the mandatory gains, the adaptive gains depend on the states of agents and can be adjusted with the change of states. Secondly, it is shown that the multiagent systems without time delay can obtain mean square consensus under the adaptive gains. Moreover, in the presence of multiplicative noise and communication delay, the mean square consensus is also acquired in the same adaptive gains. Finally, the validity of the conclusion is simulated by an example.
Potential of Citrullus colocynthis L. Schrad. Immature Seed Extracts as Food Preservative against a Fungal Mycotoxigenic Contaminant
Authors: Mussi Francesca , Montalbano Serena , Marzouk Belsem , Arru Laura , Refifa Meher , Marzouk Zohra , Kraiem Jamil , Degola Francesca , Buschini Annamaria
Published: July 2021

The world of plant extracts and natural compounds have long been regarded as a promise land for the individuation of healthy alternatives to chemical preservatives, against microbial contamination, in food and feed commodities. A plethora of aromatic and medicinal plant species have been studied from decades to explore their antimicrobial and antioxidant properties, in order to both validate their ethnobotanical use for healing microbial illnesses and assess their suitability as food preservation agents. In fact, after terrestrialization and during the following evolutionary pathway, plants had to develop chemical compounds—constitutive and/or induced—for defence against specific pathogens, therefore becoming a potential source of new natural products usable with antimicrobial purposes. Aside from the most common contaminants that could occur in foodstuff, mycotoxigenic fungal species represent a big concern, mainly in cereals and derived products: aflatoxins in particular are the most dreaded among such toxic and cancerogenic secondary metabolites, and the control of the main producer Aspergillus flavus is currently one of the most pursued goals in the field of food safety. As aromatic and medicinal plants have a long history of use in the Mediterranean basin for both food preservation and pest control in crops, the exploitation of native species for the control of mycotoxigenic phytopathogens is almost rationale. The present work provides novel insights into the possible use of C. colocynthis seed organic extracts as antimycotoxigenic additives, demonstrating, for some of them, a feasible application as crop and food protectants with specific regard to aflatoxin contamination. Additionally, the evaluation of their cytotoxic potential and nitric oxide production on human cell lines has been reported for the first time.
Effects of the Cistanche tubulosa Aqueous Extract on the Gut Microbiota of Mice with Intestinal Disorders
Authors: Bao Xiaowei , Bai Dongwen , Liu Xiaolu , Wang Ying , Zeng Lanjun , Wei Chenye , Jin Weiquan
Published: July 2021

Disorders of the gut microbiota are associated with many diseases. The aqueous extract from Cistanche tubulosa (CT), a traditional Chinese herbal formula, has been reported to play a role in protecting the human intestine. However, little is known about its effects on the gut microbiota. The present study was carried out to determine whether the CT aqueous extract can modulate the gut microbiome in mice with intestinal disorders. We found that the damaged intestinal morphology resulting from treatment with cefixime could be rescued using the CT aqueous extract. The comparison of microbial diversity between mice treated with the CT extract and control mice also indicated that the disorder in the microbiome community of model groups could be restored by treatment with high and medium concentrations of the CT aqueous extract. Treatment with cefixime led to a significant decrease in lactic acid bacteria; however, the supplementation of the CT aqueous extract recovered the growth of these lactic acid bacteria. Furthermore, the CT aqueous extract was able to moderate the dramatic changes in the metabolic pathways of the gut microbiome induced by cefixime. These findings provided an insight into the beneficial effects of the CT aqueous extract on gut microbiota, and they also provided an important reference for the development of related drugs in the future.
The Overseas Experience of Audit Committee and Audit Fees: Empirical Evidence from China
Authors: Li Chengai , Pan Lin , Chen Meilan
Published: July 2021

The complexity of audit committee experience, including the overseas experience, has an important impact on corporate governance. In this paper, we study the impact of the overseas experiences of the members of audit committee on audit fees. Our empirical analysis and results show that the audit committee overseas experience can significantly increase audit fees. Further, the positive influence of the audit committee overseas experience on audit fees is more pronounced in state‐owned enterprises and regions with weak marketization. In addition, we divide the overseas experience into overseas learning experience and overseas working experience. We find that both types of experience present in the audit committee significantly increase the audit fees. Finally, we find that the audit committee overseas experience can significantly improve the quality of accounting information and play a positive role in corporate governance.