bluuebunny/crossref_metadata_2025 huggingface dataset:
Decolonizing Open Science: Southern Interventions
Authors: Dutta Mohan , Ramasubramanian Srividya , Barrett Mereana , Elers Christine , Sarwatay Devina , Raghunath Preeti , Kaur Satveer , Dutta Debalina , Jayan Pooja , Rahman Mahbubur , Tallam Edwin , Roy Sudeshna , Falnikar Ashwini , Johnson Gayle Moana , Mandal Indranil , Dutta Uttaran , Basnyat Iccha , Soriano Cheryll , Pavarala Vinod , Sreekumar T T , Ganesh Shiv , Pandi Asha Rathina , Zapata Dazzelyn
Published: September 2021

Hegemonic Open Science, emergent from the circuits of knowledge production in the Global North and serving the economic interests of platform capitalism, systematically erase the voices of the subaltern margins from the Global South and the Southern margins inhabiting the North. Framed within an overarching emancipatory narrative of creating access for and empowering the margins through data exchanged on the global free market, hegemonic Open Science processes co-opt and erase Southern epistemologies, working to create and reproduce new enclosures of extraction that serve data colonialism-capitalism. In this essay, drawing on our ongoing negotiations of community-led culture-centered advocacy and activist strategies that resist the racist, gendered, and classed structures of neocolonial knowledge production in the metropole in the North, we attend to Southern practices of Openness that radically disrupt the whiteness of hegemonic Open Science. These decolonizing practices foreground data sovereignty, community ownership, and public ownership of knowledge resources as the bases of resistance to the colonial-capitalist interests of hegemonic Open Science.
The Forest Ranger (and the Legislator): How Local Congressional Politics Shape Policy Implementation in Agency Field Offices
Authors: Struthers Cory L , Scott Tyler A , Fleischman Forrest , Arnold Gwen
Published: September 2021

Research on political control over government bureaucracy has primarily focused on direct exercises of power such as appointments, funding, agency design, and procedural rules. In this analysis, we extend this literature to consider politicians who leverage their institutional standing to influence the decisions of local field officials over whom they have no explicit authority. Using the case of the US Forest Service (USFS), we investigate whether field-level decisions are associated with the political preferences of individual congressional representatives. Our sample encompasses 7,681 resource extraction actions initiated and analyzed by 107 USFS field offices between 2005 and 2018. Using hierarchical Bayesian regression, we show that under periods of economic growth and stability, field offices situated in the districts of congressional representatives who oppose environmental regulation initiate more extractive actions (timber harvest, oil and gas drilling, grazing) and conduct less rigorous environmental reviews than field offices in the districts of representatives who favor environmental regulation. By extending existing theories about interactions between politicians and bureaucrats to consider informal means of influence, this work speaks to (1) the role of local political interests in shaping agency-wide policy outcomes and (2) the importance of considering informal and implicit means of influence that operate in concert with explicit control mechanisms to shape bureaucratic behavior.
Are rapid antigen SARS-Cov-2 tests effective for mass screening of travelers at airports? The Olympic experience
Authors: Torres Jaime R
Published: September 2021

Usefulness of mass screening of arriving travelers at airports through rapid antigenic tests to reduce the importation of SARS-Cov-2 into low incidence settings remains unproven. Recent successful Olympic experience indicates the need for additional strategies, including supervised quarantines, frequent retesting and close follow-up of positive individuals to achieve this goal.
Control of travel-related COVID-19 in Bhutan
Authors: Tamang Saran Tenzin , Lhendup Karma , Dorji Thinley
Published: September 2021

Bhutan—a landlocked country in South Asia—has reported 3381 COVID-19 cases per million population and three deaths until August 2021. The country implemented stringent public health measures to prevent widespread outbreak of COVID-19. This paper describes travel-related measures taken by Bhutan and discusses the way forward after COVID-19 vaccination.
Recombination Marks the Evolutionary Dynamics of a Recently Endogenized Retrovirus
Authors: Yang Lei , Malhotra Raunaq , Chikhi Rayan , Elleder Daniel , Kaiser Theodora , Rong Jesse , Medvedev Paul , Poss Mary
Published: September 2021

