bluuebunny/crossref_metadata_2025 huggingface dataset:
An Open-Label, Randomized Trial Comparing Fidaxomicin With Oral Vancomycin for the Treatment of Clostridioides difficile Infection in Hospitalized Patients Receiving Concomitant Antibiotics for Concurrent Infections
Authors: Rao Krishna , Zhao Qianzi , Bell Justin , Krishnan Jay , Henig Oryan , Daniel Jolene , Sawaya Kara , Albin Owen , Mills John P , Petty Lindsay A , Gregg Kevin , Kaul Daniel , Malani Anurag N , Pogue Jason , Kaye Keith S
Published: October 2023

Background

Recurrent Clostridioides difficile infection (rCDI) occurs frequently, and concomitant antibiotic (CA) during the initial episode for treatment of non-CDI is a major risk factor. We sought to address the comparative efficacy of fidaxomicin versus vancomycin in the setting of CA during the initial CDI episode.

Methods

We conducted a randomized, controlled, open-label trial at 2 hospitals in Ann Arbor, Michigan. We consecutively consented and enrolled hospitalized patients ≥18 years old with diarrhea, a positive test for C. difficile, and ≥1 qualifying CA. Complicated CDI, CDI treatment for >24 hours prior to enrollment, and planned long-term (>12 weeks) CA use were notable exclusions. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until 2 days after therapy, and rCDI as recurrent diarrhea with positive testing ≤30 days after initial treatment. Patients were randomized to fidaxomicin or vancomycin.

Results

Baseline characteristics were similar in the 2 groups of 144 patients. Rates of clinical cure (73% vs 62.9%, P = .195) and rCDI (3.3% vs 4.0%; P > .99) were similar for fidaxomicin and vancomycin in the intention-to-treat and per-protocol cohorts, respectively. Only 4 patients developed rCDI.

Conclusions

In this study of patients with CDI receiving CA, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared with previous studies that did not extend duration of CDI treatment during CA.

Clinical Trials Registration

www.clinicaltrials.gov (NCT02692651).
Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants: a nationwide cohort study
Authors: Grymonprez Maxim , Carnoy Laura , Capiau Andreas , Boussery Koen , Mehuys Els , De Backer Tine L , Steurbaut Stephane , Lahousse Lies
Published: October 2023

Aims

The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated.

Methods and results

AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18–1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02–1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21–1.34)], diltiazem [aHR 1.28, 95% CI (1.13–1.46)], verapamil [aHR 1.36, 95% CI (1.03–1.80)], ticagrelor [aHR 1.50, 95% CI (1.20–1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14–2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06–1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16–1.34)], and apixaban users [aHR 1.27, 95% CI (1.16–1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94–1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03–1.68)], but not with bleeding or all-cause mortality.

Conclusion

Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks.
Professionalization of the public health workforce: scoping review and call to action
Authors: Czabanowska Katarzyna , Rodriguez Feria Pablo , Kuhlmann Ellen , Kostoulas Polychronis , Middleton John , Magana Laura , Sutton Gabriella , Goodman Julien , Burazeri Genc , Aleksandrova Olga , Piven Natalia
Published: October 2023

Background

The ‘WHO-ASPHER Roadmap to Professionalizing the Public Health Workforce in the European Region’ provides recommendations for strategic and systematic workforce planning around professionalization levers including: (i) competencies, (ii) training and education, (iii) formal organization, (iv) professional credentialing and (v) code of ethics and professional conduct as well as taxonomy and enumeration. It was based on a literature review till 2016. This scoping review aims to explore how the professionalization was documented in the literature between 2016 and 2022.

Methods

Following the Joanna Briggs Institute guidelines, we searched Medline via PubMed, Web of Science, ERIC via EBSCO and Google Scholar and included studies on professionalization levers. Four critical appraisal tools were used to assess qualitative, quantitative, mixed methods studies and grey literature. The PRISMA Extension for Scoping Reviews (PRISMA-ScR) was used for reporting.

Results

Eleven articles included in this review spanned 61 countries, targeting undergraduate, master’s, doctoral degrees and continuing professional development. Most of these documents were reviews. About half provided a definition of the public health workforce; more than half covered the taxonomy and included information about competences, but the use of frameworks was sporadic and inconsistent. Formal organization and the necessity of a code of conduct for the public health workforce were acknowledged in only two studies.

