bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender Differences in Physical Activity Engagement Among Adolescents With Congenital Heart Disease
Authors: Jackson Jamie L , Fox Kristen R , Swenski Taylor N , Neville Steven P , Marousis Noelle C , Korth Christina X , Rausch Joseph R , Cua Clifford L , Garg Vidu , Vannatta Kathryn
Published: October 2021

Objective

The current study aimed to (a) describe moderate-to-vigorous physical activity (MVPA), sedentary behavior (SB), and cardiorespiratory fitness (VO2Peak) via objective assessment among adolescents with congenital heart disease (CHD), (b) examine gender differences on MVPA, SB, VO2Peak, and the Theory of Planned Behavior elements, and (c) identify whether gender moderates the relationships between the Theory of Planned Behavior elements and MVPA, SB, and VO2Peak.

Methods

Adolescent CHD survivors (N = 86; ages 15–18 years) wore an accelerometer to assess MVPA and SB, underwent an exercise stress test to assess VO2Peak, and completed a survey of the Theory of Planned Behavior elements as measured by perceived benefits (attitudes), family/friend support and perceived norms (social norms), and self-efficacy and barriers (perceived behavioral control) to engaging in physical activity.

Results

On average, CHD survivors engaged in 22.3 min (SD = 15.3) of MVPA/day and 9 hr of SB/day (M = 565.8, SD = 102.5 min). Females engaged in less MVPA but not more SB had a lower mean VO2Peak, reported lower self-efficacy, and perceived greater barriers than males. In a regression model, barriers explained unique variance in MVPA and VO2Peak, but the relationship between barriers and MVPA/VO2Peak did not vary by gender. Self-efficacy did not explain unique variance in MVPA and VO2Peak when included in a model with gender and barriers.

Conclusions

Family/friend support for physical activity engagement may be an important consideration when developing physical activity interventions for adolescent CHD survivors. The role of gender differences in self-efficacy and perceived barriers on physical activity engagement warrants further investigation.
Rescued from oblivion: detailed analysis of archival Spitzer data of SN 1993J
Authors: Zsíros Szanna , Nagy Andrea P , Szalai Tamás
Published: October 2021

We present an extensive analysis of the late-time mid-infrared (mid-IR) evolution of the Type IIb SN 1993J from 10–26 yr post-explosion based on archival – mostly previously unpublished – photometric data from the Spitzer Space Telescope in conjunction with an archival InfraRed Spectrograph spectrum. SN 1993J is one of the best-studied supernovae (SNe) with an extensive decade-long multiwavelength data set published in various papers; however, its detailed late-time mid-IR analysis is still missing from the literature. Mid-IR data follow not just the continuously cooling SN ejecta but also late-time dust-formation and circumstellar-interaction processes. We provide evidence that the observed late-time mid-IR excess of SN 1993J can be described by the presence of two-component local dust with a dust mass of ∼(3.5–6.0) × 10−3 M⊙ in the case of a partly silicate-based dust composition. The source of these components could be either newly formed dust grains or heating of pre-existing dust via ongoing circumstellar matter interaction also detected at other wavelengths. If it is newly formed, the dust is assumed to be located both in the unshocked inner ejecta and in the outer cold dense shell, just as in the Cassiopeia A remnant and also assumed in other dust-forming SNe a few years after explosion.
The fast radio burst population evolves, consistent with the star formation rate
Authors: James C W , Prochaska J X , Macquart J-P , North-Hickey F O , Bannister K W , Dunning A
Published: October 2021

Fast radio bursts (FRBs) are extremely powerful sources of radio waves observed at cosmological distances. We use a sophisticated model of FRB observations – presented in detail in a companion paper – to fit FRB population parameters using large samples of FRBs detected by ASKAP and Parkes, including seven sources with confirmed host galaxies. Our fitted parameters demonstrate that the FRB population evolves with redshift in a manner consistent with, or faster than, the star formation rate (SFR), ruling out a non-evolving population at better than 98 per cent CL (depending on modelling uncertainties). Our estimated maximum FRB energy is $\log _{10} E_{\rm max} [{\rm erg}] = 41.70_{-0.06}^{+0.53}$ (68 per cent CL) assuming a 1 GHz emission bandwidth, with slope of the cumulative luminosity distribution $\gamma =-1.09_{-0.10}^{+0.14}$. We find a log-mean host DM contribution of $129_{-48}^{+66}$ pc cm−3 on top of a typical local (interstellar medium and halo) contribution of ∼80 pc cm−3, which is higher than most literature values. These results are insensitive to assumptions of the FRB spectral index, and are consistent with the model of FRBs arising as the high-energy limit of magnetar bursts, but allow for FRB progenitors that evolve faster than the SFR.
Deeplasmid: deep learning accurately separates plasmids from bacterial chromosomes
Authors: Andreopoulos William B , Geller Alexander M , Lucke Miriam , Balewski Jan , Clum Alicia , Ivanova Natalia N , Levy Asaf
Published: October 2021

