bluuebunny/crossref_metadata_2025 huggingface dataset:
Unanticipated CNS Safety Signal in a Placebo‐Controlled, Randomized Trial of Co‐Administered Atovaquone‐Proguanil and Amodiaquine
Authors: Chalon Stephan , Chughlay M. Farouk , Abla Nada , Marie Tchouatieu Andre , Haouala Amina , Hutter Ben , Lorch Ulrike , Macintyre Fiona
Published: August 2021

Atovaquone‐proguanil (ATV‐PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine‐pyrimethamine plus AQ for seasonal malaria chemoprevention in African children. This randomized, double‐blind, placebo‐controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PKs) of ATV‐PG plus AQ in healthy adult males and females of Black sub‐Saharan African origin. Participants were randomized to four treatment groups: ATV‐PG/AQ (n = 8), ATV‐PG/placebo (n = 12), AQ/placebo (n = 12), and placebo/placebo (n = 12). Treatments were administered orally once daily for 3 days (days 1–3) at daily doses of ATV‐PQ 1000/400 mg and AQ 612 mg. Co‐administration of ATV‐PG/AQ had no clinically relevant effect on PK parameters for ATV, PG, the PG metabolite cycloguanil, AQ, or the AQ metabolite N‐desethyl‐amodiaquine. Adverse events occurred in 8 of 8 (100%) of participants receiving ATV‐PG/AQ, 11 of 12 (91.7%) receiving ATV‐PG, 11 of 12 (91.7%) receiving AQ, and 3 of 12 (25%) receiving placebo. The safety and tolerability profiles of ATV‐PG and AQ were consistent with previous reports. In the ATV‐PG/AQ group, 2 of 8 participants experienced extrapyramidal adverse effects (EPAEs) on day 3, both psychiatric and physical, which appeared unrelated to drug plasma PKs or cytochrome P450 2C8 phenotype. Although rare cases are reported with AQ administration, the high incidence of EPAE was unexpected in this small study. Owing to the unanticipated increased frequency of EPAE observed, the combination of ATV‐PQ plus AQ is not recommended for further evaluation in prophylaxis of malaria in African children.
Mapping clubroot resistance of Brassica rapa introgressed into Brassica napus and development of molecular markers for the resistance
Authors: Hasan Muhammad Jakir , Shaikh Rubeena , Basu Urmila , Rahman Habibur
Published: August 2021

To date, more than 20 clubroot resistance (CR) loci have been reported in the A‐genome of Brassica rapa; however, only a few of them has been introgressed into B. napus canola. The introgression of additional CR loci will broaden the genetic base of resistance of this crop. In this paper, we report the genetic basis of CR of B. rapa var. pekinensis cultivar ‘Bilko’ introgressed into B. napus, mapping this resistance using a recombinant inbred line (RIL) population developed from B. napus × Bilko‐CR interspecific cross. Evaluation of the F2 and F3 populations of Bilko revealed that a single gene controls resistance to pathotype 3 in this cultivar. Quantitative trait loci‐seq approach using whole‐genome resequencing identified a genomic region of chromosome A03 associated with this resistance in the RIL population. Single nucleotide polymorphism (SNP)‐based allele‐specific markers from the TIR‐NB‐LRR (TNL) gene Bra012688 co‐segregated with this resistance, however, with 0.4–0.8% recombination. Bra012688 is located at 23,877,250–23,883,169 bp of B. rapa cultivar Chiifu‐401 whole‐genome assembly v.3.0, and at 378 bp downstream of another TNL gene Bra012689. Molecular markers, linked to previously reported CR loci of A03, did not co‐segregate with the resistance in the RIL population; this demonstrates the need for the development of new markers for the CR loci following introgression into the recipient species. The knowledge and the SNP allele‐specific markers developed in this study could be used in breeding for clubroot resistance in B. napus.
Groundwater, biodiversity, and the role of flow system scale
Authors: Aldous Allison R. , Gannett Marshall W.
Published: August 2021

Groundwater‐dependent ecosystems and species (GDEs) are found throughout watersheds at locations of groundwater discharge, yet not all GDEs are the same, nor are the groundwater systems supporting them. Groundwater moves along a variety of flow paths of different lengths and with different contributing areas, ranging from shorter local flow paths with low discharge and large seasonal variability to streams, springs and wetlands to longer regional flow paths with potentially larger discharge and low seasonal variability, commonly at low basin elevations. How does this variation in physical hydrology affect the type and distribution of GDEs? Using data on hypsographic position, groundwater‐dependent species distributions, groundwater pumping and streamflow from Oregon, USA, we provide a conceptual model and initial supporting evidence demonstrating that spatial variation in groundwater flow path scales, illustrated using basin hypsography, is a driver of non‐random distribution of GDEs across watersheds. Further, we posit that the spatial variation in primary stressors to groundwater (e.g. pumping and climate change) will differentially affect GDEs depending on their hypsographic position. Furthermore, because of their use for irrigation and municipal water supply, regional groundwater systems and associated species are more likely to be studied and receive regulatory protection. Our initial data point to a disproportionate focus on larger discharge, lower elevation GDEs, which leads to a bias in our understanding of the full suite of biodiversity associated with groundwater discharge as well as their stressors and potential mechanisms for protection.
Development and validation of an environmental DNA protocol to detect an invasive Caribbean freshwater fish, the guppy (Poecilia reticulata)
Authors: Smith Sierra N. , Schlupp Ingo , Higgins Edward D. , Watters Jessa L. , Bennett Kerri‐Ann , Bräger Stefan , Siler Cameron D.
Published: August 2021

