bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced heart sound analysis as a new prognostic marker in stable coronary artery disease
Authors: Winther Simon , Nissen Louise , Schmidt Samuel Emil , Westra Jelmer , Andersen Ina Trolle , Nyegaard Mette , Madsen Lene Helleskov , Knudsen Lars Lyhne , Urbonaviciene Grazina , Larsen Bjarke Skogstad , Struijk Johannes Jan , Frost Lars , Holm Niels Ramsing , Christiansen Evald Høj , Bøtker Hans Erik , Bøttcher Morten
Published: March 2021

Aims

Recent technological advances enable diagnosing of obstructive coronary artery disease (CAD) from heart sound analysis with a high negative predictive value. However, the prognostic impact of this approach remains unknown. To investigate the prognostic value of heart sound analysis as two scores, the Acoustic-score and the CAD-score, in patients with suspected CAD which is treated according to standard of care.

Methods and results

Consecutive patients with angina symptoms referred for coronary computed tomography angiography (CTA) were enrolled. The Acoustic-score was developed from eight acoustic CAD-related features. This score was combined with risk factors to generate the CAD-score. A cut-off score >20 was pre-specified for both scores to indicate disease. If coronary CTA raised suspicion of obstructive CAD, patients were referred to invasive angiography and revascularized when indicated. Of 1675 enrolled patients, 1464 (87.4%) were included in this substudy. The combined primary endpoint was all-cause mortality and myocardial infarction (n = 26). Follow-up was 3.1 (2.7–3.4) years. Of patients with primary endpoints, the Acoustic-score was >20 in 25 (96%); the CAD-score was >20 in 22 (85%). In an unadjusted Cox analysis of the primary endpoints, the hazard ratio for scores >20 under current standard clinical care was 12.6 (1.7–93.2) for the Acoustic-score and 5.4 (1.9–15.7) for the CAD-score. The CAD-score contained prognostic information even after adjusting for lipid-lowering therapy initiation, stenosis at CTA, and early revascularization.

Conclusion

Heart sound analysis seems to carry prognostic information and may improve initial risk stratification of patients with suspected CAD.

Clinicaltrials.org ID

NCT02264717.
Area-level indicators of income and total mortality during the COVID-19 pandemic
Authors: Colombo Fabio Riccardo , Alicandro Gianfranco , La Vecchia Carlo
Published: March 2021

Background

There is mounting evidence that socioeconomic inequalities in mortality have widened during the COVID-19 pandemic. This study aimed at evaluating the relationship between area-level indicators of income and total mortality during the first phase of COVID-19 pandemic in the most hit Italian region.

Methods

We conducted an ecological study based on the number of deaths registered in the municipalities of the Lombardy region (Italy) between January 2019 and June 2020. Municipalities were grouped according to quintiles of average income and pension of their resident population. Monthly age-standardized mortality ratios (MRs) between the poorest and the richest municipalities and the corresponding 95% CI were computed to evaluate whether the pre-existing socioeconomic inequalities widened during the pandemic.

Results

Over the study period, 175 853 deaths were registered. During the pre-pandemic period (January 2019 to February 2020) the MR between the poorest and the richest municipalities ranged between 1.12 (95% CI: 1.00–1.25) and 1.33 (95% CI: 1.20–1.47). In March 2020, when the pandemic began to rapidly spread in the region, it raised up to 1.61 (95% CI: 1.51–1.72) and decreased thereafter, reaching the pre-pandemic values in April 2020. Similar results were observed in the analysis of the mortality at ages 65 and over in municipalities grouped according to average pension, where the MR increased up to 1.82 (95% CI: 1.70–1.94) in March 2020.

Conclusions

The socioeconomic inequalities in mortality widened in Lombardy, the Italian region most severely hit during the first phase of the COVID-19 pandemic.
Factors influencing the biodiversity of three microbial groups within and among islands of the Baltic Sea
Authors: Teittinen Anette , Virta Leena , Li Mingjia , Wang Jianjun
Published: March 2021

Islands provide ideal model systems to examine the factors influencing biodiversity, yet knowledge of microbial biodiversity on islands remains scarce. We collected a dataset from 101 rock pools along a freshwater to brackish water transition on islands of the Baltic Sea and investigated the patterns and drivers of community composition and species richness of diatoms, cyanobacteria and non-cyanobacteria bacteria among islands. We also examined whether environmental heterogeneity increased beta diversity and species richness within islands. Among islands, the patterns in community composition were concordant among the microbial groups, with distinct changes along the freshwater–brackish gradient. The patterns in species richness were context-dependent for each microbial group. In general, richness patterns were most strongly associated with nutrient concentrations or the distances to potential sources of immigrants, whereas no positive relationships between ecosystem size and richness were found. Within islands, environmental heterogeneity was positively correlated with the beta diversity of each microbial group, but not species richness. Our findings provide novel insights into the factors influencing microbial biodiversity. The results suggest that island microbial biodiversity patterns are influenced by species sorting and dispersal-related mechanisms and highlight the importance of environmental heterogeneity for beta diversity.
Genomic plasticity and antibody response of Bordetella bronchiseptica strain HT200, a natural variant from a thermal spring
Authors: Badhai Jhasketan , Das Subrata K
Published: March 2021

