bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nicotine Metabolism Predicted byCYP2A6Genotypes in Relation to Smoking Cessation: A Systematic Review
Authors: Jones Stephanie K , Wolf Bethany J , Froeliger Brett , Wallace Kristin , Carpenter Matthew J , Alberg Anthony J 
Published: September 2021

AbstractIntroductionIdentifying genetic factors associated with smoking cessation could inform precision cessation interventions. Of major interest is genetic variation in nicotine metabolism, largely predicted by CYP2A6 variations.Aims and MethodsWe conducted a systematic literature review to summarize the population-based evidence of the association between CYP2A6 and smoking cessation. In the 12 studies meeting the inclusion criteria, the known functional metabolic effect of CYP2A6 variants was used to classify nicotine metabolism as normal (&gt;75% metabolic activity), intermediate (50.1%–75% activity), slow (25%–50% activity), and poor (&lt;25% activity). Summary odds ratios of smoking cessation were calculated across metabolic groups, stratified by ancestry and whether participants received pharmacotherapy or placebo/no treatment.ResultsAmong untreated people of European ancestry (n = 4 studies), those with CYP2A6 reduced metabolism were more likely to quit smoking than those with normal metabolism (Summary OR = 2.05, 95% CI 1.23 to 3.42) and the likelihood of cessation increased as nicotine metabolism decreased. Nicotine replacement therapy attenuated the association at end-of-treatment, while bupropion modified the association such that intermediate/slow metabolizers were less likely to quit than normal metabolizers (Summary OR = 0.86, 95% CI 0.79 to 0.94). Among untreated Asian people (n = 3 studies), results differed compared with those with European ancestry: those with slow metabolism were less likely to have quit smoking than normal metabolizers (Summary OR = 0.52, 95% CI 0.38 to 0.71). Evidence for people of African ancestry (n = 1 study) suggested the CYP2A6 association with cessation may differ compared with those of European ancestry.Conclusions and ImplicationsMost studies included in this review were of European ancestry populations; these showed slower nicotine metabolism was associated with increased likelihood of smoking cessation in a dose-related manner. Pharmacotherapy appeared to attenuate or modify this association among people of European ancestry, but it is unclear whether the change in the association remains consistent after treatment ceases. This finding has implications for precision medicine cessation interventions. Based on only a few studies of people of Asian or African ancestry, the association between CYP2A6 variants and cessation may differ from that observed among those of European ancestry, but more evidence is needed.
Development and Dynamics of Cytomegalovirus UL97 Ganciclovir Resistance Mutations in Transplant Recipients Detected by Next-Generation Sequencing
Authors: Lodding Isabelle P , Jørgensen Mette , Bennedbæk Marc , Kirkby Nikolai , Naegele Klaudia , Gustafsson Finn , Perch Michael , Rasmussen Allan , Sengeløv Henrik , Sørensen Søren S , Hirsch Hans H , Lundgren Jens D 
Published: September 2021

Abstract

Background
(Val)ganciclovir resistance mutations in CMV UL97 (UL97-GCV-R) complicate anti-CMV therapy in recipients of solid organ and hematopoietic stem cell transplants, but comprehensive data on prevalence, emergence, and outcome are scarce.

Methods
Using next-generation sequencing (NGS; Illumina MiSeq platform), we analyzed UL97-GCV-R in patients with available plasma samples and refractory CMV replication/DNAemia (n = 87) containing viral loads ≥910 IU/mL. Twenty-one patients with CMV DNAemia resolving under antiviral therapy were analyzed as controls. Detected mutations were considered induced and of potential clinical significance if they increased by ≥10% compared with the first detected frequency or if they had a maximum frequency ≥25%.

Results
Nineteen of 87 (21.8%) with refractory CMV replication had ≥1 UL97-GCV-R detected by NGS, in comparison to 0/21 of the controls (P = .02). One-third of the recipients had 2 or more induced UL97-GCV-R mutations. The most frequently induced mutations affected codons 595 (42% [8/19]), 594 (32% [6/19]), and 603 (32% [6/19]). C592G was present in all episodes of both cases and controls at frequencies &lt;15%, but never induced. UL97-GCV-R tended to be more frequent in donor/recipient CMV immunoglobulin G mismatch or following failure to complete primary prophylaxis, and many developed invasive CMV disease.

