bluuebunny/crossref_metadata_2025 huggingface dataset:
Explicit minimal representation of variance matrices, and its implication for dynamic volatility models
Authors: Abadir Karim M
Published: August 2022

We propose a minimal representation of variance matrices of dimension k, where parameterization and positive-definiteness conditions are both explicit. Then we apply it to the specification of dynamic multivariate volatility processes. Compared to the most parsimonious unrestricted formulation currently available, the required number of covariance parameters (hence processes) is reduced by about a half, which makes them estimable in full parametric generality if needed. Our conditions are easy to implement: there are only k of them, and they are explicit and univariate. To illustrate, we forecast minimum-variance portfolios and show that risk is always reduced (by a factor of 2 to 3 in spite of us using the simplest dynamics) compared to the standard benchmark used in finance, while also improving returns on the investment. Because of our representation, we do not get the usual dimensionality problems of existing unrestricted models, and the performance relative to the benchmark is actually improved substantially as k increases.
Genomic and transcriptomic characterization of theCollimonasquorum sensing genes and regulon
Authors: Uroz Stephane , Geisler Océane , Fauchery Laure , Lami Raphaël , Rodrigues Alice M S , Morin Emmanuelle , Leveau Johan H J , Oger Philippe
Published: August 2022

Collimonads are well-adapted to nutrient-poor environments. They are known to hydrolyse chitin, produce antifungal metabolites, weather minerals, and are effective biocontrol agents protecting plants from fungal diseases. The production of N-acyl homoserine lactones (AHLs) was suggested to be a conserved trait of collimonads, but little is known about the genes that underlie this production or the genes that are controlled by AHLs. To improve our understanding of the role of AHLs in the ecology of collimonads, we carried out transcriptomic analyses, combined with chemical and functional assays, on strain Collimonas pratensis PMB3(1). The main AHLs produced by this strain were identified as 3-hydroxy-hexa- and octa-noyl-homoserine lactone. Genome analysis permitted to identify putative genes coding for the autoinducer synthase (colI) and cognate transcriptional regulator (colR). The ability to produce AHLs was lost in ΔcolI and ΔcolR mutants. Functional assays revealed that the two mutants metabolized glucose, formate, oxalate, and leucine better than the wild-type (WT) strain. Transcriptome sequencing analyses revealed an up-regulation of different metabolic pathways and of motility in the QS-mutants compared to the WT strain. Overall, our results provide insights into the role of the AHL-dependent regulation system of Collimonas in environment colonization, metabolism readjustment, and microbial interactions.
Investigations into metabolic properties and selected nutritional metabolic byproducts of different non-Saccharomyces yeast strains when producing nonalcoholic beer
Authors: Methner Yvonne , Weber Nadine , Kunz Oliver , Zarnkow Martin , Rychlik Michael , Hutzler Mathias , Jacob Fritz
Published: August 2022

Nonalcoholic beers are becoming increasingly popular, in part due to consumers’ awareness of a healthier lifestyle. Additionally, consumers are demanding diversification in the product range, which can be offered by producing nonalcoholic beers using non-Saccharomyces yeasts for fermentation to create a wide variety of flavors. So far, little is known about the nutritionally relevant byproducts that these yeasts release during wort fermentation and whether these yeasts can be considered safe for food fermentations. To gain insights into this, the B vitamins of four different nonalcoholic beers fermented with the yeast species Saccharomycodes ludwigii, Cyberlindnera saturnus (two strains), and Kluyveromyces marxianus were analyzed. Furthermore, a total of 16 beers fermented with different non-Saccharomyces yeast strains were analyzed for biogenic amines. Additionally, stress tolerance tests were performed at 37°C and in synthetic human gastric juice in vitro. B vitamins were found in the four nonalcoholic beers in nutritionally relevant amounts so they could serve as a supplement for a balanced diet. Biogenic amines remained below the limit of determination in all 16 beers, and thus likely had no influence, while the stress tolerance tests gave a first indication that seven yeast strains could possibly tolerate the human gastric juice milieu.
Statistical quantification of confounding bias in machine learning models
Authors: Spisak Tamas
Published: August 2022

Background

The lack of nonparametric statistical tests for confounding bias significantly hampers the development of robust, valid, and generalizable predictive models in many fields of research. Here I propose the partial confounder test, which, for a given confounder variable, probes the null hypotheses of the model being unconfounded.

Results

The test provides a strict control for type I errors and high statistical power, even for nonnormally and nonlinearly dependent predictions, often seen in machine learning. Applying the proposed test on models trained on large-scale functional brain connectivity data (N= 1,865) (i) reveals previously unreported confounders and (ii) shows that state-of-the-art confound mitigation approaches may fail preventing confounder bias in several cases.