We describe the development and validation of a qPCR assay to detect Poecilia reticulata, a highly invasive species of freshwater fish invasive to the Caribbean islands, through environmental DNA (eDNA) sampling. Originating from Trinidad, this species is invasive and detrimental to countless native tropical fish communities. A qPCR assay, consisting of a set of primers and a fluorescent probe, amplifying a 214 base pair target region of the mitochondrial Cytochrome B gene was designed for P. reticulata from existing DNA sequence data. The assay was assessed for target specificity, with no evidence of amplification in closely related or sympatrically distributed non‐target species. In vitro tests indicate that the assay consistently detects P. reticulata down to concentrations of 2.0 × 10−5 ng/μl. The developed assay provides a new, practical tool for monitoring freshwater habitats throughout the Caribbean, allowing for early and rapid detection of invasive fish species of conservation concern.
Stress‐Regulation Design of Lithium Alloy Electrode toward Stable Battery Cycling
Authors: Li Chunhao , Tu Shuibin , Ai Xin , Gui Siwei , Chen Zihe , Wang Wenyu , Liu Xiaoxiao , Tan Yuchen , Yang Hui , Sun Yongming
Published: August 2021

Metallic tin (Sn) foil is a promising candidate anode for lithium‐ion batteries (LIBs) due to its metallurgical processability and high capacity. However, it suffers low initial Coulombic efficiency and inferior cycling stability due to its uneven alloying/dealloying reactions, large volume change and stress, and fast electrode structural degradation. Herein, we report an undulating LiSn electrode fabricated by a scalable two‐step procedure involving mechanical lithography and chemical prelithiation of Sn foil. With the combination of experimental measurements and chemo‐mechanical simulations, it was revealed the obtained undulating LiSn/Sn electrode could ensure better mechanical stability due to the pre‐swelling state from Sn to LixSn and undulating structure of lithography in comparison with plane Sn, homogenize the electrochemical alloying/dealloying reactions due to the activated surface materials, and compensate Li loss during cycling due to the introduction of excess Li from LixSn, thus enabling enhanced electrochemical performance. Symmetric cells consisting of undulating LiSn/Sn electrode with an active thickness of ∼5 um displayed stable cycling over 1000 h at 1 mA cm‐2 and 1 mAh cm‐2 with a low average overpotential of <15 mV. When paired with commercial LiNi0.6Co0.2Mn0.2O2 (NCM622) cathode with high mass loading of 15.8 mg cm‐2, the full cell demonstrated a high capacity of 2.4 mAh cm‐2 and outstanding cycling stability with 84.9% capacity retention at 0.5 C after 100 cycles. This work presents an advanced LiSn electrode with stress‐regulation design toward high‐performance LIBs, and sheds light on the rational electrode design and processing of other high‐capacity lithium alloy anodes.
Atrial fibrillation before heart transplantation is a risk factor for post‐transplant atrial fibrillation and mortality
Authors: Darche Fabrice F. , Helmschrott Matthias , Rahm Ann‐Kathrin , Thomas Dierk , Schweizer Patrick A. , Bruckner Tom , Ehlermann Philipp , Kreusser Michael M. , Warnecke Gregor , Frey Norbert , Rivinius Rasmus
Published: August 2021

Aims

Atrial fibrillation (AF) after heart transplantation (HTX) is associated with worse clinical outcomes. The current study aimed to analyse the association between AF before HTX and AF within 30 days after HTX.

Methods and results

This study included 639 adults who received HTX at Heidelberg Heart Center. Patients were subdivided into four groups depending on the status of AF before and after HTX. Analyses comprised recipient and donor data, medication, echocardiographic features, permanent pacemaker implantation, stroke, and mortality after HTX. Three hundred thirty‐two patients (52.0%) had neither AF before nor after HTX, 15 patients (2.3%) had no AF before HTX but showed AF after HTX, 219 patients (34.3%) showed AF before HTX but had no AF after HTX, and 73 patients (11.4%) had AF before and after HTX. Patients with AF before and after HTX had a higher 1 year post‐transplant mortality (39.7%) than patients without AF before or after HTX (18.1%, P < 0.01). Secondary outcomes showed a higher percentage of enlarged atria, ventricular dysfunction, mitral regurgitation, 1‐year stroke, and 1‐year permanent pacemaker implantation in patients with AF before and after HTX. Multivariate analysis revealed a six‐fold elevated risk for post‐transplant AF in patients with AF before HTX (hazard ratio: 6.59, confidence interval: 3.72–11.65; P < 0.01). Further risk factors for post‐transplant AF were higher donor age and prolonged ischaemic time, whereas total orthotopic HTX was associated with a two‐fold lower risk for post‐transplant AF.

