bluuebunny/crossref_metadata_2025 huggingface dataset:
EMC3–EIRENE simulations of neon impurity seeding effects on heat flux distribution on CFETR
Authors: Dai S.Y. , Kong D.F. , Chan V.S. , Wang L. , Feng Y. , Wang D.Z.
Published: January 2022

The numerical modelling of the heat flux distribution with neon impurity seeding on China fusion engineering test reactor has been performed by the three-dimensional (3D) edge transport code EMC3–EIRENE. The maximum heat flux on divertor targets is about 18 MW m−2 without impurity seeding under the input power of 200 MW entering into the scrape-off layer. In order to mitigate the heat loads below 10 MW m−2, neon impurity seeded at different poloidal positions has been investigated to understand the properties of impurity concentration and heat load distributions for a single toroidal injection location. The majority of the studied neon injections gives rise to a toroidally asymmetric profile of heat load deposition on the in- or out-board divertor targets. The heat loads cannot be reduced below 10 MW m−2 along the whole torus for a single toroidal injection location. In order to achieve the heat load mitigation (<10 MW m−2) along the entire torus, modelling of sole and simultaneous multi-toroidal neon injections near the in- and out-board strike points has been stimulated, which indicates that the simultaneous multi-toroidal neon injections show a better heat flux mitigation on both in- and out-board divertor targets. The maximum heat flux can be reduced below 7 MW m−2 on divertor targets for the studied scenarios of the simultaneous multi-toroidal neon injections.
Generation of
E

×

B
flow shear by finite orbit width effects from heat sources in tokamaks
Authors: Kim S.S. , Ku S. , Jhang Hogun
Published: January 2022

We present a possible mechanism for the generation of strong
E
×
B
flow shear relevant to internal transport barrier formation in tokamak plasmas. From gyrokinetic calculations, we show that strong
E
×
B
flow shear can be generated by finite orbit width (FOW) effects associated with a non-uniform heat source and is sufficient to lead to transport barrier formation in the core region with a moderate power level. Two FOW effects inducing neoclassical polarization are shown to be responsible for this: (1) the radial drift of particle orbit center due to the variation of the heat source within orbit width and (2) the non-uniformly evolved orbit width by the non-uniform heating.
Simulations of liquid metal flows over plasma-facing component edges and application to beryllium melt events in JET
Authors: Vignitchouk L. , Ratynskaia S. , Pitts R. A. , Lehnen M. , JET Contributors
Published: January 2022

Navier–Stokes simulations of liquid beryllium (Be) flows over the straight edge of plasma-facing components are carried out in conditions emulating upper dump plate (UDP) melting observed experimentally in JET. The results demonstrate the existence of three main hydrodynamic regimes featuring various degrees of downstream flow attachment to the underlying solid surface. Transitions between these regimes are characterized by critical values of the Weber number, which quantifies the relative strength of fluid inertia and surface tension, thereby providing a general stability criterion that can be applied to any instance of transient melt events in fusion devices. The predictive capabilities of the model are tested by comparing numerical output with JET data regarding the morphology of the frozen melt layers and the location of Be droplets splashed onto nearby vacuum vessel surfaces as a result of disruption current quench plasmas interacting with the solid Be tiles protecting the upper main chamber regions. Simulations accounting for the coupling between fluid flow and heat transfer confirm the key role played by re-solidification as a stabilizing process, as previously found through macroscopic melt dynamics calculations performed with the MEMOS-U code. The favourable agreement found between the simulations and the general characteristics of the JET Be UDP melt splashing give confidence that the same approach can be applied to estimate the possibility of such mechanisms occurring during disruptions on ITER.
Strong coupling in two-dimensional materials-based nanostructures: a review
Authors: Qing Ye Ming , Ren Yongze , Lei Dangyuan , Ma Hui Feng , Cui Tie Jun
Published: January 2022

Strong interaction between electromagnetic radiation and matter leads to the formation of hybrid light-matter states, making a system’s absorption and emission properties distinctively different from that at the uncoupled states. For instance, strong coupling between cavity photons and quantum emitters results in the emergence of Rabi splitting andnew polaritonic eigenmodes, exhibiting characteristic spectral anticrossing and ultrafast energy exchange. There has recnetly been a rapidly increasing number of studies focusing on strong coupling between photonic nanostructures and two-dimensional materials (2DMs), demonstrating exceptional nanoscale optical properties and applications. Here, we review the recent advances and important developments of strong light-matter interactions in hybrid photonic systems based on 2DMs, including graphene, black phosphorus, and transition-metal dichalcogenides. We adopt the coupled oscillator model to describe the strong coupling phenomena and give an overview of three classes of 2DMs-based nanostructures realizing this regime. Following this, we discuss potential applications that can benefit from strong coupling induced effects and conclude our review with a perspective on the future of this rapidly emerging field.
Weakly measured while loops: peeking at quantum states
Authors: Andrés-Martínez Pablo , Heunen Chris
Published: January 2022

A while loop tests a termination condition on every iteration. On a quantum computer, such measurements perturb the evolution of the algorithm. We define a while loop primitive using weak measurements, offering a trade-off between the perturbation caused and the amount of information gained per iteration. This trade-off is adjusted with a parameter set by the programmer. We provide sufficient conditions that let us determine, with arbitrarily high probability, a worst-case estimate of the number of iterations the loop will run for. As an example, we solve Grover’s search problem using a while loop and prove the quadratic quantum speed-up is maintained.
Aberrant neuronal connectivity in the cortex drives generation of seizures in rat absence epilepsy
Authors: Studer Florian , Jarre Guillaume , Pouyatos Benoit , Nemoz Christian , Brauer-Krisch Elke , Muzelle Clémence , Serduc Raphael , Heinrich Christophe , Depaulis Antoine
Published: January 2022