Classical Bordetella species are primarily isolated from animals and humans causing asymptomatic infection to lethal pneumonia. However, isolation of these bacteria from any extra-host environmental niche has not been reported so far. Here, we have characterized the genomic plasticity and antibody response of Bordetella bronchiseptica strain HT200, isolated from a thermal spring. Genomic ANI value and SNPs-based phylogenetic tree suggest a divergent evolution of strain HT200 from a human-adapted lineage of B. bronchiseptica. Growth and survivability assay showed strain HT200 retained viability for more than 5 weeks in the filter-sterilized spring water. In addition, genes or loci encoding the Bordetella virulence factors such as DNT, ACT and LPS O-antigen were absent in strain HT200, while genes encoding other virulence factors were highly divergent. Phenotypically, strain HT200 was non-hemolytic and showed weak hemagglutination activity, but was able to colonize in the respiratory organs of mice. Further, both infection and vaccination with strain HT200 induced protective antibody response in mouse against challenge infection with virulent B. bronchiseptica strain RB50. In addition, genome of strain HT200 (DSM 26023) showed presence of accessory genes and operons encoding predicted metabolic functions pertinent to the ecological conditions of the thermal spring.
Artificial Intelligence and Unfair Competition – Unveiling an Underestimated Building Block of the AI Regulation Landscape
Authors: Scheuerer Stefan
Published: March 2021

The article illustrates the underestimated role unfair competition law (UCL) can play as a building block of the regulatory landscape relating to artificial intelligence (AI). To this end, it examines to what extent overarching, prominent principles of AI regulation such as fairness, transparency, autonomy and innovation are reflected in paradigms of UCL, and on this basis evaluates how the latter can contribute to the realisation of the former. In this way, prominent problems raised by AI that are commonly discussed under different legal regimes are reconsidered from a UCL perspective, showing that this perspective may complement or even substitute traditional regulatory approaches. Finally, the article indicates how AI could inversely give an impulse to the doctrinal advancement of UCL as a still ambiguous and insufficiently understood body of law.
The paradoxical effect of prior operating experience and observational learning on new market entry
Authors: Terlaak Ann , Kim June Young
Published: March 2021

We study how prior operating experience interacts with observational learning to exert paradoxical effects on market entry. When a new market disrupts a firm’s standing routines, greater operating experience with these routines complicates adaptation and increases the firm’s uncertainty about the feasibility of entering, thereby delaying its entry. Yet, this entry uncertainty simultaneously prompts the firm to rely more heavily on learning from the observation of others entering which, in turn, hastens its entry. Patterns are opposite for firms that can leverage their standing routines into the new market. Here, greater operating experience and resultant momentum to extrapolate existing routines reduce a firm’s uncertainty about the feasibility of entry. This directly accelerates their entry but also diminishes the indirect, accelerating influence of observational learning. Because of these opposite dynamics, entry rates between firms with these different types of prior operating experience begin to diminish. Empirical analysis of entry patterns into the deregulation-created electric power trading market supports our theory and calls for modifications to previous expectations of prior operating experience exerting either a purely delaying or accelerating effect on entry, and, further, draws attention to the indirect pathways through which prior experience shapes entry patterns.
Technological regimes, patent growth, and catching-up in green technologies
Authors: Corrocher Nicoletta , Malerba Franco , Morrison Andrea
Published: March 2021

This article explores how the components of the technological regime affect catching-up and leadership change in green technologies in countries that are leaders and successful latecomers. We look at the extent to which technological opportunity, cumulativeness, originality and complexity of the knowledge base, and the maturity of technology contribute to the growth of patenting in green technologies. We test the relationships using USPTO patent data in green technologies over a 40-year time span (1975–2015), distinguishing two periods (1975–1999 and 2000–2015) and controlling for country-specific variables. Our results show that opportunity, complexity, originality, and maturity of the technology are positively associated with countries’ growth of patenting in green technologies, while cumulativeness has a negative effect, but only in the second period (2000–2015). The stock of knowledge has a positive effect in the first period and a negative effect in the second one. Furthermore, we find confirmation that the process of growth in green patenting has been remarkable in successful latecomer countries (i.e., South Korea, Taiwan, and China).
SC5005 dissipates the membrane potential to kill Staphylococcus aureus persisters without detectable resistance
Authors: Lu Chieh-Hsien , Shiau Chung-Wai , Chang Yung-Chi , Kung Hsiu-Ni , Wu Jui-Ching , Lim Chui-Hian , Yeo Hui-Hui , Chang Han-Chu , Chien Han-Sheng , Huang Sheng-Hsuan , Hung Wei-Kang , Wei Jun-Rong , Chiu Hao-Chieh
Published: March 2021

Objectives

In the past few decades, multiple-antibiotic-resistant Staphylococcus aureus has emerged and quickly spread in hospitals and communities worldwide. Additionally, the formation of antibiotic-tolerant persisters and biofilms further reduces treatment efficacy. Previously, we identified a sorafenib derivative, SC5005, with bactericidal activity against MRSA in vitro and in vivo. Here, we sought to elucidate the resistance status, mode of action and anti-persister activity of this compound.