Conclusions

The proposed test (implemented in the package mlconfound; https://mlconfound.readthedocs.io) can aid the assessment and improvement of the generalizability and validity of predictive models and, thereby, fosters the development of clinically useful machine learning biomarkers.
Data-driven multi-step self-de-aliasing approach for GRACE and GRACE-FO data processing
Authors: Abrykosov Petro , Murböck Michael , Hauk Markus , Pail Roland , Flechtner Frank
Published: August 2022

Temporal aliasing errors resulting from the undersampling of non-tidal atmospheric as well as oceanic mass variations constitute the largest limitation towards the retrieval of monthly gravity solutions based on GRACE and GRACE-FO satellite gravity missions. Their mitigation is thus a primary goal of current research. Unfortunately, the two-step co-parametrization approach proposed for application in Bender-type gravity retrieval scenario in Wiese et al. yields no added value for a single satellite pair. A detailed study of this parametrization strategy is carried out and it is shown that the reason for this is the flawed central assumption of the proposed method, that is that signals of different spatial wavelengths can be perfectly captured and separated with respect to their temporal extent. Based on this finding, we derive a multi-step self-de-aliasing approach (DMD) which aims to rectify the shortcoming of the Wiese et al. method specifically for the single-pair case while retaining its independence from background-model-based de-aliasing of non-tidal atmosphere and ocean (AO) signal components. The functionality and added value of this novel approach is validated within a set of numerical closed-loop simulations as well as in real GRACE and GRACE-FO data processing. The simulation results show that the DMD may improve the gravity retrieval performance in the high-degree spectrum by more than one order of magnitude if one aims to retrieve the full AOHIS (i.e. atmosphere, ocean, hydrology, ice, solid earth) signal, and by at least a factor 5 if a priori AO de-aliasing is applied. Simultaneously, the DMD is shown to degrade the retrieval of the low degrees, but it is also demonstrated that this issue can be mitigated by introducing a constraint into the processing scheme. The simulation results are widely confirmed by results obtained from applying the DMD to real GRACE/GRACE-FO data of the test years 2007, 2014 and 2019. The applicability of the DMD is further shown for Bender-type gravity retrieval. It is demonstrated that in case of a double-pair-based gravity retrieval this approach is at least equivalent to the Wiese et al. method.
Delineating the Spread and Prevalence of SARS-CoV-2 Omicron Sublineages (BA.1–BA.5) and Deltacron Using Wastewater in the Western Cape, South Africa
Authors: Johnson Rabia , Mangwana Noluxabiso , Sharma Jyoti R , Muller Christo J F , Malemela Kholofelo , Mashau Funanani , Dias Stephanie , Ramharack Pritika , Kinnear Craig , Glanzmann Brigitte , Viraragavan Amsha , Louw Johan , Surujlal-Naicker Swastika , Nkambule Sizwe , Webster Candice , Mdhluli Mongezi , Gray Glenda , Mathee Angela , Preiser Wolfgang , Vorster Alvera , Dalvie Shareefa , Street Renee
Published: August 2022

This study was one of the first to detect Omicron sublineages BA.4 and BA.5 in wastewater from South Africa. Spearman rank correlation analysis confirmed a strong positive correlation between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA in wastewater samples and clinical cases (r = 0.7749, P < .0001). SARS-CoV-2 viral load detected in wastewater, resulting from the Delta-driven third wave, was significantly higher than during the Omicron-driven fourth wave. Whole-genome sequencing confirmed presence of Omicron lineage defining mutations in wastewater with the first occurrence reported 23 November 2021 (BA.1 predominant). The variant spread rapidly, with prevalence of Omicron-positive wastewater samples rising to >80% by 10 January 2022 with BA.2 as the predominant sublineage by 10 March 2022, whilst on 18 April 2022 BA.4 and BA.5 were detected in selected wastewater sites. These findings demonstrate the value of wastewater-based epidemiology to monitor the spatiotemporal spread and potential origin of new Omicron sublineages.
Cancer Hazard Evaluations for Contemporary Needs: Highlights From New National Toxicology Program Evaluations and Methodological Advancements
Authors: Lunn Ruth M , Mehta Suril S , Jahnke Gloria D , Wang Amy , Wolfe Mary S , Berridge Brian R
Published: August 2022

The National Toxicology Program strives to raise awareness of cancer hazards in our environment. Identifying cancer hazards is key to primary prevention, informing public health decision making, and decreasing the global cancer burden. In December 2021, the US congressionally mandated 15th Report on Carcinogens was released, adding 8 new substances to the cumulative report. Chronic infection with Helicobacter pylori is listed as “known to be a human carcinogen.” Antimony trioxide and 6 haloacetic acids found as water disinfection by-products—dichloroacetic acid, dibromoacetic acid, bromochloroacetic acid, tribromoacetic acid, bromodichloroacetic acid, chlorodibromoacetic acid—are listed as “reasonably anticipated to be a human carcinogen.” A new dashboard provides interactive visualization and interrogation of the 256 listed substances, their uses, and associated cancers. Also, the National Toxicology Program recently published a Cancer Hazard Assessment Report on exposure scenarios associated with circadian disruption, concluding that persistent night shift work can cause breast cancer and certain lighting conditions may cause cancer. As highlighted in these reports and evaluations, we are evolving our approaches to meet contemporary challenges. These approaches include focusing on real-world exposures and advancing our methods to address challenges in cancer hazard assessments (eg, developing more structured approaches to evaluate mechanistic data and incorporating read-across approaches to assess chemicals lacking adequate human or animal cancer data). To promote public health, we provide information on environmental health disparities and disease prevention. Building on these efforts, we aim to continue our contributions to the war on cancer, declared 50 years ago.
A Logic for Desire Based on Causal Inference
Authors: Xie Kaibo , Yan Jialiang
Published: August 2022