Conclusions

Atrial fibrillation before HTX is a risk factor for post‐transplant AF, permanent pacemaker implantation, and mortality after HTX.
Enhancing affinity‐based electroanalytical biosensors by integrated AC electrokinetic enrichment—A mini review
Authors: Song Min , Lin Xiaogang , Peng Zhijia , Zhang Maoxiao , Wu Jayne
Published: August 2021

Biosensors play a central role in moving diagnostics to being on‐site or decentralized. Affinity biosensor, an important category of biosensors, has important applications in clinical diagnosis, pharmaceuticals, immunology, and other fields. Affinity biosensors rely on specific binding between target analytes and biological ligands such as antibodies, nucleic acids, or other receptors to generate measurable signals. Oftentimes the target analytes in practical samples are of low abundance in a complex matrix. Traditional affinity biosensors mainly rely on random diffusion of analytes in solution to conjugate with biorecognition elements on the sensor surface of electrodes. The process may take hours or even days, which is not conducive to rapid and sensitive detection of biosensors. Therefore, it is strongly desired to incorporate an enrichment mechanism for target analytes into biosensor‐based detection. AC electrokinetic (ACEK) effect can realize rapid enrichment of analytes by application of AC electric fields, which holds great promise for achieving high sensitivity, low detection limit, and rapid turnaround. This article reviews the studies of affinity biosensors integrated with ACEK enrichment in the past decade, and summarizes the latest detection methods, detection devices and applications, hoping to provide some insights and references for researchers in related fields.
In‐bone protein digestion followed by LC‐MS/MS peptide analysis as a new way towards the routine proteomic characterization of human maxillary and mandibular bone tissue in oral surgery
Authors: Hynek Radovan , Michalus Iva , Cejnar Pavel , Šantrůček Jiří , Seidlová Sabina , Kučková Štěpánka , Sázelová Petra , Kašička Václav
Published: August 2021

Proteomic characterization of alveolar bones in oral surgery represents an analytical challenge due to their insoluble character. The implementation of a straightforward technique could lead to the routine use of proteomics in this field. This work thus developed a simple technique for the characterization of bone tissue for human maxillary and mandibular bones. It is based on the direct in‐bone tryptic digestion of proteins in both healthy and pathological human maxillary and mandibular bone samples. The released peptides were then identified by the LC‐MS/MS. Using this approach, a total of 1120 proteins were identified in the maxillary bone and 1151 proteins in the mandibular bone. The subsequent partial least squares–discrimination analysis (PLS‐DA) of protein data made it possible to reach 100% discrimination between the samples of healthy alveolar bones and those of the bone tissue surrounding the inflammatory focus. These results indicate that the in‐bone protein digestion followed by the LC‐MS/MS and subsequent statistical analysis can provide a deeper insight into the field of oral surgery at the molecular level. Furthermore, it could also have a diagnostic potential in the differentiation between the proteomic patterns of healthy and pathological alveolar bone tissue. Data are available via ProteomeXchange with the identifier PXD026775.
Gas Production from Fractured Hydrate Reservoirs: Numerical Modeling and Evaluation
Authors: Han Dongyan , Wang Ziming , Xu Aiguo
Published: August 2021

Fractured natural gas hydrate (NGH) reservoirs are widely tested all over the world. Existence of fractures will aggravate the basin‐scale heterogeneity in both NGH distribution and seepage properties and, therefore, inevitably challenge some of our former understanding on gas production. However, gas productivities of the fractured NGH reservoirs have not been evaluated so far due to the rare accessible logging data for detailed characterization of fractures. Gas production from the fractured NGH reservoirs is modeled and the differences made by position, width, and length of the single conducive fracture and the single hydrate‐filled fracture (HFF), respectively, are systematically analyzed. Sequentially, randomly distributed fracture networks are also considered in the gas productivity estimation. Results show that the conducive fractures in the overburden influence water production dramatically. When hydrate‐bearing layers (HBLs) are characterized with HFFs, there will be obvious secondary formation near the HFFs, which together with its initial high NGH saturation hinders the pressure dissipation and the gas migration, generally shortening the production duration and reducing the accumulated gas. When the overburden and the HBLs are characterized with a randomly distributed fracture network, input fluid from upward could enhance gas production to some extent and lead to a fluctuated gas productive rate.
Multiphysics‐Enabled Liquid State Thermal Harvesting: Synergistic Effects between Pyroelectricity and Triboelectrification
Authors: Chiolerio Alessandro , Garofalo Erik , Bevione Matteo , Cecchini Luca
Published: August 2021

Energy consumption levels show a never‐ending increase since the industrial era. Toward sustainability objectives, it is of outstanding importance to reduce the amount of wasted energy, that typically comes as waste heat, as a consequence of nonunitary efficiency of any thermodynamic process. Herein, a breakthrough in conversion of low enthalpy heat into electricity is presented, based on a liquid state device that operates through multiphysics effects: thermomagnetic advection, triboelectricity, pyroelectricity, and Ludwig–Sorét effect. A synergistic interaction between ferroelectric surfaces and a complex composition colloidal suspension is evidenced, owing to an enhancement of the generated potential of 365% in comparison with pyroelectric effect and 267% in comparison with triboelectric effect, while the current extracted is 54% higher than the pyroelectric effect only and the power extracted by induction remains substantially unperturbed. The impact of this technology on society is also analyzed, on the basis of a set of practical applications, by means of a computational analysis.
High‐resolution hyperspectral imagery from pushbroom scanners on unmanned aerial systems
Authors: Kim Jae‐In , Chi Junhwa , Masjedi Ali , Flatt John Evan , Crawford Melba M. , Habib Ayman F. , Lee Joohan , Kim Hyun‐Cheol
Published: August 2021