Methods

The propensity of S. aureus to develop SC5005 resistance was evaluated by assessment of spontaneous resistance and by multi-passage selection. The mode of action of SC5005 was investigated using macromolecular synthesis, LIVE/DEAD and ATPlite assays and DiOC2(3) staining. The effect of SC5005 on the mammalian cytoplasmic membrane was measured using haemolytic and lactate dehydrogenase (LDH) assays and flow cytometry.

Results

SC5005 depolarized and permeabilized the bacterial cytoplasmic membrane, leading to reduced ATP production. Because of this mode of action, no resistance of S. aureus to SC5005 was observed after constant exposure to sub-lethal concentrations for 200 passages. The membrane-perturbing activity of SC5005 was specific to bacteria, as no significant haemolysis or release of LDH from human HT-29 cells was detected. Additionally, compared with other bactericidal antibiotics, SC5005 exhibited superior activity in eradicating both planktonic and biofilm-embedded S. aureus persisters.

Conclusions

Because of its low propensity for resistance development and potent persister-eradicating activity, SC5005 is a promising lead compound for developing new therapies for biofilm-related infections caused by S. aureus.
Energy and the TRIMs and GATS agreements
Authors: Zedalis Rex J
Published: March 2021

The international energy sector has always involved a wide range of activities, with energy mineral extraction residing at its core. Technological advancements and job specialisation have resulted in segmentation within the industry as traditionally conceived. With sensitivity to the relationship between energy use and climate change, the growth of interest in renewable energy sources have further contributed to segmentation within the industry. Thus, when writ large, the international energy sector has become increasingly subject to certain WTO rules governing trade-related investment measures and generally agreed rules governing trade in services, Central obligations found in these rules are examined in this commentary and analysed in the context of three hypothetical situations, all with an eye towards an increasing understanding of what relevant countries hosting efforts by the international energy sector may and may not do to affect the sector.
Artificial selection for grain yield has increased net CO2 exchange of the ear leaf in maize crops
Authors: Cagnola Juan I , Parco Martín , Rotili Diego H , Ploschuk Edmundo L , Curin Facundo , Amas Juan I , Luque Sergio F , Maddonni Gustavo A , Otegui María E , Casal Jorge J
Published: March 2021

Identifying the physiological traits indirectly selected during the search for high-yielding maize hybrids is useful for guiding further improvements. To investigate such traits, in this study we focused on the critical period of kernel formation because kernel number is the main yield component affected by breeding. Our results show that breeding has increased the number of florets per ear and ear growth rate but not the vegetative shoot growth rate, suggesting localised effects around the ear. Consistent with this possibility, breeding has increased the net CO2 exchange of the ear leaf in field-grown crops grown at high population densities. This response is largely accounted for by increased light interception (which increases photosynthesis) and by reduced rates of respiration of the ear leaf in modern hybrids compared to older ones. Modern hybrids show increased ear-leaf area per unit leaf dry matter (specific leaf area), which accounts for the reduced respiratory load per unit leaf area. These observations are consistent with a model where the improved ear leaf CO2 exchange helps the additional florets produced by modern hybrids to survive the critical period of high susceptibility to stress and hence to produce kernels.
Adjusting plant nutrient acquisition to fluctuating availability: transcriptional co-regulation of the nitrate and phosphate deprivation responses in roots
Authors: Ludewig Uwe , Vatov Emil , Hedderich Dominik , Neuhäuser Benjamin
Published: March 2021

This article comments on:

Safi A, Medici A, Szponarski W, Martin F, Clement-Vidal A, Marshall-Colon A, Ruffel S, Gaymard F, Rouached H, Leclercq J, Coruzzi G, Lacombe B, Krouk G. 2021. GARP transcription factors repress Arabidopsis nitrogen starvation response via ROS-dependent and -independent pathways. Journal of Experimental Botany 72, 3881–3901.
Phosphorolytic degradation of leaf starch via plastidic α-glucan phosphorylase leads to optimized plant growth and water use efficiency over the diel phases of Crassulacean acid metabolism
Authors: Ceusters Nathalie , Ceusters Johan , Hurtado-Castano Natalia , Dever Louisa V , Boxall Susanna F , Kneřová Jana , Waller Jade L , Rodick Rebecca , Van den Ende Wim , Hartwell James , Borland Anne M
Published: March 2021

In plants with Crassulacean acid metabolism (CAM), it has been proposed that the requirement for nocturnal provision of phosphoenolpyruvate as a substrate for CO2 uptake has resulted in a re-routing of chloroplastic starch degradation from the amylolytic route to the phosphorolytic route. To test this hypothesis, we generated and characterized four independent RNAi lines of the obligate CAM species Kalanchoë fedtschenkoi with a >10-fold reduction in transcript abundance of plastidic α-glucan phosphorylase (PHS1). The rPHS1 lines showed diminished nocturnal starch degradation, reduced dark CO2 uptake, a reduction in diel water use efficiency (WUE), and an overall reduction in growth. A re-routing of starch degradation via the hydrolytic/amylolytic pathway was indicated by hyperaccumulation of maltose in all rPHS1 lines. Further examination indicated that whilst operation of the core circadian clock was not compromised, plasticity in modulating net dark CO2 uptake in response to changing photoperiods was curtailed. The data show that phosphorolytic starch degradation is critical for efficient operation of the CAM cycle and for optimizing WUE. This finding has clear relevance for ongoing efforts to engineer CAM into non-CAM species as a means of boosting crop WUE for a warmer, drier future.
Constraints on wide-band radiative changes after a glitch in PSR J1452–6036
Authors: Jankowski F , Keane E F , Stappers B W
Published: March 2021