Absence epilepsy belongs to genetic epilepsies and is characterized by recurrent generalized seizures that are concomitant with alterations of consciousness and associated with cognitive comorbidities. Little is known about the mechanisms leading to occurrence of epileptic seizures (i.e. epileptogenesis) and, in particular, it remains an open question as to whether neuronal hypersynchronization, a key feature in seizure initiation, could result from aberrant structural connectivity within neuronal networks endowing them with epileptic properties. In the present study, we addressed this question using a genetic model of absence epilepsy in the rat where seizures initiate in the whisker primary somatosensory cortex (wS1). We hypothesized that alterations in structural connectivity of neuronal networks within wS1 contribute to pathological neuronal synchronization responsible for seizures.

First, we used rabies virus-mediated retrograde synaptic tracing and showed that cortical neurons located in both upper- and deep-layers of wS1 displayed aberrant and significantly increased connectivity in the genetic model of absence epilepsy, as highlighted by a higher number of presynaptic partners. Next, we showed at the functional level that disrupting these aberrant wS1 neuronal networks with synchrotron X-ray-mediated cortical microtransections drastically decreased both the synchronization and seizure power of wS1 neurons, as revealed by in vivo local field potential recordings with multichannel probes.

Taken together, our data provide for the first time strong evidence that increased structural connectivity patterns of cortical neurons represent critical pathological substrates for increased neuronal synchronization and generation of absence seizures.
α5-nAChR associated with Ly6E modulates cell migration via TGF-β1/Smad signaling in non-small cell lung cancer
Authors: Zhang Qian , Jia Ying , Pan Pan , Zhang Xiuping , Jia Yanfei , Zhu Ping , Chen Xiaowei , Jiao Yang , Kang Guiyu , Zhang Lulu , Ma Xiaoli
Published: January 2022

The α5-nicotinic acetylcholine receptor (α5-nAChR) is closely associated with nicotine-related lung cancer, offering a novel perspective for investigating the molecular pathogenesis of this disease. However, the mechanism by which α5-nAChR functions in lung carcinogenesis remains to be elucidated. Lymphocyte antigen 6 (Ly6) proteins, like snake three-finger alpha toxins such as α-bungarotoxin, can modulate nAChR signaling. Ly6E, a member of the Ly6 family, is a biomarker of poor prognosis in smoking-induced lung carcinogenesis and is involved in the regulation of TGF-β1/Smad signaling. Here, we explored the underlying mechanisms linking α5-nAChR and Ly6E in non-small cell lung cancer (NSCLC). The expression of α5-nAChR was correlated with Ly6 expression, smoking status and lower survival in NSCLC tissues. In vitro, α5-nAChR mediated Ly6E, the phosphorylation of the TGF-β1 downstream molecule Smad3 (pSmad3, a key mediator of TGF-β1 signaling), the epithelial-mesenchymal transition (EMT) markers Zeb1, N-cadherin and vimentin expression in NSCLC cells. The downregulation of Ly6E reduced α5-nAChR, pSmad3, Zeb1, N-cadherin and vimentin expression. Functionally, silencing both α5-nAChR and Ly6E significantly inhibited cell migration compared to silencing α5-nAChR or Ly6E alone. Furthermore, the functional effects of α5-nAchR and Ly6E were confirmed in chicken embryo chorioallantoic membrane (CAM) and mouse xenograft models. Therefore, our findings uncover a new interaction between α5-nAChR and Ly6E that inhibits cancer cell migration by modulating the TGF-β1/Smad signaling pathway in NSCLC, which may serve as a novel target for therapeutic intervention.
Combination Therapy for Mycoplasma genitalium, and New Insights Into the Utility of parC Mutant Detection to Improve Cure
Authors: Vodstrcil Lenka A , Plummer Erica L , Doyle Michelle , Murray Gerald L , Bodiyabadu Kaveesha , Jensen Jorgen S , Whiley David , Sweeney Emma , Williamson Deborah A , Chow Eric P F , Fairley Christopher K , Bradshaw Catriona S
Published: January 2022

Background

Mycoplasma genitalium (MG) infection is challenging to cure because of rising antimicrobial resistance and limited treatment options.

Methods

This was a prospective evaluation of the efficacy and tolerability of resistance-guided combination antimicrobial therapy for MG treatment at Melbourne Sexual Health Centre (August 2019–December 2020). All patients received 7 days of doxycycline before combination therapy based on the macrolide-resistant profile. Macrolide-susceptible infections received combination doxycycline + azithromycin (1 g, day 1; 500 mg, days 2–4) and macrolide-resistant infections combination doxycycline + moxifloxacin (400 mg daily for 7 days). Adherence and adverse effects were recorded at test-of-cure, recommended 14–28 days after antimicrobial completion. Sequencing was performed to determine the prevalence of single nucleotide polymorphisms (SNPs) in the parC gene and their association with moxifloxacin treatment outcomes in macrolide-resistant infections.