Conclusions

In spite of some efforts to professionalize the public health workforce, this process is fragmented and not fully recognized and supported. There is an urgent need to engage policymakers and stakeholders to prioritize investments in strengthening the public health workforce worldwide.
The Clostridium-infecting filamentous phage CAK1 genome analysis allows to define a new potential clade of Tubulavirales
Authors: Billaud Maud , Petit Marie-Agnès , Lossouarn Julien
Published: October 2023

What we know about Tubulavirales, i.e. filamentous phages, essentially comes from Gram-negative-infecting Inoviridae. However, metagenomics recently suggests filamentous phages are much more widespread and diverse. Here, we report the complete sequence and functional annotation of CAK1, a 6.6 kb filamentous phage that was shown to chronically infect Clostridium beijerinckii 30 years ago and only represents the second filamentous phage cultivated on a Gram-positive bacterium. CAK1 has a typical filamentous phage modular genome with no homologs in databases and we were interested to compare it with a pig gut filamentous phage metagenomics dataset that we previously assembled and for which many filamentous phages were predicted to infect Clostridium species by bioinformatics means. CAK1 is distantly related to nine of these sequences, two of which have been predicted as Clostridium-associated. In itself, this small cluster of CAK1-connected sequences sheds light on the diversity of filamentous phages that putatively infect Clostridium species, and probably many other Gram-positive genera.
Editorial: making the invisible visible in STEMM
Authors: Hinton Antentor , Shuler Haysetta D
Published: October 2023

Our editorial focused on the concept of “Making the Invisible Visible in Science, Technology, Engineering, Mathematics, and Medicine (STEMM).” We highlight 11 manuscripts submitted to our research topic, which offer unique and innovative, evidence-backed solutions to improve diversity, equity, and inclusion in STEMM. Notably, often racial, and ethnic minority scientists are forgotten and placed in the background even when they make a significant contribution to research. The manuscripts highlighted here begin to undo this and empower by making the invisible visible.
Expanding the genome editing toolbox ofSaccharomyces cerevisiaewith the endonucleaseErCas12a
Authors: Bennis Nicole X , Anderson Jonah P , Kok Siebe M C , Daran Jean-Marc G
Published: October 2023

ErCas12a is a class 2 type V CRISPR–Cas nuclease isolated from Eubacterium rectale with attractive fundamental characteristics, such as RNA self-processing capability, and lacks reach-through royalties typical for Cas nucleases. This study aims to develop a ErCas12a-mediated genome editing tool applicable in the model yeast Saccharomyces cerevisiae. The optimal design parameters for ErCas12a editing in S. cerevisiae were defined as a 21-nt spacer flanked by 19 nt direct repeats expressed from either RNApolII or III promoters, achieving near 100% editing efficiencies in commonly targeted genomic locations. To be able to transfer the ErCas12a genome editing tool to different strain lineages, a transportable platform plasmid was constructed and evaluated for its genome editing efficiency. Using an identical crRNA expression design, the transportable ErCas12a genome editing tool showed lower efficiency when targeting the ADE2 gene. In contrast to genomic Ercas12a expression, episomal expression of Ercas12a decreases maximum specific growth rate on glucose, indicating ErCas12a toxicity at high expression levels. Moreover, ErCas12a processed a multispacer crRNA array using the RNA self-processing capability, which allowed for simultaneous editing of multiple chromosomal locations. ErCas12a is established as a valuable addition to the genetic toolbox for S. cerevisiae.
Dissection of the role of a Src homology 3 domain in the evolution of binding preference of paralogous proteins
Authors: Lemieux Pascale , Bradley David , Dubé Alexandre K , Dionne Ugo , Landry Christian R
Published: October 2023

Protein–protein interactions (PPIs) drive many cellular processes. Some interactions are directed by Src homology 3 (SH3) domains that bind proline-rich motifs on other proteins. The evolution of the binding specificity of SH3 domains is not completely understood, particularly following gene duplication. Paralogous genes accumulate mutations that can modify protein functions and, for SH3 domains, their binding preferences. Here, we examined how the binding of the SH3 domains of 2 paralogous yeast type I myosins, Myo3 and Myo5, evolved following duplication. We found that the paralogs have subtly different SH3-dependent interaction profiles. However, by swapping SH3 domains between the paralogs and characterizing the SH3 domains freed from their protein context, we find that very few of the differences in interactions, if any, depend on the SH3 domains themselves. We used ancestral sequence reconstruction to resurrect the preduplication SH3 domains and examined, moving back in time, how the binding preference changed. Although the most recent ancestor of the 2 domains had a very similar binding preference as the extant ones, older ancestral domains displayed a gradual loss of interaction with the modern interaction partners when inserted in the extant paralogs. Molecular docking and experimental characterization of the free ancestral domains showed that their affinity with the proline motifs is likely not the cause for this loss of binding. Taken together, our results suggest that a SH3 and its host protein could create intramolecular or allosteric interactions essential for the SH3-dependent PPIs, making domains not functionally equivalent even when they have the same binding specificity.
Culturally adapted safer sex skills building: development and initial testing of an HIV prevention intervention for Black women using substances in the United States
Authors: Burlew A K , McCuistian C , Lanaway D
Published: October 2023