Conclusions
UL97-GCV-R is common among transplant patients with refractory CMV replication. Early testing by NGS allows for identification of major mutations at codons 595, 594, and 603 and excludes a major role of C592G in ganciclovir resistance. Large prospective studies on UL97-GCV-R are warranted.
Citrus sinensis CBF1 Functions in Cold Tolerance by Modulating Putrescine Biosynthesis through Regulation of Arginine Decarboxylase
Authors: Song Jie , Wu Hao , He Feng , Qu Jing , Wang Yue , Li Chunlong , Liu Ji-Hong 
Published: September 2021

Abstract
C-repeat (CRT) binding factors (CBFs) are well known to act as crucial transcription factors that function in cold stress response. Arginine decarboxylase (ADC)- mediated putrescine (Put) biosynthesis has been reported to be activated in plants exposed to cold conditions, but it remains elusive whether CBFs can regulate ADC expression and Put accumulation. In this study, we show that cold upregulated ADC gene (Citrus sinensis ADC;CsADC) and elevated endogenous Put content in sweet orange (C.sinensis). The promoter of CsADC contains two CRT sequences that are canonical elements recognized by CBFs. Sweet orange genome contains four CBFs (CsCBF1-4), in which CsCBF1 was significantly induced by cold. CsCBF1, located in the nucleus, was demonstrated to bind directly and specifically to the promoter of CsADC and acted as a transcriptional activator. Overexpression of CsCBF1 led to notable elevation of CsADC and Put levels in sweet orange transgenic plants, along with remarkably enhanced cold tolerance, relative to the wild type. However, pretreatment with D-arginine, an ADC inhibitor, caused a prominent reduction of endogenous Put levels in the overexpressing lines, accompanied by greatly compromised cold tolerance. Taken together, these results demonstrate that the CBF1 of sweet orange directly regulates ADC expression and modulates Put synthesis for orchestrating the cold tolerance. Our findings shed light on the transcriptional regulation of Put accumulation through targeting the ADC gene in the presence of cold stress. Meanwhile, this study illustrates a new mechanism underlying the CBF-mediated cold stress response.
An update on passive transport in and out of plant cells
Authors: Tomkins Melissa , Hughes Aoife , Morris Richard J 
Published: September 2021

Abstract
Transport across membranes is critical for plant survival. Membranes are the interfaces at which plants interact with their environment. The transmission of energy and molecules into cells provides plants with the source material and power to grow, develop, defend, and move. An appreciation of the physical forces that drive transport processes is thus important for understanding the plant growth and development. We focus on the passive transport of molecules, describing the fundamental concepts and demonstrating how different levels of abstraction can lead to different interpretations of the driving forces. We summarize recent developments on quantitative frameworks for describing diffusive and bulk flow transport processes in and out of cells, with a more detailed focus on plasmodesmata, and outline open questions and challenges.
Phototropin-mediated perception of light direction in leaves regulates blade flattening
Authors: Legris Martina , Szarzynska-Erden Bogna Maria , Trevisan Martine , Allenbach Petrolati Laure , Fankhauser Christian 
Published: September 2021

Abstract
One conserved feature among angiosperms is the development of flat thin leaves. This developmental pattern optimizes light capture and gas exchange. The blue light (BL) receptors phototropins are required for leaf flattening, with the null phot1phot2 mutant showing curled leaves in Arabidopsis (Arabidopsis thaliana). However, key aspects of their function in leaf development remain unknown. Here, we performed a detailed spatiotemporal characterization of phototropin function in Arabidopsis leaves. We found that phototropins perceive light direction in the blade, and, similar to their role in hypocotyls, they control the spatial pattern of auxin signaling, possibly modulating auxin transport, to ultimately regulate cell expansion. Phototropin signaling components in the leaf partially differ from hypocotyls. Moreover, the light response on the upper and lower sides of the leaf blade suggests a partially distinct requirement of phototropin signaling components on each side. In particular, NON PHOTOTROPIC HYPOCOTYL 3 showed an adaxial-specific function. In addition, we show a prominent role of PHYTOCHROME KINASE SUBSTRATE 3 in leaf flattening. Among auxin transporters, PIN-FORMED 3,4,7 and AUXIN RESISTANT 1 (AUX1)/LIKE AUXIN RESISTANT 1 (LAX1) are required for the response while ABCB19 has a regulatory role. Overall, our results show that directional BL perception by phototropins is a key aspect of leaf development, integrating endogenous and exogenous signals.
Do Patients with Acute Low Back Pain in Emergency Departments Have More Severe Symptoms than Those in General Practice? ASystematic Review with Meta-Analysis
Authors: Oliveira Crystian B , Hamilton Melanie , Traeger Adrian , Buchbinder Rachelle , Richards Bethan , Rogan Eileen , Maher Chris G , Machado Gustavo C 
Published: September 2021

