bluuebunny/crossref_metadata_2025 huggingface dataset:
Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity
Authors: Perelroizen Rita , Philosof Bar , Budick-Harmelin Noga , Chernobylsky Tom , Ron Ariel , Katzir Rotem , Shimon Dor , Tessler Adi , Adir Orit , Gaoni-Yogev Anat , Meyer Tom , Krivitsky Avivit , Shidlovsky Nuphar , Madi Asaf , Ruppin Eytan , Mayo Lior
Published: July 2022

Malignant brain tumours are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumours, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumour-associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain’s metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumour-associated astrocyte translatome revealed astrocytes initiate transcriptional programmes that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumour-associated macrophages and promotes a pro-tumourigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumour progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumour microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. These findings suggest that targeting astrocyte immunometabolic signalling may be useful in treating this uniformly lethal brain tumour.
Longitudinal Immune Response to 3 Doses of Messenger RNA Vaccine Against Coronavirus Disease 2019 (COVID-19) in Pediatric Patients Receiving Chemotherapy for Cancer
Authors: Lehrnbecher Thomas , Sack Ulrich , Speckmann Carsten , Groll Andreas H , Boldt Andreas , Siebald Benjamin , Hettmer Simone , Demmerath Eva-Maria , Reemtsma Judith , Schenk Barbara , Ciesek Sandra , Klusmann Jan-Henning , Jassoy Christian , Hoehl Sebastian
Published: July 2022

Our study in 21 pediatric cancer patients demonstrates that 3 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccine (BioNTech/Pfizer) elicited both humoral and cellular immunity in most patients during chemotherapy. Immunity was stronger in children with solid tumors and during maintenance therapy compared to those with hematological malignancies or during intensive chemotherapy.

Clinical Trials Registration.ȃGerman Registry for Clinical Trials (DRKS00025254).
An international multi-sectoral approach to financialisation
Authors: Torchinsky Landau Matías
Published: July 2022

Many studies attempted to measure the degree of financialisation of an economy, generally on a country-by-country basis, given the heterogeneity of indicators and data availability. In this paper, a simple but common measure of financialisation of non-financial corporations (NFCs) is developed, namely, the participation of services provided by the financial sector (both directly and indirectly) on their value-added creation process, inspired by the methodology developed by Dávila-Fernández and Punzo (2020). To do this, we use the inter-country input-output (ICIO) matrices built by the OECD, which allow us to understand the role played by the financial sector (local or foreign) in the ‘value-added production function’ of NFCs from 45 industries, in 67 countries for the period 1995–2018. We find three main stylised facts. First, the financial sector plays a relevant role in the value-added creation process of NFCs, and its importance has increased during the last years, although there is high diversity among countries. Second, this process has been heterogeneous when different productive sectors are considered. Primary industries evidenced a low degree of financialisation, while manufacturing and the service sector generally presented a higher reliance on finance. Third, between 1995 and the global financial crisis, NFCs increased their dependence on foreign financial value-added, followed by a partial reversion of this process. Moreover, the origin of these exports of financial services changed: while some traditional financial hubs such as the UK, Switzerland and Japan decreased their importance as providers of financial value-added to NFCs, China, Russia and India became important global players.
Neoadjuvant versus definitive chemoradiation in locally advanced esophageal cancer for patients of advanced age or significant comorbidities
Authors: Jensen Garrett L , Hammonds Kendall P , Haque Waqar
Published: July 2022

The addition of surgery to chemoradiation for esophageal cancer has not shown a survival benefit in randomized trials. Patients with more comorbidities or advanced age are more likely to be given definitive chemoradiation due to surgical risk. We aimed to identify subsets of patients in whom the addition of surgery to chemoradiation does not provide an overall survival (OS) benefit. The National Cancer Database was queried for patients with locally advanced esophageal cancer who received either definitive chemoradiation or neoadjuvant chemoradiation followed by surgery. Bivariate analysis was used to assess the association between patient characteristics and treatment groups. Log-rank tests and Cox proportional hazards models were performed to assess for differences in survival. A total of 15,090 with adenocarcinoma and 5,356 with squamous cell carcinoma met the inclusion criteria. Patients treated with neoadjuvant chemoradiation and surgery had significantly improved survival by Cox proportional hazards model regardless of histology if <50, 50–60, 61–70, or 71–80 years old. There was no significant benefit or detriment in patients 81–90 years old. Survival advantage was also significant with a Charlson/Deyo comorbidity condition score of 0, 1, 2, and ≥3 in adenocarcinoma squamous cell carcinoma with scores of 2 or ≥3 had no significant benefit or detriment. Patients 81–90 years old or with squamous cell carcinoma and a Charlson/Deyo comorbidity score ≥ 2 lacked an OS benefit from neoadjuvant chemoradiation followed by surgery compared with definitive chemoradiation. Careful consideration of esophagectomy-specific surgical risks should be used when recommending treatment for these patients.
Influence of the healthcare pathway on the outcome of patients with infective endocarditis
Authors: Arregle Florent , Iline Nicolas , Giorgi Roch , Philip Mary , Hubert Sandrine , Gouriet Frederique , Casalta Jean Paul , Collart Frédéric , Riberi Alberto , Martel Hélène , Renard Sébastien , Camoin Laurence , Casalta Anne Claire , Lepidi Hubert , Raoult Didier , Drancourt Michel , Habib Gilbert
Published: July 2022

Aims

To determine the prognosis of patients treated for infective endocarditis (IE) according to their healthcare pathway. To assess how the ESC guidelines are implemented concerning the performance of transoesophageal echocardiography, the use of antibiotic therapy, and the performance of valve surgery; and to compare the epidemiological profile of IE according to the type of centres in which the patients are hospitalized.

