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Introduction: Patients with chronic hypoparathyroidism are at increased risk of cardiovascular disease. This study evaluated the risk of developing cardiovascular conditions over a period of 5 years in adult patients with chronic hypoparathyroidism treated with recombinant human parathyroid hormone (1-84), rhPTH(1-84), compared with a historical control cohort of patients not treated with rhPTH(1-84)., Methods: This retrospective cohort study comprised patients with chronic hypoparathyroidism treated with rhPTH(1-84) in the REPLACE (NCT00732615), RELAY (NCT01268098), and RACE (NCT01297309) clinical trials, and controls selected from the IBM ® Explorys electronic medical record database (January 2007-August 2019) who did not receive parathyroid hormone but who had enrollment criteria similar to those for the clinical trials. Cardiovascular outcomes were the first diagnosis of cerebrovascular, coronary artery, peripheral vascular disease, or heart failure during the study period., Results: We evaluated 113 adult patients with chronic hypoparathyroidism treated with rhPTH(1-84) and 618 control patients who did not receive rhPTH(1-84). Over the 5-year follow-up period, 3.5% of patients (n = 4) in the rhPTH(1-84) cohort had a cardiovascular event compared with 16.3% (n = 101) in the control cohort. Kaplan-Meier analysis demonstrated that patients in the rhPTH(1-84) cohort had lower risk of experiencing a cardiovascular event compared with patients in the control cohort (P = 0.005). Multivariable analyses adjusted for baseline variables showed that patients in the rhPTH(1-84) cohort had 75% lower risk for a cardiovascular event compared with patients in the control cohort (adjusted hazard ratio, 0.25 [95% CI 0.08-0.81]; P = 0.020)., Conclusion: Long-term treatment with rhPTH(1-84) was associated with a lower risk of incident cardiovascular conditions compared with conventional therapy in patients with chronic hypoparathyroidism. Previous studies demonstrated that mineral homeostasis was maintained with lower use of calcium and active vitamin D when rhPTH(1-84) was added to conventional therapy. Future studies are needed to understand whether improved regulation of mineral homeostasis conferred by rhPTH(1-84) may provide long-term cardiovascular benefits to patients with chronic hypoparathyroidism., (© 2022. The Author(s).)

Pseudomonas aeruginosa is a ubiquitous opportunistic bacterial pathogen, which is a leading cause of nosocomial pneumonia. Early identification of the risk factors is urgently needed for severe infection patients with P. aeruginosa. However, no detailed relevant investigation based on machine learning has been reported, and little research has focused on exploring relationships between key risk clinical variables and clinical outcome of patients. In this study, we collected 571 severe infections with P. aeruginosa patients admitted to the Xijing Hospital of the Fourth Military Medical University from January 2010 to July 2021. Basic clinical information, clinical signs and symptoms, laboratory indicators, bacterial culture, and drug related were recorded. Machine learning algorithm of XGBoost was applied to build a model for predicting mortality risk of P. aeruginosa infection in severe patients. The performance of XGBoost model (AUROC = 0.94 ± 0.01, AUPRC = 0.94 ± 0.03) was greater than the performance of support vector machine (AUROC = 0.90 ± 0.03, AUPRC = 0.91 ± 0.02) and random forest (AUROC = 0.93 ± 0.03, AUPRC = 0.89 ± 0.04). This study also aimed to interpret the model and to explore the impact of clinical variables. The interpretation analysis highlighted the effects of age, high-alert drugs, and the number of drug varieties. Further stratification clarified the necessity of different treatment for severe infection for different populations., (Copyright © 2022 Cui, Mu, Tang, Lin, Wang, Zhao, Guan and Wang.)

T cell receptor-engineered T cells (TCR-Ts) have emerged as potent cancer immunotherapies. While most research focused on classical cytotoxic CD8 + T cells, the application of CD4 + T cells in adoptive T cell therapy has gained much interest recently. However, the cytotoxic mechanisms of CD4 + TCR-Ts have not been fully revealed. In this study, we obtained an MHC class I-restricted MART-1 27-35 -specific TCR sequence based on the single-cell V(D)J sequencing technology, and constructed MART-1 27-35 -specific CD4 + TCR-Ts and CD8 + TCR-Ts. The antitumor effects of CD4 + TCR-Ts were comparable to those of CD8 + TCR-Ts in vitro and in vivo . To delineate the killing mechanisms of cytotoxic CD4 + TCR-Ts, we performed single-cell RNA sequencing and found that classical granule-dependent and independent cytolytic pathways were commonly used in CD4 + and CD8 + TCR-Ts, while high expression of LTA and various costimulatory receptors were unique features for cytotoxic CD4 + TCR-Ts. Further signaling pathway analysis revealed that transcription factors Runx3 and Blimp1/Tbx21 were crucial for the development and killing function of cytotoxic CD4 + T cells. Taken together, we report the antitumor effects and multifaceted killing mechanisms of CD4 + TCR-Ts, and also indicate that MHC class I-restricted CD4 + TCR-Ts could serve as potential adoptive T cell therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liang, Xu, Liu, Li, Wang, Li, Liao, Lu, Li, Mu, Sun and Zhu.)

Methods: Data from TCMSP and GEO databases were utilized to identify targets for Celastrol on DCM. The relationship between the major targets and conventional glycolipid metabolism was obtained with Spearman correlation analysis. Experiments on animals were conducted utilizing healthy control (HC), low-dose Celastrol interventions (CL), and no intervention groups (NC), all of which had 8 SD rats in each group. To study alterations in signaling molecules, RT-PCR was performed., Results: There were 76 common targets and 5 major targets for Celastrol-DCM. Celastrol have been found to regulate AGE-RAGE, TNF, MAPK, TOLL-like receptors, insulin resistance, and other signaling pathways, and they are closely linked to adipocytokines, fatty acid metabolism, glycolipid biosynthesis, and glycosylphosphati-dylinositol biosynthesis on DCM. These five major targets have been found to regulate these pathways. Experiments on rats indicated that P38 MAPK was considerably elevated in the cardiac tissue from rats in the CL and NC groups compared to the HC group, and the difference was statistically significant ( P < 0.01). Significant differences were seen between the CL and NC groups in P38 MAPK levels, with a statistical significance level of less than 0.05., Conclusion: Celastrol may play a role in reversing energy remodeling, anti-inflammation, and oxidative stress via modulating p38 protein expression in the MAPK pathway, which have been shown in the treatment of DCM., Competing Interests: Authors confirm that there is no conflicts of interest., (Copyright © 2022 Rui Xi et al.)

Metastasis is one of the characteristics of advanced cancer and the primary cause of cancer-related deaths from cancer, but the mechanism underlying metastasis is unclear, and there is a lack of metastasis markers. PTPRT is a protein-coding gene involved in both signal transduction and cellular adhesion. It is also known as a tumor suppressor gene that inhibits cell malignant proliferation by inhibiting the STAT3 pathway. Recent studies have reported that PTPRT is involved in the early metastatic seeding of colorectal cancer; however, the correlation between PTPRT and metastasis in other types of cancer has not been revealed. A combined analysis using a dataset from the genomics evidence neoplasia information exchange (GENIE) and cBioPortal revealed that PTPRT mutation is associated with poor prognosis in pan-cancer and non-small-cell lung cancer. The mutations of PTPRT or "gene modules" containing PTPRT are significantly enriched in patients with metastatic cancer in multiple cancers, suggesting that the PTPRT mutations serve as potential biomarkers of cancer metastasis., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Chao Chen et al.)

Summary: The increasing prevalence and importance of machine learning in biological research have created a need for machine learning training resources tailored towards biological researchers. However, existing resources are often inaccessible, infeasible or inappropriate for biologists because they require significant computational and mathematical knowledge, demand an unrealistic time-investment or teach skills primarily for computational researchers. We created the Machine Learning for Biologists (ML4Bio) workshop, a short, intensive workshop that empowers biological researchers to comprehend machine learning applications and pursue machine learning collaborations in their own research. The ML4Bio workshop focuses on classification and was designed around three principles: (i) emphasizing preparedness over fluency or expertise, (ii) necessitating minimal coding and mathematical background and (iii) requiring low time investment. It incorporates active learning methods and custom open-source software that allows participants to explore machine learning workflows. After multiple sessions to improve workshop design, we performed a study on three workshop sessions. Despite some confusion around identifying subtle methodological flaws in machine learning workflows, participants generally reported that the workshop met their goals, provided them with valuable skills and knowledge and greatly increased their beliefs that they could engage in research that uses machine learning. ML4Bio is an educational tool for biological researchers, and its creation and evaluation provide valuable insight into tailoring educational resources for active researchers in different domains., Availability and Implementation: Workshop materials are available at https://github.com/carpentries-incubator/ml4bio-workshop and the ml4bio software is available at https://github.com/gitter-lab/ml4bio., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

Tumor-specific antigens can activate T cell-based antitumor immune responses and are ideal targets for cancer immunotherapy. However, their identification is still challenging. Although mass spectrometry can directly identify human leukocyte antigen (HLA) binding peptides in tumor cells, it focuses on tumor-specific antigens derived from annotated protein-coding regions constituting only 1.5% of the genome. We developed a novel proteogenomic integration strategy to expand the breadth of tumor-specific epitopes derived from all genomic regions. Using the colorectal cancer cell line HCT116 as a model, we accurately identified 10,737 HLA-presented peptides, 1293 of which were non-canonical peptides that traditional database searches could not identify. Moreover, we found eight tumor neo-epitopes derived from somatic mutations, four of which were not previously reported. Our findings suggest that this new proteogenomic approach holds great promise for increasing the number of tumor-specific antigen candidates, potentially enlarging the tumor target pool and improving cancer immunotherapy.