Plasmids are mobile genetic elements that play a key role in microbial ecology and evolution by mediating horizontal transfer of important genes, such as antimicrobial resistance genes. Many microbial genomes have been sequenced by short read sequencers and have resulted in a mix of contigs that derive from plasmids or chromosomes. New tools that accurately identify plasmids are needed to elucidate new plasmid-borne genes of high biological importance. We have developed Deeplasmid, a deep learning tool for distinguishing plasmids from bacterial chromosomes based on the DNA sequence and its encoded biological data. It requires as input only assembled sequences generated by any sequencing platform and assembly algorithm and its runtime scales linearly with the number of assembled sequences. Deeplasmid achieves an AUC–ROC of over 89%, and it was more accurate than five other plasmid classification methods. Finally, as a proof of concept, we used Deeplasmid to predict new plasmids in the fish pathogen Yersinia ruckeri ATCC 29473 that has no annotated plasmids. Deeplasmid predicted with high reliability that a long assembled contig is part of a plasmid. Using long read sequencing we indeed validated the existence of a 102 kb long plasmid, demonstrating Deeplasmid's ability to detect novel plasmids.
ONQUADRO: a database of experimentally determined quadruplex structures
Authors: Zok Tomasz , Kraszewska Natalia , Miskiewicz Joanna , Pielacinska Paulina , Zurkowski Michal , Szachniuk Marta
Published: October 2021

ONQUADRO is an advanced database system that supports the study of the structures of canonical and non-canonical quadruplexes. It combines a relational database that collects comprehensive information on tetrads, quadruplexes, and G4-helices; programs to compute structure parameters and visualise the data; scripts for statistical analysis; automatic updates and newsletter modules; and a web application that provides a user interface. The database is a self-updating resource, with new information arriving once a week. The preliminary data are downloaded from the Protein Data Bank, processed, annotated, and completed. As of August 2021, ONQUADRO contains 1,661 tetrads, 518 quadruplexes, and 30 G4-helices found in 467 experimentally determined 3D structures of nucleic acids. Users can view and download their description: sequence, secondary structure (dot-bracket, classical diagram, arc diagram), tertiary structure (ball-and-stick, surface or vdw-ball model, layer diagram), planarity, twist, rise, chi angle (value and type), loop characteristics, strand directionality, metal ions, ONZ, and Webba da Silva classification (the latter by loop topology and tetrad combination), origin structure ID, assembly ID, experimental method, and molecule type. The database is freely available at https://onquadro.cs.put.poznan.pl/. It can be used on both desktop computers and mobile devices.
Contemporary adaptive evolution in fragmenting river landscapes: evidence from the native waterflea Ceriodaphnia cornuta
Authors: Zhang Haoran , He Yuanwen , Yang Jiashen , Mao Hongzhen , Jiang Xiaodong
Published: October 2021

The hypothesis that adaptive evolution in cities can occur on both contemporary and microgeographic scales was tested by investigating morphological, genetic and life history traits of waterflea Ceriodaphnia cornuta in an urbanized river. After the partial isolation from the Yingtao River by urban construction 16 years ago, the population of C. cornuta in the Shangyi Pond showed a different pattern of genotypic composition. Nuclear microsatellite markers revealed significant population genetic structure of C. cornuta among the Shangyi Pond, the Yingtao River and the Dianshan Lake in the upstream area. Migration analyses demonstrated little gene flow among different waters. In a common garden experiment, the changes in multivariate reaction norms provided evidence of local adaptation to dietary cyanobacteria in the river and lake populations. The results indicated that fragmenting river landscapes with urbanization resulted in the significant genetic differentiation and subsequent adaptive evolution in zooplankton populations on a short temporal and geographical scale.
Biosynthesis and antifungal activity of fungus-induced O-methylated flavonoids in maize
Authors: Förster Christiane , Handrick Vinzenz , Ding Yezhang , Nakamura Yoko , Paetz Christian , Schneider Bernd , Castro-Falcón Gabriel , Hughes Chambers C , Luck Katrin , Poosapati Sowmya , Kunert Grit , Huffaker Alisa , Gershenzon Jonathan , Schmelz Eric A , Köllner Tobias G
Published: October 2021

Fungal infection of grasses, including rice (Oryza sativa), sorghum (Sorghum bicolor), and barley (Hordeum vulgare), induces the formation and accumulation of flavonoid phytoalexins. In maize (Zea mays), however, investigators have emphasized benzoxazinoid and terpenoid phytoalexins, and comparatively little is known about flavonoid induction in response to pathogens. Here, we examined fungus-elicited flavonoid metabolism in maize and identified key biosynthetic enzymes involved in the formation of O-methylflavonoids. The predominant end products were identified as two tautomers of a 2-hydroxynaringenin-derived compound termed xilonenin, which significantly inhibited the growth of two maize pathogens, Fusarium graminearum and Fusarium verticillioides. Among the biosynthetic enzymes identified were two O-methyltransferases (OMTs), flavonoid OMT 2 (FOMT2), and FOMT4, which demonstrated distinct regiospecificity on a broad spectrum of flavonoid classes. In addition, a cytochrome P450 monooxygenase (CYP) in the CYP93G subfamily was found to serve as a flavanone 2-hydroxylase providing the substrate for FOMT2-catalyzed formation of xilonenin. In summary, maize produces a diverse blend of O-methylflavonoids with antifungal activity upon attack by a broad range of fungi.
Unequal Ties: Immigrants’ Initial Social Capital and Labor Market Stratification
Authors: Park Sung S , Lai Tianjian , Waldinger Roger D
Published: October 2021