We present high-sensitivity, wide-band observations (704–4032 MHz) of the young to middle-aged radio pulsar J1452–6036, taken at multiple epochs before and, serendipitously, shortly after a glitch occurred on 2019 April 27. We obtained the data using the new ultra-wide-bandwidth low-frequency (UWL) receiver at the Parkes radio telescope, and we used Markov chain Monte Carlo techniques to estimate the glitch parameters robustly. The data from our third observing session began 3 h after the best-fitting glitch epoch, which we constrained to within ∼4 min. The glitch was of intermediate size, with a fractional change in spin frequency of 270.52(3) × 10−9. We measured no significant change in spin-down rate and found no evidence for rapidly decaying glitch components. We systematically investigated whether the glitch affected any radiative parameters of the pulsar and found that its spectral index, spectral shape, polarization fractions, and rotation measure stayed constant within the uncertainties across the glitch epoch. However, its pulse-averaged flux density increased significantly by about 10 per cent in the post-glitch epoch and decayed slightly before our fourth observation a day later. We show that the increase was unlikely caused by calibration issues. While we cannot exclude that it was due to refractive interstellar scintillation, it is hard to reconcile with refractive effects. The chance coincidence probability of the flux density increase and the glitch event is low. Finally, we present the evolution of the pulsar’s pulse profile across the band. The morphology of its polarimetric pulse profile stayed unaffected to a precision of better than 2 per cent.
Exploring a Local Genetic Interaction Network Using Evolutionary Replay Experiments
Authors: Vignogna Ryan C , Buskirk Sean W , Lang Gregory I
Published: March 2021

Understanding how genes interact is a central challenge in biology. Experimental evolution provides a useful, but underutilized, tool for identifying genetic interactions, particularly those that involve non-loss-of-function mutations or mutations in essential genes. We previously identified a strong positive genetic interaction between specific mutations in KEL1 (P344T) and HSL7 (A695fs) that arose in an experimentally evolved Saccharomyces cerevisiae population. Because this genetic interaction is not phenocopied by gene deletion, it was previously unknown. Using “evolutionary replay” experiments, we identified additional mutations that have positive genetic interactions with the kel1-P344T mutation. We replayed the evolution of this population 672 times from six timepoints. We identified 30 populations where the kel1-P344T mutation reached high frequency. We performed whole-genome sequencing on these populations to identify genes in which mutations arose specifically in the kel1-P344T background. We reconstructed mutations in the ancestral and kel1-P344T backgrounds to validate positive genetic interactions. We identify several genetic interactors with KEL1, we validate these interactions by reconstruction experiments, and we show these interactions are not recapitulated by loss-of-function mutations. Our results demonstrate the power of experimental evolution to identify genetic interactions that are positive, allele specific, and not readily detected by other methods, shedding light on an underexplored region of the yeast genetic interaction network.
DNA molecular combing-based replication fork directionality profiling
Authors: Blin Marion , Lacroix Laurent , Petryk Nataliya , Jaszczyszyn Yan , Chen Chun-Long , Hyrien Olivier , Le Tallec Benoît
Published: March 2021

The replication strategy of metazoan genomes is still unclear, mainly because definitive maps of replication origins are missing. High-throughput methods are based on population average and thus may exclusively identify efficient initiation sites, whereas inefficient origins go undetected. Single-molecule analyses of specific loci can detect both common and rare initiation events along the targeted regions. However, these usually concentrate on positioning individual events, which only gives an overview of the replication dynamics. Here, we computed the replication fork directionality (RFD) profiles of two large genes in different transcriptional states in chicken DT40 cells, namely untranscribed and transcribed DMD and CCSER1 expressed at WT levels or overexpressed, by aggregating hundreds of oriented replication tracks detected on individual DNA fibres stretched by molecular combing. These profiles reconstituted RFD domains composed of zones of initiation flanking a zone of termination originally observed in mammalian genomes and were highly consistent with independent population-averaging profiles generated by Okazaki fragment sequencing. Importantly, we demonstrate that inefficient origins do not appear as detectable RFD shifts, explaining why dispersed initiation has remained invisible to population-based assays. Our method can both generate quantitative profiles and identify discrete events, thereby constituting a comprehensive approach to study metazoan genome replication.
Randomized multi-reader evaluation of automated detection and segmentation of brain tumors in stereotactic radiosurgery with deep neural networks
Authors: Lu Shao-Lun , Xiao Fu-Ren , Cheng Jason Chia-Hsien , Yang Wen-Chi , Cheng Yueh-Hung , Chang Yu-Cheng , Lin Jhih-Yuan , Liang Chih-Hung , Lu Jen-Tang , Chen Ya-Fang , Hsu Feng-Ming
Published: March 2021

Background

Stereotactic radiosurgery (SRS), a validated treatment for brain tumors, requires accurate tumor contouring. This manual segmentation process is time-consuming and prone to substantial inter-practitioner variability. Artificial intelligence (AI) with deep neural networks have increasingly been proposed for use in lesion detection and segmentation but have seldom been validated in a clinical setting.