Methods and results

In a prospective multicentric study including 22 hospitals in the South-East of France, 342 patients were classified into three groups according to their healthcare pathway: 119 patients diagnosed and taken care entirely in a reference centre or hospital with cardiac surgery [Referral Center (RC) group], 111 patients diagnosed and initially taken care in a non-RC (NRC), then referred in a centre including cardiac surgery [transferred to the Referral Center (TRC) group] and 112 patients totally taken care in the NRC (NRC group). One-year mortality was 26% (88 deaths) and was not significantly different between Groups 1 and 2 (20 vs. 21%, P = 0.83). Patients in the NRC group had a higher mortality (37%) compared with patients in the RC and TRC groups (P < 0.001). ESC guidelines were not implemented similarly depending on the healthcare pathway (P = 0.04). Patients in the NRC group were significantly older (P < 0.001) and had more comorbidities (P < 0.001) than patients treated in referral centres.

Conclusion

Prognosis of patients with IE is influenced by their healthcare pathway. Patients treated exclusively in NRC have a worse prognosis than patients treated in referral or surgical centres.
Interaction between secondary mitral regurgitation and left atrial function and their prognostic implications after cardiac resynchronization therapy
Authors: Stassen Jan , Galloo Xavier , Hirasawa Kensuke , van der Bijl Pieter , Leon Martin B , Marsan Nina Ajmone , Bax Jeroen J
Published: July 2022

Aims

Left atrial (LA) function is a strong prognostic marker in patients with heart failure and functional mitral regurgitation (MR). Although cardiac resynchronization therapy (CRT) has shown to improve MR severity, the interaction between a reduction in MR severity and an increase in LA function, as well as its association with outcomes, has not been investigated.

Methods and results

LA reservoir strain (RS) was evaluated with speckle tracking echocardiography in patients with at least moderate functional MR undergoing CRT implantation. MR improvement was defined as at least 1 grade improvement in MR severity at 6 months after CRT implantation. The primary endpoint was all-cause mortality. A total of 340 patients (mean age 66 ± 10 years, 73% male) were included, of whom 200 (59%) showed MR improvement at 6 months follow-up. On multivariable analysis, an improvement in MR severity was independently associated with an increase in LARS (odds ratio 1.008; 95% confidence interval 1.003–1.013; P = 0.002). After multivariable adjustment, including baseline and follow-up variables, an increase in LARS was significantly associated with lower mortality. MR improvers showing LARS increasement had the lowest mortality rate, whereas outcomes were not significantly different between MR non-improvers and MR improvers showing no LARS increasement (P = 0.236).

Conclusion

A significant reduction in MR severity at 6 months after CRT implantation is independently associated with an increase in LARS. In addition, an increase in LARS is independently associated with lower all-cause mortality in patients with heart failure and significant functional MR.
Vascular senescence in progeria: role of endothelial dysfunction
Authors: Xu Qiu , Mojiri Anahita , Boulahouache Luay , Morales Elisa , Walther Brandon K , Cooke John P
Published: July 2022

Aims

Hutchinson–Gilford progeria syndrome (HGPS) is a pre-mature aging disorder caused by the mutation of the LMNA gene leading to an irreversibly farnesylated lamin A protein: progerin. The major causes of death in HGPS are coronary and arterial occlusive disease. In the murine model of HGPS, vascular smooth muscle cell (VSMC) loss is the primary vascular manifestation, which is different from the arterial occlusive disease seen in older patients.

Methods and results

To identify the mechanisms of HGPS vascular disease in humans, we differentiated isogenic endothelial cells (ECs) and VSMCs from HGPS-induced pluripotent stem cells (iPSCs) and control-iPSCs. Both HGPS-ECs and HGPS-VSMCs manifested cellular hallmarks of aging, including dysmorphic nuclei, impaired proliferation, increased β-galactosidase staining, shortened telomeres, up-regulated secretion of inflammatory cytokines, increased DNA damage, loss of heterochromatin, and altered shelterin protein complex (SPC) expression. However, at similar days after differentiation, even with lower levels of progerin, HGPS-ECs manifested more severe signs of senescence, as indicated in part by a higher percentage of β-galactosidase positive cells, shorter telomere length, and more DNA damage signals. We observed increased γH2A.X binding to RAP1 and reduced TRF2 binding to lamin A in HGPS-ECs but not in HGPS-VSMCs. The expression of γH2A.X was greater in HGPS-ECs than in HGPS-VSMCs and is associated with greater telomere shortening, impaired SPC interactions, and loss of heterochromatin.