Social capital (SC) plays a fundamental role in immigration by easing entry into a new environment. We advance a novel approach to assessing the role of SC for immigrants’ labor market incorporation. First, we isolate the impact of SC activation from the mere presence of potential help. Second, we disentangle the diverse components of migration-related SC by distinguishing between individual migration- (IM) and community migration-level (CM) connections in the country of destination. Third, we trace the roles of IM SC and CM SC across multiple labor market outcomes, ranging from the search to secure the first job to the quality of the first job to longer-term occupational mobility. Absent activation, IM SC has virtually no impact on any of the outcomes. Rather, migrants’ IM SC yield their fundamental impact when activated, contributing to a successful job search while steering them into first jobs that are of lower-quality relative to their pre-migration occupation. By contrast, CM SC facilitates the initial job search and filters immigrants into higher-quality first jobs. Moreover, immigrants who arrive when CM SC is at its most mature stage reap the clearest benefits in improving their occupational status. These findings underscore the importance of both early settlement IM SC and CM SC in the processes of immigrants’ labor market stratification.
Successful healthcare transition for youth with special healthcare needs is a team effort
Authors: Cady Rhonda G. , Erickson Catherine , Harris Debbi Simmons , Nickelsen Tracy
Published: October 2021

NPs care for persons across the age continuum and transitions commonly occur. Some are unexpected, like hospitalizations for acute illness or injury. Others are an expected consequence of growing up, like moving from pediatric to adult care models. Understanding the factors impacting healthcare transition is critical for successful outcomes.
ZIP12 Contributes to Hypoxic Pulmonary Hypertension by Driving Phenotypic Switching of Pulmonary Artery Smooth Muscle Cells
Authors: Zhu Tiantian , Wang Xuan , Zheng Zijie , Quan Jinping , Liu Yuhao , Wang Yuting , Liu Tianheng , Liu Xu , Wang Mi , Zhang Zheng
Published: October 2021

ZIP12, a plasmalemmal zinc transporter, reportedly promotes pulmonary vascular remodeling (PVR) by enhancing proliferation of pulmonary artery smooth muscle cells (PASMCs). However, the mechanisms of ZIP12 facilitating PASMCs proliferation remain incompletely appreciated. It has been acknowledged that proliferation-predisposing phenotypic switching of PASMCs can lead to PVR. Given that hypoxia triggers phenotypic switching of PASMCs and ZIP12 mediates PVR, this study aims to explore whether ZIP12-mediated phenotypic switching of PASMCs contributes to hypoxia-induced PVR. Rats were exposed to hypoxia (10% O2) for 3 weeks to induce PVR, and primary rat PASMCs were cultured under hypoxic condition (3% O2) for 48 hours to induce proliferation. Immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and Western blot analysis were performed to detect the expression of target mRNAs and proteins. EdU incorporation and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay were conducted to measure the proliferation of PASMCs. Hypoxia upregulated ZIP12 expression (both mRNA and protein) in pulmonary arteries and PASMCs. Knockdown of ZIP12 inhibited phenotypic switching of PASMCs induced by hypoxia. We propose that HIF-1α/ZIP12/pERK pathway could represent a novel mechanism underlying hypoxia-induced phenotypic switching of PASMCs. Therapeutic targeting of ZIP12 could be exploited to treat PVR.
Vaginal mesh hysteropexy: a review
Authors: DiCarlo-Meacham Angela , Mazloomdoost Donna
Published: October 2021

Purpose of review

Pelvic organ prolapse surgery is performed via native tissue or graft augmented repair. Graft augmentation with synthetic mesh was introduced to improve long-term surgical outcomes compared with vaginal native tissue repairs. Vaginal hysteropexy has recently become increasingly popular due to patient preference and an improved morbidity profile over hysterectomy, while maintaining comparable efficacy. As long-term outcomes remain unanswered, mesh augmentation to vaginal hysteropexy has sought to improve efficacy while minimizing complications.

Recent findings

Recent studies have demonstrated superiority of vaginal mesh hysteropexy to vaginal hysterectomy with native tissue vault suspension. Short-term follow-up of vaginal mesh hysteropexy has also demonstrated lower blood loss and operative time with improved vaginal length compared with hysterectomy. Mesh exposure rates across studies were low and comparable to those of abdominally placed prolapse mesh.

Vaginal mesh hysteropexy is a comparably well tolerated and effective surgical treatment option for women with uterovaginal prolapse. Although vaginal mesh kits are not commercially available, this procedure may be a viable treatment option in select patients.
Neuropathogenesis of severe acute respiratory syndrome coronavirus 2
Authors: Patel Payal B. , Bearden David
Published: October 2021

Purpose of review

The purpose of this review is to address our current understanding of the pathophysiology of neurologic injury resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection on the developing nervous system.

Recent findings

SARS-CoV2 may enter the brain through three potential mechanisms: transsynaptic spread from the olfactory bulb following intranasal exposure, migration across the blood–brain barrier through endothelial cell infection, and migration following disruption of the blood–brain barrier from resulting inflammation. SARS-CoV2 does not appear to directly infect neurons but rather may produce an inflammatory cascade that results in neuronal injury. Additionally, autoantibodies targeting neuronal tissue resulting from the immune response to SARS-CoV2 are present in select patients and may contribute to central nervous system (CNS) injury.