Primary liver cancer, mainly comprising hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), remains a major global health problem. Although ICC is clinically different from HCC, their molecular differences are still largely unclear. In this study, precision N-glycoproteomic analysis was performed on both ICC and HCC tumors as well as paracancer tissues to investigate their aberrant site-specific N-glycosylation. By using our newly developed glycoproteomic methods and novel algorithm, termed 'StrucGP', a total of 486 N-glycan structures attached on 1235 glycosites were identified from 894 glycoproteins in ICC and HCC tumors. Notably, glycans with uncommon LacdiNAc (GalNAcβ1-4GlcNAc) structures were distinguished from their isomeric glycans. In addition to several bi-antennary and/or bisecting glycans that were commonly elevated in ICC and HCC, a number of LacdiNAc-containing, tri-antennary, and core-fucosylated glycans were uniquely increased in ICC. More interestingly, almost all LacdiNAc-containing N-glycopeptides were enhanced in ICC tumor but not in HCC tumor, and this phenomenon was further confirmed by lectin histochemistry and the high expression of β1-4 GalNAc transferases in ICC at both mRNA and protein expression levels. The novel N-glycan alterations uniquely detected in ICC provide a valuable resource for future studies regarding to the discovery of ICC diagnostic biomarkers, therapeutic targets, and mechanism investigations., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Real-world evidence characterizing the clinical outcomes and economic impact on patients with severe eosinophilic asthma treated with benralizumab is limited., Objective: To characterize patients with severe asthma treated with benralizumab and assess its clinical and economic impact in the United States., Methods: A pre-post benralizumab comparison was performed using a large US insurance claims database between November 2016 and November 2019. The primary cohort included patients with asthma aged 12 years or more with 2 or more records of benralizumab. Secondary cohorts included persistent users (6 or more records of benralizumab), patients switching to benralizumab from mepolizumab or omalizumab, and stratified by Medicaid vs non-Medicaid. Exacerbations, concomitant medications, and exacerbation-related health care resource utilization (HCRU) and costs were compared in the 12-month periods pre- and post-benralizumab initiation (index)., Results: Of the 204 patients in the primary cohort, mean age at index was 45.3 years and 68.6% were of female sex. The patients experienced a significant 55% reduction in rates of exacerbations post-benralizumab initiation (3.25 pre-index vs 1.47 post-index per person-year; P < .001), and 41% of the patients had no exacerbations post-benralizumab initiation. The proportion of oral corticosteroid-dependent patients decreased from 82% to 50% (P < .001). Reductions in HCRU were 42%, 46%, and 57% for asthma exacerbation-related inpatient hospitalizations, emergency department, and outpatient visits, respectively (all P < .001). Exacerbation-related costs decreased by $6439 ($13,559 vs $7120; P < .001). Similar results for all outcomes were observed for the persistent cohort, switch cohorts, and Medicaid vs non-Medicaid cohorts., Conclusion: Patients with severe asthma treated with benralizumab experienced clinical and economic benefits in the real world, as demonstrated by the reduction in exacerbations and HCRU., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fremanezumab, a fully humanized monoclonal antibody (mAb; IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for the preventive treatment of migraine in adults. The efficacy and safety of fremanezumab for migraine prevention have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world effectiveness data are needed to complement clinical trial data. This study assessed the effectiveness of fremanezumab across different subgroups of adult patients with episodic migraine (EM), chronic migraine (CM), or difficult-to-treat (DTT) migraine in real-world clinical settings., Methods: This retrospective, panel-based online chart review used electronic case report forms. Patient inclusion criteria were a physician diagnosis of EM or CM; age ≥ 18 years at the time of first fremanezumab initiation; ≥ 1 dose of fremanezumab treatment; ≥ 1 follow-up visit since first initiation; and ≥ 2 measurements of monthly migraine days (MMD; with 1 within a month before or at first initiation and ≥ 1 after first initiation). Changes in MMD and monthly headache days were assessed during the follow-up period. These endpoints were evaluated in subgroups of patients by migraine type (EM/CM) and in subgroups with DTT migraine (diagnosis of medication overuse [MO], major depressive disorder [MDD], generalized anxiety disorder [GAD], or prior exposure to a different CGRP pathway-targeted mAb [CGRP mAb])., Results: Data were collected from 421 clinicians and 1003 patients. Mean (percent) reductions from baseline in MMD at Month 6 were - 7.7 (77.0%) in EM patients, - 10.1 (68.7%) in CM patients, - 10.8 (80.6%) in the MO subgroup, - 9.9 (68.3%) in the MDD subgroup, - 9.5 (66.4%) in the GAD subgroup, and - 9.0 (68.7%) in the prior CGRP mAb exposure subgroup. Improvements in MDD or GAD severity were reported by 45.5% and 45.8% of patients with comorbid MDD or GAD, respectively., Conclusions: In this real-world study, fremanezumab demonstrated effectiveness for migraine regardless of migraine type or the presence of factors contributing to DTT migraine (MO, GAD, MDD, or prior exposure to a different CGRP mAb)., (© 2022. The Author(s).)

Spatially resolved transcriptomic technologies are promising tools to study complex biological processes such as mammalian embryogenesis. However, the imbalance between resolution, gene capture, and field of view of current methodologies precludes their systematic application to analyze relatively large and three-dimensional mid- and late-gestation embryos. Here, we combined DNA nanoball (DNB)-patterned arrays and in situ RNA capture to create spatial enhanced resolution omics-sequencing (Stereo-seq). We applied Stereo-seq to generate the mouse organogenesis spatiotemporal transcriptomic atlas (MOSTA), which maps with single-cell resolution and high sensitivity the kinetics and directionality of transcriptional variation during mouse organogenesis. We used this information to gain insight into the molecular basis of spatial cell heterogeneity and cell fate specification in developing tissues such as the dorsal midbrain. Our panoramic atlas will facilitate in-depth investigation of longstanding questions concerning normal and abnormal mammalian development., Competing Interests: Declaration of interests The chip, procedure, and applications of Stereo-seq are covered in pending patents. J.W. and H.Y. are founders of BGI-Shenzhen, and employees of BGI have stock holdings in BGI., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

RNA viruses usually have linear genomes and are encapsidated by their own capsids. Here, we newly identified four mycoviruses and two previously reported mycoviruses (a fungal reovirus and a botybirnavirus) in the hypovirulent strain SCH941 of Sclerotinia sclerotiorum. One of the newly discovered mycoviruses, Sclerotinia sclerotiorum yadokarivirus 1 (SsYkV1), with a nonsegmented positive-sense single-stranded RNA (+ssRNA) genome, was molecularly characterized. SsYkV1 is 5,256 nucleotides (nt) in length, excluding the poly(A) structure, and has a large open reading frame that putatively encodes a polyprotein with the RNA-dependent RNA polymerase (RdRp) domain and a 2A-like motif. SsYkV1 was phylogenetically positioned into the family Yadokariviridae and was most closely related to Rosellinia necatrix yadokarivirus 2 (RnYkV2), with 40.55% identity (78% coverage). Although SsYkV1 does not encode its own capsid protein, the RNA and RdRp of SsYkV1 are trans -encapsidated in virions of Sclerotinia sclerotiorum botybirnavirus 3 (SsBV3), a bisegmented double-stranded RNA (dsRNA) mycovirus within the genus Botybirnavirus . In this way, SsYkV1 likely replicates inside the heterocapsid comprised of the SsBV3 capsid protein, like a dsRNA virus. SsYkV1 has a limited impact on the biological features of S. sclerotiorum. This study represents an example of a yadokarivirus trans -encapsidated by an unrelated dsRNA virus, which greatly deepens our knowledge and understanding of the unique life cycles of RNA viruses. IMPORTANCE RNA viruses typically encase their linear genomes in their own capsids. However, a capsidless +ssRNA virus (RnYkV1) highjacks the capsid of a nonsegmented dsRNA virus for the trans -encapsidation of its own RNA and RdRp. RnYkV1 belongs to the family Yadokariviridae , which already contains more than a dozen mycoviruses. However, it is unknown whether other yadokariviruses except RnYkV1 are also hosted by a heterocapsid, although dsRNA viruses with capsid proteins were detected in fungi harboring yadokarivirus. It is noteworthy that almost all presumed partner dsRNA viruses of yadokariviruses belong to the order Ghabrivirales (most probably a totivirus or toti-like virus). Here, we found a capsidless +ssRNA mycovirus, SsYkV1, from hypovirulent strain SCH941 of S. sclerotiorum , and the RNA and RdRp of this mycovirus are trans -encapsidated in virions of a bisegmented dsRNA virus within the free-floating genus Botybirnavirus . Our results greatly expand our knowledge of the unique life cycles of RNA viruses.