Black women who use substances in the United States face unique human immunodeficiency virus (HIV) risk factors. However, interventions addressing cultural factors relevant for preventing HIV risk behaviors among Black women are limited. This project aimed to develop and initially test the effectiveness of a culturally adapted version of safer sex skills building (SSSB), an evidence-based HIV prevention intervention for reducing HIV risk among Black women who use substances. The cultural adaptation procedures involved (i) review of existing literature, (ii) use of Delphi process and theater testing to generate an adapted version, (iii) theater testing of the culturally adapted version and (iv) initial testing. Forty-eight Black women recruited from a substance use treatment clinic in the United States participated in three 2.5-h sessions of a culturally adapted or a generic version of the intervention. More (48%) women in the culturally adapted version self-reported condom use with casual partners compared to women in the generic (29%) version at a 6-week follow-up. The two groups did not differ on self-reported condom use with main partners. The culturally adapted SSSB offers a promising intervention for sexual risk reduction among Black women who use substances. Moreover, the findings advance the field by illustrating a concrete methodology for cultural adaptation.
The Efficacy of an Over-the-Counter Multivitamin and Mineral Supplement to Prevent Infections in Patients With Inflammatory Bowel Disease in Remission With Immunomodulators and/or Biological Agents: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Authors: Laheij Robin L H , van Knippenberg Yara M W , Heil Annelijn L J , Mannaerts Britt J W , Bruin Karlien F , Lutgens Maurice W M D , Sikkema Marjolein , de Wit Ulrike , Laheij Robert J F
Published: October 2023

Background

Patients with inflammatory bowel disease (IBD) treated with immunomodulators or biologic therapy are at increased risk of infections. Malnutrition and vitamin or mineral deficiencies are common among patients with IBD. The results of various studies have indicate that vitamin deficiencies might increase the risk of infections. To evaluate the efficacy of a multivitamin and mineral supplement on the incidence of infections in patients with IBD treated with immunomodulators, biologic therapy, or combination therapy.

Methods

This was a single-center, randomized, double-blind, placebo-controlled clinical trial to compare a multivitamin and mineral supplement (supplemented group) vs identical-in-appearance placebo (placebo group) in a total of 320 non–vitamin-deficient patients with IBD (Crohn’s disease or ulcerative colitis) in remission with immunomodulators, biologic therapy, or combination therapy. Participants were asked to take a daily multivitamin and mineral supplement or placebo and report the occurrence of infections during a 24-week period of follow-up.

Results

Treatment arms consisted of 162 and 158 patients for the supplement and placebo, respectively. In both treatment groups, 107 patients reported an infection during the 24-week follow-up period (unadjusted odds ratio, 0.93; 95% confidence interval, 0.56-1.48). In the supplemented group, 32 patients received antibiotics for an infection compared with 21 patients in the placebo group (unadjusted odds ratio, 1.61; 95% confidence interval, 0.88-2.93).

Conclusions

An over-the-counter multivitamin and mineral supplement did not reduce the risk of infection for patients with IBD in remission with immunomodulators, biologic therapy, or combination therapy.
Appearance of the Bowel and Mesentery During Surgery Is Not Predictive of Postoperative Recurrence After Ileocecal Resection for Crohn’s Disease: A Prospective Monocentric Study
Authors: Bislenghi Gabriele , Van Den Bossch Julie , Fieuws Steffen , Wolthuis Albert , Ferrante Marc , de Hertogh Gert , Vermeire Severine , D’Hoore André
Published: October 2023

Background

Very few risk factors for postoperative recurrence (POR) of Crohn’s Disease (CD) after ileocecal resection have been identified. The aim of the present study was to verify the association between an a priori defined list of intraoperative macroscopic findings and POR.

Methods

This was a prospective observational study including patients undergoing primary ileocecal resection for CD. Four intraoperative factors were independently evaluated by 2 surgeons: length of resected ileum, mesentery thickness, presence of areas of serosal fat infiltration, or abnormal serosal vasodilation on normal bowel proximal to the resected bowel. The primary end point was early endoscopic POR at month 6 and defined as modified Rutgeerts score ≥i2b. Secondary end points were clinical and surgical recurrence.

Results

Between September 2020 and November 2022, 83 consecutive patients were included. Early endoscopic recurrence occurred in 45 of 76 patients (59.2%). Clinical and biochemical recurrence occurred in 17.3% (95% confidence interval, [CI], 10.4%-28.0%) and 14.6% of the patients after 12 months. The risk of developing endoscopic and clinical recurrence was 1.127 (95% CI, 0.448;2.834, P = .799) and 0.896 (95% CI, 0.324-2.478, P = .832) when serosal fat infiltration was observed, and 1.388 (95% CI, 0.554-3.476, P = .484), and 1.153 (95% CI, 0.417;3.187, P = .783) when abnormal serosal vasodilation was observed. Similarly, length of the resected bowel and mesentery thickness showed no association with POR. A subgroup analysis on patients who received no postoperative medical prophylaxis did not identify any risk factor for endoscopic POR.