Reasoning about desire plays a significant role in logic, artificial intelligence and philosophy, etc. In this paper, we propose an interpretation of desire that takes into account causal inference. To formalize this idea, we build a desire-causality model by combing the betterness model in preference logic and the causal model in the logic for causal reasoning. We then develop a logic for desire based on this semantics, and an axiomatization for our formal system is given.
Higher order initial conditions with massive neutrinos
Authors: Elbers Willem , Frenk Carlos S , Jenkins Adrian , Li Baojiu , Pascoli Silvia
Published: August 2022

The discovery that neutrinos have mass has important consequences for cosmology. The main effect of massive neutrinos is to suppress the growth of cosmic structure on small scales. Such growth can be accurately modelled using cosmological N-body simulations, but doing so requires accurate initial conditions (ICs). There is a trade-off, especially with first-order ICs, between truncation errors for late starts and discreteness and relativistic errors for early starts. Errors can be minimized by starting simulations at late times using higher order ICs. In this paper, we show that neutrino effects can be absorbed into scale-independent coefficients in higher order Lagrangian perturbation theory (LPT). This clears the way for the use of higher order ICs for massive neutrino simulations. We demonstrate that going to higher order substantially improves the accuracy of simulations. To match the sensitivity of surveys like DESI and Euclid, errors in the matter power spectrum should be well below $1{{\ \rm per\ cent}}$. However, we find that first-order Zel’dovich ICs lead to much larger errors, even when starting as early as z = 127, exceeding $1{{\ \rm per\ cent}}$ at z = 0 for k > 0.5 Mpc−1 for the power spectrum and k > 0.1 Mpc−1 for the equilateral bispectrum in our simulations. Ratios of power spectra with different neutrino masses are more robust than absolute statistics, but still depend on the choice of ICs. For all statistics considered, we obtain $1{{\ \rm per\ cent}}$ agreement between 2LPT and 3LPT at z = 0.
The population of Galactic Centre filaments – III. Candidate radio and stellar sources
Authors: Yusef-Zadeh F , Arendt R G , Wardle M , Heywood I , Cotton W
Published: August 2022

Recent MeerKAT radio continuum observations of the Galactic Centre at 20 cm show a large population of non-thermal radio filaments (NRFs) in the inner few hundred pc of the Galaxy. We have selected a sample of 57 radio sources, mainly compact objects, in the MeerKAT mosaic image that appear to be associated with NRFs. The selected sources are about four times the number of radio point sources associated with filaments than would be expected by random chance. Furthermore, an apparent correlation between bright IR stars and NRFs is inferred from their similar latitude distributions, suggesting that they both co-exist within the same region. To examine if compact radio sources are related to compact IR sources, we have used archival 2MASS, and Spitzer data to make spectral energy distribution of individual stellar sources coincident or close to radio sources. We provide a catalogue of radio and IR sources for future detailed observations to investigate a potential three-way physical association between NRFs, compact radio and IR stellar sources. This association is suggested by models in which NRFs are cometary tails produced by the interaction of a large-scale nuclear outflow with stellar wind bubbles in the Galactic Centre.
Human TRUB1 is a highly conserved pseudouridine synthase responsible for the formation of Ψ55 in mitochondrial tRNAAsn, tRNAGln, tRNAGlu and tRNAPro
Authors: Jia Zidong , Meng Feilong , Chen Hui , Zhu Gao , Li Xincheng , He Yunfan , Zhang Liyao , He Xiao , Zhan Huisen , Chen Mengquan , Ji Yanchun , Wang Meng , Guan Min-Xin
Published: August 2022

Pseudouridine (Ψ) at position 55 in tRNAs plays an important role in their structure and function. This modification is catalyzed by TruB/Pus4/Cbf5 family of pseudouridine synthases in bacteria and yeast. However, the mechanism of TRUB family underlying the formation of Ψ55 in the mammalian tRNAs is largely unknown. In this report, the CMC/reverse transcription assays demonstrated the presence of Ψ55 in the human mitochondrial tRNAAsn, tRNAGln, tRNAGlu, tRNAPro, tRNAMet, tRNALeu(UUR) and tRNASer(UCN). TRUB1 knockout (KO) cell lines generated by CRISPR/Cas9 technology exhibited the loss of Ψ55 modification in mitochondrial tRNAAsn, tRNAGln, tRNAGlu and tRNAPro but did not affect other 18 mitochondrial tRNAs. An in vitro assay revealed that recombinant TRUB1 protein can catalyze the efficient formation of Ψ55 in tRNAAsn and tRNAGln, but not in tRNAMet and tRNAArg. Notably, the overexpression of TRUB1 cDNA reversed the deficient Ψ55 modifications in these tRNAs in TRUB1KO HeLa cells. TRUB1 deficiency affected the base-pairing (18A/G-Ψ55), conformation and stability but not aminoacylation capacity of these tRNAs. Furthermore, TRUB1 deficiency impacted mitochondrial translation and biogenesis of oxidative phosphorylation system. Our findings demonstrated that human TRUB1 is a highly conserved mitochondrial pseudouridine synthase responsible for the Ψ55 modification in the mitochondrial tRNAAsn, tRNAGln, tRNAGlu and tRNAPro.
2′-O-Methylation of the second transcribed nucleotide within the mRNA 5′ cap impacts the protein production level in a cell-specific manner and contributes to RNA immune evasion
Authors: Drazkowska Karolina , Tomecki Rafal , Warminski Marcin , Baran Natalia , Cysewski Dominik , Depaix Anaïs , Kasprzyk Renata , Kowalska Joanna , Jemielity Jacek , Sikorski Pawel J
Published: August 2022