Hyperspectral data are gaining popularity in remote sensing and signal processing communities because of the increased spectral information relative to multispectral data. Several airborne and spaceborne hyperspectral datasets are publicly available, facilitating the development of various applications and algorithms. However, hyperspectral data are usually limited by their narrow, highly correlated and contiguous spectral bands in both processing and analysis. Moreover, the resolution of available hyperspectral datasets is not sufficiently high for the identification of small objects. Nevertheless, with the rapidly advancing technology, hyperspectral imaging systems can now be mounted on small aerial vehicles for detecting small objects at low altitude. To properly handle these high spectral and spatial resolution data, new or redesigned data processing or analysis pipelines must be developed, but such datasets are limited. In this study, we describe two hyperspectral datasets acquired by a drone and evaluate their radiometric and geometric quality. Based on appropriate data acquisition and processing approaches, our datasets are expected to be useful as testbeds for new algorithms and applications.
Flood hazard in a semi‐closed basin in northern Ethiopia: Impact and resilience
Authors: Demissie Biadgilgn , Teklemariam Dereje , Haile Mitiku , Meaza Hailemariam , Nyssen Jan , Billi Paolo , Abera Wuletawu , Gebrehiwot Misgina , Haug Ruth , Van Eetvelde Veerle
Published: August 2021

Even though flooding is a threat to rural communities in plains drained by ephemeral rivers, the magnitude of its impact, coping/prevention mechanisms, and the implications for river management are not well known. In this study, data were collected using a phenomenological‐based research design. Field observations, a questionnaire (n = 440), key informant interviews (10), and one focus group discussion (with seven discussants) were used to collect the desired data from flood‐prone farmers. As the results show, 42% of the respondents believe that flooding has become stronger over the past 20 years, whereas 38% believe there has been no change. As mitigation measures, 52% of the respondents suggested evacuating to neighbouring villages as the best option. Most of the damage was experienced in farmlands (including crops, either harvested or standing) and settlements. As coping mechanisms, 31% of the respondents were displaced, whereas an additional 40% were forced to construct new houses for their settlement. Chi‐square testing showed that the farmers’ responses statistically varied among different groups (p < .001). In the meantime, community participation in flood control and catchment management is important. Improving flood management knowledge and the skills of different groups in a community is equally important. In this case, a qualitative inquiry approach was a good option to assess the hydrological conditions of rivers.
The moderating role of polycentric institutions in the relationship between effectuation/causation logics and corporate entrepreneur's decision‐making processes
Authors: Garrido Ivan , Vasconcellos Sílvio , Faccin Kadígia , Monticelli Jefferson Marlon , Carpenedo Caroline
Published: August 2021

Research Summary

This study analyzes how firms respond to institutional polycentrism, a governance system that emerges from multiple and independent centers of power that interact to determine and regulate an evolutionary overarching comprehensive social system of rules. We propose that institutional polycentrism moderates corporate entrepreneurs' decision‐making processes. We conducted a case study at a multinational corporation over four decades of internationalization using process data analysis. We found that institutional polycentrism determines a calibration between causation and effectuation logics. The study offers two contributions: (a) expanding the explanatory power of institutional polycentrism by understanding how it moderates the corporate entrepreneur's decision‐making process in polycentric institutional contexts and (2) proposing a relatively novel contingency dimension of the effectuation versus causation and establishing new boundary conditions of the effectuation versus causation.

Managerial summary

This study analyzes the decision‐making process of corporate entrepreneurs of a multinational steel producer throughout its internationalization trajectory. The article highlights that decisions based on rules established with past experience are unsuitable in contexts characterized by a multiplicity of foreign institutional forces. The joint interaction of these forces on the firm induces corporate entrepreneurs to respond to such pressures under a new, more flexible, and experimental approach. Finally, the results indicate that institutional multiplicity generates a kind of calibration between these decision‐making approaches, contributing to innovation processes in the company.
Novel characterization of the relationship between verbal list‐learning outcomes and hippocampal subfields in healthy adults
Authors: Cremona Sandrine , Zago Laure , Mellet Emmanuel , Petit Laurent , Laurent Alexandre , Pepe Antonietta , Tsuchida Ami , Beguedou Naka , Joliot Marc , Tzourio Christophe , Mazoyer Bernard , Crivello Fabrice
Published: August 2021

The relationship between hippocampal subfield volumetry and verbal list‐learning test outcomes have mostly been studied in clinical and elderly populations, and remain controversial. For the first time, we characterized a relationship between verbal list‐learning test outcomes and hippocampal subfield volumetry on two large separate datasets of 447 and 1,442 healthy young and middle‐aged adults, and explored the processes that could explain this relationship. We observed a replicable positive linear correlation between verbal list‐learning test free recall scores and CA1 volume, specific to verbal list learning as demonstrated by the hippocampal subfield volumetry independence from verbal intelligence. Learning meaningless items was also positively correlated with CA1 volume, pointing to the role of the test design rather than word meaning. Accordingly, we found that association‐based mnemonics mediated the relationship between verbal list‐learning test outcomes and CA1 volume. This mediation suggests that integrating items into associative representations during verbal list‐learning tests explains CA1 volume variations: this new explanation is consistent with the associative functions of the human CA1.
What is the role of the surgeon in the management of head and neck mucosal melanoma in the immunotherapy era?
Authors: Edmond Mark , Nenclares Pablo , Harrington Kevin , Ap Dafydd Derfel , Bagwan Izhar , Begg Donna , Lingley Ken , Patterson Gillian , Payne Miranda , Steven Neil , Turnbull Nancy , Yip Kent , Silva Priyamal , Kerawala Cyrus , Paleri Vinidh , King Emma
Published: August 2021