Methods

We conducted a randomized, cross-modal, multi-reader, multispecialty, multi-case study to evaluate the impact of AI assistance on brain tumor SRS. A state-of-the-art auto-contouring algorithm built on multi-modality imaging and ensemble neural networks was integrated into the clinical workflow. Nine medical professionals contoured the same case series in two reader modes (assisted or unassisted) with a memory washout period of 6 weeks between each section. The case series consisted of 10 algorithm-unseen cases, including five cases of brain metastases, three of meningiomas, and two of acoustic neuromas. Among the nine readers, three experienced experts determined the ground truths of tumor contours.

Results

With the AI assistance, the inter-reader agreement significantly increased (Dice similarity coefficient [DSC] from 0.86 to 0.90, P < 0.001). Algorithm-assisted physicians demonstrated a higher sensitivity for lesion detection than unassisted physicians (91.3% vs 82.6%, P = .030). AI assistance improved contouring accuracy, with an average increase in DSC of 0.028, especially for physicians with less SRS experience (average DSC from 0.847 to 0.865, P = .002). In addition, AI assistance improved efficiency with a median of 30.8% time-saving. Less-experienced clinicians gained prominent improvement on contouring accuracy but less benefit in reduction of working hours. By contrast, SRS specialists had a relatively minor advantage in DSC, but greater time-saving with the aid of AI.

Conclusions

Deep learning neural networks can be optimally utilized to improve accuracy and efﬁciency for the clinical workflow in brain tumor SRS.
Adverse Events in Neurosurgery: The Novel Therapy-Disability-Neurology Grade
Authors: Terrapon Alexis Paul Romain , Zattra Costanza Maria , Voglis Stefanos , Velz Julia , Vasella Flavio , Akeret Kevin , Held Ulrike , Schiavolin Silvia , Bozinov Oliver , Ferroli Paolo , Broggi Morgan , Sarnthein Johannes , Regli Luca , Neidert Marian Christoph
Published: March 2021

BACKGROUND

The most widely used classifications of adverse events (AEs) in neurosurgery define their severity according to the therapy used to treat them. This concept has substantial shortcomings because it does not reflect the severity of AEs that are not treated, such as new neurological deficits.

OBJECTIVE

To present a novel multidimensional and patient-centered classification of the severity of AE in neurosurgery and evaluate its applicability.

METHODS

The Therapy-Disability-Neurology (TDN) grading system classifies AEs depending on the associated therapy, disability, and neurological deficits. We conducted a 2-center retrospective observational study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between 2013 and 2019 at 2 institutions from 2 countries.

RESULTS

Using the first patient cohort (4680 interventions), a positive correlation was found between severity of AE and LOS as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. When using the same methods on the external validation cohort (1391 interventions), correlations between the grades of AE, LOS, and KPS at discharge were even more pronounced.

CONCLUSION

Our results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is easily interpreted and enables comparison between different medical centers. The standardized report of the severity of AE in the scientific literature could constitute an important step forward toward a more critical, patient-centered, and evidence-based decision-making in neurosurgery.
Making Milton’s Bogey
Authors: Dodds Lara
Published: March 2021

In The Madwoman in the Attic: The Woman Writer and the Nineteenth-Century Literary Imagination (1979), Gilbert and Gubar posit Milton and Paradise Lost as a ‘bogey’ for women writers. Wittreich’s Feminist Milton (1987) suggests an alternative reception history in which Milton’s poetry provided the basis for a more inclusive literary canon. This chapter re-examines the question of the relationship between Milton’s poetry, primarily Paradise Lost, and women’s literary history through a case study of the poetry of Anne Finch, Countess of Winchilsea (1661–1720). Though Finch acknowledges Milton’s influence explicitly in her blank-verse pastoral ‘Fanscomb Barn’, implicit debts are present throughout Finch’s 1713 Miscellany Poems and the fair-copy manuscript compilation ‘Miscellany Poems with Two Plays by Ardelia’ (1691–1701). The very different status of Milton and his verse in these two contexts illustrates the conflicted legacy of Paradise Lost for women’s literary history.
Clinical use of Jak 1 inhibitors for rheumatoid arthritis
Authors: Nash Peter
Published: March 2021

The uptake of Jak inhibitors in the RA space has been among the most rapid in rheumatology, based on the results of comprehensive clinical trial programmes of five agents. Newer generations of Jak inhibitors, like upadacitinib and filgotinib, target Jak 1 selectively with the aim of maximizing efficacy and to improve safety. This article will review the clinical significance of evidence on: (i) Jak 1 selectivity; (ii) efficacy from the SELECT and FINCH clinical trial programmes including patient intolerant or inadequately responding to MTX (MTX-IR) and other csDMARDs patients who are bDMARD-IR) and those using monotherapy when MTX is not tolerated or contraindicated and those treated when methotrexate naive; and (iii) safety from the clinical trial programmes of these two agents will be discussed.
How Heads of Departments Find It Meaningful to Engage with Gender Balance Policies
Authors: Lagesen Vivian Anette
Published: March 2021