Background: There is considerable research value and extensive application perspectives to explore the link between gut microbiota and heart failure. The purpose of this study is to provide an overview of overall characteristics, evolutionary pathways, frontier research hotspots, and future trends in this field., Methods: Research datasets were acquired from the Web of Science Core Collection (WoSCC) between January 1, 2006 and December 31, 2021. Three different analysis tools including one online platform, VOS viewer V1.6.17.0, and CiteSpace V5.8.R2 software were used in order to conduct collaboration network analysis, co-cited analysis, co-occurring analysis, and citation burst detection., Results: A total of 873 publications in the WoSCC database met the requirement. The overall characteristics analysis showed that a steady growth trend in the number of publications and citations, with the predominant literature type being articles and the most frequent subject category being cardiac cardiovascular systems. The United States was the most prolific country and the center of national collaboration. Cleveland Clinic and Nathalie M. Delzenne provided the leading influence with publications, the cooperation between the institutes and authors were relatively weak. Moreover, gut microbiota, heart failure, risk factor, obesity, and inflammation were the keywords that appeared more frequently in the clustering analysis of reference co-citation and keyword co-occurrence. Burst detection analysis of top keywords showed that trimethylamine N -oxide (TMAO), bile acid, blood pressure, hypertension, and fermentation were the new research foci on the association between gut microbiota and heart failure. Strategies to improve gut microbiota hold promise as a new approach to treat heart failure., Conclusion: The comprehensive bibliometric study indicates that the structured information may be helpful in understanding research trends in the link between gut microbiota and heart failure, and locating research hotspots and gaps in this domain, especially further advances in this field will lead to significant breakthroughs in the development of novel therapeutic tools for metabolic modulation of heart failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mu, Tang, Guan, Lin, Zhao, Zhao, Huang, Zhang, Wang and Tang.)

A challenging task for the biological neural signal-based human-exoskeleton interface is to achieve accurate lower limb movement prediction of patients with hemiplegia in rehabilitation training scenarios. The human-exoskeleton interface based on single-modal biological signals such as electroencephalogram (EEG) is currently not mature in predicting movements, due to its unreliability. The multimodal human-exoskeleton interface is a very novel solution to this problem. This kind of interface normally combines the EEG signal with surface electromyography (sEMG) signal. However, their use for the lower limb movement prediction is still limited-the connection between sEMG and EEG signals and the deep feature fusion between them are ignored. In this article, a Dense con-attention mechanism-based Multimodal Enhance Fusion Network (DMEFNet) is proposed for predicting lower limb movement of patients with hemiplegia. The DMEFNet introduces the con-attention structure to extract the common attention between sEMG and EEG signal features. To verify the effectiveness of DMEFNet, an sEMG and EEG data acquisition experiment and an incomplete asynchronous data collection paradigm are designed. The experimental results show that DMEFNet has a good movement prediction performance in both within-subject and cross-subject situations, reaching an accuracy of 82.96 and 88.44%, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shi, Mu, Huang, Huang, Peng, Zou, Yang and Cheng.)

A novel 2D/3D S-scheme carbon nitride/iodine-deficient bismuth oxyiodide (g-C 3 N 4 /BiO 1.2 I 0.6 ) heterojunction was constructed for the first time by calcining a mixture of g-C 3 N 4 nanosheets and flower-like BiOI. Irradiated by visible light, this g-C 3 N 4 /BiO 1.2 I 0.6 heterojunction exhibited excellent photocatalytic hydrogen production and BPA degradation activity with high cycle stability. In particular, the photocatalytic activity of 0.2-C 3 N 4 /BiO 1.2 I 0.6 could reach 1402.7 μmol g -1 h -1 (hydrogen production rate) and 0.01155 min -1 (apparent rate of bisphenol A degradation), which were 3.5 and 3.2 times that of g-C 3 N 4 respectively. The remarkable photocatalytic performance was due to the efficient charge separation of g-C 3 N 4 /BiO 1.2 I 0.6 and the formation of S-scheme heterojunction, which maintained strong photocatalytic reduction and oxidation potentials. Noticeably, the charge density difference and band offsets of the g-C 3 N 4 /BiO 1.2 I 0.6 were calculated. The results revealed that a built-in electric field (IEF) was created. The values of the valence band offset (ΔE VBO ) and the conduction band offset (ΔE CBO ) were -0.84 and -1.27 eV, respectively, which further demonstrated the formation of S-scheme photocatalytic charge transfer mechanism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The efficacy and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP) and is approved for the preventive treatment of migraine in adults, have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world data can further support those clinical trial data and demonstrate the full clinical benefits of fremanezumab. This chart review assessed the effectiveness of fremanezumab for improving clinical outcomes in adult patients with migraine treated according to real-world clinical practice., Methods: This retrospective, panel-based, online physician chart review study used electronic case report forms with US physicians. Patient inclusion criteria were a physician diagnosis of migraine, fremanezumab treatment initiation at ≥ 18 years of age after US Food and Drug Administration approval, ≥ 1 dose of fremanezumab treatment, and ≥ 2 assessments of monthly migraine days (MMD; 1 within 30 days before treatment initiation and ≥ 1 after initiation). Changes from baseline in MMD, monthly headache days (MHD), and Migraine Disability Assessment (MIDAS) and 6-item Headache Impact Test (HIT-6) scores were assessed over 6 months. These endpoints were evaluated in the overall population and subgroups divided by dosing schedule and number of prior migraine preventive treatment failures., Results: This study included data from 421 clinicians and 1003 patients. Mean age at fremanezumab initiation was 39.7 years, and most patients were female (75.8%). In the overall population, mean baseline MMD and MHD were 12.7 and 14.0, respectively. Mean (percent) reductions from baseline in MMD and MHD, respectively, were - 4.6 (36.2%) and - 4.7 (33.6%) at Month 1, - 6.7 (52.8%) and - 6.8 (48.6%) at Month 3, and - 9.2 (72.4%) and - 9.8 (70.0%) at Month 6. Mean (percent) reductions from baseline in MIDAS and HIT-6 scores also increased over the 6-month study period, from - 6.2 (21.6%) and - 8.4 (14.0%) at Month 1 to - 18.1 (63.1%) and - 16.2 (27.0%) at Month 6, respectively. Improvements in these outcomes over 6 months were observed across all evaluated subgroups., Conclusions: This real-world study demonstrated effectiveness of fremanezumab treatment for up to 6 months, irrespective of dosing regimen or number of prior migraine preventive treatment failures, reflecting ongoing, clinically meaningful improvements in patient outcomes., (© 2022. The Author(s).)

To evaluate the impact of bottom aquaculture on benthic ecosystems, characteristics of benthic food web were studied using stable isotope techniques during four seasons in a Manila clam (Ruditapes philippinarum) bottom aquaculture area in a semi-enclosed bay, China. Results showed that although nitrogen stable isotope values of food sources (particulate organic matter and phytoplankton) had significant seasonal differences, there were no significant seasonal changes for benthic food web structure. Manila clam bottom aquaculture can enhance the secondary productivity and improve the basic trophic pathways by providing bio-deposits. Besides particulate organic matter and phytoplankton, Manila clam could feed on self-generated feces with high nitrogen stable isotope values, and benthic micro- and macroalga with high carbon stable isotope values. Secondary productivity of the stations with a high degree of aquaculture was higher than that of stations with a low degree. Bivalve bottom culture may have a positive impact on benthic ecosystem functioning., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Polymer adhesives have emerged as a promising dielectric passivation layer in hybrid bonding for 3D integration, but they raise misalignment problems during curing. In this work, the synergistic effect of oxygen plasma surface activation and wetting is utilized to achieve bonding between completed cured polyimides. The optimized process achieves a void-less bonding with a maximum shear strength of 35.3 MPa at a low temperature of 250 °C in merely 2 min, significantly shortening the bonding period and decreasing thermal stress. It is found that the plasma activation generates hydrophilic groups on the polyimide surface, and the wetting process further introduces more -OH groups and water molecules on the activated polyimide surface. The synergistic process of plasma activation and wetting facilitates the bridging of polyimide interfaces to achieve bonding, providing an alternative path for adhesive bonding in 3D integration.

Objective: Antipsychotic medications may cause tardive dyskinesia (TD), an often-irreversible movement disorder characterized by involuntary movements that are typically stereotypic, choreiform, or dystonic and may impair quality of life. This study evaluated others' perceptions of abnormal TD movements in professional and social situations., Methods: This was an experimental, randomized, blinded, digital survey in a general population sample. Participants were randomized 1:1 into a test or control group to view a video of a professional actor simulating TD movements or no TD movements prior to completing surveys on employment, dating, and friendship domains. Assessments for mild-to-moderate and moderate-to-severe TD movements were conducted separately. Authenticity of abnormal movements and Abnormal Involuntary Movement Scale (AIMS) scores were evaluated by physician experts., Results: Surveys were completed by 2,400 participants each for mild-to-moderate and moderate-to-severe TD. In all domains, participants responded significantly less favorably to persons with TD movements (both mild-to-moderate and moderate-to-severe) than those without TD movements. Fewer participants in the test versus control group for mild-to-moderate and moderate-to-severe TD, respectively, considered the candidate as a potential employee (29.2% and 22.7% fewer), found him/her attractive (20.5% and 18.7% fewer), and were interested in becoming friends with him/her (12.3% and 16.5% fewer)., Conclusion: Professional actors simulating TD movements were perceived more negatively than those without TD movements in employment, dating, and friendship domains. To our knowledge, this is the first randomized study to quantify professional and social stigma associated with TD movements that may reduce opportunities for gainful employment, marital status, and an effective support system.