All vertebrate genomes have been colonized by retroviruses along their evolutionary trajectory. Although endogenous retroviruses (ERVs) can contribute important physiological functions to contemporary hosts, such benefits are attributed to long-term coevolution of ERV and host because germline infections are rare and expansion is slow, and because the host effectively silences them. The genomes of several outbred species including mule deer (Odocoileus hemionus) are currently being colonized by ERVs, which provides an opportunity to study ERV dynamics at a time when few are fixed. We previously established the locus-specific distribution of cervid ERV (CrERV) in populations of mule deer. In this study, we determine the molecular evolutionary processes acting on CrERV at each locus in the context of phylogenetic origin, genome location, and population prevalence. A mule deer genome was de novo assembled from short- and long-insert mate pair reads and CrERV sequence generated at each locus. We report that CrERV composition and diversity have recently measurably increased by horizontal acquisition of a new retrovirus lineage. This new lineage has further expanded CrERV burden and CrERV genomic diversity by activating and recombining with existing CrERV. Resulting interlineage recombinants then endogenize and subsequently expand. CrERV loci are significantly closer to genes than expected if integration were random and gene proximity might explain the recent expansion of one recombinant CrERV lineage. Thus, in mule deer, retroviral colonization is a dynamic period in the molecular evolution of CrERV that also provides a burst of genomic diversity to the host population.
Evolution of Methyltransferase-Like (METTL) Proteins in Metazoa: A Complex Gene Family Involved in Epitranscriptomic Regulation and Other Epigenetic Processes
Authors: Wong Juliet M , Eirin-Lopez Jose M
Published: September 2021

The methyltransferase-like (METTL) proteins constitute a family of seven-beta-strand methyltransferases with S-adenosyl methionine-binding domains that modify DNA, RNA, and proteins. Methylation by METTL proteins contributes to the epigenetic, and in the case of RNA modifications, epitranscriptomic regulation of a variety of biological processes. Despite their functional importance, most investigations of the substrates and functions of METTLs within metazoans have been restricted to model vertebrate taxa. In the present work, we explore the evolutionary mechanisms driving the diversification and functional differentiation of 33 individual METTL proteins across Metazoa. Our results show that METTLs are nearly ubiquitous across the animal kingdom, with most having arisen early in metazoan evolution (i.e., occur in basal metazoan phyla). Individual METTL lineages each originated from single independent ancestors, constituting monophyletic clades, which suggests that each METTL was subject to strong selective constraints driving its structural and/or functional specialization. Interestingly, a similar process did not extend to the differentiation of nucleoside-modifying and protein-modifying METTLs (i.e., each METTL type did not form a unique monophyletic clade). The members of these two types of METTLs also exhibited differences in their rates of evolution. Overall, we provide evidence that the long-term evolution of METTL family members was driven by strong purifying selection, which in combination with adaptive selection episodes, led to the functional specialization of individual METTL lineages. This work contributes useful information regarding the evolution of a gene family that fulfills a variety of epigenetic functions, and can have profound influences on molecular processes and phenotypic traits.
UBA1 and DNMT3A mutations in VEXAS syndrome. A case report and literature review
Authors: Shaukat Farah , Hart Melissa , Burns Timothy , Bansal Pankaj
Published: September 2021

Vacuoles, E1 enzyme, X linked, autoinflammatory, somatic (VEXAS) syndrome is a recently described X-linked autoinflammatory condition associated with somatic mutation of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. It often coexists with myelodysplastic syndrome, which can occur due to DNA (cytosine-5)-methyltransferase 3A (DNMT3A) mutation. These patients, predominantly males, present after the fifth decade of life with unique systemic inflammatory clinical features and have haematological abnormalities and vacuolated precursor cells on bone marrow pathology. Here we describe a unique case of VEXAS syndrome in a patient harbouring DNMT3A gene mutation with coexisting UBA1 mutation with a review of literature.
Glioblastoma as an age-related neurological disorder in adults
Authors: Kim Miri , Ladomersky Erik , Mozny Andreas , Kocherginsky Masha , O’Shea Kaitlyn , Reinstein Zachary Z , Zhai Lijie , Bell April , Lauing Kristen L , Bollu Lakshmi , Rabin Erik , Dixit Karan , Kumthekar Priya , Platanias Leonidas C , Hou Lifang , Zheng Yinan , Wu Jennifer , Zhang Bin , Hrachova Maya , Merrill Sarah A , Mrugala Maciej M , Prabhu Vikram C , Horbinski Craig , James Charles David , Yamini Bakhtiar , Ostrom Quinn T , Johnson Margaret O , Reardon David A , Lukas Rimas V , Wainwright Derek A
Published: September 2021

Background

Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM.

Methods

The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship.

Results

Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve.