In mammals, m7G-adjacent nucleotides undergo extensive modifications. Ribose of the first or first and second transcribed nucleotides can be subjected to 2′-O-methylation to form cap1 or cap2, respectively. When the first transcribed nucleotide is 2′-O-methylated adenosine, it can be additionally modified to N6,2′-O-dimethyladenosine (m6Am). Recently, the crucial role of cap1 in distinguishing between ‘self’ and ‘non-self’ in mammalian cells during viral infection was revealed. Here, we attempted to understand the impact of cap methylations on RNA-related processes. Therefore, we synthesized tetranucleotide cap analogues and used them for RNA capping during in vitro transcription. Using this tool, we found that 2′-O-methylation of the second transcribed nucleotide within the mRNA 5′ cap influences protein production levels in a cell-specific manner. This modification can strongly hamper protein biosynthesis or have no influence on protein production levels, depending on the cell line. Interestingly, 2′-O-methylation of the second transcribed nucleotide and the presence of m6Am as the first transcribed nucleotide serve as determinants that define transcripts as ‘self’ and contribute to transcript escape from the host innate immune response. Additionally, cap methylation status does not influence transcript affinity towards translation initiation factor eIF4E or in vitro susceptibility to decapping by DCP2; however, we observe the resistance of cap2-RNA to DXO (decapping exoribonuclease)-mediated decapping and degradation.
Patterns in Mental Health Symptomatology and Cigarette, E-cigarette, and Marijuana Use Among Texas Youth and Young Adults Amid the Coronavirus Disease 2019 Pandemic
Authors: Clendennen Stephanie L , Chen Baojiang , Sumbe Aslesha , Harrell Melissa B
Published: August 2022

Introduction

This study examined patterns in mental health symptomatology and smoking and vaping behaviors among youth and young adults over a 1-year period from before to during the first year of the Coronavirus Disease 2019 (COVID-19) pandemic.

Aims and Methods

Participants (n = 2148) were 16–24-year-olds who completed three waves of the Texas Adolescent Tobacco and Marketing Surveillance Study (TATAMS). Descriptive statistics and mixed effects logistic regression models were used to examine changes in anxiety symptoms, depressive symptoms, perceived stress, and cigarette, e-cigarette, and marijuana use from before COVID-19 (fall 2019) to 6-month follow-up (spring 2020) and 12-month follow-up (fall 2020) periods during COVID-19. Longitudinal associations between mental health symptomatology and smoking and vaping were examined.

Results

Modest increases in symptoms of anxiety and depression were observed from before to during COVID-19. Perceived stress remained high and unchanged. Ever marijuana use increased at 6- and 12-month follow-up, while ever cigarette and e-cigarette use increased significantly only at 12-month follow-up. Marijuana use frequency increased significantly at 6- and 12-month follow-ups. Adjusting for sociodemographic factors, increased symptoms of anxiety and depression predicted increases in ever cigarette, e-cigarette, and marijuana use, and past 30-day cigarette and e-cigarette use, but not past 30-day marijuana use. Higher perceived stress predicted increases in ever use of cigarettes and e-cigarettes and past 30-day cigarette use.

Conclusions

Changes in mental health symptomatology and smoking and vaping behaviors among young people in Texas varied during this period of the COVID era. Increases in mental health symptomatology predicted increases in cigarette, e-cigarette, and marijuana use behaviors.

Implications

This study adds to the limited research on the longitudinal impact of anxiety symptoms, depressive symptoms, and perceived stress on cigarette, e-cigarette, and marijuana use from before to during the first year of the COVID-19 pandemic. Findings warrant health messaging and interventions that address the significant impact of worse mental health on increased smoking and vaping behavior, especially during crises like COVID-19 that may exacerbate mental health and substance use behaviors.
Towards a Poetic Sociology of Iran
Authors: Manoukian Setrag
Published: August 2022

Media and scholarly narratives often see an essential connection between Iranians and their poems and use poetry to explain Iranian politics, morality, and the self. Instead of this sociology of Iranian poetry, the chapter proposes a poetic sociology of Iran. Through an ethnography of poetic assemblies in the city of Shiraz, the chapter aims at describing a specific poetic modality of existence in several of its domains of relevance: geography, physics, logic, pedagogy, and sociology. In dialogue with the rich lineage of social studies of poetry in the Middle East and literary studies of Arabo-Persian traditions, the chapter suggests that the power of poetry in Iran, and perhaps elsewhere, resides in its potential to elide the constitutive opposition between norms and passions, between what a life should be and how it is, instituting an existential “bio-poetic” ground.
The Empty Tahrir Square
Authors: Raouf Ezzat Heba
Published: August 2022

The political implications of the changing urban maps that start from Tahrir Square and expand to the rest of Egypt need an interdisciplinary approach that combines political theory with traffic routes maps, and de-densification of Tahrir with the new urban forms emerging across the country.

