bluuebunny/crossref_metadata_2025_split huggingface dataset:
Group 2 innate lymphoid cells in bone marrow regulate osteoclastogenesis in a reciprocal manner via RANKL, GM-CSF and IL-13
Authors: Momiuchi Yoshiki , Motomura Yasutaka , Suga Emiko , Mizuno Hiroki , Kikuta Junichi , Morimoto Akito , Mochizuki Miho , Otaki Natsuko , Ishii Masaru , Moro Kazuyo 
Published: September 2021

Abstract
Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells that play different roles in different organs by sensing surrounding environmental factors. Initially, it was thought that ILC2s in bone marrow (BM) are progenitors for systemic ILC2s, which migrate to other organs and acquire effector functions. However, accumulating evidence that ILC2s differentiate in peripheral tissues suggests that BM ILC2s may play a specific role in the BM as a unique effector per se. Here, we demonstrate that BM ILC2s highly express the receptor activator of nuclear factor κB ligand (RANKL), a robust cytokine for osteoclast differentiation and activation, and RANKL expression on ILC2s is up-regulated by interleukin (IL)-2, IL-7 and all-trans retinoic acid (ATRA). BM ILC2s co-cultured with BM-derived monocyte/macrophage lineage cells (BMMs) in the presence of IL-7 induce the differentiation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in a RANKL-dependent manner. In contrast, BM ILC2s stimulated with IL-33 down-regulate RANKL expression and convert BMMs differentiation into M2 macrophage-like cells rather than osteoclasts by granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-13 production. Intravital imaging using two-photon microscopy revealed that a depletion of ILC2s prominently impaired in vivo osteoclast activity in an IL-7 plus ATRA-induced bone loss mouse model. These results suggest that ILC2s regulate osteoclast activation and contribute to bone homeostasis in both steady state and IL-33-induced inflammation.
The discovery of group 2 innate lymphoid cells has changed the concept of type 2 immune diseases
Authors: Kobayashi Tetsuro , Motomura Yasutaka , Moro Kazuyo 
Published: September 2021

Abstract
Group 2 innate lymphoid cells (ILC2s), discovered in 2010, have been recognized as immune cells with unique functions and their involvement in various diseases has been clarified. Before 2010, the antigen-specific response was a primary focus of immunology research, and immune responses were considered almost equivalent to biological responses to foreign antigens. However, with the emergence of ILC2s, the importance of ‘antigen-independent responses’ was confirmed, and this concept has permeated basic and clinical research as well as drug development. When ILC2s were discovered, their function in the acute phase of diseases garnered attention because of their rapid and potent type 2 immune response. However, several studies have revealed that the main role of ILC2s is more closely related to the chronicity of diseases, such as allergy and fibrosis, than to the induction of diseases. In this review, we discuss how ILC2 research has affected the concept of ‘Taishitsu’, a Japanese term describing the overall nature of an individual as determined by the interaction of genetic and acquired predisposition.
Creative Agency as Executive Agency: Grounding the Artistic Significance of Automatic Images
Authors: Anscomb Claire 
Published: September 2021

AbstractThis article examines the artistic potential of forms of image-making that involve registering the features of real objects using mind-independent processes. According to skeptics, these processes limit an agent’s intentional control over the features of the resultant “automatic images,” which in turn limits the artistic potential of the work, and the form as a whole. I argue that this is true only if intentional control is understood to mean that an agent produces the features of the work by their own bodily movements alone. Not only is this an unrealistic standard to uphold, but I show that a definition of intentional control based on the skeptic’s position does not prohibit an agent from realizing the features of an image by means beyond their own actions. An agent can exercise intentional control over the features of an image if they successfully anticipate the effect that the remote consequences of their actions will have on these. This, I argue, entails that to exert intentional control over the features of an image is to exercise “creative agency,” which is a species of executive agency. Consequently, I defend the idea that the origin of automatic images in creative agency grounds their artistic significance.
Embodied Metaphor: Playing with Gender in South Asian Sufism
Authors: Ewing Katherine Pratt 
Published: September 2021