Growing evidence indicates that gut microbiota factors cannot be viewed as independent in the occurrence of obesity. Because the gut microbiome is highly dimensional and complex, studies on interactions between gut microbiome and host in obesity are still rare. To explore the relationship of gut microbiome-host interactions with obesity, we performed multi-omics associations of gut metagenome, intestinal transcriptome, and host obesity phenotypes in divergently selected obese-lean broiler lines. Metagenomic shotgun sequencing generated a total of 450 gigabases of clean data from 80 intestinal segment contents of 20 broilers (10 of each line). The microbiome comparison showed that microbial diversity and composition in the duodenum, jejunum, ileum, and ceca were altered variously between the lean- and fat-line broilers. We identified two jejunal microbes ( Escherichia coli and Candidatus Acetothermia bacterium ) and four cecal microbes ( Alistipes sp. CHKCI003 , Ruminococcaceae bacterium CPB6 , Clostridiales bacterium , and Anaeromassilibacillus sp. An200 ), which were significantly different between the two lines (FDR < 0.05). When comparing functional metagenome, the fat-line broilers had an intensive microbial metabolism in the duodenum and jejunum but degenerative microbial activities in the ileum and ceca. mRNA-sequencing identified a total of 1,667 differentially expressed genes (DEG) in the four intestinal compartments between the two lines (| log2FC| > 1.5 and FDR < 0.05). Multi-omics associations showed that the 14 microbial species with abundances that were significantly related with abdominal fat relevant traits (AFRT) also have significant correlations with 155 AFRT-correlated DEG ( p < 0.05). These DEG were mainly involved in lipid metabolism, immune system, transport and catabolism, and cell growth-related pathways. The present study constructed a gut microbial gene catalog of the obese-lean broiler lines. Intestinal transcriptome and metagenome comparison between the two lines identified candidate DEG and differential microbes for obesity, respectively. Multi-omics associations suggest that abdominal fat deposition may be influenced by the interactions of specific gut microbiota abundance and the expression of host genes in the intestinal compartments in which the microbes reside. Our study explored the interactions between gut microbiome and host intestinal gene expression in lean and obese broilers, which may expand knowledge on the relationships between obesity and gut microbiome., Competing Interests: YY, PW, and RG were employed by the company Novogene Bioinformatics Technology Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jing, Yuan, Monson, Wang, Mu, Zhang, Na, Zhang, Wang, Leng, Li, Luan, Wang, Guo, Lamont, Li and Yuan.)

Sclerotinia sclerotiorum reovirus 1 (SsReV1) was previously reported to infect hypovirulent strain SCH941 of the phytopathogenic fungus Sclerotinia sclerotiorum and to contain 11 double-stranded RNA (dsRNA) segments (S1-S11). Here, we report that SsReV1 is actually composed of 12 dsRNA segments instead of 11. The full-length nucleotide sequence of the twelfth segment (S12) was determined using a combination of RACE and high-throughput sequencing methods. S12 is 1217 nucleotides in length and has highly conserved terminal sequences that resemble those of the other 11 segments of SsReV1. S12 contains a single open reading frame encoding a protein (VP12) of 311 amino acids. Although regular BLAST analysis did not reveal any similarity of VP12 to known sequences, it was found to be homologous to the VP11 of Colorado tick fever virus of the genus Coltivirus when a hidden-Markov-model-based HHpred analysis was performed. A single-protoplast regeneration experiment suggested that S12 and S2 were maintained or lost in parallel. In summary, the SsReV1 genome consists of 12 dsRNA segments., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Introduction: Hyperkalemia is often managed in the emergency department (ED) and it is important to understand how ED management and post-discharge outcomes vary by hyperkalemia severity. This study was conducted to characterize ED management and post-discharge outcomes across hyperkalemia severities., Methods: Adults with an ED visit with hyperkalemia (at least one serum potassium lab measure above 5.0 mEq/L) were selected from US electronic medical record data (2012-2018). Patient characteristics, potassium levels, treatments, and monitoring prior to and during the ED visit were compared by hyperkalemia severity (mild [> 5.0-5.5 mEq/L], moderate [> 5.5-6.0], severe [> 6.0]) using unadjusted analyses. Death, immediate inpatient admission, 30-day hyperkalemia recurrence, and 30-day inpatient admission were also assessed by severity., Results: Of 6222 patients included, 4432 (71.2%) had mild hyperkalemia, 1085 (17.4%) had moderate, and 705 (11.3%) had severe hyperkalemia. Chronic kidney disease (39.9-50.1%) and heart failure (21.6-24.3%) were common. In the ED, electrocardiograms (mild, 56.5%; moderate, 69.6%; severe, 81.0%) and patients with at least two potassium laboratory values increased with severity (15.0%; 40.4%; 75.5%). Among patients with at least two potassium laboratory values, over half of patients (60.4%) had potassium levels ≤ 5.0 mEq/L prior to discharge. Use of potassium-binding treatments (sodium polystyrene sulfonate: mild = 4.1%; moderate = 17.1%; severe = 27.4%), temporizing agents (5.6%; 15.5%; 31.6%), or dialysis (0.4%; 0.8%; 3.0%) increased with severity; treatment at discharge was not common. Death (1.1%; 3.7%; 10.6%), immediate admission to inpatient care (5.8%; 8.7%; 12.7%), 30-day hyperkalemia recurrence (2.9%; 19.0%; 32.5%), 30-day inpatient admission with hyperkalemia (6.5%; 7.9%; 9.3%) also increased with severity., Conclusion: Patients with moderate and severe hyperkalemia experienced elevated risk of hyperkalemia recurrence and hyperkalemia-related inpatient readmission following discharge from the ED from a descriptive analysis. Future research to assess strategies to reduce hyperkalemia recurrence and inpatient admission in this patient population would be beneficial., (© 2021. The Author(s).)

Introduction: Thromboembolic events (TEs) are associated with considerable costs. However, there is a paucity of evidence quantifying the economic burden associated with TEs among patients with immune-mediated diseases (IMDs)., Methods: This retrospective cohort study used the IBM MarketScan ® Commercial and Medicare Supplemental Claims databases (2014-2018). Commercially insured adults with IMDs were classified into two cohorts based on diagnosis of TEs (deep vein thrombosis, pulmonary embolism, ischemic stroke, myocardial infarction). Patients in the TE cohort were matched on type of IMD, age, sex, and year of diagnosis to patients in the no TE cohort. In the TE cohort, the index date was the date of first TE following first IMD diagnosis. In the no TE cohort, the index date was assigned so the duration from first IMD diagnosis to index date matched the duration for the corresponding patient in the TE cohort. All-cause total healthcare costs were compared between cohorts in the 30-day and 1-year periods following the index date (inclusive). Unadjusted comparisons were conducted using Wilcoxon signed-rank tests. Adjusted results were estimated using generalized estimating equations with robust sandwich estimator., Results: Overall, 9681 matched patients were included in each cohort (mean age 61.1 years; 63.7% female). The TE cohort had higher proportions of comorbidities than the no TE cohort (Charlson Comorbidity Index [1.5 vs. 0.9]; p < 0.0001). Adjusted all-cause total healthcare costs were significantly greater in the TE cohort versus no TE cohort in the 30-day and 1-year periods following the index date (cost difference: 30-day, $17,574; 1-year, $36,459; both p < 0.0001) and were driven by inpatient costs (cost difference: 30-day, $14,864; 1-year, $23,360; both p < 0.0001). TE-related healthcare costs were $15,955 and $20,239 in the 30-day and 1-year periods, respectively., Conclusion: Among patients with IMDs, TEs are associated with substantial economic burden within 30-days and 1-year following the event., (© 2021. The Author(s).)

Introduction: Inflammatory bowel disease (IBD) is associated with greater risk of thromboembolic events (TEs) due to the link between systemic inflammation and hypercoagulability. This study assessed the rates of TEs among patients with IBD versus patients without immune-mediated disease (IMD) and the cost of TEs among patients with IBD in the United States., Methods: This study used the IBM MarketScan ® Commercial and Medicare Supplemental Databases (2014-2018). To assess the incremental rates of TEs (deep vein thrombosis [DVT], pulmonary embolism [PE], ischemic stroke [IS], myocardial infarction [MI]), patients with IBD were matched to patients without IMD. Unadjusted and adjusted incidence rate ratios (IRRs) of TEs were used to compare cohorts. To assess the cost of TEs, patients with IBD with TEs were matched to patients with IBD without TEs. Costs were assessed 30 days and 1 year post index date., Results: There were 34,687 matched pairs included in the rates of TE analyses. Compared to patients without IMD, patients with IBD had greater rates of DVT (adjusted IRR [95% confidence interval] 2.44 [2.00, 2.99]; p < 0.01) and PE (1.90 [1.42, 2.54]; p < 0.01). Increased rates were not observed for IS and MI. There were 1885 matched pairs included in the cost of TE analyses. Patients with IBD with TEs incurred greater healthcare costs over 30 days and 1 year versus patients without TEs (adjusted total cost difference: 30 days $20,784; 1 year $44,630; p < 0.01 for both)., Conclusions: Patients with IBD experienced greater rates of DVT and PE compared to patients without IMD; this elevated risk was associated with a substantial economic burden., (© 2021. The Author(s).)