Conclusion

Although progerin expression has a deleterious effect on both ECs and VSMCs, the dysfunction is greater in HGPS-ECs compared with HGPS-VSMCs. This study suggests that an endothelial-targeted therapy may be useful for HGPS patients.
Resolving Conflicting Emotions: Obama's Quandaries on the Red Line and the Fight against ISIS
Authors: Beauregard Philippe
Published: July 2022

The study of emotions in foreign policymaking has emphasized dominant discrete emotions and how they each lead to specific action tendencies. Scholars often focus on one emotion to explain decisions and have an additive view of emotions. This article argues that decision-makers often feel conflicting emotions and that emotions are not simply additive. What are conflicting emotions’ consequences for foreign policymaking? How are these conflicts resolved? The cases of President Obama's response to the Syrian chemical weapon attack in 2013 and the rise of ISIS in 2014 provide an occasion to study these questions on major security issues surrounding military intervention. This article argues that when decision-makers feel conflicted emotions their anxiety level rises, and that they are likely to attempt to gain time through procrastination, to resolve their conflict by focusing their attention on new developments, and to seek support to bolster confidence in their decision.
Modular safe-harbor transgene insertion for targeted single-copy and extrachromosomal array integration in Caenorhabditis elegans
Authors: El Mouridi Sonia , Alkhaldi Faisal , Frøkjær-Jensen Christian
Published: July 2022

Efficient and reproducible transgenesis facilitates and accelerates research using genetic model organisms. Here, we describe a modular safe-harbor transgene insertion (MosTI) for use in Caenorhabditis elegans which improves targeted insertion of single-copy transgenes by homology directed repair and targeted integration of extrachromosomal arrays by nonhomologous end-joining. MosTI allows easy conversion between selection markers at insertion site and a collection of universal targeting vectors with commonly used promoters and fluorophores. Insertions are targeted at three permissive safe-harbor intergenic locations and transgenes are reproducibly expressed in somatic and germ cells. Chromosomal integration is mediated by CRISPR/Cas9, and positive selection is based on a set of split markers (unc-119, hygroR, and gfp) where only animals with chromosomal insertions are rescued, resistant to antibiotics, or fluorescent, respectively. Single-copy insertion is efficient using either constitutive or heat-shock inducible Cas9 expression (25–75%) and insertions can be generated from a multiplexed injection mix. Extrachromosomal array integration is also efficient (7–44%) at modular safe-harbor transgene insertion landing sites or at the endogenous unc-119 locus. We use short-read sequencing to estimate the plasmid copy numbers for 8 integrated arrays (6–37 copies) and long-read Nanopore sequencing to determine the structure and size (5.4 Mb) of 1 array. Using universal targeting vectors, standardized insertion strains, and optimized protocols, it is possible to construct complex transgenic strains which should facilitate the study of increasingly complex biological problems in C. elegans.
Quantitative evaluation of nonlinear methods for population structure visualization and inference
Authors: Ubbens Jordan , Feldmann Mitchell J , Stavness Ian , Sharpe Andrew G
Published: July 2022

Population structure (also called genetic structure and population stratification) is the presence of a systematic difference in allele frequencies between subpopulations in a population as a result of nonrandom mating between individuals. It can be informative of genetic ancestry, and in the context of medical genetics, it is an important confounding variable in genome-wide association studies. Recently, many nonlinear dimensionality reduction techniques have been proposed for the population structure visualization task. However, an objective comparison of these techniques has so far been missing from the literature. In this article, we discuss the previously proposed nonlinear techniques and some of their potential weaknesses. We then propose a novel quantitative evaluation methodology for comparing these nonlinear techniques, based on populations for which pedigree is known a priori either through artificial selection or simulation. Based on this evaluation metric, we find graph-based algorithms such as t-SNE and UMAP to be superior to principal component analysis, while neural network-based methods fall behind.
Tourmaline: A containerized workflow for rapid and iterable amplicon sequence analysis using QIIME 2 and Snakemake
Authors: Thompson Luke R , Anderson Sean R , Den Uyl Paul A , Patin Nastassia V , Lim Shen Jean , Sanderson Grant , Goodwin Kelly D
Published: July 2022

Background

Amplicon sequencing (metabarcoding) is a common method to survey diversity of environmental communities whereby a single genetic locus is amplified and sequenced from the DNA of whole or partial organisms, organismal traces (e.g., skin, mucus, feces), or microbes in an environmental sample. Several software packages exist for analyzing amplicon data, among which QIIME 2 has emerged as a popular option because of its broad functionality, plugin architecture, provenance tracking, and interactive visualizations. However, each new analysis requires the user to keep track of input and output file names, parameters, and commands; this lack of automation and standardization is inefficient and creates barriers to meta-analysis and sharing of results.

Findings

We developed Tourmaline, a Python-based workflow that implements QIIME 2 and is built using the Snakemake workflow management system. Starting from a configuration file that defines parameters and input files—a reference database, a sample metadata file, and a manifest or archive of FASTQ sequences—it uses QIIME 2 to run either the DADA2 or Deblur denoising algorithm; assigns taxonomy to the resulting representative sequences; performs analyses of taxonomic, alpha, and beta diversity; and generates an HTML report summarizing and linking to the output files. Features include support for multiple cores, automatic determination of trimming parameters using quality scores, representative sequence filtering (taxonomy, length, abundance, prevalence, or ID), support for multiple taxonomic classification and sequence alignment methods, outlier detection, and automated initialization of a new analysis using previous settings. The workflow runs natively on Linux and macOS or via a Docker container. We ran Tourmaline on a 16S ribosomal RNA amplicon data set from Lake Erie surface water, showing its utility for parameter optimization and the ability to easily view interactive visualizations through the HTML report, QIIME 2 viewer, and R- and Python-based Jupyter notebooks.