Results

Of 100 patients with macrolide-susceptible MG treated with doxycycline + azithromycin, 93 were cured (93.0%; 95% confidence interval [CI], 86.1–97.1). Of 247 patients with macrolide-resistant MG receiving doxycycline + moxifloxacin, 210 were cured (85.0%; 95% CI, 80.0–89.2). parC sequencing was available for 164 (66%) macrolide-resistant infections; 29% had SNPs at parC S83 or D87 (23% S83I). The absence of SNPs at parC S83/D87 was associated with 98.3% cure (95% CI, 93.9–99.8) following doxycycline + moxifloxacin. The presence of the parC S83I-SNP was associated with failure in 62.5% (95% CI, 45.8–77.3). Side effects were common (40%–46%) and predominantly mild and gastrointestinal.

Conclusions

Combination doxycycline + azithromycin achieved high cure for macrolide-susceptible infections. However, in the context of a high prevalence of the parC S83I mutation (23%) in macrolide-resistant infections, doxycycline + moxifloxacin cured only 85%. Infections that were wild-type for S83/D87 experienced high cure following doxycycline + moxifloxacin, supporting the use of a parC-resistance/susceptibility testing strategy in clinical care.
Whole-Blood 3-Gene Signature as a Decision Aid for Rifapentine-based Tuberculosis Preventive Therapy
Authors: Huang Hung Ling , Lee Jung Yu , Lo Yu Shu , Liu I Hsin , Huang Sing Han , Huang Yu Wei , Lee Meng Rui , Lee Chih Hsin , Cheng Meng Hsuan , Lu Po Liang , Wang Jann Yuan , Yang Jinn Moon , Chong Inn Wen
Published: January 2022

Background

Systemic drug reaction (SDR) is a major safety concern with weekly rifapentine plus isoniazid for 12 doses (3HP) for latent tuberculosis infection (LTBI). Identifying SDR predictors and at-risk participants before treatment can improve cost-effectiveness of the LTBI program.

Methods

We prospectively recruited 187 cases receiving 3HP (44 SDRs and 143 non-SDRs). A pilot cohort (8 SDRs and 12 non-SDRs) was selected for generating whole-blood transcriptomic data. By incorporating the hierarchical system biology model and therapy–biomarker pathway approach, candidate genes were selected and evaluated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Then, interpretable machine learning models presenting as SHapley Additive exPlanations (SHAP) values were applied for SDR risk prediction. Finally, an independent cohort was used to evaluate the performance of these predictive models.

Results

Based on the whole-blood transcriptomic profile of the pilot cohort and the RT-qPCR results of 2 SDR and 3 non-SDR samples in the training cohort, 6 genes were selected. According to SHAP values for model construction and validation, a 3-gene model for SDR risk prediction achieved a sensitivity and specificity of 0.972 and 0.947, respectively, under a universal cutoff value for the joint of the training (28 SDRs and 104 non-SDRs) and testing (8 SDRs and 27 non-SDRs) cohorts. It also worked well across different subgroups.

Conclusions

The prediction model for 3HP-related SDRs serves as a guide for establishing a safe and personalized regimen to foster the implementation of an LTBI program. Additionally, it provides a potential translational value for future studies on drug-related hypersensitivity.
Evaluating the performance of GIS methodologies for quantifying spatial accessibility to healthcare in Multi-Island Micro States (MIMS)
Authors: Brizan-St. Martin Roxanne , Paul Juel
Published: January 2022

There has been limited information on spatial accessibility to healthcare in Multi-island Micro States (MIMS). This is partly due to the application of methodologies that do not sufficiently consider the dynamic or unique characteristics of MIMS. The objective of the paper is to evaluate the performance of different Geographic Information Systems (GIS) methodologies for quantifying spatial accessibility to public healthcare in Multi-island States (MIMS). Spatial accessibility was measured using three GIS-based methodologies: Temporally Available Two-Step Floating Catchment Area (TA2SFCA) and traditional models [Two-Step Floating Catchment Area (2SFCA) and the Gravity Model]. Unlike the Gravity Model and the 2SFCA which only used population and health facilities locations along with travel times to quantify spatial accessibility, the TA2SFCA also included information on the hours of operations and health schedules in its assessment. These additional variables were used to develop the time windows to assess differences in capacity among available service sites. TA2SFCA results showed that spatial accessibility was linked to a ‘traveling doctor’ dynamic with access to healthcare services reflecting changes in the supply of services. As such, the Gravity Model and 2SFCA which did not account for this peculiarity were inadequate for measuring spatial accessibility in MIMS. The TA2SFCA addressed both the temporal and spatial aspects of health which were most reflective of the health system of these islands. Given the spatial-temporal dynamics, improving accessibility to healthcare requires periodic assessments and reassessments of health service delivery since this is affected by operating times and changes in capacity. Furthermore, there is the need for more research to develop methodologies that are more reflective or sensitive to MIMS dynamics.
Making health public: a philosophy café in a disadvantaged neighbourhood
Authors: Raap Sanne , Knibbe Mare , Horstman Klasien
Published: January 2022