AbstractIntroductionThere is a common belief that patients presenting to emergency departments have more severe pain levels and functional limitations than those who are seen in general practice. The aim of this systematic review was to compare pain and disability levels of patients with acute low back pain presenting to general practice vs those presenting to emergency departments.MethodsElectronic searches were conducted in MEDLINE, EMBASE, and CINAHL from database inception to February 2019. Observational studies including patients with acute non-specific low back pain presenting to emergency departments and/or general practice were eligible. Pain and/or disability scores expressed on a 0–100 scale were the primary outcomes. Risk of bias was evaluated with a validated tool for observational studies, and the overall quality of evidence was assessed with Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Meta-analysis with random effects and meta-regression were used to test for differences between the two settings.ResultsWe included 12 records reporting results for 10 unique studies with a total of 6,999 participants from general practice (n = 6) and emergency departments (n = 4). There was low-quality evidence (downgraded for indirectness and inconsistency) that patients presenting to emergency departments had higher pain scores than those in general practice, with a mean difference of 17.3 points (95% confidence interval: 8.8 to 25.9 on a 0–100 scale). Similarly, there was low-quality evidence (downgraded for indirectness and inconsistency) that patients presenting to emergency departments had higher disability scores than those in general practice (mean difference: 21.7; 95% confidence interval: 4.6 to 38.7 on a 0–100 scale).ConclusionPatients with acute non-specific low back pain presenting to emergency departments may report higher levels of pain and disability than those seen in general practice.
The Relationship Between Pain and Psychological Distress During the COVID-19 Pandemic: Is Social Technology Use Protective?
Authors: Yang Yulin , Grol-Prokopczyk Hanna , Reid M Carrington , Pillemer Karl 
Published: September 2021

Abstract

Objectives
The COVID-19 pandemic and resulting shelter-in-place orders have profoundly changed the everyday social environment. This study examines the relationship between pain and psychological distress (depression, anxiety, and loneliness) among U.S. adults ages 54 and older during the pandemic. We also test whether use of technology for social purposes moderates the association between pain severity and psychological distress.

Methods
Using cross-sectional data on 1,014 adults ages 54 and older (pain free, n = 637; mild pain, n = 106; moderate pain, n = 227; and severe pain, n = 64) from the 2020 Health and Retirement Study COVID-19 Project (Early, Version 1.0), we conducted regression analyses to test the association between pain severity and psychological outcomes and to assess social technology use frequency as a moderator.

Results
Compared with their pain-free peers, participants with mild-to-moderate pain reported more depressive symptoms and greater loneliness; those with severe pain reported higher levels of depression, anxiety, and loneliness. Social technology use was associated with lower levels of depression and loneliness. However, interaction analyses show that social technology use predicted an increase in depression for individuals with pain but a decrease in depression among pain-free individuals. For anxiety and loneliness, no significant effects of social technology use were observed.

Conclusion
Older adults with pain are at high risk of depression, anxiety, and loneliness during the pandemic. Although social technologies have become a common alternative to face-to-face interactions during the COVID-19 crisis, and overall they can provide mental health benefits, our results suggest that social technologies can be detrimental to psychological well-being among people with pain. These findings can inform technology-based interventions aiming to promote well-being among older adults with pain.
Effectiveness, Safety, and Tolerability of Nabiximols Oromucosal Spray vs Typical Oral Long-Acting Opioid Analgesics in Patients with Severe Neuropathic Back Pain: Analysis of 6-Month Real-World Data from the German Pain e-Registry
Authors: Ueberall Michael A , Vila Silván Carlos , Essner Ute , Mueller-Schwefe Gerhard H H 
Published: September 2021

Abstract

Objective
To compare the effectiveness, safety, and tolerability of add-on nabiximols (NBX) oromucosal spray vs typical oral long-acting opioid (LAO) analgesics in patients with severe (± chronic) peripheral neuropathic back pain poorly responsive to other treatments.