Conclusion

Automated workflows like Tourmaline enable rapid analysis of environmental amplicon data, decreasing the time from data generation to actionable results. Tourmaline is available for download at github.com/aomlomics/tourmaline.
ETS1 loss in mice impairs cardiac outflow tract septation via a cell migration defect autonomous to the neural crest
Authors: Lin Lizhu , Pinto Antonella , Wang Lu , Fukatsu Kazumi , Yin Yan , Bamforth Simon D , Bronner Marianne E , Evans Sylvia M , Nie Shuyi , Anderson Robert H , Terskikh Alexey V , Grossfeld Paul D
Published: July 2022

Ets1 deletion in some mouse strains causes septal defects and has been implicated in human congenital heart defects in Jacobsen syndrome, in which one copy of the Ets1 gene is missing. Here, we demonstrate that loss of Ets1 in mice results in a decrease in neural crest (NC) cells migrating into the proximal outflow tract cushions during early heart development, with subsequent malalignment of the cushions relative to the muscular ventricular septum, resembling double outlet right ventricle (DORV) defects in humans. Consistent with this, we find that cultured cardiac NC cells from Ets1 mutant mice or derived from iPS cells from Jacobsen patients exhibit decreased migration speed and impaired cell-to-cell interactions. Together, our studies demonstrate a critical role for ETS1 for cell migration in cardiac NC cells that are required for proper formation of the proximal outflow tracts. These data provide further insights into the molecular and cellular basis for development of the outflow tracts, and how perturbation of NC cells can lead to DORV.
Outcomes following surgical repair of absent pulmonary valve syndrome: 30 years of experience from a Swedish tertiary referral centre
Authors: Avdikos Vasileios , Johansson Ramgren Jens , Hanséus Katarina , Malm Torsten , Liuba Petru
Published: July 2022

Surgical approach with reduction pulmonary artery plasty and valved conduit in patients with respiratory compromise prior to repair is associated with excellent long-term survival at the cost of a higher reintervention rate.

OBJECTIVES

Absent pulmonary valve syndrome is a rare congenital heart defect with pulmonary artery dilatation and secondary airway compression. Although preoperative respiratory support and early surgical repair with pulmonary arterioplasty are often required in patients with airway compromise, the need for extensive plasty in these patients and for plasty in general in those with no or mild respiratory issues remains debatable.

METHODS

We performed a retrospective survey of patients with this diagnosis and repair from 1988 to 2018.

RESULTS

Twenty patients were identified. The median age and weight at repair were 0.8 (0.1–2.4) years and 7.0 (2.5–13.8) kg and included a valved conduit in 17 (85%) patients and a transannular patch in 3 patients. Five (29%) patients were ventilator-dependent prior to repair at the age of 0.3 (0.1–0.4) years. Pulmonary arterioplasty was performed in 7 patients (35%), including all 5 with ventilator dependency and 2 with respiratory symptoms due to recurrent infections. Two patients (10%) with preoperative ventilator dependency underwent extensive intrahilar arterioplasty. Preoperative ventilator dependency was associated with earlier repair and reinterventions (P < 0.05). There were 3 late deaths among cases with repair after 2000 (n = 14), none with preoperative ventilator dependency.

CONCLUSIONS

The long-term outcomes of patients with this rare defect are good, comparable to those of other previous studies. Reduction pulmonary arterioplasty, which in this study was used only in patients with respiratory distress and ventilator dependency, is associated with excellent survival. Reinterventions are common in these patients.
Splitting Hairs with Transcendental Entire Functions
Authors: Pardo-Simón Leticia
Published: July 2022

In recent years, there has been significant progress in the understanding of the dynamics of transcendental entire functions with bounded postsingular set. In particular, for certain classes of such functions, a complete description of their topological dynamics in terms of a simpler model has been given inspired by methods from polynomial dynamics. In this paper, and for the 1st time, we give analogous results in cases when the postsingular set is unbounded. More specifically, we show that if $f$ is of finite order, has bounded criticality on its Julia set $J(f)$, and its singular set consists of finitely many critical values that escape to infinity and satisfy a certain separation condition, then $J(f)$ is a collection of dynamic rays or hairs, which split at critical points, together with their corresponding landing points. In fact, our result holds for a much larger class of functions with bounded singular set. Moreover, this result is a consequence of a significantly more general one: we provide a topological model for the action of $f$ on its Julia set.
Elliptic Stable Envelopes of Affine Type A Quiver Varieties
Authors: Dinkins Hunter
Published: July 2022

We generalize Smirnov’s formula for the elliptic stable envelopes of the Hilbert scheme of points in $\mathbb {C}^2$ to the case of affine type $A$ Nakajima quiver varieties constructed with positive stability condition. We allow for arbitrary choices of polarization and a fairly general choice of chamber. This paper is a companion to the Maple code developed by the author, which implements the formulas described in this paper.
Antimicrobial activity of cefepime/zidebactam (WCK 5222), a β-lactam/β-lactam enhancer combination, against clinical isolates of Gram-negative bacteria collected worldwide (2018–19)
Authors: Sader Helio S , Mendes Rodrigo E , Duncan Leonard R , Carvalhaes Cecilia G , Castanheria Mariana
Published: July 2022

Background

Zidebactam, a bicyclo-acyl hydrazide β-lactam ‘enhancer’ antibiotic, in combination with cefepime (WCK 5222) is under clinical development for the treatment of resistant Gram-negative infections.