These findings suggest that neuronal injury during SARS-CoV2 infection is immune mediated rather than through direct viral invasion. Further multimodal studies evaluating the pathophysiology of neurologic conditions in pediatric patients specifically following SARS-CoV2 infection are needed to improve our understanding of mechanisms driving neurologic injury and to identify potential treatment options.
Coping Under Extreme Conditions
Authors: Eterović Marija , Lucijanić Dijana , Kranjčević Matija , Marinić Igor , Marinić Lana Mužinić
Published: October 2021

The role of coping dispositions in predicting coping with a potentially traumatic event (PTE; situational coping) has been bypassed. We explored the degree to which the dispositional coping of 103 mountain rescuers predicted coping with their last PTE. Dispositional venting of emotions and turning to religion explained more than half of the variance in the use of the same strategy to cope with the PTE. Most coping dispositions predicted about 30% to 40% of the variance in comparable situational coping. Dispositional denial did not predict situational use of denial. Multivariate dispositional coping style explained a great deal of the variance in most situational coping responses. Dispositional coping was more relevant than situational to participants' global psychological distress and explained about one-fourth of the variance in distress. These results suggest that most dispositional styles considerably impact coping with PTE but to the extent that varies across different coping styles.
Olfactory Dysfunction
Authors: Kaya Ender , Göker Ayşe Enise
Published: October 2021

Olfactory disorders may be observed together with cognitive impairment in patients with major depressive disorder (MDD). This study compared olfactory performances between patients with MDD and healthy controls and investigated the relationship between olfactory performance and subjective cognitive impairment in these patients. This study included 52 patients diagnosed with MDD and 46 healthy controls. The participants were evaluated in terms of their olfactory capacities (threshold, discrimination, and identification), subjective cognitive impairment, and depression. Although the olfactory threshold (OT) and olfactory discrimination scores were lower in patients with MDD compared with those in the control group, their olfactory identification scores did not differ significantly. OT was negatively correlated with subjective cognitive impairment and may serve as a determinant for subjective cognitive changes. Consequently, patients with MDD had lower olfactory performances compared with healthy controls. Finally, OT may be a component of subjective cognitive impairment in MDD.
The Relationship Between Degree of Nasal Septum Deviation With Sinonasal Structures and Variations
Authors: Atsal Görkem , Demir Emine , Yildirim Oben , Edizer Deniz Tuna , Olgun Levent
Published: October 2021

We aimed to evaluate whether the nasal septum deviation affects the development of sinonasal structures. Patients who had undergone paranasal sinus computed tomography (PNS-CT) imaging due to nasal obstruction were divided into 3 groups according to the septal deviation angle; group I: 0° to 9°, group II: 10° to 15°, and group III: >15°. The features of sinonasal structures were recorded when evaluating PNS-CT. There were totally 234 patients, 119 patients in group I, 68 in group II, and 47 in group III. On the opposite side of the deviation, keros 3 was significantly more in group III (P < 0.001). Although the incidence of concha bullosa and agger nasi cell were not affected by the degree of deviation (P > 0.05), the incidence of Haller and Onodi cells were significantly higher in group III (P < 0.001). In addition, all cells were observed more in the opposite side of the deviation in each group (P < 0.001). Maxillary sinus retention cysts and hypoplasia of maxillary and frontal sinuses, as an indicator of the low pneumatization of the sinuses, are seen more on the same side of nasal septum deviation, increasing with the degree of deviation increases (P < 0.001). Nasal septum deviation affects the development of sinonasal structures by affecting the pneumatization. Preoperative PNS-CT evaluation is important in order to be aware of the situations that we may encounter during surgery and to provide adequate treatment.
Early Evidence Indicates Vitamin D Improves Symptoms of Irritable Bowel Syndrome
Authors: Matthews Sarah W. , Heitkemper Margaret M. , Kamp Kendra
Published: October 2021

Irritable bowel syndrome (IBS) affects approximately 11.2% of the population. Yet, full understanding of its etiology and optimal treatment remains elusive. Understanding of the underlying pathophysiology of IBS has been limited. However, research is beginning to identify the cause as multifactorial (e.g., low-grade local mucosal inflammation, systemic immune activation, altered intestinal permeability, intestinal hypersensitivity, altered central nervous system processing, changes in intestinal microbiota). Understanding of the role of vitamin D in intestinal inflammation, immunity, and gastrointestinal conditions is increasing but is not yet fully understood. Growing evidence has linked vitamin D deficiency with a variety of gastrointestinal disorders, including inflammatory bowel disease, diverticulitis, colorectal cancer, and IBS. Several studies have demonstrated that individuals with IBS are more likely to have vitamin D deficiency than healthy controls. Recent vitamin D supplementation studies have shown improvement in quality of life and reduction in IBS symptoms (including abdominal pain, distention, flatulence, constipation, and visceral sensitivity) but the mechanism remains unclear. Nurses are well positioned to educate patients about the importance of sufficient vitamin D for overall health in individuals with IBS as well as participate in well-designed therapeutic studies to explore whether enhanced vitamin D status will ultimately help treat IBS more effectively.
Neuroprotective effect of paeoniflorin in the mouse model of Parkinson’s disease through α-synuclein/protein kinase C δ subtype signaling pathway
Authors: Guo Kedong , Zhang Yingbo , Li Libo , Zhang Jingyan , Rong Hua , Liu Deshui , Wang Junping , Jin Ming , Luo Nan , Zhang Xiaojie
Published: October 2021

Objectives

Paeoniflorin, an active component of Radix Paeoniae Alba, has a neuroprotective effect in Parkinson’s animal models. However, its mechanism of action remains to be determined.