Conclusions

The macroscopic appearance of the bowel and associated mesentery during surgery does not seem to be predictive of POR after ileocecal resection for CD.
The dose–response relationship of pre-menopausal alcohol consumption with age at menopause: a population study of 280 497 women in Norway
Authors: Langås Julie R , Eskild Anne , Hofvind Solveig , Bjelland Elisabeth K
Published: October 2023

Background

Previous research suggests that alcohol consumption is associated with high age at menopause. Yet, knowledge about the dose–response relationship is inconsistent. Thus, we studied the pattern of the association of pre-menopausal alcohol consumption with age at natural menopause.

Methods

We performed a retrospective population-based study using self-reported data from 280 497 women aged 50–69 years attending the Norwegian breast cancer screening programme (BreastScreen Norway) during 2006–15. Associations of weekly alcohol consumption between the age of 20 and 49 years with age at menopause were estimated as hazard ratios (HRs) using Cox proportional hazard models with restricted cubic splines to allow for non-linear associations. We adjusted for year and place of birth, number of childbirths, educational level, body mass index and smoking habits.

Results

Mean age at natural menopause was 51.20 years (interquartile range: 49–54 years). The adjusted HR of reaching menopause was highest for women with no alcohol consumption (reference) and the HR decreased by alcohol consumption up to 50 grams per week (adjusted HR 0.87; 95% CI: 0.86–0.88). Above 50 grams, there was no further decrease in the HR of reaching menopause (P for non-linearity of <0.001).

Conclusions

Women who did not consume alcohol were youngest at menopause. The lack of a dose–response association among alcohol consumers implies virtually no relation of alcohol consumption with age at menopause. Our findings may suggest that characteristics of the women who did not consume alcohol, not accounted for in the data analyses, explain their younger age at menopause.
Resistance patterns and transmission of mono- and polyresistant TB: clinical impact of WGS
Authors: Dohál Matúš , Dvořáková Věra , Šperková Miluše , Pinková Martina , Spitaleri Andrea , Rasmussen Erik Michael , Škereňová Mária , Krivošová Michaela , Gondáš Eduard , Porvazník Igor , Solovič Ivan , Cirillo Daniela Maria , Mokrý Juraj
Published: October 2023

Objectives

Rapidly diagnosing drug-resistant TB is crucial for improving treatment and transmission control. WGS is becoming increasingly accessible and has added value to the diagnosis and treatment of TB. The aim of the study was to perform WGS to determine the rate of false-positive results of phenotypic drug susceptibility testing (pDST) and characterize the molecular mechanisms of resistance and transmission of mono- and polyresistant Mycobacterium (M.) tuberculosis.

Methods

WGS was performed on 53 monoresistant and 25 polyresistant M. tuberculosis isolates characterized by pDST. Sequencing data were bioinformatically processed to infer mutations encoding resistance and determine the origin of resistance and phylogenetic relationship between isolates studied.

Results

The data showed the variable sensitivity and specificity of WGS in comparison with pDST as the gold standard: isoniazid 92.7% and 92.3%; streptomycin 41.9% and 100.0%; pyrazinamide 15% and 94.8%; and ethambutol 75.0% and 98.6%, respectively. We found novel mutations encoding resistance to streptomycin (in gidB) and pyrazinamide (in kefB). Most isolates belonged to lineage 4 (80.1%) and the overall clustering rate was 11.5%. We observed lineage-specific gene variations encoding resistance to streptomycin and pyrazinamide.

Conclusions

This study highlights the clinical potential of WGS in ruling out false-positive drug resistance following phenotypic or genetic drug testing, and recommend this technology together with the WHO catalogue in designing an optimal individualized treatment regimen and preventing the development of MDR TB. Our results suggest that resistance is primarily developed through spontaneous mutations or selective pressure.
Hope in the Ruins of Home: Narrative Meaning-Making of Forced Displacement, Place Attachment, and Deferred Future Resettlement in Varosha
Authors: Akdeniz Nafia
Published: October 2023

In 1974, the Cyprus War turned the seaside resort of Varosha into a derelict and decaying town, captured by the Turkish army and held for subsequent decades as a political bargaining chip in the peace negotiations of the unresolved reconflict. In 2020, the city partially opened to public visits, allowing its former residents to tour a landscape of ruination. This paper explores the contested narratives of the city’s future revival that have emerged in the wake of this opening. In particular, the paper describes forcibly displaced Varoshians’ narratives as discursive practices that reclaim the lost ‘homeplace’ and insist on the right to return. These narratives, the paper shows, become a mnemonic means of communicative meaning-making, with four main themes: loss, threshold, transformation, and the future. The paper uses these themes to show how such narratives may enable refugees to maintain hope even in the ruins of hoped-for futures. The thematic analysis also shows how place attachment narratives transmitting memories of home may transform with a vibrant present-ness related to people’s imaginations of a future Varosha. Speaking to the possibilities of return, this study calls for further explorations towards the narrative of restitution beyond legal property and political territory.
Staging grounds: dialectics of the spectacular and the infrastructural in international conference-hosting
Authors: Quiroga-Villamarín Daniel Ricardo
Published: October 2023