Objectives

To evaluate the in vitro activity of cefepime/zidebactam and comparators against 24 220 Gram-negative bacteria.

Methods

Organisms were consecutively collected in 2018–19 from 137 medical centres located in the USA (n = 9140), Western Europe (W-EU; n = 5929), Eastern Europe (E-EU; n = 3036), the Asia-Pacific region (APAC; n = 3791) and Latin America (LATAM; n = 2324). The isolates were susceptibility tested using the broth microdilution method as part of the SENTRY Program. Cefepime/zidebactam was tested at a 1:1 ratio.

Results

Cefepime/zidebactam was highly active against Enterobacterales (MIC50/90 0.03/0.25 mg/L; 99.9% inhibited at ≤8 mg/L) and retained potent activity against carbapenem-resistant Enterobacterales (CRE) isolates (97.8% inhibited at ≤8 mg/L). CRE rates varied widely from 1.1% in the USA to 1.9% in W-EU, 3.6% in APAC and 14.6% in E-EU (3.9% overall). The most common carbapenemase genes observed overall were blaKPC (37.6% of CRE), blaOXA-48-like (30.0%) and blaNDM (23.8%). Resistance to ceftazidime/avibactam among CRE was elevated in APAC (64.8%), E-EU (25.5%) and LATAM (20.7%). Against Pseudomonas aeruginosa, cefepime/zidebactam inhibited 99.2% of isolates at ≤8 mg/L and susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam was lowest in E-EU (83.9% and 82.0%, respectively). Cefepime/zidebactam exhibited good activity against Stenotrophomonas maltophilia (80.0% inhibited at ≤8 mg/L) and Burkholderia cepacia (89.4% inhibited at ≤8 mg/L).

Conclusions

Cefepime/zidebactam demonstrated potent in vitro activity against a large worldwide collection of contemporary clinical isolates of Gram-negative bacteria.
TLR2 and TLR4 activity in monocytes and macrophages after exposure to amoxicillin, ciprofloxacin, doxycycline and erythromycin
Authors: Silva Lagos Luis , Luu Thy Viet , De Haan Bart , Faas Marijke , De Vos Paul
Published: July 2022

Background

Antibiotics are used to treat bacterial infections but also impact immunity. This is usually attributed to antibiotic-induced dysbiosis of the microbiota, but antibiotics may have a direct effect on immune cells and immunity-associated receptors, such as Toll-like receptors (TLRs).

Objectives

To investigate whether antibiotics alter TLR2/1, TLR2/6 and TLR4 activity in immune cells.

Methods

We evaluated the effects of amoxicillin, ciprofloxacin, doxycycline and erythromycin on TLR2/1-, TLR2/6- and TLR4-induced NF-κB activation in THP1-XBlue™-MD2-CD14 cells. Furthermore, we studied TNF-α and IL-6 levels in THP-1-derived macrophages after exposure to these antibiotics and TLR ligands.

Results

Amoxicillin had no effect on any of the TLRs studied. However, ciprofloxacin reduced TLR2/1, TLR2/6 and TLR4 activity in THP1-XBlue™-MD2-CD14 cells and decreased TLR2/1-induced TNF-α and IL-6 in macrophages. Doxycycline reduced TLR2/6 and TLR4 activity in THP1-XBlue™-MD2-CD14 cells and TNF-α and IL-6 levels in response to TLR2/6 stimulation in macrophages. Erythromycin decreased TLR2/1 and TLR4 activity in THP1-XBlue™-MD2-CD14 cells without changes in TNF-α and IL-6 levels in macrophages. In addition, ciprofloxacin decreased the expression of TLR2 mRNA.

Conclusions

These results suggest that some antibiotics may attenuate TLR-dependent monocyte/macrophage responses and likely reduce bacterial clearance. The latter is particularly important in infections with AMR bacteria, where misprescribed antibiotics not only fail in control of AMR infections but might also weaken host defence mechanisms by limiting innate immune responses. Our data suggest that efforts should be made to prevent the deterioration of the immune response during and after antibiotic treatment.
Comprehensive Diabetes Autoantibody Laboratory-Based Clinical Service Testing in 6044 Consecutive Patients: Analysis of Age and Sex Effects
Authors: Dahl Amanda , Jenkins Sarah , Pittock Sean J , Mills John , Foster Jesica , McKeon Andrew , Pittock Siobhan
Published: July 2022

Background

In 2017, Mayo Clinic Laboratories commenced offering a comprehensive type 1 diabetes mellitus (T1DM) autoantibody (Ab) evaluation including 4 known Abs targeting glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and zinc transporter 8 protein (ZnT8) antigens.

Methods

The objective of this study was to evaluate real-time data on the frequency and patterns of all 4 Abs stratified by age and sex from 6044 unique consecutive adult and pediatric patients undergoing evaluation for suspected diabetes.