The uprising in Egypt on the 25th of January and the following courses of revolution and counter-revolution entail a spatial dimension that is wider than dismantling the multitude in urban centers and securitizing the public space. Besides changing the geo-semiotics of Tahrir and their symbolism, a systematic de-densification of a wider plan de-densification in Cairo started unfolding, with traffic logics that are changing the urban and social fabric in the city. With the construction of a number of new cities, the new urban pattern emerging is polycentric, and coupled with constructing military bases in each region. The new map indicates a partial re-distribution of population, but also a high degree of urban segregation. To examine the unfolding changes and the political implications the flux between hierarchy and heterarchy is highlighted, as well as the relation between urban nodality and nodal security.
Genesis of Oceanic Oxide Gabbros and Gabbronorites During Reactive Melt Migration at Transform Walls (Doldrums Megatransform System; 7–8°N Mid-Atlantic Ridge)
Authors: Basch V , Sanfilippo A , Skolotnev S G , Ferrando C , Muccini F , Palmiotto C , Peyve A A , Ermolaev B V , Okina O I , Ligi M
Published: August 2022

The Doldrums Megatransform System (~7–8°N, Mid-Atlantic Ridge) shows a complex architecture including four intra-transform ridge segments bounded by five active transform faults. Lower crustal rocks are exposed along the Doldrums and Vernadsky transform walls that bound the northernmost intra-transform ridge segment. The recovered gabbros are characterized by variably evolved chemical compositions, ranging from olivine gabbros to gabbronorites and oxide gabbros, and lack the most primitive gabbroic endmembers (troctolites, dunites). Notably, the numerous recovered gabbronorites show up to 20 vol. % of coarse-grained orthopyroxene. Although covariations in mineral and bulk-rock chemical compositions of the olivine and oxide gabbros define trends of crystallization from a common parental melt, the gabbronorites show elevated light over heavy rare earth elements (LREE/HREE) ratios in both bulk-rock and mineral compositions. These features are not consistent with a petrological evolution driven solely by fractional crystallization, which cannot produce the preferential enrichments in highly incompatible elements documented in the orthopyroxene-bearing lithologies. We suggest that gabbronorites crystallized from evolved melts percolating and partly assimilating a pre-existing olivine gabbro matrix. Saturation in orthopyroxene and selective enrichments in LREE relative to M-HREE are both triggered by an increase in assimilated crystal mass, which ranges from negligible in the oxide-gabbros to abundant in the gabbronorites. This melt–rock reaction process has been related to lateral melt migration beneath ridge-transform intersections, where variably evolved melts injected from the peripheral parts of the melting region towards the transform zone may interact with a gabbroic crystal mush to form abundant oxide-bearing gabbronoritic associations.
Tracing Volatiles, Halogens, and Chalcophile Metals during Melt Evolution at the Tolbachik Monogenetic Field, Kamchatka
Authors: Iveson Alexander A , Humphreys Madeleine C S , Jenner Frances E , Kunz Barbara E , Savov Ivan P , De Hoog Jan C M , Churikova Tatiana G , Gordeychik Boris N , Hammond Samantha J , Plechov Pavel Yu , Blundy Jon , Agostini Samuele
Published: August 2022

Melt storage and supply beneath arc volcanoes may be distributed between a central stratovolcano and wider fields of monogenetic cones, indicating complex shallow plumbing systems. However, the impact of such spatially variable magma storage conditions on volatile degassing and trace element geochemistry is unclear. This study explores magma generation and storage processes beneath the Tolbachik volcanic field, Kamchatka, Russia, in order to investigate the evolution of the magmatic volatile phase and, specifically, the strong enrichment of chalcophile metals (in particular, Cu) in this system. We present new geochemical data for a large suite of olivine- and clinopyroxene-hosted melt inclusions (and host phenocrysts) from five separate monogenetic cones within the Tolbachik volcanic field. These high-Al composition magmas likely reflect the homogenised fractionation products of primitive intermediate-Mg melt compositions, stored at shallow depths after significant fractional crystallisation. Boron isotope compositions and incompatible trace element ratios of the melt inclusions suggest a deeper plumbing system that is dominated by extensive fractional crystallisation and fed by melts derived from an isotopically homogeneous parental magma composition. Volatile components (H2O, CO2, S, Cl, F) show that magmas feeding different monogenetic cones had variable initial volatile contents and subsequently experienced different fluid-saturated storage conditions and degassing histories. We also show that melts supplying the Tolbachik volcanic field are strongly enriched in Cu compared with almost all other Kamchatka rocks, including samples from the Tolbachik central stratocones, and other volcanoes situated in close proximity in the Central Kamchatka Depression. The melt inclusions record Cu concentrations ≥450 μg/g at ca. 4–5 wt.% MgO, which can only be explained by bulk incompatible partitioning behaviour of Cu, i.e. evolution under sulphide-undersaturated conditions. We suggest that initial mantle melting in this region exhausted mantle sulphides, leading to sulphide undersaturated primitive melts. This sulphide-free model for the high-Al cone melts is further supported by S/Se and Cu/Ag values that overlap those of the primitive mantle and MORB array, with bulk rock Cu/Ag ratios also overlapping other with other global arc datasets for magma evolution prior to fractionation of a monosulfide solid solution. We therefore demonstrate that the combination of novel chalcophile metal analyses with trace element, isotopic, and volatile data is a powerful tool for deciphering complex magmatic evolution conditions across the entire volcanic field.
Impact of initial therapy with upadacitinib or adalimumab on achievement of 48-week treatment goals in patients with rheumatoid arthritis: post hoc analysis of SELECT-COMPARE
Authors: Mysler Eduardo , Tanaka Yoshiya , Kavanaugh Arthur , Aletaha Daniel , Taylor Peter C , Song In-Ho , Shaw Tim , Song Yanna , DeMasi Ryan , Ali Mira , Fleischmann Roy
Published: August 2022

Objectives

Evaluate the importance of treatment sequencing in SELECT-COMPARE, assessing potential differences between starting upadacitinib or adalimumab therapy following inadequate MTX response.