Methods

In this study, we hypothesized that the neuroprotective effect of paeoniflorin occurs through the α-synuclein/protein kinase C δ subtype (PKC-δ) signaling pathway. We tested our hypothesis in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease. We evaluated the effects of paeoniflorin on the expression levels of signal components of the α-synuclein/PKC-δ pathway, cellular apoptosis and motor performance.

Results

Our results demonstrated that paeoniflorin restored the motor performance impairment caused by MPTP, inhibited apoptosis, and protected the ultrastructure of neurons. Paeoniflorin treatment also resulted in the dose-dependent upregulation of an antiapoptotic protein, B-cell lymphoma-2, at the mRNA and protein levels, similar to the effects of the positive control, selegiline. In contrast, paeoniflorin treatment downregulated the expression of pro-apoptotic proteins BCL2-Associated X2, α-synuclein, and PKC-δ at the mRNA and protein levels, as well as the level of the activated form of nuclear factor kappa B (p-NF-κB p65).

Conclusions

Thus, our results showed that paeoniflorin exerts its neuroprotective effect by regulating the α-synuclein/PKC-δ signaling pathway to reduce neuronal apoptosis.
Optimal ECG-lead selection increases generalizability of deep learning on ECG abnormality classification
Authors: Lai Changxin , Zhou Shijie , Trayanova Natalia A.
Published: October 2021

Deep learning (DL) has achieved promising performance in detecting common abnormalities from the 12-lead electrocardiogram (ECG). However, diagnostic redundancy exists in the 12-lead ECG, which could impose a systematic overfitting on DL, causing poor generalization. We, therefore, hypothesized that finding an optimal lead subset of the 12-lead ECG to eliminate the redundancy would help improve the generalizability of DL-based models. In this study, we developed and evaluated a DL-based model that has a feature extraction stage, an ECG-lead subset selection stage and a decision-making stage to automatically interpret multiple common ECG abnormality types. The data analysed in this study consisted of 6877 12-lead ECG recordings from CPSC 2018 (labelled as normal rhythm or eight types of ECG abnormalities, split into training (approx. 80%), validation (approx. 10%) and test (approx. 10%) sets) and 3998 12-lead ECG recordings from PhysioNet/CinC 2020 (labelled as normal rhythm or four types of ECG abnormalities, used as external text set). The ECG-lead subset selection module was introduced within the proposed model to efficiently constrain model complexity. It detected an optimal 4-lead ECG subset consisting of leads II, aVR, V1 and V4. The proposed model using the optimal 4-lead subset significantly outperformed the model using the complete 12-lead ECG on the validation set and on the external test dataset. The results demonstrated that our proposed model successfully identified an optimal subset of 12-lead ECG; the resulting 4-lead ECG subset improves the generalizability of the DL model in ECG abnormality interpretation. This study provides an outlook on what channels are necessary to keep and which ones may be ignored when considering an automated detection system for cardiac ECG abnormalities.

This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.
Functional brain–heart interplay extends to the multifractal domain
Authors: Catrambone Vincenzo , Barbieri Riccardo , Wendt Herwig , Abry Patrice , Valenza Gaetano
Published: October 2021

The study of functional brain–heart interplay has provided meaningful insights in cardiology and neuroscience. Regarding biosignal processing, this interplay involves predominantly neural and heartbeat linear dynamics expressed via time and frequency domain-related features. However, the dynamics of central and autonomous nervous systems show nonlinear and multifractal behaviours, and the extent to which this behaviour influences brain–heart interactions is currently unknown. Here, we report a novel signal processing framework aimed at quantifying nonlinear functional brain–heart interplay in the non-Gaussian and multifractal domains that combines electroencephalography (EEG) and heart rate variability series. This framework relies on a maximal information coefficient analysis between nonlinear multiscale features derived from EEG spectra and from an inhomogeneous point-process model for heartbeat dynamics. Experimental results were gathered from 24 healthy volunteers during a resting state and a cold pressor test, revealing that synchronous changes between brain and heartbeat multifractal spectra occur at higher EEG frequency bands and through nonlinear/complex cardiovascular control. We conclude that significant bodily, sympathovagal changes such as those elicited by cold-pressure stimuli affect the functional brain–heart interplay beyond second-order statistics, thus extending it to multifractal dynamics. These results provide a platform to define novel nervous-system-targeted biomarkers.

This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.
Intraoperative Hydromorphone Decreases Post-Operative Pain Who Would Have Thought? An Instrumental Variable Analysis
Authors: Ershoff Brent
Published: October 2021

Background

A growing body of literature suggests that intraoperative opioid administration can lead to both increased post-operative pain and opioid requirements. However, there has been minimal data regarding the effects of the intraoperative administration of intermediate duration opioids such as hydromorphone on post-operative outcomes. Causal inference using observational studies is often hampered by unmeasured confounding, where classical adjustment techniques, such as multivariable regression, are insufficient. Instrumental variable analysis is able to generate unbiased causal effect estimates in the presence of unmeasured confounding, assuming a valid instrumental variable can be found. We previously demonstrated, using a natural experiment, how hydromorphone presentation dose, i.e. the unit dose provided to the clinician, affects intraoperative administration dose, with the switch from a 2-mg to a 1-mg vial associated with decreased administration. As the change in hydromorphone presentation dose was unrelated to any external factors, presentation dose could serve as an instrumental variable to estimate the effect of intraoperative hydromorphone administration dose on post-operative outcomes.