Results

At least one Ab was found in 3370 (56%) of all samples: 67% of children (aged 0–17), 49% of young adults (aged 18–35), and 41% for both middle-aged (aged 36–55) and older (aged >55) adults (P ≤ 0.0001). GAD65-Abs were the most common in all age groups, followed by ZnT8-Ab in those <36 years, or IAA-Ab in those ≥36. Frequencies of IA2- and ZnT8-Abs drop significantly with increasing age. Clusters of 3 or 4 Abs were more frequently encountered in younger patients (41% of children vs 12% in middle- and 13% in older age groups, P ≤ 0.0001).

Conclusions

Children undergoing serological evaluation for T1DM were more commonly positive for autoantibodies than older age groups. The frequency of ZnT8- and IA2-Abs decreases, and IAA-Ab frequency increases with increasing age, and clusters of 2 to 4 autoantibodies are more common in children. In clinical practice, comprehensive testing for diabetes autoantibodies resulted in a switch in diagnosis to T1DM for patients previously classified as type 2 diabetes mellitus.
Reevaluating the Icterus Index Cutoff of a Jaffé Creatinine Method
Authors: Alvarez Yasel F , Kelliher Michael T , Hubbard Jacqueline A , Nerenz Robert D , Cervinski Mark A
Published: July 2022

Background

The aim of this study was to redefine the icterus index cutoff for the Roche Jaffé creatinine method using both conjugated and unconjugated bilirubin on 3 Roche cobas modules (c311, c501, and c701/c702) at laboratories across our hospital network.

Methods

Interference was evaluated by adding conjugated bilirubin (as bilirubin conjugate, ditaurate) and unconjugated bilirubin to pooled remnant plasma. The effects of conjugated and unconjugated bilirubin were tested separately to assess the contribution of each species. The magnitude of interference was calculated as both absolute and percentage error with total allowable error limits set at 0.1 mg/dL (8 µmol/L or 8%).

Results

Analysis of interference data across the 3 Roche modules did not show bias exceeding our total allowable error limits for plasma creatinine up to a conjugated bilirubin icterus index of 16.2 (approximately 16.2 mg/dL or 277 μmol/L) or an unconjugated bilirubin icterus index of 18.5 (approximately 18.5 mg/dL or 316 μmol/L), the highest concentrations tested.

Conclusions

Our results demonstrate that the Roche Jaffé method exhibits acceptable performance in the presence of icterus at icterus indexes above the manufacturer’s current recommendations of 5 (approximately 5 mg/dL or 86 μmol/L) and 10 (approximately 10 mg/dL or 171 μmol/L) for conjugated and unconjugated bilirubin, respectively. We have updated the icterus index in our hospital system to 16 for conjugated bilirubin and 18 for unconjugated bilirubin.
Digital interventions for antimicrobial prescribing and monitoring: a qualitative meta-synthesis of factors influencing user acceptance
Authors: Van Dort Bethany A , Carland Jane E , Penm Jonathan , Ritchie Angus , Baysari Melissa T
Published: July 2022

Objective

To understand and synthesize factors influencing user acceptance of digital interventions used for antimicrobial prescribing and monitoring in hospitals.

Materials and Methods

A meta-synthesis was conducted to identify qualitative studies that explored user acceptance of digital interventions for antimicrobial prescribing and/or monitoring in hospitals. Databases were searched and qualitative data were extracted and systematically classified using the unified theory of acceptance and use of technology (UTAUT) model.

Results

Fifteen qualitative studies met the inclusion criteria. Eleven papers used interviews and four used focus groups. Most digital interventions evaluated in studies were decision support for prescribing (n = 13). Majority of perceptions were classified in the UTAUT performance expectancy domain in perceived usefulness and relative advantage constructs. Key facilitators in this domain included systems being trusted and credible sources of information, improving performance of tasks and increasing efficiency. Reported barriers were that interventions were not considered useful for all settings or patient conditions. Facilitating conditions was the second largest domain, which highlights the importance of users having infrastructure to support system use. Digital interventions were viewed positively if they were compatible with values, needs, and experiences of users.

Conclusions

User perceptions that drive users to accept and utilize digital interventions for antimicrobial prescribing and monitoring were predominantly related to performance expectations and facilitating conditions. To ensure digital interventions for antimicrobial prescribing are accepted and used, we recommend organizations ensure systems are evaluated and benefits are conveyed to users, that utility meets expectations, and that appropriate infrastructure is in place to support use.
Consent Builder: an innovative tool for creating research informed consent documents
Authors: Sward Katherine A , Enriquez Rene , Burr Jeri , Ozier Julie , Roebuck Megan , Elliott Carrie , Dean J Michael
Published: July 2022

Objective

To describe process innovations related to research informed consent documents, and development and formative evaluation of Consent Builder, a platform for generating consent documents for multicenter studies.

Materials and Methods

Analysis of Institutional Review Board workflows and documents, followed by process redesign, document redesign, and software development. Locally developed software leverages REDCap and LaTeX. A small-scale usability study was conducted.

Results

Process innovations were combining document types, and conceptualizing 2-part informed consent documents: part 1 standardizing the study description and part 2 with local site verbiage. Consent Builder was implemented in the Trial Innovation Network. User survey scores were acceptable; but areas for improvement were noted. LaTeX coding was the biggest challenge for users.

Discussion

The process changes were generally well accepted. The software implementation uncovered un-accounted for assumptions, and variability in IRB review workflow across centers. Technical modifications may be needed before widespread implementation.