AbstractThis paper brings the life and social world of a cross-dressing Sufi in rural Pakistan into relationship with the Sufi textual tradition to demonstrate that living gendered practices of sexual difference may serve as a form of what I call embodied metaphor that carries multiple layers of significance. Such embodied metaphors are not mere expressions or negotiations of identity but go beyond gender to point to other desires and realities. Drawing on a Lacanian interpretation of metaphor and metonymy, I argue that gender play allows confrontation with an aporia of sexual difference that unsettles the speaking subject. I demonstrate the rich intertextuality of the Sufi body as metaphor while also addressing how the metaphorical possibilities of the Sufi body have been affected by the recent development of a legal discourse of the third gender in Pakistan and the intensification of efforts to reform or purify Islam.
Spread of ESC-, carbapenem- and colistin-resistant Escherichia coli clones and plasmids within and between food workers in Lebanon
Authors: Al-Mir Hiba , Osman Marwan , Drapeau Antoine , Hamze Monzer , Madec Jean-Yves , Haenni Marisa 
Published: September 2021

Abstract

Objectives
Knowledge on the dynamic of MDR Escherichia coli in the human community is still limited, especially in low- and middle-income countries. Our goal was to decipher the dynamics of E. coli lineages and plasmids resistant to ESC, carbapenem and colistin within and between food workers in Lebanon using genomic-based approaches.

Methods
Eighty-four healthy adults working in three bakeries were sampled twice at a 6 monthly interval. E. coli resistant to ESC (ESC-E), carbapenem (CP-E) and colistin (CO-E) were collected on selective plates. Non-duplicate isolates were whole-genome sequenced using the Illumina technology and plasmid transmission was assessed by long-read sequencing. Data were analysed using bioinformatics tools and SNP-based phylogeny.

Results
ESC-E carriage rate reached 34.5% (t0) and 52.9% (t6), and 15 workers were positive at both t0 and t6. Carbapenem resistance (blaOXA-181, blaOXA-204, blaNDM-5) was found in five workers at t0 and two at t6, while colistin resistance (mcr-1.1) was found in five workers at t0 and one at t6. Forty-seven different STs were identified, of which three STs were predominant (ST131, n = 9; ST10, n = 5; ST69, n = 5). One worker presented the same ESC-E clone at t0 and t6. Twelve different events of clonal transmission among individuals were exemplified while plasmid transmission was only shown once.

Conclusions
Our study revealed a high carriage rate of MDR E. coli (60.7%) and the emergence of CP and colistin resistance in the Lebanese community. Incidental and long-term ESC-E carriage was observed in 41.7% and 17.9% of the workers, respectively. The high clonal diversity suggests an important dynamic of acquisition and loss of MDR E. coli and limited plasmid spread.
Cerebrospinal fluid exposure to bictegravir/emtricitabine/tenofovir in HIV-1-infected patients with CNS impairment
Authors: Gelé Thibaut , Chéret Antoine , Castro Gordon Alicia , Nkam Lionelle , Furlan Valérie , Pallier Coralie , Becker Pierre-Hadrien , Catalan Pilartxo , Goujard Cécile , Taburet Anne-Marie , Gasnault Jacques , Gouget Hélène , Barrail-Tran Aurélie 
Published: September 2021

Abstract

Objectives
The penetration of antiretroviral drugs into deep compartments, such as the CNS, is a crucial component of strategies towards an HIV cure. This study aimed to determine CSF concentrations of bictegravir, emtricitabine and tenofovir in patients with HIV-related CNS impairment (HCI) enrolled in a real-life observational study.

Methods
Patients with HCI treated by optimized ART, including bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) for at least 1 month were enrolled. Plasma and CSF concentrations were measured by quality control-validated assays (LC-MS/MS). The inhibitory quotient (IQARV) was calculated as the ratio of unbound (bictegravir) or total (emtricitabine and tenofovir) concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir). All numerical variables are expressed as median (range).