Conclusions

Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.
The Impact of Smoke-Free Air Laws and Conventional Cigarette Taxes on Cardiovascular Hospitalizations
Authors: Oliver Jon F
Published: September 2021

Introduction

Smoke-free air legislation and conventional cigarette taxes have long been used to reduce smoking initiation, prevalence, and conventional cigarette consumption. However, the extent to which these policies affect population health across a range of diagnoses and age groups remains less well understood.

Methods

Analyses use 2005–2014 hospital inpatient discharge data from up to 40 US states to estimate the effects of smoke-free air laws and conventional cigarette taxes on cardiovascular hospitalizations among working age and older adults.

Results

An increase in the percent of a county’s population covered by smoke-free air laws yielded a significant decline of 2.4% (Relative risk [RR]: 0.976, 95% confidence interval [95% CI]: 0.954, 0.997) in acute cerebrovascular disease hospitalizations among older adults. Moreover, significant declines of 2.0% (RR: 0.980, 95% CI: 0.967, 0.994) and 2.8% (RR: 0.972, 95% CI: 0.949, 0.996) in acute cerebrovascular disease were observed among older adults in the first year and subsequent years after smoke-free air legislation was implemented, respectively. Conventional cigarette taxes did not yield a significant change in acute cerebrovascular disease hospitalizations, nor did either tobacco control policy lead to a significant decline in acute myocardial infarction hospitalizations.

Conclusions

Smoke-free air laws play an important role in reducing adult cardiovascular hospitalizations. These findings confirm existing research on acute cerebrovascular disease outcomes, as well as the modest effects on acute myocardial infarction hospitalizations observed in state- and national-level analyses.

Implications

Current research at the local level finds smoke-free air laws yield 40% declines in acute myocardial infarction hospitalizations and 29% declines in acute cerebrovascular disease. State- and national-level analyses find smaller effects of smoke-free air laws, and largely omit analyses of working age adults. Existing research likely suffers from omitted variable bias, including state-level tobacco control funding and local-level conventional cigarette taxes. Using adult hospitalization data from up to 40 states, this study confirms existing evidence at the national and state level, and provides new evidence that smoke-free air laws significantly reduce acute cerebrovascular disease hospitalizations among older adults.
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

Introduction

Identifying 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 Methods

We 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 (>75% metabolic activity), intermediate (50.1%–75% activity), slow (25%–50% activity), and poor (<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.

Results

Among 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 Implications

Most 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

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 <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

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

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

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

Introduction

There 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.

Methods

Electronic 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.

Results

We 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).

Conclusion

Patients 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

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

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 < 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 < 0.001). Fewer patients treated with NBX than LAO experienced treatment-related adverse events (25.5% vs 76.0%; P < 0.001) or discontinued treatment because of treatment-related adverse events (7.9% vs 29.3%; P < 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

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

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

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 < 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 < 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

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 < 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

This 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.
Effects of Patient and Surgery Characteristics on Persistent Postoperative Pain
Authors: Mi Xinlei , Zou Baiming , Rashidi Parisa , Baharloo Raheleh , Fillingim Roger B. , Wallace Margaret R. , Crispen Paul L. , Parvataneni Hari K. , Prieto Hernan A. , Gray Chancellor F. , Machuca Tiago N. , Hughes Steven J. , Murad Gregory J.A. , Thomas Elizabeth , Iqbal Atif , Tighe Patrick J.
Published: September 2021

Objective:

Acute postoperative pain intensity is associated with persistent postsurgical pain (PPP) risk. However, it remains unclear whether acute postoperative pain intensity mediates the relationship between clinical factors and persistent pain.

Materials and Methods:

Participants from a mixed surgical population completed the Brief Pain Inventory and Pain Catastrophizing Scale before surgery, and the Brief Pain Inventory daily after surgery for 7 days and at 30 and 90 days after surgery. We considered mediation models using the mean of the worst pain intensities collected daily on each of postoperative days (PODs) 1 to 7 against outcomes of worst pain intensity at the surgical site endpoints reflecting PPP (POD 90) and subacute pain (POD 30).

Results:

The analyzed cohort included 284 participants for the POD 90 outcome. For every unit increase of maximum acute postoperative pain intensity through PODs 1 to 7, there was a statistically significant increase of mean POD 90 pain intensity by 0.287 after controlling for confounding effects. The effects of female versus male sex (m=0.212, P=0.034), pancreatic/biliary versus colorectal surgery (m=0.459, P=0.012), thoracic cardiovascular versus colorectal surgery (m=0.31, P=0.038), every minute increase of anesthesia time (m=0.001, P=0.038), every unit increase of preoperative average pain score (m=0.012, P=0.015), and every unit increase of catastrophizing (m=0.044, P=0.042) on POD 90 pain intensity were mediated through acute PODs 1 to 7 postoperative pain intensity.