Conclusion

We demonstrated proof-of-concept of an approach to generate research consent documents that are consistent across sites in study description, but which allow for customization of local site verbiage. The Consent Builder tool is an example of an operational innovation, helping meet a need that arose in part due to regulations around use of Single IRB for multicenter trials.
Leadership Diversity and Development in the Nation’s Cancer Centers
Authors: Lerman Caryn , Hughes-Halbert Chanita , Falcone Mary , Gosky David M , Jensen Roy A , Lee Kelvin P , Mitchell Edith , Odunsi Kunle , Pegher Jennifer W , Rodriguez Elisa , Sanchez Yolanda , Shaw Reuben , Weiner George , Willman Cheryl L
Published: July 2022

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute–designated and 18 emerging centers. Among these 82 respondents, non-Hispanic White individuals comprised 79% of center directors, 82% of deputy directors, 72% of associate directors, and 72% of program leaders. Women are underrepresented in all leadership roles (ranging from 16% for center directors to 45% for associate directors). Although the limited gender, ethnic, and racial diversity of center directors and perhaps deputy directors is less surprising, the demographics of current research program leaders and associate directors exposes a substantial lack of diversity in the traditional cancer center senior leadership pipeline. Sole reliance on the cohort of current center leaders and leadership pipeline is unlikely to produce the diversity in cancer center leadership needed to facilitate the ability of those centers to address the needs of the diverse populations they serve. Informed by these data, this commentary describes some best practices to build a pipeline of emerging leaders who are representative of the diverse populations served by these institutions and who are well positioned to succeed.
Monkeypox virus containment: the application of ring vaccination and possible challenges
Authors: Sah Ranjit , Abdelaal Abdelaziz , Asija Ankush , Basnyat Soney , Sedhai Yub Raj , Ghimire Sadikshya , Sah Sanjit , Bonilla-Aldana D Katterine , Rodriguez-Morales Alfonso J
Published: July 2022

Due to the pandemic potential of monkeypox, the application of ring vaccination would be of great value in breaking the chain of transmission as well as in preventing the occurrence of this severe disease. Accompanying challenges should be overcome to properly contain the disease before it is declared as pandemic.
Inactivated COVID-19 vaccines: durability of Covaxin/BBV152 induced immunity against variants of concern
Authors: Kumar Nathella Pavan , Banurekha V V , Kumar C P Girish , Nancy Arul , Padmapriyadarsini Chandrasekaran , Shankar Sakila , Hanna Luke Elizabeth , Murhekar Manoj , Devi K R Uma , Babu Subash
Published: July 2022

Background

Covaxin/BBV152 is one of the most widely used vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and one of the few vaccines used extensively in low- and middle-income countries (LMIC).

Methods

We investigated the effect of Covaxin on the SARS-CoV-2 specific IgG and IgA and neutralizing antibody (NAb) levels at baseline (M0) and at Months 1 (M1), 2 (M2), 3 (M3), 4 (M4), 6 (M6) and 12 (M12) following vaccination in healthcare workers. In addition, we also examined the NAb levels against variant lineages of B.1.617.2 (Delta, India), B.1.617.2.1 (Delta Plus, India), B.1.351 (Beta, SA), B.1.1.7 (Alpha, UK) and B.1.1.529 (Omicron).

Results

Covaxin induces enhanced SARS-CoV-2 binding antibodies of IgG and IgA responses against both spike (S) and nucleocapsid (N) antigens at M1, M2, M3, M4, M6 and M12 in comparison with M0. Our data also reveal that NAb levels against the ancestral strain (Wuhan, wild type) are elevated and sustained at M1, M2, M3, M4, M6 and M12 in comparison with M0 and against variant lineages of B.1.617.2 (Delta, India), B.1.617.2.1 (Delta Plus, India), B.1.351 (Beta, SA) and B.1.1.7 (Alpha, UK) are elevated at M3, M6 and M12 in comparison with M0. However, NAb levels against B.1.1.529 (Omicron) was consistently below the limit of detection except at M12.

Conclusion

Thus, Covaxin induces an enhanced humoral immune response, with persistence till at least 12 months post-vaccination against most SARS-CoV-2 variants.
An Experimental Study on Kinetics-Controlled Ca-Carbonate Aqueous Reduction into CH4 (1 and 2 GPa, 550°C): Implications for C Mobility in Subduction Zones
Authors: Peng Weigang , Tumiati Simone , Zhang Lifei , Tiraboschi Carla , Vitale Brovarone Alberto , Toffolo Luca , Poli Stefano
Published: July 2022