Introduction

The advent of immunotherapy has impacted both the management and, to a lesser extent, the outcomes for patients with head and neck mucosal melanoma. As a consequence, one might expect that the role of the surgeon would be limited to the diagnostic work‐up and that systemic therapies would be the mainstay of treatment.

Methods and Results

Here, we present the surgical aspects of the recently published United Kingdom Head and Neck Mucosal Melanoma Guideline to highlight the continued role of surgeons in the management of this disease. We highlight key areas where surgeons remain the lead clinician and reinforce the multidisciplinary requirement for exemplary patient care.

Conclusions

Despite the advent of immunotherapy, surgeons continue to have a key role to play in this disease. When indicated, it is essential that appropriate surgery is offered by a suitably experienced team.
Metabolic dysfunction–associated fatty liver disease improves detection of high liver stiffness: The Rotterdam Study
Authors: van Kleef Laurens A. , Ayada Ibrahim , Alferink Louise J.M. , Pan Qiuwei , de Knegt Robert J.
Published: August 2021

Background and Aims

Recently metabolic dysfunction–associated fatty liver disease (MAFLD) has been introduced and was defined as hepatic steatosis with either overweight, diabetes, and/or a combination of other metabolic risk factors. We investigated the application of the MAFLD criteria as compared with NAFLD.

Approach and Results

We performed a cross‐sectional analysis within the Rotterdam Study, a large prospective population‐based cohort. Participants who attended the liver ultrasound and transient elastography program between 2009 and 2014 were eligible for inclusion. Subsequently, individuals with viral hepatitis, alcohol intake >60 g/day, missing alcohol data, and/or missing body mass index were excluded. According to their NAFLD and MAFLD status based on metadata and ultrasound, participants were allocated in overlap fatty liver disease (FLD), NAFLD‐only, MAFLD‐only, or no FLD. Fibrosis was defined as liver stiffness ≥8.0 kPa. In our analysis, 5445 participants were included: 1866 (34.3%) had MAFLD and 1604 (29.5%) [Correction added on December 27, 2021 after first online publication: The preceding fragment was changed from “1623 (29.8%)”] had NAFLD. This resulted in 1547 (28.4%) [Correction added on December 27, 2021 after first online publication: The preceding fragment was changed from “1566 (28.8%)”] individuals with overlap FLD, 319 (5.9%) [Correction added on December 27, 2021 after first online publication: The preceding fragment was changed from “300 (5.5%)”] with MAFLD‐only, 57 (1.0%) with NAFLD‐only, and 3522 (64.7%) with no FLD. The MAFLD‐only group was strongly associated with fibrosis (adjusted OR 5.30 [Correction added on December 27, 2021 after first online publication: The preceding fragment was changed from "OR 5.27"], p < 0.001) and log‐transformed liver stiffness (adjusted beta 0.116, p < 0.001), as opposed to the NAFLD‐only group, in which no cases of fibrosis were identified and no association with liver stiffness (adjusted beta 0.006, p = 0.90) was found.

Conclusions

FLD is highly prevalent in the general population. However, not the NAFLD‐only, but the MAFLD‐only group was associated with fibrosis and higher liver stiffness—independent of demographic and lifestyle factors. We believe that using the MAFLD criteria will help improve the identification and treatment of patients with FLD at risk for fibrosis.
Protective Effects of Statin Therapy in Cirrhosis Are Limited by a Common SLCO1B1 Transporter Variant
Authors: Merkel Melissa , Schneider Christina , Greinert Robin , Zipprich Alexander , Ripoll Cristina , Lammert Frank , Reichert Matthias C.
Published: August 2021

Complications of cirrhosis and portal hypertension (PH) can be reduced by statin therapy. The common loss‐of‐function variant p.V174A in the solute carrier organic anion transporter gene 1B1 (SLCO1B1) gene encoding the organic anion transporting polypeptide 1B1 results in decreased hepatic uptake of statins. Our specific aim was to assess the impact of this variant in patients with cirrhosis and statin treatment while controlling for the stage of cirrhosis and other potential confounders with propensity score matching (PSM), availing of a large cohort of genotyped study patients. In total, from 1,088 patients with cirrhosis in two German academic medical centers, PSM yielded 154 patients taking statins and 154 matched controls. The effect on PH was assessed by the liver stiffness–spleen size–to–platelet score (LSPS), and complications of cirrhosis were retrospectively recorded applying consensus criteria. As hypothesized, patients on statin treatment presented less frequently with signs of PH: Esophageal varices (41% vs. 62%; P < 0.001) were less common, and LSPS (4.8 ± 11.5 vs. 5.6 ± 6.4; P = 0.01) was reduced. Correspondingly, decompensation events were also reduced in patients on statins (odds ratio [OR] = 0.54, 95% confidence interval [CI] 0.32‐0.90; P = 0.02). When the variant in SLCO1B1 was present in patients on statins, esophageal varices (OR = 2.68, 95% CI 1.24‐5.81; P = 0.01) and bacterial infections (OR = 2.50, 95% CI 1.14‐5.47; P = 0.02) were more common as compared with wild type carriers on statins.