Despite demonstrating high levels of academic and professional competence, Asians are underrepresented in leadership roles in North America. The limited research on this topic has found that Asian Americans are perceived by others as poorer leaders than White Americans due to perceptions that Asians lack the ideal traits of a Western leader (i.e., agentic) relative to White Americans. However, we contend that, in addition to poorly activating ideal leader traits, Asian Americans may strongly activate ideal follower traits (e.g., industrious and reliable), and being seen as a good follower may pigeonhole Asian Americans in non-managerial roles. Across 4 studies, our findings generally supported our arguments regarding the activation of ideal follower traits and lack of activation of ideal leader traits for Asian American workers. However, compared to their majority group counterparts, we found some unexpected evidence for a more favorable view of Asian Americans as leaders, which was primarily driven by the greater activation of ideal follower traits (i.e., industry and good citizen) among Asian American workers. Yet, we uncover an important boundary condition in that these "good follower" advantages did not accrue when observers experienced threat-revealing how the benefits of so-called positive stereotypes of Asian American workers are context dependent., Supplementary Information: The online version contains supplementary material available at 10.1007/s10869-022-09794-3., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, corrected publication 2022.)

Dysregulated lipid metabolism of macrophages contributes to thrombosis and antiphospholipid syndrome (APS). The long non-coding RNAs (lncRNA) myocardial infarction-associated transcript 2 (Mirt2) has been reported to inhibit inflammation and lipid accumulation; therefore, this study intended to clarify whether Mirt2 served a role in lipid metabolism. THP-1-derived macrophages with or without Mirt2-knockdown or overexpression, were exposed to oxidized low-density lipoprotein (ox-LDL), then cell migration, lipid accumulation, cholesterol efflux and inflammation were assessed using wound healing, oil red staining, commercial kits and western blot assays. Besides, ML385 was used to treat THP-1-derived macrophages to inhibit nuclear factor erythroid-related factor 2 (NRF2) expression. The expression of proteins involved in the above processes were measured by western blot. Results demonstrated that phorbol 12-myristate 13-acetate (PMA) significantly increased Mirt2 expression in THP-1 cells. Mirt2-knockdown enhanced ox-LDL-induced macrophage migration, lipid accumulation, inflammation, and inhibited cholesterol efflux. By contrast, Mirt2 overexpression displayed the opposite effects. Furthermore, Mirt2-knockdown inhibited NRF2 signaling and enhanced mitogen-activated protein kinase (MAPK) signaling, while Mirt2 overexpression displayed the opposite effects. Finally, the NRF2 inhibitor ML385 significantly reversed the above effects of Mirt2. In summary, Mirt2 served an important role in regulating lipid metabolism in macrophages via inhibiting MAPK signaling and activating the NRF2 signaling pathway.

Recurrent spontaneous abortion (RSA) is a troublesome pregnancy disorder that manifests as sequential early pregnancy losses; its causes are diverse and complex. Among the known possible causes of RSA, the development of an immune disorder in response to the embryo appears to be the most pronounced. The imbalance between immune rejection and immune tolerance contributes to pregnancy loss in females with RSA, wherein the abnormal ratio of T helper (Th)1 cell‑related cytokines [predominantly tumor necrosis factor (TNF)‑α] and Th2 cell‑related cytokines is a strong risk factor for RSA. TNF‑α is a pro‑inflammatory cytokine and TNF inhibitors have been effective in the treatment of various autoimmune diseases, such as ankylosing spondylitis, and inflammatory diseases, such as ulcerative colitis. Based on their immunomodulatory properties, TNF inhibitors have been used in the treatment of RSA to reduce the immune rejection rate and improvement in pregnancy outcomes has been observed in females suffering from RSA who were treated with TNF inhibitors. The aim of the present review was to interpret the involvement of TNF‑α in the immunological disorder underlying RSA and summarize the clinical outcomes of TNF inhibitor treatment in patients with RSA.

Objective: To investigate the molecular mechanism by which α -synuclein ( α -Syn) regulates interferon regulatory factor 1 (IRF-1) expression., Methods: SH-SY5Y cells overexpressing α -Syn and transgenic mouse model carrying human α -Syn gene with A53T mutation (3 and 6 months old) were examined for IRF-1 mRNA and protein expressions using real-time PCR and Western blotting, respectively. The subcellular localization of IRF-1 was determined with immunofluorescence staining and cytoplasmic/nuclear protein isolation. The optimal concentrations of the proteasome inhibitor MG132 (0.01-2.0 μmol/L) and lysosomal inhibitor chloroquine (5-200 μmol/L) for treatment of SH-SY5Y cells for 24 h were determined by examining the cell viability. SH-SY5Y cells were treated with 0.2 μmol/L MG132 and 30 μmol/L chloroquine for 24 h (the maximum dose that did not cause cell damage), and the changes of IRF-1 protein expressions was analyzed. The effects of α -Syn on MDM2 protein expression and IRF-1 ubiquitylation were analyzed using Western blotting and ubiquitylation assay., Results: α -Syn overexpression did not affect the mRNA level of IRF-1 but significantly increased its protein level ( P < 0.01). In α -Synoverexpressing SH-SY5Y cells, IRF-1 translocation was observed from the cytoplasm to the nucleus ( P < 0.001). Treatment of the cells with 0.2 μmol/L MG132 significantly aggravated α -Syn-induced increase of IRF-1 protein expression ( P < 0.01) while 30 μmol/L chloroquine produced no significant changes in IRF-1 level. α -Syn overexpression caused an obvious decrease of MDM2 protein level and further inhibited the ubiquitylation of IRF-1 ( P < 0.01)., Conclusion: α -Syn blocks MDM2-mediated ubiquitylation of IRF-1 through ubiquitin proteasome pathway, thereby enhancing IRF-1 protein expression.

The human-robot interface (HRI) based on biological signals can realize the natural interaction between human and robot. It has been widely used in exoskeleton robots recently to help predict the wearer's movement. Surface electromyography (sEMG)-based HRI has mature applications on the exoskeleton. However, the sEMG signals of paraplegic patients' lower limbs are weak, which means that most HRI based on lower limb sEMG signals cannot be applied to the exoskeleton. Few studies have explored the possibility of using upper limb sEMG signals to predict lower limb movement. In addition, most HRIs do not consider the contribution and synergy of sEMG signal channels. This paper proposes a human-exoskeleton interface based on upper limb sEMG signals to predict lower limb movements of paraplegic patients. The interface constructs an channel synergy-based network (MCSNet) to extract the contribution and synergy of different feature channels. An sEMG data acquisition experiment is designed to verify the effectiveness of MCSNet. The experimental results show that our method has a good movement prediction performance in both within-subject and cross-subject situations, reaching an accuracy of 94.51 and 80.75%, respectively. Furthermore, feature visualization and model ablation analysis show that the features extracted by MCSNet are physiologically interpretable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shi, Huang, Peng, Mu and Yang.)

The human-robot interface (HRI) based on surface electromyography(sEMG) can realize the natural interaction between human and robot. It has been widely used in exoskeleton robots recently to help predict the wearer's movement. The sEMG signal of the paraplegic patients' lower limbs is weak. How to achieve accurate prediction of the lower limb movement of patients with paraplegia has always been the focus of attention in the field of HRI. Few studies have explored the possibility of using upper limb sEMG signals to predict lower limb movement. In addition, most HRIs do not consider the contribution and synergy of sEMG signal channels. This paper proposes a human-exoskeleton interface based on upper limb sEMG signals to predict lower limb movements of paraplegic patients. The interface constructs a channel synergy-based network (MCSNet) to extract the contribution and synergy of different feature channels. An sEMG data acquisition experiment is designed to verify the effectiveness of MCSNet. The experimental results show that our method has a good movement prediction performance in both within-subject and cross-subject situations, reaching an accuracy of 94.51% and 80.75% respectively.

Introduction: The progression of mild hyperkalemia and the predictors of progression have not been well characterized. In this study we aimed to characterize the progression of hyperkalemia and identify the risk factors for hyperkalemia progression., Methods: Adults with mild hyperkalemia (at least one serum potassium measure > 5.0 and ≤ 5.5 mEq/L) were identified using electronic medical records from the Research Action for Health Network (2012-2018). Progression to moderate-to-severe and progression to severe hyperkalemia were defined as the first occurrences of a serum potassium measure > 5.5 and > 6.0 mEq/L, respectively. Kaplan-Meier analyses were conducted to estimate progression rates for all patients and by pre-specified patient subgroups. Hazard ratios (HR) of moderate-to-severe and severe hyperkalemia progression were estimated using Cox models., Results: Of 35,369 patients with mild hyperkalemia, 16.9% and 8.7% progressed to moderate-to-severe and severe hyperkalemia, respectively. Rates of hyperkalemia progression elevated with the severity of chronic kidney disease (CKD). The highest progression rates were seen in patients with CKD stage 5 (stage 5 vs. no CKD: moderate-to-severe, 50.2% vs. 12.0%; severe, 31.3% vs. 3.9%; p < 0.001). Higher progression rates were also observed in patients with heart failure, hypertension, and type II diabetes compared with patients without those conditions (all p < 0.001). The most prominent risk factors were CKD stage 5 (HR of progression to moderate-to-severe hyperkalemia, 3.32 [95% CI 3.03-3.64]; severe, 4.08 [3.55-4.69]), CKD stage 4 (2.19 [1.97-2.43], 2.28 [1.92-2.71]), CKD stage 3 (1.57 [1.46-1.68], 1.65 [1.46-1.87]), type I diabetes (1.37 [1.18-1.61], 1.54 [1.23-1.93]), and serum potassium (1.12 [1.10-1.15], 1.13 [1.10-1.17] per 0.1 mEq/L increase) (all p values < 0.05)., Conclusion: Hyperkalemia progression rates increased significantly with CKD stage and were also higher among patients with higher baseline potassium level, heart failure, hypertension, and diabetes., (© 2021. The Author(s).)