Abiotic methane (CH4) generation under subduction zone conditions has been experimentally investigated through aqueous reduction of pure C-bearing materials (e.g. carbonate minerals and organic matter). However, quantitative assessments of CH4 production in these experiments, as well as the potential effects of other components such as SiO2 on the reduction processes, have not yet been well established. Here, we performed experiments to quantitatively evaluate the time-resolved Ca-carbonate aqueous reduction into CH4 at P = 1 and 2 GPa and T = 550°C in the CaO + COH, CaO + SiO2 + COH, and CaO + SiO2 + MgO + COH systems, employing calcite + water ± quartz ± serpentine (synthetic chlorine (Cl)-bearing chrysotile and natural Fe−Al-bearing antigorite) as starting materials. Redox conditions of the experiments were buffered by iron−wüstite (IW) using a double capsule setting, corresponding to oxygen fugacity (fO2) values (expressed as log units relative to the fayalite–magnetite–quartz buffer, ΔFMQ) in the inner capsule of ΔFMQ ≈ −5.5 at 1 GPa and ΔFMQ ≈ −6.0 at 2 GPa. The solid products are mainly composed of portlandite ± larnite ± wollastonite ± brucite, while Ca-carbonate and/or silicate reactants commonly occur as relicts. Quadrupole mass spectrometric analysis shows that CH4 and H2O are the major COH molecular species in the fluid products, with molar ratios between CH4 and starting calcite representing the reaction progress ranging from ~0.13 to ~1.00. Comparisons of experimental run products with thermodynamically predicted phase assemblages, together with time-series experiments, indicate that the reduction processes are primarily controlled by reaction kinetics. At 1 GPa and 550°C, rate constants of 4.0 × 10−6 s−1, 7.4 × 10−6 s−1, and 2.6 × 10−6 s−1 were retrieved for reactions starting with calcite + quartz + water, calcite + synthetic Cl-bearing chrysotile + water, and calcite + natural Fe−Al-bearing antigorite + water, respectively, significantly higher than the constant of 0.8 × 10−6 s−1 for the silicate-absent reaction. Besides, an increase in pressures can also enhance the reduction efficiency of Ca-carbonates until reaching equilibrium with the fluids. Our data provide experimental evidence for kinetics-controlled Ca-carbonate aqueous reduction into CH4 in subduction zones, indicating that silicate involvement and/or pressure increase can accelerate the reaction rates through short-lived fluid–rock interactions, which may have important implications for deep C mobility.
Arabidopsis ERdj3B coordinates with ERECTA-family receptor kinases to regulate ovule development and the heat stress response
Authors: Leng Ya-Jun , Yao Ya-Sen , Yang Ke-Zhen , Wu Pei-Xiang , Xia Yu-Xin , Zuo Chao-Ran , Luo Jing-Hong , Wang Pu , Liu Yang-Yang , Zhang Xue-Qin , Ye De , Le Jie , Chen Li-Qun
Published: July 2022

The endoplasmic reticulum-localized DnaJ family 3B (ERdj3B), is a component of the stromal cell-derived factor 2 (SDF2)–ERdj3B–binding immunoglobulin protein (BiP) chaperone complex, which functions in protein folding, translocation, and quality control. We found that ERdj3B mutations affected integument development in the Ler ecotype but not in the Col-0 ecotype of Arabidopsis (Arabidopsis thaliana). Map-based cloning identified the ERECTA (ER) gene as a natural modifier of ERdj3B. The double mutation of ERdj3B and ER caused a major defect in the inner integument under heat stress. Additional mutation of the ER paralog ERECTA-LIKE 1 (ERL1) or ERL2 to the erdj3b er double mutant exacerbated the defective integument phenotype. The double mutation of ER and SDF2, the other component of the SDF2–ERdj3B–BiP complex, resulted in similar defects in the inner integument. Furthermore, both the protein abundance and plasma membrane partitioning of ER, ERL1, and ERL2 were markedly reduced in erdj3b plants, indicating that the SDF2–ERdj3B–BiP chaperone complex might control the translocation of ERECTA-family proteins from the endoplasmic reticulum to the plasma membrane. Our results suggest that the SDF2–ERdj3B–BiP complex functions in ovule development and the heat stress response in coordination with ERECTA-family receptor kinases.
Argonaute 2 modulates EGFR–RAS signaling to promote mutantHRASandNRAS-driven malignancies
Authors: Siebenaler Ronald F , Chugh Seema , Waninger Jessica J , Dommeti Vijaya L , Kenum Carson , Mody Malay , Gautam Anudeeta , Patel Nidhi , Chu Alec , Bawa Pushpinder , Hon Jennifer , Smith Richard D , Carlson Heather , Cao Xuhong , Tesmer John J G , Shankar Sunita , Chinnaiyan Arul M
Published: July 2022

Activating mutations in RAS GTPases drive nearly 30% of all human cancers. Our prior work described an essential role for Argonaute 2 (AGO2), of the RNA-induced silencing complex, in mutant KRAS-driven cancers. Here, we identified a novel endogenous interaction between AGO2 and RAS in both wild-type (WT) and mutant HRAS/NRAS cells. This interaction was regulated through EGFR-mediated phosphorylation of Y393-AGO2, and utilizing molecular dynamic simulation, we identified a conformational change in pY393-AGO2 protein structure leading to disruption of the RAS binding site. Knockdown of AGO2 led to a profound decrease in proliferation of mutant HRAS/NRAS-driven cell lines but not WT RAS cells. These cells demonstrated oncogene-induced senescence (OIS) as evidenced by β-galactosidase staining and induction of multiple downstream senescence effectors. Mechanistically, we discovered that the senescent phenotype was mediated via induction of reactive oxygen species. Intriguingly, we further identified that loss of AGO2 promoted a novel feed forward pathway leading to inhibition of the PTP1B phosphatase and activation of EGFR–MAPK signaling, consequently resulting in OIS. Taken together, our study demonstrates that the EGFR–AGO2–RAS signaling axis is essential for maintaining mutant HRAS and NRAS-driven malignancies.