Conclusion: In this cohort, signs and complications of PH were reduced in patients with cirrhosis treated with statins. Notably, this effect was diminished by the common loss‐of‐function variant in SLCO1B1. Further prospective studies in independent cohorts are warranted to confirm these genotype‐specific observations.
The Integrated “Multiomics” Landscape at Peak Injury and Resolution From Alcohol‐Associated Liver Disease
Authors: Das Sukanta , Ge Xiaodong , Han Hui , Desert Romain , Song Zhuolun , Athavale Dipti , Chen Wei , Gaskell Harriet , Lantvit Daniel , Guzman Grace , Nieto Natalia
Published: August 2021

Alcohol‐associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol‐induced liver injury, female and male wild‐type mice were fed the control or ethanol Lieber‐DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho‐GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator–activated receptor signaling. During resolution from ALD, there was up‐regulation of vitamin D receptor/retinoid X receptor, toll‐like receptor, p38 and Stat3, and down‐regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune‐response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl‐L‐leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen‐activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender‐specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD.
Transcriptomic Cross‐Species Analysis of Chronic Liver Disease Reveals Consistent Regulation Between Humans and Mice
Authors: Holland Christian H. , Ramirez Flores Ricardo O. , Myllys Maiju , Hassan Reham , Edlund Karolina , Hofmann Ute , Marchan Rosemarie , Cadenas Cristina , Reinders Jörg , Hoehme Stefan , Seddek Abdel‐latif , Dooley Steven , Keitel Verena , Godoy Patricio , Begher‐Tibbe Brigitte , Trautwein Christian , Rupp Christian , Mueller Sebastian , Longerich Thomas , Hengstler Jan G. , Saez‐Rodriguez Julio , Ghallab Ahmed
Published: August 2021

Mouse models are frequently used to study chronic liver diseases (CLDs). To assess their translational relevance, we quantified the similarity of commonly used mouse models to human CLDs based on transcriptome data. Gene‐expression data from 372 patients were compared with data from acute and chronic mouse models consisting of 227 mice, and additionally to nine published gene sets of chronic mouse models. Genes consistently altered in humans and mice were mapped to liver cell types based on single‐cell RNA‐sequencing data and validated by immunostaining. Considering the top differentially expressed genes, the similarity between humans and mice varied among the mouse models and depended on the period of damage induction. The highest recall (0.4) and precision (0.33) were observed for the model with 12‐months damage induction by CCl4 and by a Western diet, respectively. Genes consistently up‐regulated between the chronic CCl4 model and human CLDs were enriched in inflammatory and developmental processes, and mostly mapped to cholangiocytes, macrophages, and endothelial and mesenchymal cells. Down‐regulated genes were enriched in metabolic processes and mapped to hepatocytes. Immunostaining confirmed the regulation of selected genes and their cell type specificity. Genes that were up‐regulated in both acute and chronic models showed higher recall and precision with respect to human CLDs than exclusively acute or chronic genes. Conclusion: Similarly regulated genes in human and mouse CLDs were identified. Despite major interspecies differences, mouse models detected 40% of the genes significantly altered in human CLD. The translational relevance of individual genes can be assessed at https://saezlab.shinyapps.io/liverdiseaseatlas/.
Outcomes in primary cutaneous diffuse large B‐cell lymphoma, leg type
Authors: Kraft Robert M. , Ansell Stephen M. , Villasboas Jose C. , Bennani N. Nora , Wang Yucai , Habermann Thomas M. , Thanarajasingam Gita , Lester Scott C. , Macon William , Inwards David J. , Porrata Luis F. , Micallef Ivana N. , Witzig Thomas E. , Thompson Carrie A. , Johnston Patrick B. , Nowakowski Grzegorz S. , Lin Yi , Paludo Jonas
Published: August 2021

Primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL, LT) is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. Immunochemotherapy with or without involved‐site radiation therapy (ISRT) is considered standard front‐line therapy. Over‐expression of PD‐L1/PD‐L2 is seen in a high proportion of PCDLBCL, LT cases, but efficacy of immune checkpoint inhibitors (ICI) in relapsed/refractory, PCDLBCL, LT has not been thoroughly studied. We conducted a retrospective cohort study of patients diagnosed with PCDLBCL, LT seen at Mayo Clinic from 1 January 2000 to 31 December 2020. Using the Kaplan–Meier method, we calculated progression‐free survival, duration of response, and overall survival in patients who received front‐line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) with and without ISRT, and salvage ICI therapy for relapsed/refractory disease. A total of 28 patients with PCDLBCL, LT were identified. The median PFS in patients treated with R‐CHOP plus ISRT was 58 months (95% CI: 18–112) compared to 14 months (95% CI: 5–not reached; p = 0.04) in those treated with R‐CHOP without ISRT. The median PFS from salvage ICI therapy was 10 months (95% CI: 4–not reached), and median DOR from salvage ICI therapy was 23 months [95% CI: 4–26]. R‐CHOP with ISRT had a significantly longer median PFS compared to R‐CHOP without ISRT as front‐line therapy for PCDLBCL, LT. ICIs may have a role in treating relapsed/refractory disease as reasonable activity in heavily pre‐treated patients was observed in this study.
Evaluation of skin sensitization induced by four ionic liquids
Authors: Frawley Rachel P. , Germolec Dori R. , Johnson Victor J. , Gulledge Travis , Manheng Wimolnut , White Kimber , Shockley Keith R. , Harris Shawn F. , Hooth Michelle , Ryan Kristen
Published: August 2021