Methods
Retrospective analysis of anonymized, propensity score–matched data from the German Pain e-Registry of adult outpatients who initiated NBX or LAO between March 2017 and March 2020.

Results
Data were analyzed from propensity score–matched patients treated with NBX (n = 655) or LAO (n = 655): mean age ≈51 years; 57% female; mean pain duration ≈2.6 years; chronic pain 61%; severe dysfunctional pain 93%. At 6 months, NBX was noninferior to LAO for overall symptom relief, based on the least-squares mean difference between cohorts in change from baseline in patient-reported, pain-related aggregated nine-item scale scores (−27.84%; 95% confidence interval [CI] −29.71 to −25.96; P &lt; 0.001) and individual pain-related scale scores. Subsequent prespecified superiority analysis of the primary endpoint showed that NBX was superior to LAO: all secondary endpoints measuring symptoms of pain and physical function improved significantly with NBX and LAO, with between-group differences favoring NBX (all P &lt; 0.001). Fewer patients treated with NBX than LAO experienced treatment-related adverse events (25.5% vs 76.0%; P &lt; 0.001) or discontinued treatment because of treatment-related adverse events (7.9% vs 29.3%; P &lt; 0.001).

Conclusion
Within study limitations (e.g., observational design, all potential biases), add-on NBX was superior to and better tolerated than add-on treatment with typical oral LAO analgesics in patients with neuropathic back pain inadequately controlled by recommended/established systemic therapies.
Ξ hypernuclear states predicted by next-to-leading-order chiral baryon–baryon interactions
Authors: Kohno M , Miyagawa K 
Published: September 2021

Abstract
The $\Xi$ single-particle potential obtained in nuclear matter with next-to-leading-order baryon–baryon interactions in chiral effective field theory is applied to finite nuclei by an improved local-density approximation method. As a premise, phase shifts of $\Xi N$ elastic scattering and the results of Faddeev calculations for the $\Xi NN$ bound state problem are presented to show the properties of the $\Xi N$ interactions in the present parametrization. First, the $\Xi$ states in $^{14}$N are revisited because of recent experimental progress, including discussion on the $\Xi N$ spin–orbit interaction that is relevant to the location of the $p$-state. Then the $\Xi$ levels in $^{56}$Fe are calculated. In particular, the level shift which is expected to be measured experimentally in the near future is predicted. The smallness of the imaginary part of the $\Xi$ single-particle potential is explicitly demonstrated.
Higher-dimensional inhomogeneous composite fluids: energy conditions
Authors: Brassel Byron P , Maharaj Sunil D , Goswami Rituparno 
Published: September 2021

Abstract
The energy conditions are studied, in the relativistic astrophysical setting, for higher-dimensional Hawking–Ellis Type I and Type II matter fields. The null, weak, dominant and strong energy conditions are investigated for a higher-dimensional inhomogeneous, composite fluid distribution consisting of anisotropy, shear stresses, non-vanishing viscosity as well as a null dust and null string energy density. These conditions are expressed as a system of six equations in the matter variables where the presence of the higher dimension $N$ is explicit. The form and structure of the energy conditions is influenced by the geometry of the $(N-2)$-sphere. The energy conditions for the higher-dimensional Type II fluid are also generated, and it is shown that under certain restrictions the conditions for a Type I fluid are regained. All previous treatments for four dimensions are contained in our work.
Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem
Authors: Ufer Mike , Kelsh Debra , Schoedel Kerri A , Dingemanse Jasper 
Published: September 2021

Abstract

Study Objectives
Abuse potential properties have been reported for the dual orexin receptor antagonists (DORAs) suvorexant and lemborexant. Daridorexant is a new DORA currently in late-stage clinical development. This randomized, double-blind, double-dummy, placebo- and active-controlled six-period crossover study assessed its abuse potential in healthy recreational sedative drug users (n = 63).