Methods

Patients from SELECT-COMPARE were randomized to upadacitinib 15 mg once daily, placebo or adalimumab 40 mg. Per protocol, patients with <20% improvement in tender or swollen joint counts (weeks 14, 18, 22) or failure to achieve Clinical Disease Activity Index (CDAI) low disease activity (LDA) at week 26 were blindly switched from upadacitinib to adalimumab or vice versa. Treatment outcomes, including clinical remission/LDA, physical function, pain and a novel combined endpoint for deep response, were evaluated through 48 weeks and corresponding time-averaged response rates determined. Data were analysed by initial randomized group regardless of any subsequent switch in therapy.

Results

This post hoc analysis included 651 patients initially randomized to upadacitinib (of whom 252 switched to adalimumab) and 327 patients initially randomized to adalimumab (of whom 159 switched to upadacitinib). At week 48, patients randomized to either therapy demonstrated similar achievement of most treatment endpoints. Greater improvements in the total time spent in a lower disease state were observed for initial upadacitinib vs initial adalimumab therapy across most clinical and patient-reported outcomes through 48 weeks, and the median time to DAS28(CRP) <2.6/≤3.2 occurred 6–8 weeks earlier among those randomized to upadacitinib.

Conclusion

Following a modified treat-to-target strategy, rates of CDAI remission/LDA and DAS28(CRP) <2.6/≤3.2 at 48 weeks were similar, regardless of starting therapy. However, patients initially receiving upadacitinib reached treatment targets more quickly and spent more time in clinical targets over the initial 48 weeks of treatment.

Trial registration

ClinicalTrials.gov, https://clinicaltrials.gov, NCT02629159
Novel therapeutic agents for myelofibrosis after failure or suboptimal response to JAK2 inhbitors
Authors: Breccia Massimo , Assanto Giovanni Manfredi , Laganà Alessandro , Scalzulli Emilia , Martelli Maurizio
Published: August 2022

Purpose of review

JAK2 inhibitors have changed the therapeutic strategies for the management of primary and secondary myelofibrosis. Ruxolitinib, the first available agent, improved disease-related symptoms, spleen volume, and overall survival compared to conventional chemotherapy. It has been revealed that after 3 years of treatment, about 50% of patients discontinued ruxolitinib for resistance and/or intolerance and should be candidate to a second line of treatment.

Recent findings

Second-generation tyrosine kinase inhibitors have been tested in this setting, but all these new drugs do not significantly impact on disease progression. Novel agents are in developments that target on different pathways, alone or in combination with JAK2 inhibitors.

In this review, we summarize all the clinical efficacy and safety data of these drugs providing a vision of the possible future.
Modern treatment approaches to adult acute T-lymphoblastic and myeloid/T-lymphoblastic leukemia: from current standards to precision medicine
Authors: Leoncin Matteo , La Starza Roberta , Roti Giovanni , Pagliaro Luca , Bassan Renato , Mecucci Cristina
Published: August 2022

Purpose of review

To review the most recent advancements in the management of adult T-cell acute lymphoblastic leukemia (T-ALL), we summarize insights into molecular diagnostics, immunotherapy, targeted therapy and new techniques of drug sensitivity profiling that may support further therapeutic progress in T-ALL subsets.

Recent findings

With current induction/consolidation chemotherapy and/or risk-oriented allogeneic stem cell transplantation programs up to 95% adult T-ALL patients achieve a remission and >50% (up to 80% in adolescents and young adults) are cured. The group of patients who fail upfront therapy, between 25% and 40%, is enriched in high-risk characteristics (unfavorable genetics, persistent minimal residual disease) and represents the ideal setting for the study of molecular mechanisms of disease resistance, and consequently explore novel ways of restoration of drug sensitivity and assess patient/subset-specific patterns of drug vulnerability to targeting agents, immunotherapy and cell therapy.

The emerging evidence supports the contention that precision medicine may soon allow valuable therapeutic chances to adult patients with high-risk T-ALL. The ongoing challenge is to identify the best way to integrate all these new data into the therapeutic path of newly diagnosed patients, with a view to optimize the individual treatment plan and increase the cure rate.
Humanized CD19-directed CAR-T Cell Therapy in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia With CNSL or Neurological Comorbidity
Authors: Zhang Na , Shao Jingbo , Li Hong , Zhu Jiashi , Xia Min , Chen Kai , Jiang Hui
Published: August 2022