A new genus of Parastenheliidae, Johnwellsia gen. nov., is proposed for its type and only species, J. bipartita sp. nov., collected from Dadeji Beach in Xiamen, Taiwan Strait, China. The intricate taxonomic history of the family is reviewed with special emphasis on its type genus Parastenhelia Thompson Scott, 1903. It is concluded that P. hornelli Thompson Scott, 1903 is the type of the genus and that the widely adopted previous designation of Harpacticus spinosus Fischer, 1860 as type species of Parastenhelia is invalid. The taxonomic concept of Parastenhelia is restricted to the hornelli-group which includes four valid species: P. hornelli, P. similis Thompson Scott, 1903, P. oligochaeta Wells Rao, 1987, and P. willemvervoorti sp. nov. The currently accepted concept of Parastenhelia spinosa as a highly variable cosmopolitan species is rejected. The genus Microthalestris Sars, 1905 (type: Thalestris forficula Claus, 1863) is resurrected to accommodate most Parastenhelia species that were previously placed in the spinosa-group. Two species, Thalestris forficuloides Scott Scott, 1894 and Parastenhelia antarctica Scott, 1912, are reinstated as valid members of the genus which further includes Parastenhelia gracilis Brady, 1910, Microthalestris littoralis Sars, 1911, P. costata Pallares, 1982, P. minuta Pallares, 1982, P. bulbosa Gee, 2006 and five new species: M. campbelliensis sp. nov.; M. polaris sp. nov.; M. santacruzensis sp. nov.; M. sarsi sp. nov. and M. variabilis sp. nov. Both the type species, Thalestris forficula, and Harpacticus spinosus are considered species inquirendae in Microthalestris. Three new genera are proposed to accommodate the remaining Parastenhelia species. Porirualia gen. nov. contains P. megarostrum Wells, Hicks Coull, 1982 (type) and P. pyriformis Song, Kim Chang, 2003, and is the sistergroup of Johnwellsia gen. nov. Parastenhelia aydini Kuru Karaytu, 2015 is placed in the monotypic genus Karaytugia gen. nov. while all species with penicillate elements on the antenna and P1 are transferred to Penicillicaris gen. nov., including Thalestris pectinimana Car, 1884, which is removed from the synonyms of the Parastenhelia spinosa (Fischer, 1860) complex, and three new species: P. maldivensis sp. nov., P. penicillata sp. nov., and P. sewelli sp. nov. The genus Karllangia Noodt, 1964 (type: K. arenicola Noodt, 1964) is relegated to a junior subjective synonym of Thalestrella Monard, 1935a (type: T. ornatissima Monard, 1935a). New or updated diagnoses for each genus, and differential diagnoses for species where appropriate, are provided. A key to the ten currently recognized genera in the Parastenheliidae is presented as well as keys to species for Parastenhelia, Microthalestris, Thalestrella and Penicillicaris gen. nov.

A new species of the genus Helmutkunzia Wells Rao, 1976 (Miraciidae) is described from specimens collected from an intertidal sandy beach in Xiamen, Fujian Province, China. Helmutkunzia xiamenensis sp. nov. differs from its two congeners by the length/width ratio of the female P5 exopod, the number or length of the setae on the sexually dimorphic P2 endopod in the male and the relative length of the spines on the endopodal lobe of the male P5. The Chinese species is morphologically closest to H. variabilis Wells Rao, 1987 from the Andaman and Nicobar island chain. Females of both species can readily be differentiated by the relative length of the P5 exopod while males can be differentiated by the length of the armature elements on P2 enp-2 and the endopodal lobe of P5. The genus Balucopsylla Rao, 1972 is reviewed, resulting in the proposal of Pseudobalucopsylla gen. nov. to accommodate the type species Balucopsylla triarticulata Wells Rao, 1987 and three new Indo-Pacific species previously identified with it: P. obscura sp. nov. from the Andaman Islands, P. costaricensis sp. nov. from the Pacific coast of Costa Rica and P. mielkei sp. nov. from the Galpagos archipelago. A key to species of Pseudobalucopsylla sp. nov. is provided.

Background: Heilongjiang Province is a high-quality japonica rice cultivation area in China. One in ten bowls of Chinese rice is produced here. Increasing yield is one of the main aims of rice production in this area. However, yield is a complex quantitative trait composed of many factors. The purpose of this study was to determine how many genetic loci are associated with yield-related traits. Genome-wide association studies (GWAS) were performed on 450 accessions collected from northeast Asia, including Russia, Korea, Japan and Heilongjiang Province of China. These accessions consist of elite varieties and landraces introduced into Heilongjiang Province decade ago., Results: After resequencing of the 450 accessions, 189,019 single nucleotide polymorphisms (SNPs) were used for association studies by two different models, a general linear model (GLM) and a mixed linear model (MLM), examining four traits: days to heading (DH), plant height (PH), panicle weight (PW) and tiller number (TI). Over 25 SNPs were found to be associated with each trait. Among them, 22 SNPs were selected to identify candidate genes, and 2, 8, 1 and 11 SNPs were found to be located in 3' UTR region, intron region, coding region and intergenic region, respectively., Conclusions: All SNPs detected in this research may become candidates for further fine mapping and may be used in the molecular breeding of high-latitude rice., (© 2021. The Author(s).)

Sclerotinia sclerotiorum ourmiavirus 17 (SsOV17) was isolated from the hypovirulent strain GF3 of Sclerotinia sclerotiorum. The genome of SsOV17 is 2,802 nt in length and contains a single long open reading frame (ORF) flanked by a short structured 5'-untranslated region (5'-UTR) (28 nt) and a long 3'-UTR (788 nt), respectively. The ORF encodes a protein with 663 amino acids and a predicted molecular mass of 75.0 kDa. A BLASTp search indicated that the protein encoded by SsOV17 is closely related to the putative RNA-dependent RNA polymerase (RdRp) of Sclerotinia sclerotiorum ourmiavirus 13 (71% identity). A multiple sequence alignment indicated that eight conserved amino acid motifs were present in the RdRp conserved region of SsOV17. Phylogenetic analysis demonstrated that SsOV17 clustered with members of the genus Botoulivirus., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Antipsychotic medications are used to treat schizophrenia and may be associated with adverse effects, including tardive dyskinesia (TD), following prolonged use or upon changes in dosing regimen., Objective: This retrospective analysis evaluated the burden of antipsychotic dose reduction in Medicare patients with schizophrenia., Methods: This matched cohort study used Medicare claims data (2006-2017) analyzed for patients with schizophrenia and two or more claims for antipsychotics, with one or more antipsychotic monotherapy period ≥ 90 days. Cohorts were defined for patients with antipsychotic dose reductions ≥ 10% and stable doses. A separate analysis was conducted using patients with dose reductions ≥ 30%. Outcomes included all-cause emergency room (ER) visits, all-cause inpatient visits, schizophrenia relapse, other psychiatric relapse, and TD diagnosis. Covariates included age, disease duration, comorbidities, and medication use., Results: The analysis included 276,030 patients with ≥ 10% dose reductions and 211,575 patients with ≥ 30% dose reductions. Patient characteristics were balanced between cohorts. Patients with ≥ 10% or ≥ 30% dose reductions had a shorter time to ER visit, inpatient visit, schizophrenia relapse, other psychiatric relapse, and TD diagnosis versus those receiving stable doses (all p < 0.001). Significance was maintained when unmatched baseline characteristics were adjusted., Conclusions: Patients with antipsychotic dose reductions may be at risk for increased ER visits, increased hospitalizations, and significant unfavorable mental health-related clinical outcomes, suggesting that dose reduction may increase overall health care burden in some patients with schizophrenia. This work highlights the need for alternative strategies in the management of patients with TD., (© 2021. The Author(s).)