Methods
In each study period, a single, oral, morning dose of either daridorexant (50, 100, and 150 mg), placebo, or active control, i.e. suvorexant (150 mg) or zolpidem (30 mg), was administered. Primary pharmacodynamic (PD) endpoint was the Emax of the drug-liking visual analog scale (VAS) assessed over 24 h. Several secondary subjective and objective PD endpoints were also assessed.

Results
Study validity was confirmed based on drug-liking of suvorexant and zolpidem greater than placebo applying a predefined 15-point validity margin (p &lt; 0.0001). Drug-liking VAS Emax (mean; 95% confidence interval) of daridorexant at 50 mg (73.2; 69.0–77.5) was significantly lower compared to suvorexant (80.7; 77.0–84.5) and zolpidem (79.9; 76.2–83.5) (p &lt; 0.001), but similar at 100 mg (79.1; 75.0–83.3) and 150 mg (81.3; 77.7, 84.8). Such dose-related patterns were also observed for most secondary endpoints. At each daridorexant dose, Drug-liking VAS scores were greater than placebo. Both control drugs and daridorexant were safe and the pharmacokinetics of daridorexant was consistent with earlier trials indicating quick absorption and elimination.

Conclusions
In this large, valid human abuse potential study, daridorexant showed dose-related drug-liking among recreational sedative drug users with lower effects at the highest phase-3 dose, and similar effects at higher doses compared to supratherapeutic doses of suvorexant and zolpidem.

Clinical Trial Registration
Study to Evaluate the Abuse Potential of ACT-541468 in Healthy Recreational Drug Users, https://www.clinicaltrials.gov/ct2/show/NCT03657355?term=ACT-541468&draw=3&rank=18, NCT03657355.
Spectrum of Multiorgan Dysfunction in Scrub Typhus Infection
Authors: Mahajan Vidushi , Guglani Vishal , Singla Nidhi , Chander Jagdish 
Published: September 2021

Abstract

Objectives
We planned this study to determine the clinical spectrum and compare incidence of multiorgan dysfunction in children hospitalized with scrub typhus with other etiologies of tropical fever.

Design
Prospective cohort study.

Setting
Pediatric emergency and PICU services of a university teaching hospital situated in the sub-Himalayan region.

Patient
Children aged 2 months to 14 years with acute undifferentiated fever of more than 5 days.

Interventions
Detailed fever workup was performed in all children. We compared scrub typhus IgM positive children (cases) with remaining febrile children who were negative for scrub IgM assay (controls) for mortality and morbidity.

Main results
We enrolled 224 febrile children; 76 children (34%) were positive for scrub typhus IgM ELISA. Scrub typhus group had a significantly higher incidence of multiorgan dysfunction [OR 3.5 (95% CI 2.0–6.3); p &lt; 0.001] as compared to non-scrub typhus group requiring supportive care. The incidence of altered sensorium [OR 8.8 (95% CI 3.1–24.9)], seizures [OR 3.0 (95% CI 1.1–8.3)], acute respiratory distress syndrome [OR 17.1 (95% CI 2.1–140.1)], acute renal failure (5% vs. 0%), meningitis [OR 6.2 (95% CI 1.2–31.6)], thrombocytopenia [OR 2.8 (95% CI 1.5–5.1)], transaminitis [OR 2.7 (95% CI 1.6–4.8)], requirement of oxygen [OR 17.8 (95% CI 4.0–80.3)], positive pressure support [OR 3.7 (95% CI 1.2–10.5)] and shock requiring inotropes [OR 3.0 (95% CI 1.3–6.7)] was significantly higher in scrub typhus group as compared to the non-scrub typhus group (Table 1).

Conclusions
Pediatric scrub typhus who were hospitalized had severe systemic manifestations when compared to other causes of fever.
XII Literature 1780–1830: The Romantic Period
Authors: Coffey Bysshe Inigo , Davies Colette , Hawley-Sibbett Ruby , Falk Michael , Greentree Shane , Kiek Miranda 
Published: September 2021

AbstractThis chapter has four sections: 1. General and Prose; 2. The Novel; 3. Poetry; 4. Drama. Section 1 is by Bysshe Inigo Coffey; section 2 is by Colette Davies and Ruby Hawley-Sibbett; section 3 is by Michael Falk and Shane Greentree; section 4 is by Miranda Kiek.