For international lawyers, the international conference appears as a rather anodyne place. While attention has been paid to who partakes in the ‘invisible college’, scant scrutiny has been directed to where we sit. To counter this, I argue we should interrogate conference spaces as material stages for the dramas of global governance.
The period bouncer system SDSS J105754.25+275947.5: first radial velocity study
Authors: Echevarría J , Zharikov S , Mora Zamora I
Published: October 2023

We report the first radial velocity spectroscopic study of the eclipsing period bouncer SDSS J105754.25+275947.5. Together with eclipse light-curve modelling, we re-determined the system parameters and studied the accretion disc structure. We confirm that the system contains a white dwarf with MWD = 0.83(3) M⊙ and an effective temperature of 11 500(400) K. The mass of the secondary is M2 = 0.056 M⊙ with an effective temperature of T2 = 2100 K or below. The system inclination is i = 84.3(6)°. The data are in good agreement with our determination of K1  = 33(4) km s−1. We estimate the mass transfer rate as $\dot{M}=1.9(2)\times 10^{-11}$ M⊙ yr −1. Based on an analysis of the SDSS and OSIRIS spectra, we conclude that the optical continuum is formed predominantly by the radiation from the white dwarf. The contribution of the accretion disc is low and originates from the outer part of the disc. The Balmer emission lines are formed in a plasma with log N0 = 12.7 (cm−1) and a kinetic temperature of T ∼ 10 000 K. The size of the disc, where the emission lines are formed, expands up to Rd,out = 0.29 R⊙. The inner part of the emission line forming region goes down to Rd,in ≈ 2RWD. The Doppler tomography and trailed spectra show the presence of a hotspot and a clumpy structure in the disc, with variable intensity along the disc position angle. There is an extended region at the side opposite the hotspot with two bright clumps caused more probably by non-Keplerian motion there.
A comprehensive hydrodynamical study of SB DEM L50: understanding off-centre SNe and soft X-ray luminosity
Authors: Orozco-Duarte Rogelio , García-Segura Guillermo , Wofford Aida , Toalá Jesús A
Published: October 2023

The superbubbles (SBs) carved in the interstellar medium by stellar winds and supernovae (SNe) are filled with hot (T > 106 K) gas that produces soft X-ray emission (0.3–2.0 keV). Models that assume a constant density medium and central SNe events fail to reproduce the soft X-ray luminosity that is observed in some SBs. We address this problem by generating models that trace the history of SNe in the SB, and produce off-centre SNe, and account for the missing soft X-ray emission. We test the models against archival, radio, optical, and X-ray observations of the SB DEM L50 located in the Large Magellanic Cloud. The soft X-ray properties of DEM L50, including its high luminosity, make it a perfect candidate to test our models. Furthermore, the multiple wave-band observations of this object will help us assess how well our models can reproduce other SB properties beside its soft X-ray properties. We find that a configuration where DEM L50 forms at the edge of a filament reproduces the observed soft X-ray luminosity, optical morphology, shell velocity, and swept-up mass of neutral gas. This configuration is supported by IR observations of the LMC. In addition, we find that off-centre SNe, which enhance soft X-ray emission, naturally occur for all of the initial ambient conditions we tested in our models. Finally, we show that an off-centre SN can explains the observed soft X-ray luminosity of DEM L50, and that the resulting luminosity is consistent with a plasma in non-equilibrium ionization.
Tracing the colliding winds of η Carinae in He i
Authors: Grant David , Blundell Katherine , Godden Emma , Lee Steven , McCowage Chris
Published: October 2023

η Carinae is an extremely luminous and energetic colliding-wind binary. The combination of its orbit and orientation, with respect to our line of sight, enables direct investigation of the conditions and geometry of the colliding winds. We analyse optical He i 5876 and 7065 Å line profiles from the Global Jet Watch observatories covering the last 1.3 orbital periods. The sustained coverage throughout apastron reveals the distinct dynamics of the emitting versus absorbing components: the emission lines follow orbital velocities, while one of the absorption lines is detected only around apastron (0.08 < ϕ < 0.95) and exhibits velocities that deviate substantially from the orbital motion. To interpret these deviations, we conjecture that this He i absorption component is formed in the post-shock primary wind, and is only detected when our line of sight intersects with the shock cone formed by the collision of the two winds. We formulate a geometrical model for the colliding winds in terms of a hyperboloid in which the opening angle and location of its apex are parametrized in terms of the ratio of the wind momentum of the primary star to that of companion. We fit this geometrical model to the absorption velocities, finding results that are concordant with the panchromatic observations and simulations of η Carinae. The model presented here is an extremely sensitive probe of the exact geometry of the wind momentum balance of binary stars, and can be extended to probe the latitudinal dependence of mass-loss.
Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo
Authors: Kour Sukhleen , Fortuna Tyler , Anderson Eric N , Mawrie Darilang , Bilstein Jessica , Sivasubramanian Ramakrishnan , Ward Caroline , Roy Rishit , Rajasundaram Dhivyaa , Sterneckert Jared , Pandey Udai Bhan
Published: October 2023

Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832–5p, which differentially regulate the expression, solubility and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832–5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.
How obesity and metabolic syndrome affect cardiovascular events, progression to kidney failure and all-cause mortality in chronic kidney disease
Authors: Kang Shin Yeong , Lee Yu Ho , Jeong Su Jin , Kim Jin Sug , Jeong Kyung Hwan , Hwang Hyeon Seok
Published: October 2023

Background

Obesity and metabolic syndrome (MetS) are prevalent among chronic kidney disease (CKD) patients. However, it is unclear whether obesity without MetS is associated with a higher risk of adverse clinical outcomes in CKD patients.

Methods

We searched the National Health Insurance Service database of Korea for patients who underwent national health screenings in 2009–11 and identified 59 725 CKD patients. Obesity was defined as a body mass index ≥25 kg/m2. MetS was defined as the presence of three or more metabolic risks.

Results

The cumulative event rate of cardiovascular (CV) events, progression to end-stage kidney disease (ESKD) and all-cause mortality was the lowest among obese patients without MetS (all P < .001). In multivariable analysis, obese (versus non-obese) patients without MetS were not at increased risks of CV events [adjusted hazard ratio (HR) 1.02 (95% confidence interval 0.94–1.11)] or progression to ESKD [0.92 (0.77–1.09)]. Their risk of all-cause mortality was significantly decreased [0.82 (0.75–0.90)]. These findings were consistently observed in overweight, obese and morbidly obese patients without MetS. Moreover, despite a linear increase in HR for each additional metabolic abnormality in both obese and non-obese patients, the slope of HR increase for CV events was significantly slower in obese patients (P for interaction = .038).

Conclusions

Obesity without MetS did not increase the risk of CV complications or progression to ESKD. The healthy effect of obesity on all-cause mortality risk and its weakening effect on the association between metabolic hazards and CV risk should be considered in CKD patients.
Effects of Modified Risk Tobacco Product Claims on Consumer Responses
Authors: Seidenberg Andrew B , Boynton Marcella H , Brewer Noel T , Lazard Allison J , Sheeran Paschal , Ribisl Kurt M
Published: October 2023

Introduction

US tobacco manufacturers can seek authorization from the US Food and Drug Administration (FDA) to market products using modified risk tobacco product (MRTP) claims. To inform regulatory decisions, we examined the impact of MRTP claim specificity and content, including whether the claims produced halo effects (ie, inferring health benefits beyond what is stated).

Aims and Methods

Participants were 3161 US adult cigarette smokers. Using a two (general vs. specific) × 2 (risk vs. exposure) plus independent control design, we randomized participants to view one message from these conditions: general risk claim (eg, “smoking-related diseases”), general exposure claim (eg, “chemicals in smoke”), specific risk claim (eg, “lung cancer”), specific exposure claim (eg, “arsenic”), or control. Claims described the benefits of completely switching from cigarettes to the heated tobacco product IQOS.

Results

MRTP claims of any sort elicited a higher willingness to try IQOS relative to control (d = 0.09, p = .043). Claims also elicited lower perceived risk of disease and exposure to harmful chemicals for completely switching from cigarettes to IQOS (d = –0.32 and –0.31) and partially switching (d = –0.25 and d = –0.26; all p < .05). Relative to specific MRTP claims, general MRTP claims led to lower perceived risk and exposure for complete switching (d = –0.13 and d = –0.16) and partial switching (d = –0.14 and d = −0.12; all p < .05). Risk and exposure MRTP claims had similar effects (all p > .05).

Discussion

MRTP claims led to lower perceived risk and exposure, and higher willingness to try IQOS. General claims elicited larger effects than specific claims. MRTP claims also promoted unintended halo effects (eg, lower perceived risk of disease and chemical exposure for partial switching).

Implications

We found evidence that MRTP claims promoted health halo effects. In light of these findings, the FDA should require research on halo effects prior to authorization. Further, if an MRTP claim is authorized, FDA should require tobacco manufacturers to conduct post-market surveillance of how the claim affects consumer understanding, including partial switching perceived risk and exposure beliefs, as well as monitoring of dual-use behaviors.
Expansion microscopy resolves the thylakoid structure of spinach
Authors: Bos Peter R , Berentsen Jarne , Wientjes Emilie
Published: October 2023