Methods

In this observational study with 6,751 patients, an instrumental variable analysis was employed to estimate the causal effect of an increased intraoperative administration dose of hydromorphone on post-operative pain and opioid administration. The study population included patients who received intraoperative hydromorphone as part of an anesthetic at the University of California, Los Angeles, from October 2016 to November 2018. Before July 2017, hydromorphone was available as a 2-mg unit dose. From July 1, 2017 to November 20, 2017, hydromorphone was only available in a 1-mg unit dose. A two-stage least squares regression analysis was performed to estimate the effect of intraoperative hydromorphone administration dose on post-operative pain scores and opioid administration.

Results

An increase in hydromorphone administration caused a statistically significant decrease in Post-Anesthesia Care Unit pain scores as well as maximum and mean pain scores on post-operative days one and two, without a statistically significant effect on post-operative opioid administration. Various sensitivity analyses support the validity of the instrumental variable assumptions and suggest that the results are robust against violations of these assumptions.

Conclusions

The results of this study suggests that the intraoperative administration of intermediate duration opioids do not cause the same effects as short acting opioids with respect to post-operative pain. Instrumental variables, when identified, can be invaluable in estimating causal effects using observation data whereby unmeasured confounding is likely present.
Tools for the assessment of quality and risk of bias in Mendelian randomization studies: a systematic review
Authors: Spiga Francesca , Gibson Mark , Dawson Sarah , Smith George Davey , Munafò Marcus R , Higgins Julian PT
Published: October 2021

Background

The use of Mendelian randomization (MR) in epidemiology has increased considerably in recent years, with a subsequent increase in systematic reviews of MR studies. We conducted a systematic review of tools designed for risk of bias and/or quality of evidence assessment in (MR) studies, and a review of systematic reviews of MR studies.

Methods

We systematically searched MEDLINE, Embase, the Web of Science, preprints servers and Google Scholar for articles containing tools for assessing, conducting and/or reporting MR studies. We also searched for systematic reviews and protocols of systematic reviews of MR. From eligible articles we collected data on tool characteristics and content, as well as details of narrative description of bias assessment.

Results

Our searches retrieved 2464 records to screen, from which 14 tools, 35 systematic reviews and 38 protocols were included in our review. Seven tools were designed for assessing risk of bias/quality of evidence in MR studies and evaluation of their content revealed that all seven tools addressed the three core assumptions of instrumental variable analysis, violation of which can potentially introduce bias in MR analysis estimates.

Conclusions

We present an overview of tools and methods to assess risk of bias/quality of evidence in MR analysis. As none of these methods has been tested and validated for general use, we do not provide recommendations on their use. Our findings should raise awareness about the importance of bias related to MR analysis and provide information that is useful for assessment of MR studies in the context of systematic reviews.
Immune response to COVID-19 vaccination is attenuated by poor disease control and antimyeloma therapy with vaccine driven divergent T cell response
Authors: Ramasamy Karthik , Sadler Ross , Jeans Sally , Weeden Paul , Varghese Sherin , Turner Alison , Larham Jemma , Gray Nathanael , Carty Oluremi , Barrett Joe , Bowcock Stella , Oppermann Udo , Cook Gordon , Kyriakou Chara , Drayson Mark , Basu Supratik , Moore Sally , McDonald Sarah , Gooding Sarah , Javaid Muhammad K
Published: October 2021

Background

Myeloma patients frequently respond poorly to bacterial and viral vaccination. A few studies have reported poor humoral immune responses in myeloma patients to COVID-19 vaccination.

Methods

Using a prospective study of myeloma patients in UK Rudy Study cohort, we assessed humoral and Interferon gamma release assay (IGRA) cellular immune responses to COVID-19 vaccination post second COVID-19 vaccine administration.

Findings

We report data from 214 adults with myeloma (n=204) or smouldering myeloma (n=10) who provided blood samples at least 3 weeks after second vaccine dose. Positive Anti-Spike antibody levels (> 50 IU/ml) were detected in 189/203 (92.7%), positive IGRA responses were seen in 97/158 (61.4%) myeloma patients. Only 10/158 (6.3%) patients were identified to have both a negative IGRA and negative Anti-Spike protein antibody response. 95/158 (60.1%) patients produced positive results for both anti-Spike protein serology and IGRA. After adjusting for disease severity and myeloma therapy, poor humoral immune response was predicted by male gender. Predictors of poor IGRA included anti-CD38/ anti-BCMA therapy and Pfizer-BioNTech (PB) vaccination.

Interpretation

Significant majority of myeloma patients elicit Anti-Spike protein antibody responses to COVID-19 vaccine with 60% of myeloma patients showing both humoral and T cell response. Predictors of a poor immune response included male gender, myeloma therapy regimen and administration of Pfizer-BioNTech vaccination. Further work is required to understand the clinical significance of divergent cellular response to vaccination.