Introduction: Although hyperkalemia and metabolic acidosis often co-occur in patients with chronic kidney disease (CKD), the prevalence of metabolic acidosis among patients with CKD and hyperkalemia is understudied. Therefore, we used medical record data from the Research Action for Health Network to estimate this prevalence., Methods: Adult patients with CKD stage 3-5, ≥ 1 outpatient potassium value > 5.0 mEq/l, and ≥ 1 outpatient bicarbonate value available were identified. Patients with end stage kidney disease (ESKD) in the prior year were excluded. The prevalence of metabolic acidosis in each calendar year from 2014 to 2017 among patients with CKD and hyperkalemia was estimated using two definitions of hyperkalemia (potassium > 5.0 mEq/l and > 5.5 mEq/l) and metabolic acidosis (bicarbonate < 18 mEq/l and < 22 mEq/l)., Results: In the 2017 patient cohort and among patients with CKD and hyperkalemia, patients with metabolic acidosis were younger (69 versus 74 years), more likely to have advanced CKD (35% versus 13%), and use oral sodium bicarbonate (21% versus 4%) than patients without metabolic acidosis. The prevalence of metabolic acidosis (< 22 mEq/l) ranged from 25 to 29% when hyperkalemia was defined by potassium > 5.0 mEq/l and ranged from 33 to 39% when hyperkalemia was defined by potassium > 5.5 mEq/l., Conclusion: Results demonstrated that prevalence estimates of metabolic acidosis varied based on the definition of hyperkalemia and metabolic acidosis utilized., (© 2021. The Author(s).)

Objectives: Patients with hyperkalemia are commonly treated in the inpatient setting; however, real-world evidence is limited. The purpose of this study was to describe the inpatient management and post-discharge outcomes among patients with hyperkalemia., Methods: Electronic medical record data (2012-2018) were used to analyze US adult patients with an inpatient stay with hyperkalemia (≥1 potassium value >5.0mEq/L). Patient characteristics, treatments, and monitoring six months prior to and during the inpatient stay, and hyperkalemia recurrence and inpatient readmissions post-discharge were summarized and compared among patients with mild (>5.0-5.5mEq/L), moderate (>5.5-6.0), and severe (>6.0) hyperkalemia., Results: Of the 21,793 patients, 69.2% had mild, 19.0% had moderate, and 11.8% had severe hyperkalemia during inpatient care. The most common inpatient treatments were temporizing agents (mild: 28.9%; moderate: 46.0%; severe: 73.0%), diuretics (32.7%; 37.1%; 34.6%), and sodium-polystyrene sulfonate (11.7%; 27.8%; 45.3%). Almost no patients (0.1%) received a potassium binder at discharge. Most patients (86.8%) had their potassium levels return to ≤5.0mEq/L during the inpatient stay. Death during the inpatient stay occurred in 12.3% of mild, 15.5% of moderate, and 19.5% of severe hyperkalemic patients. Within 30 days of discharge, hyperkalemia recurred in 13.3%, 15.4%, and 18.4% of patients with mild, moderate, and severe hyperkalemia, respectively. Additionally, 19.7%, 21.5%, and 19.6% of patients were readmitted to inpatient care within 30 days post-discharge., Conclusion: Among patients with hyperkalemia in the inpatient setting, treatment and normalization of serum potassium levels were common. However, death, readmission, and hyperkalemia recurrence were also fairly common across all cohorts. Future studies examining measures to reduce inpatient death, readmission, and hyperkalemia recurrence among patients with hyperkalemia in inpatient care are warranted.

Dalbergia Odorifera (DO) has been widely used for the treatment of cardiovascular and cerebrovascular diseasesinclinical. However, the effective substances and possible mechanisms of DO are still unclear. In this study, network pharmacology and molecular docking were used toelucidate the effective substances and active mechanisms of DO in treating ischemic stroke (IS). 544 DO-related targets from 29 bioactive components and 344 IS-related targets were collected, among them, 71 overlapping common targets were got. Enrichment analysis showed that 12 components were the possible bioactive components in DO, which regulating 9 important signaling pathways in 3 biological processes including 'oxidative stress' (KEGG:04151, KEGG:04068, KEGG:04915), 'inflammatory response'(KEGG:04668, KEGG:04064) and 'vascular endothelial function regulation'(KEGG:04066, KEGG:04370). Among these, 5 bioactive components with degree≥20 among the 12 potential bioactive components were selected to be docked with the top5 core targets using AutodockVina software. According to the results of molecular docking, the binding sites of core target protein AKT1 and MOL002974, MOL002975, and MOL002914 were 9, 8, and 6, respectively, and they contained 2, 1, and 0 threonine residues, respectively. And some binding sites were consistent, which may be the reason for the similarities and differences between the docking results of the 3 core bioactive components. The results of in vitro experiments showed that OGD/R could inhibit cell survival and AKT phosphorylation which were reversed by the 3 core bioactive components. Among them, MOL002974 (butein) had a slightly better effect. Therefore, the protective effect of MOL002974 (butein) against cerebral ischemia was further evaluated in a rat model of middle cerebral artery occlusion (MCAO) by detecting neurological score, cerebral infarction volume and lactate dehydrogenase (LDH) level. The results indicated that MOL002974 (butein) could significantly improve the neurological score of rats, decrease cerebral infarction volume, and inhibit the level of LDH in the cerebral tissue and serum in a dose-dependent manner. In conclusion, network pharmacology and molecular docking predicate the possible effective substances and mechanisms of DO in treating IS. And the results are verified by the in vitro and in vivo experiments. This research reveals the possible effective substances from DO and its active mechanisms for treating IS and provides a new direction for the secondary development of DO for treating IS., Competing Interests: The authors declare that they have no conflict of interest.

Mycoviruses are an important component of the virosphere, but our current knowledge of their genome organization diversity and evolution remains rudimentary. In this study, the mycovirus composition in a hypovirulent strain of Sclerotinia sclerotiorum was molecularly characterized. Nine mycoviruses were identified and assigned into eight potential families. Of them, six were close relatives of known mycoviruses, while the other three had unique genome organizations and evolutionary positions. A deltaflexivirus with a tripartite genome has evolved via arrangement and horizontal gene transfer events, which could be an evolutionary connection from unsegmented to segmented RNA viruses. Two mycoviruses had acquired a second helicase gene by two different evolutionary mechanisms. A rhabdovirus representing an independent viral evolutionary branch was the first to be confirmed to occur naturally in fungi. The major hypovirulence-associated factor, an endornavirus, was finally corroborated. Our study expands the diversity of mycoviruses and potential virocontrol agents, and also provides new insights into virus evolutionary modes including virus genome segmentation., Competing Interests: The authors have declared that no competing interests exist.

A computational study was contributed to explore the origin of stereoselectivity of NHC-mediated cyclization reaction between benzoic acid and o-phthalaldehyde for asymmetric construction of phthalidyl ester. The most energetically favorable pathway mainly includes the following steps: (1) nucleophilic attack on carbonyl carbon of o-phthalaldehyde by catalyst NHC, (2) formation of Breslow intermediate, (3) oxidation by DQ, (4) asymmetric formation of dual C-O bonds, and (5) dissociation of catalyst with the product. The C-O bond formation was testified as the stereoselectivity-determining step, the R-configurational pathway is more energetically favorable than the S-configurational one. The non-covalent interaction (NCI) and atom-in-molecule (AIM) analyses were performed to reveal that the O-H ⋅⋅⋅ O and C-H ⋅⋅⋅ O hydrogen-bond interactions are the key factors for controlling the stereoselectivity. The detailed mechanism and origin of stereoselectivity give useful insights for understanding organocatalytic reactions for asymmetric construction of C-O bond., (© 2021 Wiley-VCH GmbH.)