Chimeric antigen receptor T cell (CAR-T) therapy has breakthrough potential for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). However, because of the risk for neurotoxicity, trials usually exclude patients with central nervous system leukemia (CNSL) or active neurological comorbidities (NC). Here, we evaluated the efficacy and neurotoxicity of humanized CD19-directed CAR-T therapy for R/R ALL with CNSL or NC. Of 12 enrolled patients, 4 had CNSL with bone marrow (BM) or testicular recurrence, 3 had BM relapses with NC, and 5 had BM relapse without NC. Bridging chemotherapy was performed for high tumor burden before CAR-T therapy. Patients with CNSL or BM relapse with NC or without NC experienced 100% complete remission. Tumor burden reduction did not occur in 1 patient with NC, who developed grade 5 neurotoxicity before BM assessment, and one patient with CNSL developed leukoencephalopathy. Severe cytokine release syndrome and neurotoxicity developed in 0% with CNSL, 33.3% with BM relapse and NC, and 0% without NC. CAR-T cells expanded in the cerebrospinal fluid (CSF) of all patients with no difference among CNSL, BM with NC, or no NC (respective median percentages among lymphocyte: 33.7%, 48.2% and 34.5%, P=0.899; respective median concentrations: 0.82, 2.21, and 0.46/μL, P=0.719). Median CSF CAR-T cell duration was 5.5 (3–9) months with CNSL and 3 (2–3) months without CNSL (P=0.031). CAR-T can be given safely and effectively to pediatric patients with R/R ALL with CNSL or NC who have near-normal neurological status. High tumor burden may confer increased risk for severe neurotoxicity.
Polypharmacy and Major Adverse Events in Atrial Fibrillation
Authors: Caturano Alfredo , Spiezia Serenella , Brunelli Vincenzo , Galiero Raffaele , Sasso Ferdinando Carlo
Published: August 2022

Atrial fibrillation is the most common arrhythmia, ranging from 0.1% in patients <55 years to >9% in octogenarian patients. Polypharmacotherapy is crucial in atrial fibrillation management, and in many of the concomitant comorbidities, such as hypertension, heart failure, coronary artery disease, and diabetes. However, polypharmacy represents a major concern because of the associated risks of adverse events onset, with an increased risk of all-cause mortality and cardiovascular mortality. In this study, we commented data reported by Tsagkaris et al comparing them with previous reports.
Surgical Interventions for Lumbosacral Plexus Injuries: A Systematic Review
Authors: Nichols David Spencer , Fenton Jesse , Cox Elizabeth , Dang Jonathan , Garbuzov Anna , McCall-Wright Patti , Chim Harvey
Published: August 2022

Background:

Nerve reconstruction techniques for lumbosacral plexus (LSP) injuries vary. There are no clear treatment guidelines available, and summative evaluations of the literature discussing these surgeries are lacking. For these reasons, this investigation aimed to systematically review and consolidate all available literature discussing surgical interventions for LSP injuries and cohesively present patient-reported and objective postoperative outcomes.

Methods:

The authors conducted a systematic review using PubMed, Embase, Web of Science, ProQuest Dissertations and Theses Global (via Proquest.com), and ClinicalTrials.gov databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. After title and abstract screening, identified articles were read in full and selected for inclusion based on prespecified criteria.

Results:

Our literature search identified 8683 potential citations, and after duplicate removal, abstract screening, and full-text review, 62 studies remained meeting inclusion and exclusion criteria. Outcomes were extracted according to the location of injury and type of surgical repair. Injuries were classified into isolated femoral nerve injuries, isolated obturator nerve injuries, isolated sciatic nerve injuries, and multilevel LSP injuries. Surgical treatment was further classified into exploration with neurolysis, direct repair, nerve grafting, and nerve transfer surgery.

Conclusions:

Although results vary based on the location of the injury and the surgical technique used, nerve grafts and transfers demonstrated reasonable success in improving functional and pain outcomes. Overall, isolated femoral and obturator nerve injuries had the best outcomes reported with surgical treatment. Furthermore, incomplete sciatic nerve and multilevel LSP injuries had more reported surgical options and better outcomes than complete sciatic nerve injuries.
Bipedicled SIEA Flap with Deep Inferior Epigastric Artery and Vein Grafts for Breast Reconstruction
Authors: Nakamura Ryota , Tomita Koichi , Omura Nanaho , Nishimura Eriko , Higashimoto Kyuto , Kubo Tateki , Hikasa Hisashi
Published: August 2022

A superficial inferior epigastric artery (SIEA) flap can be an alternative to a deep inferior epigastric artery perforator (DIEAP) flap in cases where SIEAs are relatively well developed. Although an SIEA flap is less invasive than a DIEAP flap, the pedicles of the former are anatomically shorter, making it more difficult to choose recipient vessels when bilateral SIEAs are necessary. A 45-year-old female diagnosed with cancer of the left breast underwent mastectomy (specimen weight: 750 g) and immediate two-stage breast reconstruction using a free abdominal flap with bilateral pedicles was planned. Preoperative computed tomographic angiography showed that the bilateral DIEAPs in the flap were less than one millimeter in diameter, whereas the bilateral SIEAs were well developed enough for us to opt for a double-pedicled stacked SIEA flap. After the double-pedicled SIEA flap was elevated, folded, and temporarily placed in the subcutaneous pocket, the pedicle length on one side was found to be insufficient. Therefore, portions of the right composite deep inferior epigastric artery (DIEA) and vein (DIEV) grafts (roughly 7 cm) were collected from a short fasciotomy and anastomosed to the peripheral ends of the right SIEA and SIEV, respectively. Following this, the left SIEA and SIEV were antegradely anastomosed to the internal mammary artery and vein (IMA/IMV), while the DIEA/DIEV grafts were retrogradely anastomosed to the IMA/IMV, respectively. We recommend the proactive use of this method, as pedicle extension using the DIEA/DIEV grafts enables a higher degree of freedom in unilateral breast reconstruction using bilateral SIEA flaps.
A Comparative Analysis of the Common Injections Performed by Plastic Surgeons: 2012 and 2019
Authors: Harrington Maya T. , Kandi Lyndsay A. , Janbieh Javier , Pollock Jordan R. , Thornburg Danielle A. , Howard Michael A. , Teven Chad M.
Published: August 2022

Background:

Plastic surgeons regularly perform injections for both cosmetic and functional purposes. This article examines the most common injections utilized by plastic surgeons under Medicare and how their usage and billing has changed between 2012 and 2019.