Community Based Participatory Research (CBPR) provides important insights in how to mobilize a community for health promotion. This article explores the possibilities for shifting the frame from community to publics for building new forms of public health engagement in disadvantaged neighbourhoods. We present the results of an ethnographic research project on health and resilience in three low-income neighbourhoods in Maastricht, the Netherlands. In the context of a broader University–Citizens collaboration, citizens and researchers organized a monthly philosophy café to discuss subjects related to health and wellbeing. We analyse this in terms of public building and argue that shifting the perspective from community to publics strengthens the emancipatory tradition within CBPR. By creating an open setting, accommodating diversity and disagreements between its participants, the philosophy café constituted a local epistemic public, generating knowledge on health and wellbeing in disadvantaged neighbourhoods.
Loss-of-function and gain-of-function studies refute the hypothesis that tau protein is causally involved in the pathogenesis of Huntington’s disease
Authors: Mees Isaline , Li Shanshan , Beauchamp Leah C , Barnham Kevin J , Dutschmann Mathias , Hannan Anthony J , Renoir Thibault
Published: January 2022

Tubulin-associated unit (Tau) is a microtubule-associated protein, whose abnormal phosphorylation and deposition in the brain characterizes a range of neurodegenerative diseases called tauopathies. Recent clinical (post-mortem) and pre-clinical evidence suggests that Huntington’s disease (HD), an autosomal dominant neurodegenerative disorder, could be considered as a tauopathy. Studies have found the presence of hyperphosphorylated tau, altered tau isoform ratio and aggregated tau in HD brains. However, little is known about the implication of tau in the development of HD pathophysiology, which includes motor, cognitive and affective symptoms. To shine a light on the involvement of tau in HD, our present study aimed at (i) knocking out tau expression and (ii) expressing a transgene encoding mutant human tau in the R6/1 mouse model of HD. We hypothesized that expression of the mutant human tau transgene in HD mice would worsen the HD phenotype, while knocking out endogenous mouse tau in HD mice would improve some behavioral deficits displayed by HD mice. Our data suggest that neither the expression of a tau transgene nor the ablation of tau expression impacted the progression of the HD motor, cognitive and affective phenotypes. Supporting these behavioral findings, we also found that modulating tau expression had no effect on brain weights in HD mice. We also report that expression of the tau transgene increased the weight of WT and HD male mice, whereas tau ablation increased the weight of HD females only. Together, our results indicate that tau might not be as important in regulating the onset and progression of HD symptomatology as previously proposed.
Host, Microbiome, and Complex Space: Applying Population and Landscape Genetic Approaches to Gut Microbiome Research in Wild Populations
Authors: Couch Claire E , Epps Clinton W
Published: January 2022

In recent years, emerging sequencing technologies and computational tools have driven a tidal wave of research on host-associated microbiomes, particularly the gut microbiome. These studies demonstrate numerous connections between the gut microbiome and vital host functions, primarily in humans, model organisms, and domestic animals. As the adaptive importance of the gut microbiome becomes clearer, interest in studying the gut microbiomes of wild populations has increased, in part due to the potential for discovering conservation applications. The study of wildlife gut microbiomes holds many new challenges and opportunities due to the complex genetic, spatial, and environmental structure of wild host populations, and the potential for these factors to interact with the microbiome. The emerging picture of adaptive coevolution in host–microbiome relationships highlights the importance of understanding microbiome variation in the context of host population genetics and landscape heterogeneity across a wide range of host populations. We propose a conceptual framework for understanding wildlife gut microbiomes in relation to landscape variables and host population genetics, including the potential of approaches derived from landscape genetics. We use this framework to review current research, synthesize important trends, highlight implications for conservation, and recommend future directions for research. Specifically, we focus on how spatial structure and environmental variation interact with host population genetics and microbiome variation in natural populations, and what we can learn from how these patterns of covariation differ depending on host ecological and evolutionary traits.
Comparison of surgical outcomes after robot-assisted laparoscopic partial nephrectomy between patients continuing and discontinuing aspirin therapy: a Japanese single-centre study
Authors: Wada Arisa , Omae Kenji , Yoshida Kazuhiko , Kondo Tsunenori , Tanabe Kazunari , Takagi Toshio
Published: January 2022

Purpose

To investigate the feasibility of continuing aspirin therapy in patients with renal tumours undergoing robot-assisted laparoscopic partial nephrectomy.

Methods

This retrospective, single-centre study included 106 patients receiving aspirin therapy who underwent robot-assisted laparoscopic partial nephrectomy. The patients were divided into two groups, including those continuing and discontinuing aspirin therapy, and their surgical outcomes were compared. To minimise potential bias, variables including patient and tumour characteristics were adjusted using 1:1 propensity score matching.

Results

Aspirin therapy was used for ischaemic heart disease in 38 patients (36%), cerebrovascular disease in 21 (20%) and others in 47 (44%). Of the 106 patients, 49 were classified to the continuing group and 57 to the discontinuing group. After matching, 24 patients were included in each group. The surgical outcomes, such as changes in the estimated glomerular filtration rate, estimated blood loss, and surgical margin positivity rate, were not significantly different between the groups. In addition, no significant difference was observed in haemoglobin level changes during surgery (continuing: −2.3 g/dl; discontinuing: −1.7 g/dl, P = 0.0676) and haemorrhagic complications (continuing: 8%; discontinuing: 4%, P = 0.500). Multivariate analysis of predictors for haemoglobin level decrease >2 g/dl or haemorrhagic complications showed that, whereas tumour complexity was an independent predictor, continuation or discontinuation of aspirin therapy was not.