Funding

Funding for this study has been received from Blood Cancer Vaccine Consortium and Janssen UK. RUDY platform has been funded by NIHR.
How different pre-existing mental disorders and their co-occurrence affects clinical outcomes of COVID-19? A study based on real-world data in the Southern United States
Authors: Qiao Shan , Zhang Jiajia , Chen Shujie , Olatosi Bankole , Hardeman Suzanne , Narasimhan Meera , Bruner Larisa , Diedhiou Abdoulaye , Scott Cheryl , Mansaray Ali , Weissman Sharon , Li Xiaoming
Published: October 2021

Importance

A growing body of research focuses on the impact of pre-existing mental disorders on clinical outcomes of COVID-19 illness. Although a psychiatric history might be an independent risk factor for COVID-19 infection and mortality, no studies have systematically investigated how different clusters of pre-existing mental disorders may affect COVID-19 clinical outcomes or showed how the coexistence of mental disorder clusters is related to COVID-19 clinical outcomes.

Objective

To explore how different pre-existing mental disorders and their co-occurrence affects COVID-19-related clinical outcomes based on real-world data.

Design, Setting, and Participants

Using a retrospective cohort study design, a total of 476,775 adult patients with lab-confirmed and probable COVID-19 between March 06, 2020 and April 14, 2021 in South Carolina, United States were included in the current study. The electronic health record data of COVID-19 patients were linked to all payer-based claims data through the SC Revenue and Fiscal Affairs Office.

Main Outcomes and Measures

Key COVID-19 clinical outcomes included severity, hospitalization, and death. COVID-19 severity was defined as asymptomatic, mild, and moderate/severe. Pre-existing mental disorder diagnoses from Jan 2, 2019 to Jan 14, 2021 were extracted from the patients’ healthcare utilization data via ICD-10 codes. Mental disorders were categorized into internalizing disorders, externalizing disorders, and thought disorders.

Results

Of the 476,775 COVID-19 patients, 55,300 had pre-existing mental disorders. There is an elevated risk of COVID-19-related hospitalization and death among participants with pre-existing mental disorders adjusting for key socio-demographic covariates (i.e., age, gender, race, ethnicity, residence, smoking). Co-occurrence of any two clusters was positively associated with COVID-19-related hospitalization and death. The odds ratio of being hospitalized was 2.50 (95%CI 2.284, 2.728) for patients with internalizing and externalizing disorders, 3.34 (95%CI 2.637, 4.228) for internalizing and thought disorders, 3.29 (95%CI 2.288, 4.733) for externalizing and thought disorders, and 3.35 (95%CI 2.604, 4.310) for three clusters of mental disorders.

Conclusions and Relevance

Pre-existing internalizing disorders, externalizing disorders, and thought disorders are positively related to COVID-19 hospitalization and death. Co-occurrence of any two clusters of mental disorders have elevated risk of COVID-19-related hospitalization and death compared to those with a single cluster.
Characterization of raloxifene as potential pharmacological agent against SARS-CoV-2 and its variants
Authors: Iaconis Daniela , Talarico Carmine , Manelfi Candida , Cesta Maria Candida , Zippoli Mara , Caccuri Francesca , Matusali Giulia , Bordi Licia , Scorzolini Laura , Bucci Enrico , Caruso Arnaldo , Nicastri Emanuele , Allegretti Marcello , Beccari Andrea Rosario
Published: October 2021

The new coronavirus that emerged, called SARS-CoV-2, is the causative agent of the COVID-19 pandemic. The identification of potential drug candidates that can rapidly enter clinical trials for the prevention and treatment of COVID-19 is an urgent need, despite the recent introduction of several new vaccines for the prevention and protection of this infectious disease, which in many cases becomes severe. Drug repurposing (DR), a process for studying existing pharmaceutical products for new therapeutic indications, represents one of the most effective potential strategies employed to increase the success rate in the development of new drug therapies. We identified raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a potential pharmacological agent for the treatment of COVID-19 patients. Following a virtual screening campaign on the most relevant viral protein targets, in this work we report the results of the first pharmacological characterization of raloxifene in relevant cellular models of COVID-19 infection. The results obtained on all the most common viral variants originating in Europe, United Kingdom, Brazil, South Africa and India, currently in circulation, are also reported, confirming the efficacy of raloxifene and, consequently, the relevance of the proposed approach.

Taken together, all the information gathered supports the clinical development of raloxifene and confirms that the drug can be proposed as a viable new option to fight the pandemic in at least some patient populations. The results obtained so far have paved the way for a first clinical study to test the safety and efficacy of raloxifene, just concluded in patients with mild to moderate COVID-19.
Diverse northern Asian and Jomon-related genetic structure discovered among socially complex Three Kingdoms period Gaya region Koreans
Authors: Gelabert Pere , Blazyte Asta , Chang Yongjoon , Fernandes Daniel M. , Jeon Sungwon , Hong Jin Geun , Yoon Jiyeon , Ko Youngmin , Oberreiter Victoria , Cheronet Olivia , Özdoğan Kadir T. , Sawyer Susanna , Yang Songhyok , Greytak Ellen McRae , Choi Hansol , Kim Jungeun , Kim Jong-Il , Bae Kidong , Bhak Jong , Pinhasi Ron
Published: October 2021

The genetic history of prehistoric and protohistoric Korean populations is not well understood due to the lack of ancient Korean genomes. Here, we report the first paleogenomic data from Korea; eight shotgun-sequenced genomes (0.7×∼6.1× coverage) from two archeological sites in Gimhae: Yuha-ri shell mound and Daesung-dong tumuli, the most important funerary complex of the Gaya confederacy. All eight individuals are from the Korean Three Kingdoms period (4th-7th century CE), during which there is archaeological evidence of extensive trade connections with both northern (modern-day China) and eastern (modern-day Japan) kingdoms. All genomes are best modeled as an admixture between a northern-Chinese Iron Age genetic source and a Japanese-Jomon-related ancestry. The proportion of Jomon-related ancestry suggests the presence of two genetic groups within the population. The observed substructure indicates diversity among the Gaya population that is not related to either social status or sex.