Results
Twenty-four patients (nine women) were enrolled. The age was 45 (26–68) years. Unbound bictegravir and total emtricitabine and tenofovir CSF concentrations were 4.4 (1.6–9.6), 84.4 (28.6–337.4) and 1.6 (0.7–4.3) ng/mL, respectively. The unbound bictegravir CSF fraction was 34% (15%–82%) versus 0.33% (0.11%–0.92%) in plasma. Three patients had an IQARV above unity for the three antiretrovirals. Factors positively associated with the CSF concentration (unbound for bictegravir) were age and total plasma concentration for the three antiretrovirals. Patients aged over 51 years had higher CSF concentrations (unbound for bictegravir).

Conclusions
We observed low CSF exposure to bictegravir, emtricitabine and tenofovir. These results suggest that BIC/FTC/TAF should be used with caution as first-line treatment for people living with HIV with HCI under 51 years of age.
Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial
Authors: Garcia-Prats Anthony J , Svensson Elin M , Winckler Jana , Draper Heather R , Fairlie Lee , van der Laan Louvina E , Masenya Masebole , Schaaf H Simon , Wiesner Lubbe , Norman Jennifer , Aarnoutse Rob E , Karlsson Mats O , Denti Paolo , Hesseling Anneke C 
Published: September 2021

AbstractBackgroundRifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children.ObjectivesTo characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB.Patients and methodsThe Opti-Rif trial enrolled dosing cohorts of 20 children aged 0–12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1–14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration–time curve from 0 to 24 h (AUC0–24) among adults receiving a 35 mg/kg dose].ResultsSixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4–11.7). Evaluated doses were ∼35 mg/kg (days 1–14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1–14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65–70 mg/kg rifampicin dose was needed in children to reach the target exposure.ConclusionsHigh rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV
Authors: Neyens M , Crauwels H M , Perez-Ruixo J J , Rossenu S 
Published: September 2021

Abstract

Objectives
To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration.

Methods
Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software.

Results
A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics.

Conclusions
The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.
Molecular analysis of an increase in trimethoprim/sulfamethoxazole-resistant MRSA reveals multiple introductions into a tertiary care hospital, Germany 2012–19
Authors: Nurjadi Dennis , Klein Sabrina , Hannesen Julius , Heeg Klaus , Boutin Sébastien , Zanger Philipp 
Published: September 2021

Abstract

Objectives
Increasing spread of resistance could jeopardize the use of antifolates against MRSA infections.

Methods
We compared the prevalence of phenotypic trimethoprim/sulfamethoxazole resistance in 20 534 clinical Staphylococcus aureus isolates (19 096 MSSA and 1438 MRSA) of non-redundant patients at Heidelberg University Hospital over 8 years and performed WGS on trimethoprim/sulfamethoxazole-resistant MRSA.

Results
From 2012 to 2019, trimethoprim/sulfamethoxazole resistance in MSSA (674/19 096; 3.5%) ranged between 1.5% and 7.2% and in MRSA (135/1438; 9.4%) between 0.5% and 20.2%, reaching a peak in 2016 and 2018, respectively (Ptrend &lt; 0.001). Trimethoprim/sulfamethoxazole resistance was more likely in outpatients than inpatients (P = 0.005), younger patients (P &lt; 0.001), skin and soft tissue infections (SSTIs) (MRSA only, P = 0.05), submissions from pulmonology (MRSA only, P = 0.001), the upper respiratory tract (MSSA only, P &lt; 0.001) and general surgery (MSSA only, P = 0.001). WGS of 76 trimethoprim/sulfamethoxazole-resistant MRSA revealed that 59% belonged to major pandemic CA-MRSA clones (ST22, ST8, ST398, ST772, ST30), 47% harboured Panton–Valentine leucocidin (PVL), 97% SCCmec IV/V, 71% dfrG and 28% dfrA. SNP-based phylogeny of trimethoprim/sulfamethoxazole-resistant MRSA core genomes favoured independent introduction over clonal expansion as the source, most prominently of dfrA+ trimethoprim/sulfamethoxazole-resistant ST22 MRSA from the Gaza Strip.