Conclusion

The surgical outcomes of robot-assisted laparoscopic partial nephrectomy between patients continuing and discontinuing aspirin therapy were not significantly different, thus suggesting the feasibility of continuing aspirin therapy in selected Japanese patients.
Detection of low-frequency breaks in power density spectrum of GX 339−4 in faint low/hard state observations using AstroSat data
Authors: Husain Nazma , Misra Ranjeev , Sen Somasri
Published: January 2022

We present the spectro-timing analysis of the black hole binary system GX 339−4 using AstroSat data extracted at the beginning of outbursts in 2017 and 2019. The joint spectral fitting of Large Area X-ray Proportional Counter (LAXPC) and Soft X-ray Telescope (SXT) data revealed that the source was in a faint low/hard state for both 2017 and 2019 observations, with nearly equal photon indexes of ∼1.57 and ∼1.58 and Eddington ratios, L/LEdd, of 0.0011 and 0.0046, respectively. The addition of a reflection component into the spectral modelling improved the fit (Δχ2 ≈ 6 for 2017 and Δχ2 ≈ 7 for 2019), pointing towards the presence of weak reflection features arising due to irradiation of the accretion disc. The power density spectrum consisted of strong band-limited noise with a break at low frequencies, described by a combination of a few zero-centred Lorentzians. The fitting revealed a low-frequency break at ∼6 mHz for 2017 and ∼11 mHz for 2019 observations, whose detection is validated by results from independent detectors (LAXPCs and SXT). The break frequency is roughly consistent with results obtained from earlier observations that showed an evolution of the frequency with flux, which is in accordance with the truncated disc model. Associating the break frequency with the viscous time-scale of the accretion disc, we estimated a truncation radius of ∼93 and ∼61 gravitational radius for 2017 and 2019 observations, respectively.
Nuclear and cytoplasmic RNA exosomes and PELOTA1 prevent miRNA-induced secondary siRNA production in Arabidopsis
Authors: Vigh Maria L , Bressendorff Simon , Thieffry Axel , Arribas-Hernández Laura , Brodersen Peter
Published: January 2022

Amplification of short interfering RNA (siRNAs) via RNA-dependent RNA polymerases (RdRPs) is of fundamental importance in RNA silencing. Plant microRNA (miRNA) action generally does not involve engagement of RdRPs, in part thanks to a poorly understood activity of the cytoplasmic exosome adaptor SKI2. Here, we show that inactivation of the exosome subunit RRP45B and SKI2 results in similar patterns of miRNA-induced siRNA production. Furthermore, loss of the nuclear exosome adaptor HEN2 leads to secondary siRNA production from miRNA targets largely distinct from those producing siRNAs in ski2. Importantly, mutation of the Release Factor paralogue PELOTA1 required for subunit dissociation of stalled ribosomes causes siRNA production from miRNA targets overlapping with, but distinct from, those affected in ski2 and rrp45b mutants. We also show that in exosome mutants, miRNA targets can be sorted into producers and non-producers of illicit secondary siRNAs based on trigger miRNA levels and miRNA:target affinity rather than on presence of 5′-cleavage fragments. We propose that stalled RNA-Induced Silencing Complex (RISC) and ribosomes, but not mRNA cleavage fragments released from RISC, trigger siRNA production, and that the exosome limits siRNA amplification by reducing RISC dwell time on miRNA target mRNAs while PELOTA1 does so by reducing ribosome stalling.
Chaperone mediated autophagy contributes to the newly synthesized histones H3 and H4 quality control
Authors: Hormazabal Juan , Saavedra Francisco , Espinoza-Arratia Claudia , Martinez Nicolas W , Cruces Tatiana , Alfaro Iván E , Loyola Alejandra
Published: January 2022

Although there are several pathways to ensure that proteins are folded properly in the cell, little is known about the molecular mechanisms regulating histone folding and proteostasis. In this work, we identified that chaperone-mediated autophagy (CMA) is the main pathway involved in the degradation of newly synthesized histones H3 and H4. This degradation is finely regulated by the interplay between HSC70 and tNASP, two histone interacting proteins. tNASP stabilizes histone H3 levels by blocking the direct transport of histone H3 into lysosomes. We further demonstrate that CMA degrades unfolded histone H3. Thus, we reveal that CMA is the main degradation pathway involved in the quality control of histone biogenesis, evidencing an additional mechanism in the intricate network of histone cellular proteostasis.
Evaluating Vitamin C in Septic Shock: A Randomized Controlled Trial of Vitamin C Monotherapy*
Authors: Wacker David A. , Burton Susan L. , Berger John P. , Hegg A. J. , Heisdorffer Jamie , Wang Qi , Medcraft Emily J. , Reilkoff Ronald A.
Published: January 2022

OBJECTIVES:

To determine whether IV vitamin C therapy reduces 28-day mortality in patients with septic shock.

DESIGN:

Multicenter, double-blinded, randomized controlled trial.

SETTING:

One academic medical ICU and four community ICUs.

PATIENTS:

Of 167 adult patients within 24 hours of vasopressor initiation for septic shock, 126 consented to participation, and 124 received study drug and were included in analysis.

INTERVENTIONS:

IV vitamin C (10 mg/mL in normal saline) administered as a 1,000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hr for 96 hours or placebo of equal volumes of normal saline.