Teaser

1,700-year-old genomes reveal the genetic diversity of ancient Koreans in the Gimhae region.
Interleukin 7 receptor drives Early T lineage Progenitor expansion
Authors: Paiva Rafael A. , Martins Vera C.
Published: October 2021

Interleukin 7 (IL-7) and IL-7 receptor (IL-7r) are essential for T lymphocyte differentiation, by driving proliferation and survival of specific developmental stages. While early T lineage progenitors (ETP), the most immature thymocyte population known, have a history of IL-7r expression, it is unclear whether IL-7r is required at this stage. Here, we show that mice lacking IL-7 or IL-7r have a marked loss of ETPs that results mostly from a cell-autonomous defect in proliferation and survival, although no changes were detected in Bcl2 protein levels. Further, a fraction of ETPs responded to IL-7 stimulation ex vivo by phosphorylating Stat5, and IL-7r was enriched in the most immature Flt3+Ccr9+ ETPs. Consistently, IL-7 promoted the expansion of Flt3+ but not Flt3-ETPs on OP9-DLL4 cocultures, without affecting differentiation at either stage. Taken together, our data show that IL-7/IL-7r is necessary following thymus seeding, by promoting proliferation and survival of the most immature thymocytes.

Paiva et al. show that IL-7/IL-7r signaling upon thymus seeding is essential for proliferation and survival of the most immature early T lineage progenitors (ETP), thereby determining the physiological ETP cellularity.
Crystallization, structural characterization and kinetic analysis of a GH26 β-mannanase from Klebsiella oxytoca KUB-CW2-3
Authors: Pongsapipatana Nawapan , Charoenwattanasatien Ratana , Pramanpol Nuttawan , Nguyen Thu-Ha , Haltrich Dietmar , Nitisinprasert Sunee , Keawsompong Suttipun
Published: October 2021

β-Mannanase (EC 3.2.1.78) is an enzyme that cleaves within the backbone of mannan-based polysaccharides at β-1,4-linked D-mannose residues, resulting in the formation of mannooligosaccharides (MOS), which are potential prebiotics. The GH26 β-mannanase KMAN from Klebsiella oxytoca KUB-CW2-3 shares 49–72% amino-acid sequence similarity with β-mannanases from other sources. The crystal structure of KMAN at a resolution of 2.57 Å revealed an open cleft-shaped active site. The enzyme structure is based on a (β/α)8-barrel architecture, which is a typical characteristic of clan A glycoside hydrolase enzymes. The putative catalytic residues Glu183 and Glu282 are located on the loop connected to β-strand 4 and at the end of β-strand 7, respectively. KMAN digests linear MOS with a degree of polymerization (DP) of between 4 and 6, with high catalytic efficiency (k
cat/K
m) towards DP6 (2571.26 min−1 mM
−1). The predominant end products from the hydrolysis of locust bean gum, konjac glucomannan and linear MOS are mannobiose and mannotriose. It was observed that KMAN requires at least four binding sites for the binding of substrate molecules and hydrolysis. Molecular docking of mannotriose and galactosyl-mannotetraose to KMAN confirmed its mode of action, which prefers linear substrates to branched substrates.
The influence of Hofstede’s cultural dimension on tax compliance behaviour of tax practitioners
Authors: Seno Rohaida , Hashim Hafiza Aishah , Taha Roshaiza , Abdul Hamid Suhaila
Published: October 2021

Purpose

The purpose of this paper is to determine whether Hofstede’s cultural dimensions have a significant relationship with ethical decision-making among tax practitioners while performing their duties in ensuring tax compliance among taxpayers.

Design/methodology/approach

A structured questionnaire was used to collect data from tax practitioners in the state of Terengganu, Malaysia. Two hundred questionnaires were distributed via Google Forms and email to tax practitioners who were selected from the Inland Revenue Board of Malaysia website using a mixture of systematic random and snowball sampling approaches. The Statistical Package for Social Sciences software program was used to analyse the collected data.

Findings

The results show that power distance (PD), individualism (IND) and uncertainty avoidance (UAV) have a significant relationship with ethical decision-making, whereas masculinity (MAS) has no significant relationship with ethical decision-making among tax practitioners while carrying out their duties. The positive relationship of PD and of IND with decision-making behaviour indicates that ethical decision-making is highly practised in a low PD and low IND culture rather than in a high PD and high IND culture. In contrast, UAV shows a negative beta sign, which indicates that tax practitioners tend to practise ethical decision-making in a high UAV culture.

Originality/value

This study fills a gap in the literature in regard to the influence of culture on tax compliance particularly among tax practitioners in Malaysia. The study shows how culture is related to the decision-making practices of tax practitioners while performing their role as an intermediary between their clients and the government. It is worthwhile to examine the decision-making of tax practitioners because the results of such an examination not only provide some insights into the professional practices of accountants that will be of interest to the relevant authorities such as the Malaysian Institute of Accountants, they also offer some information that will be of assistance to higher learning institutions in formulating accounting programmes to produce the future generation of accountants.