Methods:

Using the earliest and latest data available on the Centers for Medicare and Medicaid Services’ Provider Utilization and Payment Data File, we first determined Healthcare Common Procedure Coding System injection codes most billed to Medicare in 2012 and 2019. The number of services, amount of Medicare beneficiaries, and reimbursement rates were collected and analyzed for each Healthcare Common Procedure Coding System code from the Provider Utilization and Payment Data File for years 2012 and 2019. We compared the change in reimbursement rate for each injection to the rate of inflation in US dollars over the same period.

Results:

The unadjusted Medicare reimbursement rate for eight included injection types increased an average of 31.63% during the study period. This was not significantly different from the rate of inflation during the same period (+11.33%, P = 0.311). When all Medicare reimbursement data were adjusted for inflation to 2019 dollars, the average percentage change in reimbursement for all included injections in this study increased by 17.58% from 2012 to 2019.

Conclusions:

The findings from our study suggest that injections administered by plastic surgeons appear to be unique in their general stability in reimbursement rates as compared to rates in other fields. Further research should be performed to better understand the driving factors for usage and reimbursement changes.
Time-averaged cumulative blood pressure and cardiovascular outcomes in heart failure with preserved ejection fraction: analysis from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial
Authors: Huang Rihua , Wu Runxin , Lin Yifen , Zhong Xiangbin , Ye Xiaomin , Zhuang Xiaodong , Liao Xinxue
Published: August 2022

Objective:

To determine whether time-averaged cumulative blood pressure (cumBP) is associated with the risk of cardiovascular outcomes among patients with heart failure with preserved ejection fraction.

Method:

Three thousand, three hundred and thirty participants from Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were included in this analysis with a median follow-up of 3 years. CumBP, expressed as mmHg-years, was the sum of mean BP for each pair of successive examinations multiplied by the time. Time-averaged cumBP was calculated by dividing cumBP by total exposure time, also expressed as mmHg. Clinical outcomes of our study including primary endpoint, all-cause death, cardiovascular death and heart failure hospitalization. Multivariable Cox hazard regression models and a restricted cubic spline model were used to assess the association and linearity between time-averaged cumBP and adverse outcomes.

Results:

There is a U-shaped relationship between time-averaged cumBP and primary endpoint, all-cause death, cardiovascular death and heart failure hospitalization among participants with HFpEF, with the nadir risk around 120–129 mmHg of SBP and 70–79 mmHg of DBP after adjusting for confounding variables. Treatment with spironolactone did not affect the association significantly. The finding remained robust across sensitivity analyses.

Conclusion:

Higher or lower time-averaged cumBP was significantly associated with a higher risk of adverse events. Control of time-averaged cumulative BP within a reasonable range was an important component of hypertension management in HFpEF.
Changes in blood pressure and cardiovascular disease in middle-aged to older Chinese: the Guangzhou Biobank Cohort Study
Authors: Wang Ying , Zhang Wei Sen , Hao Yuan Tao , Jiang Chao Qiang , Jin Ya Li , Cheng Kar Keung , Lam Tai Hing , Xu Lin
Published: August 2022

Background:

Most studies on the associations of blood pressure (BP) with cardiovascular disease (CVD) risk were based on single or average BP levels. Knowledge on the association between BP trajectories and CVD in middle-aged individuals who are not on antihypertensive medication may inform the care of individuals in this group whose BPs are not controlled.

Methods:

Eight thousand nine hundred and sixty-nine participants aged 50–70 years, without CVD at baseline and not taking antihypertensive medication throughout the study, were included. Four time-points data from the Guangzhou Biobank Cohort Study were used to identify BP trajectories using latent class mixed model. Cox regression was used to investigate the association of BP trajectories with fatal and nonfatal CVD till April 2021.

Results:

Three SBP trajectories were identified: ‘low-slow-increase’ characterized by SBP from 110 to 125 mmHg (86.5%); ‘low-increase’ from 110 to 150 mmHg (8.1%) and ‘moderate-increase’ from 125 to 155 mmHg (5.4%). Compared with the low-slow-increase group, the moderate-increase had the highest risk of CVD (hazard ratio = 1.76, 95% confidence interval = 1.34–2.29), ischemic heart disease (1.77, 1.01–3.09), myocardial infarction (3.52, 1.58–7.85), all strokes (1.88, 1.37–2.60), ischemic stroke (1.65, 1.10–2.49), haemorrhagic stroke (3.98, 1.30–12.12) and CVD mortality (2.41, 1.55–3.76). Higher risks of CVD (1.27, 1.01–1.61) and ischemic stroke (1.49, 1.07–2.09) in the low-increase group were also found.

Conclusion:

Most people between 50 and 70 years of age and not taking antihypertensive medication maintained a slow increase SBP trajectory over a follow-up period of approximately 7 years. However, those whose SBPs increased from low and moderate levels were associated with higher CVD risks.