MEASUREMENTS AND MAIN RESULTS:

Of 124 subjects receiving study drug and included in analysis, 60 received vitamin C and 64 placebo. The primary outcome of all-cause 28-day mortality (vitamin C, 26.7%; placebo, 40.6%; p = 0.10) was lower in the vitamin C arm but did not reach statistical significance. Initiation of renal replacement therapy was higher in the vitamin C arm (vitamin C, 16.7%; placebo, 3.3%; p = 0.015), as was volume of fluid administration within 6 hours of study drug initiation (vitamin C, 1.07 L; placebo, 0.76 L; p = 0.03). There were no statistically significant differences in other secondary outcomes. In post hoc subgroup analysis, there was a decrease in 28-day mortality in the vitamin C arm among patients requiring positive-pressure ventilation at the time of enrollment (vitamin C, 36.3%; placebo, 60.0%; p = 0.05). This trial is registered at clinicaltrials.gov under identifier NCT03338569.

CONCLUSIONS:

Vitamin C monotherapy failed to significantly reduce mortality in septic shock patients as hypothesized. Our findings do not support its routine clinical use for this purpose.
Blood pressure undulation of peripheral thrombolysis period in acute ischemic stroke is associated with prognosis
Authors: He Mingli , Wang Hongrui , Tang Yi , Wang Jin’e , Cui Bing , Xu Bingchao , Sun Yongan , Zhang Guanghui , He Xiaobing , Niu Xiaoqin , Wang Bei , Xu Bei , Li Zaipo , Zhang Yu , Wang Yibo
Published: January 2022

Background:

Evidence suggests that patients with higher blood pressure variability (BPV) have a higher risk for stroke but the relationship between BPV and stroke outcomes is unknown in those who underwent intravenous thrombolysis (IVT) for acute ischemic stroke (AIS). The objective of this study is to investigate the association among BPV, BP values and stroke outcomes.

Methods:

A retrospective analysis of about 510 consecutive thrombolysis cases for AIS from January 2015 to March 2019 in a single-center database were done. Then, these patients were followed-up for 3 months. We used univariate and multivariable models to evaluate the relationship between mean BP values, BPV and the risk of stroke outcomes from prior IVT to 72 h after IVT. Meanwhile, we also used COX regression to assess the hazard ratios of stroke outcomes with BPV within 3 months. Furthermore, we tested the effect of BP level at various time-points (prior to IVT and at 0, 2, 4, 8, 12, 24, 48 and 72 h after IVT) on development of postthrombolytic stroke outcomes.

Results:

Higher BPV from prior IVT to 72 h after IVT was associated with higher risk of stroke outcomes within 3 months [SBPV of recurrent stroke: odds ratios (OR) = 5.298, 95% confidence interval (CI) 1.339–10.968, P = 0.018; DBPV of recurrent stroke: OR = 6.397, 95% CI 1.576–25.958, P = 0.009, respectively]. In addition, patients with recurrent stroke had significantly higher mean SBP (OR=1.037, 95% CI 1.006–1.069, P = 0.019). Furthermore, higher BP at different time points were associated with greater risk of recurrent stroke from prior IVT to 72 h after IVT.

Conclusion:

Higher BPV and SBP from prior IVT to 72 h after IVT was associated with higher risk of stroke outcomes within 3 months.
Clinical Redesign: An Innovative Approach to Leading Change at an Academic Healthcare System
Authors: Li Luming , Davis Melissa , Kim Nancy , Lipka Susan , Branson Brittany , Amport Stephanie , Schwartz Ian , Sussman Scott
Published: January 2022

Goal:

We characterized the core elements of a clinical redesign program (CRDP) to represent both a team and a methodology to rapidly improve outcomes important to patients and hospitals (e.g., length of stay, unnecessary care, and cost). Unique features of our CRDP included a clinician lead, engagement from senior leadership, formal project management, and rapid cycle implementation. We aimed to examine the effectiveness of this strategy across three different project examples.

Methods:

Using an observational pre–post study design, we compared the patient-level data for three representative projects applying the core elements of the CRDP: (1) optimizing telemetry utilization, (2) creating a high flow nasal cannula protocol in the pediatric intensive care unit, and (3) standardizing care for patients with chronic obstructive pulmonary disease and pneumonia.

Principal Findings:

The primary metrics for all three projects were a project-specific clinical outcome and cost per case. Telemetry utilization was reduced from a peak of 26.0% to 19.6% with a $1,075 reduction in cost per case. Creation of a high flow nasal cannula protocol led to a decrease in median pediatric intensive care unit length of stay from 77.3 to 75.8 hours with a $2,020 decrease in cost per case. Decreasing variation of care for patients with chronic obstructive pulmonary disease and pneumonia diagnoses led to a $371 decrease in cost per case.

Applications to Practice:

The CRDP adds to existing clinical quality improvement models using a structured process for a 90-day rapid cycle project turnaround. In addition, the CRDP incorporates project management and defined team members for the completion and sustainability of projects. The CRDP also facilitates the scalable translation of projects from local to systemwide and incorporates tracking of clinical and financial outcomes through interval internal auditing. These elements provide prioritization, resource allocation, and expertise for improved patient care and high-value care delivery. The CRDP can be adapted for other contexts to lead and foster momentum and drive rapid and successful completion of clinical improvement projects.
Point-of-Care Ultrasonography for Ankle Injuries in Children
Authors: Nadler Ariella , Tsung James W. , Rabiner Joni E.
Published: January 2022

Objectives

The aim of the study was to determine whether point-of-care ultrasound (US) can decrease x-rays in children with ankle injuries. Secondary objectives were to determine the test performance characteristics for ankle US, analyze diagnostic errors, and compare US with the Ottawa Ankle Rules (OAR).