Discussion:

Our results suggest the mediating relationship of acute postoperative pain on PPP may be predicated on select patient and surgical factors.
Moderate to severe obstructive sleep apnea is independently associated with inter-arm systolic blood pressure difference: Tokyo Sleep Heart Study
Authors: Shiina Kazuki , Takata Yoshifumi , Nakano Hiroki , Fujii Masatsune , Iwasaki Yoichi , Kumai Kento , Matsumoto Chisa , Chikamori Taishiro , Tomiyama Hirofumi
Published: September 2021

Objective:

Obstructive sleep apnea (OSA) is recognized as an independent risk factor for cardiovascular disease. On the other hand, inter-arm systolic blood pressure difference (IAD), inter-ankle systolic blood pressure difference (IAND), and ankle-brachial index (ABI) are all known predictors of cardiovascular events. The aim of the present study was to investigate the association between OSA and four-limb blood pressure differences.

Methods:

We conducted this cross-sectional study in a large sleep cohort from Tokyo Sleep Heart Study. In 2643 consecutive patients who visited our sleep clinic for polysomnography between 2005 and 2017, all the patients underwent blood pressure measurement simultaneously in all the four limbs by oscillometric methods.

Results:

The prevalence rate of IAD ≥10 mmHg was significantly higher in the moderate OSA (15 ≤ apnea-hypopnea index [AHI] < 30) group (4.2%) and severe OSA (AHI ≥ 30) group (4.6%) than that in the no/mild (AHI < 15) OSA group (1.4%). Multivariate logistic regression analysis also identified moderate to severe OSA as being significantly associated with IAD ≥10 mmHg, even after adjustments for confounding variables (moderate OSA: odds ratio [OR], 4.869; 95% confidence interval [CI], 1.080–21.956; P = 0.039; severe OSA: OR, 5.301; 95% CI, 1.226–22.924; P = 0.026). However, there were no significant associations of the OSA severity with IAND ≥15 mmHg or ABI <0.9.

Conclusions:

Moderate to severe OSA was independently associated with the IAD, not but with the IAND or ABI.
Silver Russell syndrome in a preterm girl with 8q12.1 deletion encompassing PLAG1
Authors: Fernández-Fructuoso José Ramón , De la Torre-Sandoval Cristina , Harbison Madeleine D. , Chantot-Bastaraud Sandra , Temple Karen , Lloreda-Garcia Jose Maria , Olmo-Sanchez Maria , Netchine Irene
Published: September 2021

Silver Russell syndrome (SRS) is a congenital disorder characterized by intrauterine growth retardation (IUGR), feeding difficulties and postnatal growth retardation. In a small number of cases, PLAG1 variants have been described (OMIM #618907). PLAG1 haploinsufficiency decreases Insulin-like growth factor 2 expression and produces a Silver Russell syndrome-like phenotype. Here, we describe the phenotype and molecular features of a 26 months girl with clinical features of SRS, and a de novo 2.1 Mb deletion encompassing PLAG1 is reported in association with clinical features suggestive of SRS.
Multi-task deep learning-based survival analysis on the prognosis of late AMD using the longitudinal data in AREDS
Authors: Ghahramani Gregory , Brendel Matthew , Lin Mingquan , Chen Qingyu , Keenan Tiarnan , Chen Kun , Chew Emily , Lu Zhiyong , Peng Yifan , Wang Fei
Published: September 2021

Age-related macular degeneration (AMD) is the leading cause of vision loss. Some patients experience vision loss over a delayed timeframe, others at a rapid pace. Physicians analyze time-of-visit fundus photographs to predict patient risk of developing late-AMD, the most severe form of AMD. Our study hypothesizes that 1) incorporating historical data improves predictive strength of developing late-AMD and 2) state-of-the-art deep-learning techniques extract more predictive image features than clinicians do. We incorporate longitudinal data from the Age-Related Eye Disease Studies and deep-learning extracted image features in survival settings to predict development of late-AMD. To extract image features, we used multi-task learning frameworks to train convolutional neural networks. Our findings show 1) incorporating longitudinal data improves prediction of late-AMD for clinical standard features, but only the current visit is informative when using complex features and 2) “deep-features” are more informative than clinician derived features. We make codes publicly available athttps://github.com/bionlplab/AMD_prognosis_amia2021.
Mathematical modeling and adequate environmental sampling plans are essential for the public health assessment of COVID-19 pandemics : development of a monitoring indicator for SARS-CoV-2 in wastewater
Authors: Cluzel Nicolas , Courbariaux Marie , Wang Siyun , Moulin Laurent , Wurtzer Sébastien , Bertrand Isabelle , Laurent Karine , Monfort Patrick ,   Obépine consortium, Le Guyader Soizick , Boni Mickaël , Mouchel Jean-Marie , Maréchal Vincent , Nuel Grégory , Maday Yvon
Published: September 2021