Ionic liquids (ILs) are synthetic solvents used as replacements for volatile organic solvents. Human exposure occurs through dermal or oral routes. In rodents, several ILs were reported to induce dermal toxicity, irritation, and sensitization. Due to the potential for occupational exposure, and industrial use as nonvolatile solvents, 1‐ethyl‐3‐methylimidazolium chloride (EMIM, 6.25% to 50% v/v), 1‐butyl‐3‐methylimidazolium chloride (BMIM, 3.12% to 12.5% v/v), 1‐butyl‐1‐methylpyrrolidinium chloride (BMPY, 0.825% to 6.25% v/v), andN‐butylpyridinium chloride (NBuPY, 0.825% to 12.5% v/v) were nominated to the National Toxicology Program and evaluated for skin sensitization. The test compound was applied to the ears of female BALB/c mice daily for 3 days in a primary irritancy (IRR)/local lymph node assay (LLNA). Sensitization was assessed in vitro in the direct peptide reactivity assay (DPRA), KeratinoSens™ assay, and human cell line activation test (h‐CLAT). In the LLNA, the butylated ILs, BMIM, and BMPY were more potent than NBuPY (butylated) or EMIM (ethylated), which was neither an irritant nor a sensitizer. NBuPY induced skin irritation in vivo at ≥3.12% (p ≤ 0.01), and sensitization in vitro in the KeratinoSens™ assay and h‐CLAT, but was negative for sensitization in vivo and in the DPRA. Although SI3 was not achieved, dermal treatment with 12.5% BMIM or 6.25% BMPY increased (p ≤ 0.01) lymph node cell proliferation in the LLNA. In vitro, BMIM was positive for sensitization in the h‐CLAT, and BMPY was positive in the h‐CLAT and KeratinoSens™ assay; both were negative in the DPRA. Integrated data analyses, weighted toward in vivo data, suggested that BMIM and BMPY may induce weak to mild sensitization.
Psychological distress of mental health workers during the COVID‐19 pandemic: A comparison with the general population in high‐ and low‐incidence regions
Authors: Brillon Pascale , Philippe Frederick L. , Paradis Alison , Geoffroy Marie‐Claude , Orri Massimiliano , Ouellet‐Morin Isabelle
Published: August 2021

Objective

Despite their essential role during this health crisis, little is known about the psychological distress of mental health workers (MHW).

Method

A total of 616 MHW and 658 workers from the general population (GP) completed an online survey including depressive, anxiety, irritability, loneliness, and resilience measures.

Results

Overall, MHW had fewer cases with above cut‐off clinically significant depression (19% MHW vs. 27%) or anxiety (16% MHW vs. 29%) than the GP. MHW in high‐incidence regions of COVID‐19 cases displayed the same levels of depressive and anxiety symptoms than the GP and higher levels compared to MHW from low‐incidence regions. MHW in high‐incidence regions presented higher levels of irritability and lower levels of resilience than the MHW in low‐incidence regions. Moreover, MHW in high‐incidence regions reported more feelings of loneliness than all other groups.

Conclusion

Implications for social and organizational preventive strategies to minimize the distress of MHW in times of crisis are discussed.
Stable Sf9 cell pools as a system for rapid HIV‐1 virus‐like particle production
Authors: Puente‐Massaguer Eduard , Grau‐Garcia Paula , Strobl Florian , Grabherr Reingard , Striedner Gerald , Lecina Martí , Gòdia Francesc
Published: August 2021

BACKGROUND

The emergence of infectious diseases is accelerating the intensification of bioprocess strategies to support the increasing demand for the manufacture of higher quantities of vaccines in short timeframes. Here, the development of stable Sf9 cell pools producing human immunodeficiency virus serotype 1 (HIV‐1) Gag‐eGFP virus‐like particles (VLPs) is assessed.

RESULTS

Fluorescence‐activated cell sorting (FACS) was employed to select high producing cells, achieving an 8.1‐fold increase in fluorescence intensity compared to unsorted cell pools after three rounds of cell sorting. The transferability of this system to bioreactor scale was also successfully achieved, attaining a 1.4‐fold increase in VLP production and maintaining a higher cell viability than shake flask controls. Analysis of the metabolism of stable cell pools and parental Sf9 cells did not show significant differences regarding metabolite consumption and production, even though a better performance and more efficient metabolism were observed in bioreactor compared with shake flask cultures, highlighting the flexibility of these cells to adapt to different culture conditions and heterologous recombinant protein production.