Methods

This was a prospective study of children younger than 21 years presenting to an emergency department with an ankle injury requiring x-rays. Pediatric emergency medicine physicians received a 1-hour training session, performed ankle US with a standardized scanning protocol of the distal tibia and fibula, and described the US as positive, negative, or equivocal for fracture. Ankle x-ray interpretation by a radiologist was the reference standard for fracture.

Results

One hundred twenty patients with a mean age of 13.5 (±4.0) years were enrolled. Nine patients (7.5%) had an ankle fracture on x-ray, and 56 patients (47%) had open physes. Ankle US would reduce x-rays by 81 (67.5%), missing 2 intra-articular, nondisplaced, tibial fractures in patients with open physes. Ankle US had a sensitivity of 78% (95% confidence interval [CI], 40%–97%), specificity of 71% (95% CI, 62%–79%), likelihood ratio for a positive test of 2.7 (95% CI, 1.7–4.3), and likelihood ratio for a negative test of 0.31 (95% CI, 0.09–1.07). The OAR would reduce x-rays by 21 (17.5%), missing one fracture. Ultrasound with OAR would reduce x-rays by 20 (17%) with no missed fractures.

Conclusions

Point-of-care US has the potential to reduce x-rays for children with ankle injuries; however, nondisplaced, intra-articular tibial fractures may be missed. Ultrasound with OAR may reduce radiographs without missed fractures in this population.
Phosphoantigens are Molecular Glues that Promote Butyrophilin 3A1/2A1 Association Leading to Vγ9Vδ2 T Cell Activation
Authors: Yuan Linjie , Ma Xianqiang , Yang Yunyun , Li Xin , Ma Weiwei , Yang Haoyu , Huang Jian-Wen , Xue Jing , Yi Simin , Zhang Mengting , Cai Ningning , Ding Qingyang , Li Liping , Duan Jianxin , Malwal Satish , Chen Chun-Chi , Oldfield Eric , Guo Rey-Ting , Zhang Yonghui
Published: January 2022

Tumor cells and pathogen-infected cells are presented to human γδ T cells based on “inside-out” signaling in which metabolites called phosphoantigens (pAgs) inside target cells are recognized by the intracellular domain of a butyrophilin protein (BTN3A1), leading to an extracellular conformational change. Here, we report that pAgs function as molecular “glues” that initiate a heteromeric association between the intracellular domains of BTN3A1 and the structurally similar BTN2A1. Working with both exogenous and endogenous pAgs, we used x-ray crystallography, mutational studies, cellular assays, synthetic probe as well as molecular dynamics investigations to determine how pAgs glue intracellular BTN3A1 and BTN2A1 together for the “inside-out” signaling that triggers γδ T cell activation. This γδ T cell-specific mode of antigen sensing creates opportunities for the development of alternative immunotherapies against cancer and infectious diseases that do not involve αβ T cells.

One Sentence Summary

The responses of gamma-delta T cells to cancer cells or pathogens are initiated via the intracellular association of heteromeric butyrophilins that are glued together by isoprenoid metabolites.
Preparation of Labeled DNA, RNA, and Oligonucleotide Probes
Authors: Green Michael R. , Sambrook Joseph
Published: January 2022

Labeled nucleic acids and oligonucleotides are typically generated by enzymatic methods such as end-labeling, random priming, nick translation, in vitro transcription, and variations of the polymerase chain reaction (PCR). Some of these methods place the label in specific locations within the nucleic acid (e.g., at the 5′ or 3′ terminus); others generate molecules that are labeled internally at multiple sites. Some methods yield labeled single-stranded products, whereas others generate double-stranded nucleic acids. Finally, some generate probes of defined length, whereas others yield a heterogeneous population of labeled molecules. Options available for generating and detecting labeled nucleic acids, as well as advice on designing oligonucleotides for use as probes, is included here.
The impact of culture on millennials' attitudes towards luxury brands: evidence from Tokyo and Shanghai
Authors: Lu Cheng , Sang Zhencong , Song Kun , Kikuchi Kazuo , Machida Ippei
Published: January 2022

Purpose

Based on the theory of social identity mechanism, this study aimed to investigate the associations with millennial consumers' need for uniqueness (NFU), susceptibility to peer influence (SPI) and attitudes towards luxury brands (ALB) under the cross-cultural context. The mediating effect of fashion innovativeness (FI) and the moderating effect of culture were examined.

Design/methodology/approach

The data for this study were collected through a survey from 217 millennials in Shanghai and 268 millennials in Tokyo. Moderation analysis and mediation analysis using Hayes PROCESS macro were applied to test proposed hypotheses.

Findings

Results show that NFU and SPI have a significantly positive effect on millennials' ALB, and fashion innovativeness plays a mediating role in this process. Furthermore, the positive impact of NFU on millennials' ALB for relatively individualistic cities (Shanghai) is stronger than for relatively collectivist cities (Tokyo). The positive impact of susceptibility to informative influence (SII) on millennials' ALB for Tokyo is stronger than for Shanghai.

Practical implications

The research results suggest how different cultures can support marketers in effectively carrying out their business strategy.