This article investigates how heads of department (HoDs) understand and implement gender balance policies in Norway, considered to be among the most gender-equal countries in the world. Previous studies have found that HoDs often resist enacting gender equality policies. This interview-based study provides a more optimistic and nuanced picture. Employing domestication theory and narrative analysis, this study shows that HoDs understand gender balance as an important goal and responsibility in principle. However, to actively engage with implementation, HoDs needed to see how improving gender balance would benefit their departments and help reach other goals. This sense-making was pivotal for motivation to enact measures and change their practices. The article brings new knowledge on how HoDs may work to improve the gender balance among faculty and generates deeper insight into the critical co-production of sense-making and enactment of practices related to improving gender balance.
‘A British Problem Affecting British People’: Sickle Cell Anaemia, Medical Activism and Race in the National Health Service, 1975–1993
Authors: Redhead Grace
Published: March 2021

Recent historiography has explored a contradiction at the heart of the British welfare state—it was founded on and supported by migrant and non-white labour, whose own healthcare and broader welfare state entitlements were neglected. This article explores how this contradiction was exposed and challenged by some of the health service’s own workforce, who witnessed and contested racism in the National Health Service (NHS). This is discussed through the lens of the treatment of sickle cell anaemia (SCA), a genetic trait and disease more common in people of African, South Asian, Middle Eastern and Mediterranean descent, which has been highly racialized as affecting black people in particular. By pushing for improved responses to pain in sickle cell disease, and demonstrating the need for SCA screening in urban areas, healthcare professionals within the NHS—many of whom were black or migrant nurses, health visitors or doctors—articulated the status and entitlements of Black British citizenship.
Investigation Into the Role of ERK in Tyrosine Kinase Inhibitor-Induced Neuropathy
Authors: Belair David G , Sudak Katelyn , Connelly Kimberly , Collins Nathaniel D , Kopytek Stephan J , Kolaja Kyle L
Published: March 2021

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse event that can alter patient treatment options and halt candidate drug development. A case study is presented here describing the preclinical and clinical development of CC-90003, a small molecule extracellular signal-regulated kinase (ERK)1/2 inhibitor investigated as an oncology therapy. In a Phase Ia clinical trial, CC-90003 elicited adverse drug-related neuropathy and neurotoxicity that contributed to discontinued development of CC-90003 for oncology therapy. Preclinical evaluation of CC-90003 in dogs revealed clinical signs and electrophysiological changes consistent with peripheral neuropathy that was reversible. Mice did not exhibit signs of neuropathy upon daily dosing with CC-90003, supporting that rodents generally poorly predict CIPN. We sought to investigate the mechanism of CC-90003-induced peripheral neuropathy using a phenotypic in vitro assay. Translating preclinical neuropathy findings to humans proves challenging as no robust in vitro models of CIPN exist. An approach was taken to examine the influence of CIPN-associated drugs on human-induced pluripotent stem cell-derived peripheral neuron (hiPSC-PN) electrophysiology on multielectrode arrays (MEAs). The MEA assay with hiPSC-PNs was sensitive to CIPN-associated drugs cisplatin, sunitinib, colchicine, and importantly, to CC-90003 in concordance with clinical neuropathy incidence. Biochemical data together with in vitro MEA data for CC-90003 and 12 of its structural analogs, all having similar ERK inhibitory activity, revealed that CC-90003 disrupted in vitro neuronal electrophysiology likely via on-target ERK inhibition combined with off-target kinase inhibition and translocator protein inhibition. This approach could prove useful for assessing CIPN risk and interrogating mechanisms of drug-induced neuropathy.
Reimagining “Defeat” in the Transnational West: John Newman Edwards, Mexican Exile, and the Confederate Experiment 2.0
Authors: Hulbert Matthew Christopher
Published: March 2021

Rather than surrendering to Union forces in 1865, various bands of ex-Confederates chose Mexican exile. From generals and elite politicians to rank-and-file soldiers, the majority of these “Confederados” journeyed to French-controlled Mexico to escape punishment, to tap financial opportunities, and to observe how southern society would function post-emancipation. Still others, as represented by the cavalry officer and Quixotic newspaper editor John Newman Edwards, understood the U.S. Civil War on more international terms. To these men, Mexico constituted a new, imperially subsidized laboratory to continue the Confederate Experiment and recreate a mythic version of the Old South. Although cut short by the violent death of Emperor Maximilian I, their saga reveals not only how adaptation to Confederate defeat took different forms in the immediate postbellum period, but also the extent to which conceptions of defeat and even the purpose of the Confederacy itself had never been monolithic in the first place.
Eosinophilic asthma and the role of monoclonal antibodies
Authors: Jarrell Lynda
Published: March 2021

Eosinophilic asthma presents with continuous airway inflammation resistant to inhaled corticosteroids but responsive to oral glucocorticoids and monoclonal antibodies. Diagnostic criteria include significantly elevated blood or sputum eosinophils and/or fractional exhaled nitric oxide. Five monoclonal antibodies are used for treatment, with accurate diagnosis and early intervention essential to better outcomes.
Analysis of the concise etiology of pleural effusion in 3707 pediatric patients in a single clinical center
Authors: Wang Gang , Wang Yi , Wu Chun , Pan Zhengxia , Wang Junke , Wu Yuhao , Wang Quan , Li Yonggang , Dai Jiangtao
Published: March 2021

Purpose:

To summarize the concise etiology of pleural effusion in 3707 patients over a period of 13 years at the Children’s Hospital of Chongqing Medical University.