The light-harvesting reactions of photosynthesis take place on the thylakoid membrane inside chloroplasts. The thylakoid membrane is folded into appressed membranes, the grana, and nonappressed membranes that interconnect the grana, the stroma lamellae. This folding is essential for the correct functioning of photosynthesis. Electron microscopy and atomic force microscopy are commonly used to study the thylakoid membrane, but these techniques have limitations in visualizing a complete chloroplast and its organization. To overcome this limitation, we applied expansion microscopy (ExM) on isolated chloroplasts. ExM is a technique that involves physically expanding a sample in a swellable hydrogel to enhance the spatial resolution of fluorescence microscopy. Using all-protein staining, we visualized the 3D structure of spinach (Spinacia oleracea) thylakoids in detail. We were able to resolve stroma lamellae that were 60 nm apart and observe their helical wrapping around the grana. Furthermore, we accurately measured the dimensions of grana from top views of chloroplasts, which allow for precise determination of the granum diameter. Our results demonstrate that ExM is a fast and reliable technique for studying thylakoid organization in great detail.
Fluorescein staining of chloroplast starch granules in living plants
Authors: Ichikawa Shintaro , Sakata Momoko , Oba Toru , Kodama Yutaka
Published: October 2023

Chloroplast starch granules (cpSGs) store energy harvested through photosynthesis in plants, and cpSG dynamics have important roles in plant energy metabolism and stress responses. To date, cpSGs have been visualized using several methods, such as iodine staining; however, no method can be used to specifically visualize cpSGs in living cells from various plant species. Here, we report a simple method to visualize cpSGs in living plant cells in various species by staining with fluorescein, a commonly used fluorescent dye. We show that fluorescein is taken up into chloroplasts and interacts with cpSGs similarly to iodine. Fluorescein also interacts with refined starch in vitro. Using a fluorescein derivative for ultrabright cpSG imaging, we produced high-quality 3D reconstructions of cpSGs and evaluated their accumulation in multiple plant species. As fluorescein is well known and readily purchasable, our fluorescein-based staining method should contribute to all research regarding starch.
Off to a slow start: which workplace policies can limit gender pay gaps across firm tenure?
Authors: Kronberg Anne-Kathrin , Gerlach Anna
Published: October 2023

Much of the gender pay gap is generated within workplaces, making it paramount to understand which workplace policies effectively address gaps. Our article asks when policies limit gender pay gaps across employee tenure to identify potential temporal weak points. We analyze a representative panel of 10,000 establishments with over 850,000 employees using the 2005–19 waves of German-linked employer–employee data (LIAB). Two key findings emerge. First, a temporal perspective on workplace policies reveals that no policy under study—formalization, identity-based career programs, and child care assistance—reduces gender pay gaps at hire. Instead, policies only address additional disparities that accumulate after hire. Second, only identity-based career programs narrow gender disparities for all women. In contrast, seemingly gender-neutral formalization is insufficient, while providing employer-sponsored child care has mixed effects depending on employees’ education. We conclude by discussing the implications of these findings for organizational policy and future research.
Leflunomide alleviates obesity via activation of the TAK1‐AMPK pathway and induction of lipophagy
Authors: Ji Xiaoyue , Chen Junhong , You Chaoying , Sun Jing , Xu Xiulong
Published: October 2023

Lipophagy is a subset of selective autophagy that specifically degrades lipid droplets and plays an important role in obesity. Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose levels, which cannot be attributed to its known side effects. Our prior studies showed that A77 1726, the active metabolite of leflunomide, acts as an inhibitor of S6K1 to sensitize the insulin receptor and control hyperglycemia. Whether the anti‐obesity effect of leflunomide is mediated by targeting S6K1 and its underlying mechanisms remain unclear. Here, we report that A77 1726 induced LC3 lipidation and increased the formation of autophagosomes and lipoautolysosomes in 3T3‐L1 adipocytes by activating TGF‐β‐activated kinase 1 (TAK1), AMP‐activated kinase (AMPK), and Unc‐51 like autophagy‐activated kinase 1 (ULK1). A77 1726 reduced the content of lipid droplets in 3T3‐L1 adipocytes, which was blocked by bafilomycin or by beclin‐1 knockdown. Similar observations were made in murine adipocytes differentiated from S6K1−/− embryonic fibroblasts (MEFs). Leflunomide treatment restricted bodyweight gains in ob/ob mice and reduced the visceral fat deposit and the size of adipocytes. Leflunomide treatment induced autophagy in adipose and liver tissues and reduced hepatic lipid contents. Consistently, S6K1 knockout increased the levels of LC3 lipidation in the liver, muscle, and fat of S6K−/− mice. Leflunomide treatment and S6K1 deficiency both induced TAK1, AMPK, and ULK1 phosphorylation in these tissues. These observations collectively suggest that leflunomide controls obesity in part by activating AMPK and inducing lipophagy. Our study provides insights into the mechanisms of leflunomide‐mediated anti‐obesity activity.
The Psychological and Biological Benefits of Mind-Body Therapy Interventions for Informal Caregivers of Individuals With Cancer: A Systematic Review
Authors: Roderick Quinn , Kuil Kristina , Kunkler Elizabeth , Mondi Nina , Rhode Aminah , Moriello Gabriele
Published: October 2023

Background:

Caring for an individual with cancer can be physically and emotionally draining and finding an effective intervention that supports caregivers is needed. The purpose of this systematic review was to investigate the psychological and biological effects of mind-body therapies for informal caregivers of individuals with cancer.