Originality/value

Under the cross-cultural background, the social identity mechanism behind the attitudes of millennials towards luxury brands has been widely recognised. However, little is known about how culture could moderate the social identity mechanism behind millennials' ALB. By analysing these mechanisms, this study compares the cultures of Shanghai and Tokyo and expands the previous research achievements.
Diagnostic intervention program based on construction workers' internal factors for persistent reduction of unsafe behavior
Authors: Mohajeri Mehdi , Ardeshir Abdollah , Malekitabar Hassan
Published: January 2022

Purpose

This study aims to show what interventions in human factors can effectively reduce construction workers' unsafe behavior.

Design/methodology/approach

A diagnostic intervention model targeted the construction workers' weakest internal factors. The workers' behavior and cognition data were collected via a questionnaire and a video camera system from two medium-sized construction sites. A safety supervisor accompanied each site supervisor to improve construction workers' internal factors by implementing the designed intervention measures.

Findings

The statistical analysis results confirmed a persistent positive effect on construction workers' safe behavior by improving internal factors. Among the intervention programs applied, those aimed to improve the subjective norms, safety knowledge and attitudes had the most significant effect sizes.

Practical implications

The findings of this case study advise project managers to design a specific behavioral intervention that aims at improving construction workers' significant internal factors, including subjective norms, safety attitudes, habits and knowledge together with demographic characteristics to reduce construction workers' unsafe behavior.

Originality/value

While the declining rate of construction accidents approaches an asymptote which is still high, this study suggests that targeting the individual internal factors through diagnostic interventions is the key to further reduce the rate by improving construction workers' behavior.
Public debt management and the interaction between fiscal and monetary policies
Authors: Nobrega Wellington Charles Lacerda , Besarria Cássio da Nóbrega , Aragón Edilean Kleber da Silva Bejarano
Published: January 2022

Purpose

This paper aims to investigate the existing relations between the management of public bonds on the dynamics of debt, term structure of interest rates and economic cycle, through a dynamic stochastic general equilibrium model (DSGE), which was estimated through Bayesian inference techniques using data from Brazil.

Design/methodology/approach

The model developed was used to investigate the effects of the public debt average maturity management when the economy faces a monetary policy shock. For this, three management scenarios are evaluated, including Brazilian securities average term.

Findings

Contrary to what might be inferred from DSGE models that limited the analysis of the debt term by imposing only one-period bonds, a contractionary monetary policy shock does not necessarily cause public debt to increase significantly. Debt term structure plays a crucial role in this result since the government does not need to roll the debt over at higher costs when the debt term profile is longer, reducing the debt service costs and then the impact on the overall debt.

Originality/value

Despite the relevance of this theme and its implications for the dynamics of the economy, there is still a gap to be filled in the literature when using DSGE models, since most part of the work that used this methodology limited the analysis of the debt term by imposing that government issues only one-period bonds. This paper differs from the others insofar as it promotes an investigation focused on the role played by debt maturity management on the performance of the contractionary monetary policy. This approach can generate a better understanding of debt management policy and its interaction with fiscal and monetary policies.
The territorial segmentation of coastal tourism areas
Authors: Simancas Cruz Moisés , Peñarrubia Zaragoza María Pilar , Hernández-Martín Raúl , Rodríguez Rodríguez Yurena
Published: January 2022

Purpose

The purpose of this paper is to analyse the potential benefits of identifying homogeneous territorial units of the urban-tourism space at a local scale.

Design/methodology/approach

The territory is an essential variable for designing tourist activities adapted to the characteristics of each urban-tourism space. However, your consideration presents a series of problems, including the lack of alphanumeric, microscale, georeferenced statistical information. The territorial segmentation of the tourist accommodations supply is approached as a methodology, a technique and an instrument that can be used to apply marketing strategies in coastal tourism areas.

Findings

One of the most important results is that territorial segmentation is a methodology and technique that can mitigate this issue because it is well-suited to defining spatial patterns of tourist behaviour through the delimitation of territorial units that have a certain degree of homogeneity.

Originality/value

The idea of territorial segmentation is the ideal technique for understanding tourists and their behaviour in the territory by integrating all the variables that intervene in a trip, the different aspects of the destination and data regarding tourist behaviour, allowing them to be understood at the greatest level of territorial disaggregation and making it a good tool for public and private actors, capable of facilitating intelligent decisions in strategic territorial planning and in defining the marketing approach of tourism companies.
“You cannot pour from an empty cup!”: child well-being service providers’ and policymakers’ professional supervision, coping and well-being during COVID-19
Authors: Karadzhov Dimitar , Davidson Jennifer C. , Wilson Graham
Published: January 2022

Purpose

This paper aims to present findings from 440 responses regarding the experiences of supervision, coping and well-being of 83 service providers and policymakers from eight countries working to support children’s well-being during the COVID-19 pandemic.

Design/methodology/approach

A smartphone survey hosted on a custom-built app was used. The data were analysed using qualitative content analysis. The data were gathered in the last quarter of 2020.

Findings

While most respondents described the supervision they received as “useful” – both personally and professionally – and reported several characteristics of effective supervision practices, concerns about not receiving optimal support were also voiced. Respondents shared a range of stress management and other self-care practices they used but also revealed their difficulties optimally managing the stresses and anxieties during the COVID-19 pandemic. As a result, some respondents shared they were feeling helpless, unmotivated and unproductive. Yet, overall, responses were imbued with messages about hope, perseverance and self-compassion.

Originality/value

Using a bespoke smartphone app, rich and intimate insights were generated in real time from a wide range of professionals across high- and low- and middle-income countries – indicating the need to better support their well-being and service delivery.