Methods:

A total of 3707 patients with pleural effusion were included from January 2007 to December 2019 at our hospital. According to etiology, pleural effusion was divided into infectious pleural effusion and noninfectious pleural effusion. The infection factors were further subdivided as being caused by tuberculous, paragonimiasis, parapneumonic factors (including multiple bacterias, multiple viruses, mycoplasma, chlamydia, chlamydia, fungus and fever, blood routine examination shows increased white blood cells and neutrophils). The noninfectious factors were further subdivided into neoplastic, trauma, other causes. They were also divided into the infants and young children group (3 y and below), the preschool group (3–6 y) and the school-age group (above 6 y) depending on age.

Results:

Among the 3707 children, there were 2925 (78.9%) patients with infectious pleural effusions, and 782 (21.1%) patients with noninfectious pleural effusions. The incidence of infectious pleural effusions caused by parapneumonic factors decreased significantly with increasing age; however, parapneumonic factors remained the primary etiology of infectious pleural effusion in each group. The incidence of infectious pleural effusions caused by tuberculosis and paragonimiasis increased significantly with increasing of age. Tumor was the primary cause of noninfectious pleural effusion. The incidence of noninfectious pleural effusion caused by tumor and other causes increased significantly with increasing age. The incidence of noninfectious pleural effusion caused by trauma in the preschool group was significantly greater than that of the infants and young children group and school-age group. The number of noninfectious pleural effusion caused by other causes in the school-age group were significantly greater than those of in the infants and young children group and preschool group.

Conclusion:

In our center, pediatric pleural effusion was primarily caused by infections. parapneumonic factors were the primary causes of infectious pleural effusions. The proportion of noninfective pleural effusions in the etiology of pleural effusion in children was small; however, some were difficult to treat, requiring long-term treatment and possibly poor prognosis. Therefore, multidisciplinary treatment should be combined.
Association of equol with obesity in postmenopausal women
Authors: Takahashi Atsushi , Anzai Yukio , Tanji Nobuo , Imaizumi Hiromichi , Fujita Masashi , Hayashi Manabu , Abe Kazumichi , Ohira Hiromasa
Published: March 2021

Objective:

Equol, which is an active metabolite of isoflavone, has a beneficial impact on metabolic diseases such as dyslipidemia and hyperglycemia. However, the effect of equol on obesity remains uncertain. This study was performed to determine the association between equol and obesity in postmenopausal women.

Methods:

We evaluated 386 women in their 50s-60s who underwent health check-ups from February 2018 to January 2019 at Watari Hospital Health Center in Fukushima, Japan. Overweight and visceral obesity were defined as a body mass index ≥25 kg/m2 and waist circumference ≥ 90 cm, respectively. Participants were asked to complete a questionnaire about their ordinary lifestyle. Participants were defined as equol producers when urinary equol level was 1.0 μM or more. The proportion of individuals with obesity (overweight and visceral obesity) and lifestyle factors were compared between equol producers and nonproducers. In addition, the association between equol and obesity was examined using logistic regression analysis with adjustment for lifestyle factors.

Results:

Of the 386 participants, 106 (27.5%) women were equol producers. The proportions of women who were overweight (13.2% vs 25.7%) and had visceral obesity (6.6% vs 20.7%) were significantly lower in the equol-producing group than in the nonproducing group. Multivariable logistic regression analysis showed that equol production was significantly associated with overweight (odds ratio =0.47, 95% confidence interval: 0.25-0.88) and visceral obesity (odds ratio =0.30, 95% confidence interval: 0.13-0.68).

Conclusions:

Equol is significantly associated with obesity in postmenopausal women.

Video Summary:
http://links.lww.com/MENO/A727.
Momentary pain assessments reveal benefits of endoscopic discectomy: a prospective cohort study
Authors: Wakaizumi Kenta , Wu Binbin , Huang Shishi , Fan Linyu , Shen Bangli , Wu Bo , Zhang Jing , Baliki Marwan N. , Apkarian A. Vania , Huang Lejian
Published: March 2021

Introduction:

Lumbar disc herniation (LDH) is a common back disorder that evokes back and/or leg pain. Percutaneous endoscopic lumbar discectomy (PELD) is a minimally invasive surgery for patients with LDH. However, there is little evidence of effectiveness of PELD compared with conservative treatments.

Objective:

The goal of this study was to quantify the efficacy of PELD compared with conservative treatments.

Methods:

Here, we conducted a prospective observational cohort study using momentary pain assessments via a smartphone app during 3 months following surgery. The trajectories of daily ecological momentary pain assessments were fitted with an exponential model containing two parameters: a pain reduction coefficient and the percentage of persistent pain. To control for selection bias between PELD and Conservative groups (N = 167 and 34), we used inverse probability (IP) of treatment weighting for statistical comparisons.