Since many infected people experience no or few symptoms, the SARS-CoV-2 epidemic is frequently monitored through massive virus testing of the population, an approach that may be biased and may be difficult to sustain in low-income countries. Since SARS-CoV-2 RNA can be detected in stool samples, quantifying SARS-CoV-2 genome by RT-qPCR in WWTPs1 has been proposed as an alternative tool to monitor virus circulation among human populations. However, measuring SARS-CoV-2 viral load in WWTPs can be affected by many experimental and environmental factors. To circumvent these limits, we propose here a novel indicator WWI2 that partly reduces and corrects the noise associated with the SARS-CoV-2 genome quantification in wastewater. This method has been successfully applied in the context of Obepine, a French national network that has been quantifying SARS-CoV-2 genome in a representative sample of French WWTPs since March 5th 2020. On August 26th, 2021, 168 WWTPs were monitored twice a week in the metropolitan and overseas territories of France. We detail the process of elaboration of this indicator, show that it is strongly correlated to the incidence rate and that the optimal time lag between these two signals is only a few days, making our indicator an efficient complement or even a credible alternative to the incidence rate. This alternative approach may be especially important to evaluate SARS-CoV-2 dynamics in human populations when the testing rate is low.

Figure 1:

Graphical abstract.
Colorectal cancer and microbiota modulation for clinical use. A systematic review
Authors: Madrigal-Matute Julio , Bañón Escandell Sara
Published: September 2021

Colorectal cancer is one of the top contributors to the global burden of cancer incidence and mortality with genetic and environmental factors contributing to its etiology. Modifiable or environmental factors can be the cause of up to 60% of the risk of developing colorectal cancer. Hence, there is a growing interest in specifically defining what can be improved in our lifestyle to reduce this risk, improve the effectiveness of treatments, reduce side effects, and decrease the risk of recurrence. One of the elements directly related to lifestyle is gut microbiota. The microbial ecosystem has a vital role in colorectal cancer prevention and antitumoral response through modulation of the immune system and production of short-chain fatty acids. Numerous approaches have been used to identify healthy microbiota that can reduce the risk of cancer development, improve treatment efficacy, and reduce side effects.

Scientific literature in this subject is growing exponentially and, therefore, systematic reviews and meta-analysis are required to ensure that appropriate recommendations are given to patients.

This work aimed to perform a systematic analysis of the published literature to elucidate whether microbiota modulation through pre-, pro-, symbiotic treatment and/or nutritional intervention can be beneficial for patients diagnosed with colorectal cancer.

Detailed analysis of published studies shows that some prebiotics, such as inulin and resistant starch, probiotics such as lactic strains producers of short-chain fatty acids, and consumption of unprocessed plant products, can be effective recommendations for patients diagnosed with colorectal cancer. This advice should always be individually tailored and followed up by a healthcare professional with expertise in the field.
Robust coordination of collective oscillatory signaling requires single-cell excitability and fold-change detection
Authors: Huyan Chuqiao , Golden Alexander , Zhu Xinwen , Mehta Pankaj , Sgro Allyson E.
Published: September 2021

Complex multicellular behaviors are coordinated at the level of biochemical signaling networks, yet how this decentralized mechanism enables robust control in variable environments and over many orders of magnitude of spatiotemporal scales remains an open question. A stunning example of these behaviors is found in the microbe Dictyostelium discoideum, which uses the small molecule cyclic AMP (cAMP) to drive the propagation of collective signaling oscillations leading to multicellular development. The critical design features of the Dictyostelium signaling network remain unclear despite decades of mathematical modeling and experimental interrogation because each model makes different assumptions about the network architecture and in general, normalizing models for direct comparison presents a major challenge. We overcome this challenge by using recent experimental data to normalize the time and response scales of five major signal relay network models to one another and assess their ability to recapitulate experimentally-observed population and single-cell dynamics. We find that to successfully reproduce the full range of observed dynamical behaviors, single cells must be excitable and respond to the relative fold-change of environmental signals. This suggests these features represent robust principles for coordinating cellular populations through oscillatory signaling and that single-cell excitable dynamics are a generalizable route for controlling population behaviors.