CONCLUSIONS

Stable Sf9 cell pools represent a suitable system for shortening bioprocess development times and accelerating vaccine production. © 2021 Society of Chemical Industry (SCI).
Effects of simultaneous CO2 addition and biomass recycling on growth characteristics of microalgal mixed culture
Authors: Fallahi Alireza , Hajinajaf Nima , Tavakoli Omid , Mehrabadi Abbas
Published: August 2021

BACKGROUND

This study aims to investigate the effect of simultaneous carbon dioxide (CO2) addition and biomass recycling on specific performance parameters (including biomass productivity and harvestability, and species abundance) of the mixed culture of two freshwater microalgae species Chlorella vulgaris and Scenedesmus obliquus in a flat‐panel photobioreactor grown semicontinuously using secondary effluent urban wastewater as the culture medium. Recycling a portion of the gravity‐harvested biomass back to the system has positive effects on biomass productivity and harvestability by letting microalgal cells utilize more of the available light energy and promoting the dominance of settleable microalgal species of S. obliquus (owing to their large cell sizes) in the mixed culture. Furthermore, CO2 addition could supply the carbon limitation of urban wastewater and boost biomass production.

RESULTS

The work confirmed that simultaneous CO2 addition and biomass recycling improved the biomass productivity by 314%, promoted the dominance of the larger algae species S. obliquus in the mixed culture by 38%, and increased the gravity sedimentation by 85% compared to the control that had no recycling and CO2 addition. Concerning the secondary effluent urban wastewater, the interaction of CO2 addition and biomass recycling was insignificant regarding the improvement in nutrient removal efficiency.

CONCLUSION

The findings proved the potential benefits of simultaneous biomass recycling and CO2 addition for reaching a high cell density, and demonstrated its potential for high biomass harvest efficiency in microalgae‐based wastewater treatment systems. © 2021 Society of Chemical Industry (SCI).
Advances, current challenges, and future trends in bioseparation: perspective analysis of the papers published in JCTB
Authors: González‐González Mirna , Rito‐Palomares Marco
Published: August 2021

Bioseparation is a crucial process for the obtention of biological products that are essential in daily life, such as medicine and food. At first, the researchers centered their efforts on the optimization of the upstream processes, conducting to high product titer. Afterwards, they turned their attention to improving the downstream processes. Since then, a revolution of technologies has been reported for the recovery, separation, and/or purification of bioproducts. Therefore, this perspective article aims to present the advances, current challenges, and future trends in bioseparation. In this context, a practical approach to summarize the published articles in the Journal of Chemical Technology and Biotechnology regarding this topic is presented; in addition, a classification of, (i) trusted old, (ii) novel, and (iii) evolved technologies is proposed. © 2021 Society of Chemical Industry (SCI).
Preparation of chitooligosaccharides by α‐amylase from chitosan with oxidative pretreatment
Authors: Qian Junqing , Shi Bobo , Mo Luyan , Shu Dehai , Guo Hui
Published: August 2021

BACKGROUND

Chitooligosaccharides possess good physiological activity and a wide range of uses. In view of the difficulty in controlling the degree of polymerization of chitooligosaccharides prepared by chemical methods and the low efficiency of enzymatic methods, the preparation process of chitooligosaccharides prepared by H2O2 oxidation pretreatment combined with α‐amylase catalysis was studied.

RESULTS

Water‐soluble chitosan was prepared by oxidation pretreatment of chitosan and then degradation by α‐amylase. The enzymatic hydrolysis conditions were determined as follows: pH, 6.0; temperature, 60 °C; liquid–solid ratio, 5:1. The degree of polymerization of chitooligosaccharides prepared was adjusted by the amount of enzyme and hydrolysis time. The average degree of polymerization of chitooligosaccharides obtained was 5.4 when the amount of enzyme was 20 U g−1 for a hydrolysis time of 1.5 h. The results of infrared spectroscopy showed that the oxidative pretreatment and α‐amylase degradation did not affect the molecular structure of the chitosan monomer. Using electrospray ionization mass spectrometry analysis, the degree of polymerization of the products was found to be mainly 2–8.

CONCLUSIONS

H2O2 oxidative pretreatment can significantly improve the degradation efficiency of α‐amylase, and the degree of polymerization of chitooligosaccharide products can be adjusted by regulating the hydrolysis conditions of the enzyme, which has ideal application prospects. © 2021 Society of Chemical Industry (SCI).
Microalgae cultivation: photobioreactors, CO2 utilization, and value‐added products of industrial importance
Authors: Shekh Ajam , Sharma Aditi , Schenk Peer M , Kumar Gulshan , Mudliar Sandeep
Published: August 2021

Increasing world population, industrialization, and economic development demand more energy at a global scale, and this challenge is being met with the exploitation of fossil fuels that cause CO2 and CH4 emissions and contribute towards earth's rising temperature. Microalgae are considered potential sources for CO2 abatement and for combating food insecurity by ensuring a nutritional food supply for the sustainable living of an increasing population. The CO2 utilization potential of microalgae has been continuously researched for augmentation through various photobioreactor and open raceway pond designs and developments. Apart from recognition for their nutritional importance, microalgae are finding the place in the market as ‘functional foods’ due to their bioactive components. In view of this, the present study highlights the status and current attempts being made for photobioreactor development, CO2 sequestration, and the production of industrially important microalgal metabolites. This review also explains the factors responsible for microalgal growth and provides research needs and recommendations to make microalgal CO2 sequestration and value‐added compounds production an industrially competitive process. © 2021 Society of Chemical Industry (SCI).