Results:

Compared with conservative treatments, both momentary pain rating and the exponential model showed statistically significant pain recovery following PELD (p < 0.001). In addition, PELD had a faster pain recovery rate (hazard ratio (95% confidence interval): 1.75 (1.40, 2.20), p < 0.001), greater overall pain recovery rate (odds ratio (95%CI): 2.35 (2.01, 5.26), p < 0.001), faster pain reduction (t199 = 3.32, p = 0.001), and lower estimated persistent pain (Z = 2.53, p = 0.011). Greater pain intensity and lower anxiety before the surgery were predictors of faster pain reduction in the recovery subgroup following PELD.

Conclusions:

In conclusion, momentary pain rating and the model fitting revealed that PELD provided rapid pain recovery that lasted for at least three months. Greater pain intensity and lower anxiety before the surgery were predictors of faster pain reduction in the recovery subgroup following PELD. Daily momentary pain rating on a smartphone may be able to provide more informative data to evaluate effect of an intervention than pain assessment on hospital visits.
Application of error-prone PCR to functionally probe the morbillivirus Haemagglutinin protein
Authors: Gallo Giulia , Conceicao Carina , Tsirigoti Christina , Willett Brian , Graham Stephen C , Bailey Dalan
Published: March 2021

The enveloped morbilliviruses utilise conserved proteinaceous receptors to enter host cells: SLAMF1 or Nectin-4. Receptor binding is initiated by the viral attachment protein Haemagglutinin (H), with the viral Fusion protein (F) driving membrane fusion. Crystal structures of the prototypic morbillivirus measles virus H with either SLAMF1 or Nectin-4 are available and have served as the basis for improved understanding of this interaction. However, whether these interactions remain conserved throughout the morbillivirus genus requires further characterisation. Using a random mutagenesis approach, based on error-prone PCR, we targeted the putative receptor binding site for SLAMF1 interaction on peste des petits ruminants virus (PPRV) H, identifying mutations that inhibited virus-induced cell-cell fusion. These data, combined with structural modelling of the PPRV H and ovine SLAMF1 interaction, indicate this region is functionally conserved across all morbilliviruses. Error-prone PCR provides a powerful tool for functionally characterising functional domains within viral proteins.
Genomic and Chemical Diversity of Commercially Available Industrial Hemp Accessions
Authors: Johnson Matthew S. , Wallace Jason G.
Published: March 2021

High consumer demand for cannabidiol (CBD) has made industrial hemp (Cannabis sativa) an extremely high-value crop. However, high demand has resulted in the industry developing faster than the research, resulting in the sale of many hemp accessions with inconsistent performance and chemical profiles. To determine the genetic and phenotypic consistency in available CBD hemp varieties, we obtained seed or clones from 22 different named accessions. Genotypes (~48,000 SNPs) and chemical profiles (% CBD and THC by dry weight) were determined for up to 8 plants per accession. Many accessions--including several with the same name--showed little consistency either genetically or chemically. Most seed-grown accessions deviated significantly from their purported levels of CBD and THC based on the supplied certificates of analysis. Several also showed evidence of an active tetrahydrocannabinolic acid (THCa) synthase gene, leading to unacceptably high levels of THC in female flowers. We conclude that the current market for CBD-hemp varieties is highly unreliable, making many purchases risky for growers. We suggest options for addressing these issues, such using unique names and developing seed and plant certification programs to ensure the availability of high-quality, verified planting materials.
Peer presence increases adolescents’ prosocial behavior by speeding the evaluation of rewards for others
Authors: Sullivan Nicolette J. , Li Rosa , Huettel Scott A.
Published: March 2021

Peer presence can elicit maladaptive adolescent decision-making, potentially by increasing sensitivity to the rewards one receives. It remains unknown whether peer presence also increases adolescents’ sensitivity to others’ rewards, which could have an adaptive effect in contexts allowing pro-social behaviors. Here, we combine social utility modeling and real-time decision process modeling to characterize how peer presence alters adolescents’ processing of self and other rewards. We found that adolescents behaved selfishly when privately allocating rewards for themselves and a peer in an incentive-compatible task. In peer presence, however, adolescents became more altruistic. Real-time estimates of reward processing collected using computer mouse tracking showed that altruistic behavior was associated with relatively earlier processing of peer-rewards relative to self-rewards, such that peer presence sped peer-reward processing without altering self-reward processing. Our results indicate a causal mechanism through which peer presence prompts greater prosocial behavior by altering how adolescents process prosocial outcomes.
Dopamine and reward-related vigor in younger and older human participants
Authors: Hird E. J. , Beierholm U. , De Boer L. , Axelsson J. , Riklund K. , Nyberg L. , Beckman L. , Guitart-Masip M.
Published: March 2021

Vigor reflects how motivated one is to respond to a stimulus. We previously showed that humans are more vigorous when more reward is available on average, and that this relationship is modulated by the dopamine precursor levodopa. Dopamine signalling and probabilistic reward learning degrade with age, so the relationship between vigor and reward should change with age. We test this and assess whether the relationship between vigor and reward correlates with D1 dopamine receptor availability measured using Positron Emission Tomography. We measured response times of 30 older and 30 younger subjects during an oddball discrimination task where rewards varied systematically between trial. Reward rate had a similar impact on the vigor of both groups. We observed a weak positive association across subjects between ventral striatal dopamine receptor availability and effect of average reward rate on response time, which was in the opposite direction to our prediction. Overall, the effect of reward on response vigor is similar between younger and older humans and is weakly sensitive to dopamine D1 receptor availability.