Conclusions
The presented results support that trimethoprim/sulfamethoxazole-resistant S. aureus, formerly associated with SSTI from outpatients and S. aureus in the (sub)tropics, is on the rise in the temperate zone, potentially due to migration. Closer monitoring of trimethoprim/sulfamethoxazole resistance in S. aureus is recommended to safeguard the effectiveness of antifolate compounds.
The use of first-generation cephalosporin antibiotics, cefalexin and cefradine, is not associated with induction of simulated Clostridioides difficile infection
Authors: Buckley Anthony M , Moura Ines B , Altringham James , Ewin Duncan , Clark Emma , Bentley Karen , Wilkinson Vikki , Spittal William , Davis Georgina , Wilcox Mark H 
Published: September 2021

Abstract

Objectives
The use of broad-spectrum cephalosporins is associated with induction of Clostridioides difficile infection (CDI). Recent knowledge on the importance of the healthy microbiota in preventing pathogen colonization/outgrowth highlights the caution needed when prescribing broad-spectrum antibiotics. The use of historical narrow-spectrum antibiotics, such as first-generation cephalosporins, is gaining increased attention once more as they have a reduced impact on the microbiota whilst treating infections. Here, the effects of two first-generation cephalosporins, compared with a third-generation cephalosporin, on the human microbiota were investigated and their propensity to induce simulated CDI.

Methods
Three in vitro chemostat models, which simulate the physiochemical conditions of the human colon, were seeded with a human faecal slurry and instilled with either narrow-spectrum cephalosporins, cefalexin and cefradine, or a broad-spectrum cephalosporin, ceftriaxone, at concentrations reflective of colonic levels.

Results
Instillation of cefalexin was associated with reduced recoveries of Bifidobacterium and Enterobacteriaceae; however, Clostridium spp. recoveries remained unaffected. Cefradine exposure was associated with decreased recoveries of Bifidobacterium spp., Bacteroides spp. and Enterobacteriaceae. These changes were not associated with induction of CDI, as we observed a lack of C. difficile spore germination/proliferation, thus no toxin was detected. This is in contrast to a model exposed to ceftriaxone, where CDI was observed.

Conclusions
These model data suggest that the minimal impact of first-generation cephalosporins, namely cefalexin and cefradine, on the intestinal microbiota results in a low propensity to induce CDI.
Child Labour and the Arrival of Refugees: Evidence from Tanzania
Authors: Kofol Chiara , Naghsh Nejad Maryam 
Published: September 2021

Abstract
Despite efforts to reduce the incidence of child labour, about one in three children in Sub-Saharan Africa works. Using data for the Kagera region of Tanzania, we estimate how rates of child labour were impacted by a large influx of refugees fleeing from genocide in both Rwanda and Burundi. We find that the areas most affected by this population shock initially had a lower incidence of child labour. However, 10 years later, children in these areas were more likely to work on a farm and participate in domestic chores as the demand for agricultural labour increased.
From Divergence to Convergence: The Role of Intermediaries in Developing Competition Laws in ASEAN
Authors: Ng Wendy 
Published: September 2021