Methods:

A literature search was completed using 6 databases (PubMed, CINAHL, Cochrane, PsycINFO, PEDro, and OTSeekers) and 4 gray literature databases (MedNar, NY Academy of Medicine Grey Literature Report, WorldCat Dissertations and Theses, and Proquest Psychology). Studies were included if they were randomized controlled trials published after 2010; participants were informal caregivers of individuals with cancer; and the main intervention was yoga, meditation, progressive relaxation therapy and guided imagery, mindfulness therapy, tai chi, breathing exercises, qigong, or visual imagery. The researchers completed title, abstract, and full-text screens using the selection criteria. Data were synthesized descriptively according to the different types of interventions. The Physiotherapy Evidence Database (PEDro) scale was used to critically appraise the final articles.

Results:

There were a total of 11 articles included in this systematic review. There is evidence that certain mind-body therapies can have a positive effect on well-being, anxiety, and fatigue but not mindfulness or stress. One study found significant improvements in biological markers.

Conclusion:

Medical professionals should consider recommending mind-body therapies, especially to informal caregivers who present with anxiety, fatigue, and impairments in well-being. The major limitation in this review is based mostly on fair quality evidence.
Incorporating Data from Multiple Endpoints in the Analysis of Clinical Trials: Example from RSV Vaccines
Authors: Prunas Ottavia , Willemsen Joukje E. , Bont Louis , Pitzer Virginia E. , Warren Joshua L. , Weinberger Daniel M.
Published: October 2023

Background:

To meet regulatory approval, interventions must demonstrate efficacy against a primary outcome in randomized clinical trials. However, when there are multiple clinically relevant outcomes, selecting a single primary outcome is challenging. Incorporating data from multiple outcomes may increase statistical power in clinical trials. We examined methods for analyzing data on multiple endpoints, inspired by real-world trials of interventions against respiratory syncytial virus (RSV).

Method:

We developed a novel permutation test representing a weighted average of individual outcome test statistics (wavP) to evaluate intervention efficacy in a multiple endpoint analysis. We compared the power and type I error rate of this approach to the Bonferroni correction (bonfT) and the minP permutation test. We evaluated the different approaches using simulated data from three hypothetical trials varying the intervention efficacy, correlation, and incidence of the outcomes, and data from a real-world RSV clinical trial.

Results:

When the vaccine efficacy against different outcomes was similar, wavP yielded higher power than bonfT and minP; in some scenarios the improvement in power was substantial. In settings where vaccine efficacy was notably larger against one endpoint compared with the others, all three methods had similar power. We developed an R package, PERmutation basEd ANalysis of mulTiple Endpoints (PERMEATE), to guide the selection of the most appropriate method for analyzing multiple endpoints in clinical trials.

Conclusions:

Analyzing multiple endpoints using a weighted permutation method can increase power, whereas controlling the type I error rate compared with established methods under conditions mirroring real-world RSV clinical trials.
Do Unpaid Children’s Hospital Account Balances Correlate with Family Income or Insurance Type?
Authors: Yau Alice , Lentskevich Marina A. , Yau Irene , Reddy Narainsai K. , Ahmed Kaleem S. , Gosain Arun K.
Published: October 2023

Background:

Current understanding of medical debt among various income ranges and insurance carriers is limited. We analyzed median household incomes, insurance carriers, and medical debt of plastic surgery patients at a major metropolitan children’s hospital.

Methods:

A retrospective chart review for zip codes, insurance carriers, and account balances was conducted for 2018–2021. All patients were seen by members of the Division of Pediatric Plastic Surgery at Ann and Robert H. Lurie Children’s Hospital of Chicago. Blue Cross was reported separately among other commercial insurance carriers by the hospital’s business analytics department. Median household income by zip code was obtained. IBM SPSS Statistics was used to perform chi-squared tests to study the distribution of unpaid account balances by income ranges and insurance carriers.

Results:

Of the 6877 patients, 630 had unpaid account balances. Significant differences in unpaid account balances existed among twelve insurance classes (P< 0.001). There were significant differences among unpaid account balances when further examined by median household income ranges for Blue Cross (P< 0.001) and other commercial insurance carriers (P< 0.001).

Conclusions:

Although patients with insurance policies requiring higher out-of-pocket costs (ie, Blue Cross and other commercial insurance carriers) are generally characterized by higher household incomes, these patients were found to have higher unpaid account balances than patients with public insurance policies. This suggests that income alone is not predictive of unpaid medical debt and provides greater appreciation of lower income families who may make a more consistent effort in repaying their medical debt.