Purpose: This study assessed the association between thromboembolic events (TEs) and immune-mediated diseases (IMDs) and characterized the risk profile of TEs among patients with IMDs., Methods: An administrative claims database (2014-2018) was used to identify adults with ≥2 diagnoses on different dates for ≥1 IMD (IMD cohort; ankylosing spondylitis, atopic dermatitis, inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus); patients without an IMD diagnosis were assigned to the non-IMD cohort. Patients in the IMD cohort were matched 1:1 to patients in the non-IMD cohort on age, sex, and index date. Incremental risk of TE (ie, deep vein thrombosis [DVT], pulmonary embolism [PE], myocardial infarction [MI], and ischemic stroke [IS]) was assessed using adjusted incidence rate ratios (aIRRs) to control for covariates in both cohorts. Risk factors for TEs were assessed in the IMD cohort and included age, female sex, comorbidities, baseline TEs, non-IMD treatments, and IMD treatments., Findings: A total of 182,431 patients were included in each cohort (mean age, [51.3] years; 64.3% female). A higher proportion of patients in the IMD cohort versus the non-IMD cohort had ≥1 baseline TE (4.1% vs 2.7%; P < 0.0001). The IMD cohort had a 1.80 (95% CI, 1.68-1.92; P < 0.0001) times higher rate of TEs versus patients in the non-IMD cohort. After adjustments, patients in the IMD cohort had a 1.49 (95% CI, 1.40-1.59; P < 0.0001) times higher rate of TEs versus patients in the non-IMD cohort. Similar results were observed across individual TEs (DVT: aIRR = 1.78; PE: aIRR = 1.66; MI: aIRR = 1.17; IS: aIRR = 1.35; all P < 0.05). Risk factor profiles varied by TE. The greatest risk factor was respective TE during baseline (eg, patients with baseline DVT had 41.1 times the rate of DVT during the study period vs patients without baseline DVT; P < 0.001). Comorbidities, such as cardiovascular diseases, type 2 diabetes, and peripheral vascular disease, were associated with increased rates of MI (IRR = 2.60, 1.30, and 1.54, respectively; all P < 0.05) and IS (IRR = 1.53, 1.54, and 1.24, respectively; all P < 0.05). Janus kinase inhibitors were associated with an increased rate of PE (IRR = 2.52; P < 0.05) and nonsignificant, numerically higher rates of DVT (IRR = 1.23; P = NS) and IS (IRR = 1.82; P = NS). Sphingosine 1-phosphate receptor modulators were associated with decreased rates of TEs (DVT: IRR = 0.61, P = NS; PE: IRR = 0.30, P = NS; MI: IRR = 0.54, P = NS; IS: IRR = 0.33, P < 0.05)., Implications: The risk of TEs was higher among patients with IMD versus patients without IMD; several factors may affect this risk., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: In patients with chronic hypoparathyroidism disordered calcium homeostasis has been associated with risk of cardiovascular diseases, including cardiomyopathy, congestive heart failure, and arrhythmia; however, larger-scale studies are needed to examine these risks. This study evaluated the risk of cardiovascular conditions among patients with chronic hypoparathyroidism., Methods: Adults with and without chronic hypoparathyroidism were selected from a medical insurance claims database in the USA from January 2007 to June 2017, and were followed for up to 5 years. Associations between chronic hypoparathyroidism and incident atrial fibrillation (AF), tachyarrhythmia, myocardial infarction (MI), coronary artery disease (CAD), heart failure (HF), stroke, cerebrovascular disease, peripheral vascular disease (PVD), and a combined cardiovascular endpoint of cerebrovascular disease, CAD, HF, and PVD were compared between cohorts using Kaplan-Meier analyses and unadjusted and adjusted Cox proportional hazards models., Results: In 8097 patients with chronic hypoparathyroidism compared with 40,485 patients without, respectively, mean ± SD ages were 58.6 ± 16.3 and 47.3 ± 18.0 years, 76.2% and 54.4% were female, and 19.4% and 9.5% had the combination of cardiovascular findings at baseline. In adjusted analyses, patients with chronic hypoparathyroidism had significantly higher risk (adjusted hazard ratio and 95% confidence interval) of incident AF (1.72; 1.51-1.97), tachyarrhythmia (1.68; 1.32-2.14), MI (1.18; 1.01-1.38), CAD (1.39; 1.26-1.54), HF (1.64; 1.46-1.84), stroke (1.45; 1.31-1.62), cerebrovascular disease (1.48; 1.34-1.62), PVD (1.66; 1.51-1.81), and combined cardiovascular endpoint (1.63; 1.52-1.75), all P < 0.001 except P = 0.036 for MI, compared with patients without chronic hypoparathyroidism., Conclusions: This large retrospective cohort study showed that chronic hypoparathyroidism was associated with increased risk of incident cardiovascular conditions and arrhythmias. Results should be evaluated in light of limitations inherent to claims database analyses. Further studies are warranted to investigate reasons for these risks and to develop strategies for reducing cardiovascular conditions in patients with chronic hypoparathyroidism., (© 2021. The Author(s).)

Thermal resistances from interfaces impede heat dissipation in micro/nanoscale electronics, especially for high-power electronics. Despite the growing importance of understanding interfacial thermal transport, advanced thermal characterization techniques that can visualize thermal conductance across buried interfaces, especially for nonmetal-nonmetal interfaces, are still under development. This work reports a dual-modulation-frequency time-domain thermoreflectance (TDTR) mapping technique (1.61 and 9.3 MHz) to visualize the thermal conduction across buried semiconductor interfaces for β-Ga 2 O 3 -SiC samples. Both the β-Ga 2 O 3 thermal conductivity and the buried β-Ga 2 O 3 -SiC thermal boundary conductance (TBC) are visualized for an area of 200 × 200 μm simultaneously. Areas with low TBC values (≤20 MW/m 2 ·K) are identified on the TBC map, which correspond to weakly bonded interfaces caused by high-temperature annealing. Additionally, the steady-state temperature rise induced by the TDTR laser, usually ignored in TDTR analysis, is found to be able to probe TBC variations of the buried interfaces without the typical limit of thermal penetration depth. This technique can be applied to detect defects/voids in deeply buried heterogeneous interfaces nondestructively and also opens a door for the visualization of thermal conductance in nanoscale nonhomogeneous structures.

Follistatin (FST) is a secretory glycoprotein and belongs to the TGF-β superfamily. Previously, we found that two single nucleotide polymorphisms (SNPs) of sheep FST gene were significantly associated with wool quality traits in Chinese Merino sheep (Junken type), indicating that FST is involved in the regulation of hair follicle development and hair trait formation. The transcription regulation of human and mouse FST genes has been widely investigated, and many transcription factors have been identified to regulate FST gene. However, to date, the transcriptional regulation of sheep FST is largely unknown. In the present study, genome walking was used to close the genomic gap upstream of the sheep genomic FST gene and to obtain the FST gene promoter sequence. Transcription factor binding site analysis showed sheep FST promoter region contained a conserved putative binding site for signal transducer and activator of transcription 3 (STAT3), located at nucleotides -423 to -416 relative to the first nucleotide (A, +1) of the initiation codon (ATG) of sheep FST gene. The dual-luciferase reporter assay demonstrated that STAT3 inhibited the FST promoter activity and that the mutation of the putative STAT3 binding site attenuated the inhibitory effect of STAT3 on the FST promoter activity. Additionally, chromatin immunoprecipitation assay (ChIP) exhibited that STAT3 is directly bound to the FST promoter. Cell proliferation assay displayed that FST and STAT3 played opposite roles in cell proliferation. Overexpression of sheep FST significantly promoted the proliferation of sheep fetal fibroblasts (SFFs) and human keratinocyte (HaCaT) cells, and overexpression of sheep STAT3 displayed opposite results, which was accompanied by a significantly reduced expression of FST gene ( P < 0.05). Taken together, STAT3 directly negatively regulates sheep FST gene and depresses cell proliferation. Our findings may contribute to understanding molecular mechanisms that underlie hair follicle development and morphogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xu, Ma, Mu, Ning, Li and Wang.)

Background and Aims: This study aimed to identify predictors and estimate time to teduglutide response among adult patients with short bowel syndrome with intestinal failure (SBS-IF) dependent on parenteral support (PS)., Methods: Post-hoc analysis was performed on individual patient data from teduglutide-treated patients in the phase III teduglutide trial STEPS and the STEPS-2 extension. Response was defined as ≥20% PS volume reduction from baseline for two consecutive visits. Early responders experienced the reduction at 20 and 24 weeks during STEPS while late responders experienced the reduction during STEPS-2. Timing and predictors for response were assessed among the treated population using Cox proportional hazard model. Time to response was compared in aetiological subgroups using Kaplan-Meier analysis. Patient characteristics and time to response were compared between early vs. late responders., Results: A total of 34 patients were included in this analysis; overall median time to response was 4.3 months. The presence of stoma predicted a positive response to teduglutide (hazard ratio [HR]: 5.6; 95% confidence interval [CI]: 1.4-21.9; p = 0.013). Vascular disease (vs. inflammatory bowel disease [IBD]) as cause of major intestinal resection (HR: 0.2; 95% CI: 0.0-0.8; p = 0.015), presence of ileocecal valve (HR: 0.1; 95% CI: 0.0-0.8; p = 0.047), and female sex (HR: 0.3; 95% CI: 0.1-1.0; p = 0.026) are negatively associated with response. In subgroup analyses, patients with IBD (vs. vascular disease), with (vs. without) a stoma, and without (vs. with) colon-in-continuity had a shorter time to response (all p < 0.05). The mean times to response were 3.6 (standard deviation (SD): 1.1) months for early responders (n = 27) and 10.0 (SD: 6.1) months for late responders (n = 7). Fewer early responders had colon-in-continuity (51.9%) and ileocecal valve (0.0%) compared to late responders (100% and 28.6%, respectively; both p < 0.05). Early responders had a lower mean percentage of colon remaining compared to late responders (24.6% vs. 57.1%, respectively; p = 0.016)., Conclusions: Time to response to teduglutide depends on bowel anatomy and SBS-IF aetiology. IBD, presence of a stoma, and absence of ileocecal valve were associated with earlier response to teduglutide. These findings may enhance management of patients with SBS-IF; however, due to sample size limitations, additional studies are needed to confirm these findings., Competing Interests: Declaration of competing interest KC was an employee of Shire plc, a Takeda company, at the time of the study's conduct; CO was also an employee at the time of the study's conduct. FJ has served as a study investigator for NPS Pharmaceuticals, Inc. and advisory board member for Fresenius, Baxter Healthcare, Nestlé Health Sciences, Homeperf, Zealand Pharma A/S, TherAchon AG, Theradial, and Aguettant. FM, SK, and JX are employees of Analysis Group which received payment from Shire plc (a Takeda company), for research analysis. DLS has served as an advisory board member and study investigator for NPS Pharmaceuticals, Inc. and Aseptica, Inc., and as a consultant for Shire Pharmaceuticals (a Takeda company), TherAchon AG, and Zealand Pharma A/S. The clinical trial was funded by NPS Pharmaceuticals, Inc., Bedminster, NJ. NPS Pharmaceuticals, Inc., is a wholly owned indirect subsidiary of Shire plc, a Takeda company., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)