Abstract
Despite the diversity of contexts and circumstances in which competition laws are developed and exist, many countries have enacted competition laws that are broadly similar. To learn more about the dynamics shaping the development of competition law at the national, regional, and international levels, this article investigates the development of competition law in the Association of Southeast Asian Nations (ASEAN) region, a region whose competition laws remain underexplored. This article undertakes a case study on the drafting of competition law in the ASEAN member states with the most recently drafted and/or enacted new comprehensive competition laws, that being Brunei Darussalam, Cambodia, Lao PDR, Myanmar, and the Philippines. It finds that, while there were differences in the processes of drafting and enacting competition law in these countries as well as in their local contexts, their competition laws are similar in many respects. The case study also finds that intermediaries facilitated the processes of translation and adaptation that occurred in developing competition law in these ASEAN member states. This article argues that the important role that intermediaries played in developing competition laws was a key reason for the broad convergence of these competition laws across their diverse local settings.
Overcome Isomer Interference in 1α,25-Dihydroxyvitamin D Quantitation by Liquid Chromatography-Tandem Mass Spectrometry
Authors: Jin Zhicheng , Bertholf Roger L , Yi Xin 
Published: September 2021

Abstract

Background
The circulating concentration of 1α,25-dihydroxyvitamin D [1α,25(OH)2D] is very low, and the presence of multiple isomers may lead to inaccurate quantitation if not separated prior to analysis. Antibody-based immunoextraction procedures are sometimes used to remove structurally related isomers of 1α,25(OH)2D prior to an LC-MS/MS analysis. However, immunoextraction increases sample preparation time and cost. In addition, some dihydroxyvitamin D metabolites are not completely removed by immunoextraction.

Method
We developed an HPLC method using a phenyl-hexyl column to investigate interfering isomers of 1α,25(OH)2D.

Result
Using this method, 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) derivatization product of 1α,25(OH)2D was found to be present as 2 epimers, which were separated chromatographically with an area ratio of 2:1. PTAD derivatized metabolite of 25-hydroxyvitamin D3 [i.e., 4β,25-dihydroxyvitamin D3 (4β,25(OH)2D3)] eluted out between 6R and 6S epimers of derivatized 1α,25(OH)2D3. If not chromatographically resolved, 4β,25(OH)2D can affect 1α,25(OH)2D quantitation. In a method comparison study, it was found that the presence of 4β,25(OH)2D produced positive bias up to 127% on 1α,25(OH)2D3 quantitation.

Conclusion
The LC-MS/MS method we developed without an immunoextraction procedure was able to resolve the major interference peak from 1α,25(OH)2D and achieved reliable quantitation of 1α,25(OH)2D.
Practical Clinical Applications of Islet Autoantibody Testing in Type 1 Diabetes
Authors: Winter William E , Pittman David L , Jialal Ishwarlal 
Published: September 2021

Abstract

Background
The distinction between type 1 diabetes (T1D) and type 2 diabetes (T2D) is extremely important for the choice of therapy, body weight and dietary management, screening for coexistent autoimmune diseases and comorbidities, anticipated prognosis, and risk assessment in relatives. Not uncommonly, the presentation of the patient may not allow an unambiguous discrimination between T1D and T2D. To help resolve this challenge, the detection of islet autoantibodies can support the diagnosis of T1D.

Content
The presence of islet autoantibodies in a person with diabetes indicates an autoimmune etiology therefore establishing the diagnosis of T1D. Presently 5 islet autoantibodies are available for routine clinical use: islet cell cytoplasmic autoantibodies (ICA), insulin autoantibodies (IAA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma associated-2 autoantibodies (IA-2A), and zinc transporter-8 autoantibodies (ZnT8A). There are caveats to the selection of which islet autoantibodies should be measured. Islet autoantibodies can also predict the development of T1D. Therefore, once safe and effective therapies are available to prevent T1D, islet autoantibody testing is expected to become a routine part of medical practice. A very rare cause of autoimmune diabetes is the type B insulin resistance syndrome resulting from antagonistic autoantibodies to the insulin receptor. Rarely hypoglycemia can result from agonistic insulin receptor autoantibodies, or high-titer IAA causing the autoimmune insulin syndrome (i.e., Hirata disease).

Summary
In summary, autoimmune causes of dysglycemia are increasing in clinical importance requiring the scrutiny of laboratorians. The determination of islet autoantibodies can greatly aid in the diagnosis and the prediction of T1D.