bluuebunny/crossref_metadata_2025 huggingface dataset:
Designing a decision aid for cancer prevention: a qualitative study
Authors: Milton Shakira , Macrae Finlay , McIntosh Jennifer G , Saya Sibel , Alphonse Pavithran , Yogaparan Thivagar , Karnchanachari Napin , Novy Kitty , Nguyen Peter , Lau Phyllis , Emery Jon
Published: April 2023

Objectives

Australian guidelines recommend people aged 50–70 years old consider taking low-dose aspirin to reduce their risk of colorectal cancer. The aim was to design sex-specific decision aids (DAs) with clinician and consumer input, including expected frequency trees (EFTs) to communicate the risks and benefits of taking aspirin.

Methods

Semi-structured interviews were conducted with clinicians. Focus groups were conducted with consumers. The interview schedules covered ease of comprehension, design, potential effects on decision-making, and approaches to implementation of the DAs. Thematic analysis was employed; independent coding by 2 researchers was inductive. Themes were developed through consensus between authors.

Results

Sixty-four clinicians were interviewed over 6 months in 2019. Twelve consumers aged 50–70 years participated in two focus groups in February and March 2020. The clinicians agreed that the EFTs would be helpful to facilitate a discussion with patients but suggested including an additional estimate of the effects of aspirin on all-cause mortality. The consumers felt favourable about the DAs and suggested changes to the design and wording to ease comprehension.

Conclusion

DAs were designed to communicate the risks and benefits of low-dose aspirin for disease prevention. The DAs are currently being trialled in general practice to determine their impact on informed decision-making and aspirin uptake.
Implications of Cumulative Life Event Stress for Daily Stress Exposure and Cardiovascular Reactivity Among Black and White Americans
Authors: Birditt Kira S , Turkelson Angela , Javaid Sarah , Gonzalez Richard , Antonucci Toni
Published: April 2023

Objectives

Daily stress and cardiovascular reactivity may be important mechanisms linking cumulative life event stress with cardiovascular health and may help to explain racial health disparities. However, studies have yet to examine links between exposure to life event stress, daily stress exposure, and cardiovascular reactivity. This study assessed links between trajectories of life event stress exposure, daily stressors, and cardiovascular reactivity among Black and White individuals.

Methods

Participants are from the Stress and Well-being in Everyday Life Study in which 238 individuals (109 Black 129 White; ages 33–93), drawn from the longitudinal Social Relations Study, reported life event stress in 1992, 2005, 2015, and 2018. Of those individuals, 169 completed an ecological momentary assessment study in which they reported stress exposure every 3 hr, and 164 wore a heart rate monitor for up to 5 days.

Results

Latent class growth curve models revealed 2 longitudinal trajectories of life event stress: moderate-increasing and low-decreasing. Individuals in the moderate-increasing stress trajectory reported greater daily stress exposure and links did not vary by race. Black individuals in the low-decreasing trajectory and White individuals in the moderate-increasing trajectory showed positive associations between daily stress and heart rate (i.e., were reactive to daily stress exposure). The link between daily stress and heart rate was not significant among Black individuals in the moderate-increasing trajectory and White individuals in the low-decreasing trajectory.

Discussion

Individuals who experience more life events across the adult life course report greater daily stress exposure which has important implications for daily cardiovascular health. Black individuals with moderate-increasing life event stress show evidence of blunted daily stress reactivity (nonsignificant association between daily stress and heart rate) whereas Black individuals with low-decreasing life event stress show evidence of stress reactivity (positive association between daily stress and heart rate). White individuals showed the opposite pattern (albeit marginally). These findings expand the weathering hypothesis and indicate that chronic life event stress may be associated with blunted stress reactivity among Black individuals.
F-type proton-pumping ATPase mediates acid tolerance inStreptococcus mutans
Authors: Sekiya Mizuki , Ikeda Kazuya , Yonai Ayaka , Ishikawa Taichi , Shimoyama Yu , Kodama Yoshitoyo , Sasaki Minoru , Nakanishi-Matsui Mayumi
Published: April 2023

Aims

Streptococcus mutans is highly sensitive to inhibitors of proton-pumping F-type ATPase (F-ATPase) under acidic conditions. Herein, we investigated the role of S. mutans F-ATPase in acid tolerance using a bacterium expressing the F-ATPase β subunit at lower levels than the wild-type strain.

Methods and results

We generated a mutant S. mutans expressing the catalytic β subunit of F-ATPase at lower levels than the wild-type bacterium. The mutant cells exhibited a significantly slower growth rate at pH 5.30, whereas the rate was essentially the same as that of wild-type cells at pH 7.40. In addition, the colony-forming ability of the mutant was decreased at pH <4.30 but not at pH 7.40. Thus, the growth rate and survival of S. mutans expressing low levels of the β subunit were reduced under acidic conditions.

Conclusions

Together with our previous observations, this study indicates that F-ATPase is involved in the acid tolerance mechanism of S. mutans by secreting protons from the cytoplasm.
Enhanced β-carotene production inYarrowia lipolyticathrough the metabolic and fermentation engineering
Authors: Jing Yiwen , Wang Jingnan , Gao Haiyan , Jiang Yujia , Jiang Wankui , Jiang Min , Xin Fengxue , Zhang Wenming
Published: April 2023

β-Carotene is a kind of high-value tetraterpene compound, which shows various applications in medical, agricultural, and industrial areas owing to its antioxidant, antitumor, and anti-inflammatory activities. In this study, Yarrowia lipolytica was successfully metabolically modified through the construction and optimization of β-carotene biosynthetic pathway for β-carotene production. The β-carotene titer in the engineered strain Yli-C with the introduction of the carotenogenesis genes crtI, crtE, and crtYB can reach 34.5 mg/L. With the overexpression of key gene in the mevalonate pathway and the enhanced expression of the fatty acid synthesis pathway, the β-carotene titer of the engineered strain Yli-CAH reached 87 mg/L, which was 152% higher than that of the strain Yli-C. Through the further expression of the rate-limiting enzyme tHMGR and the copy number of β-carotene synthesis related genes, the β-carotene production of Yli-C2AH2 strain reached 117.5 mg/L. The final strain Yli-C2AH2 produced 2.7 g/L β-carotene titer by fed-batch fermentation in a 5.0-L fermenter. This research will greatly speed up the process of developing microbial cell factories for the commercial production of β-carotene.

One-Sentence Summary

In this study, the β-carotene synthesis pathway in engineered Yarrowia lipolytica was enhanced, and the fermentation conditions were optimized for high β-carotene production.
Constraining quenching time-scales in galaxy clusters by forward-modelling stellar ages and quiescent fractions in projected phase space
Authors: Reeves Andrew M M , Hudson Michael J , Oman Kyle A
Published: April 2023

We forward-model mass-weighted stellar ages (MWAs) and quiescent fractions (fQ) in projected phase space (PPS), using data from the Sloan Digital Sky Survey, to jointly constrain an infall quenching model for galaxies in log (Mvir/M⊙) > 14 galaxy clusters at z ∼ 0. We find the average deviation in MWA from the MWA–M⋆ relation depends on position in PPS, with a maximum difference between the inner cluster and infalling interloper galaxies of ∼1 Gyr. Our model employs infall information from N-body simulations and stochastic star-formation histories from the universemachine model. We find total quenching times of tQ = 3.7 ± 0.4 Gyr and tQ = 4.0 ± 0.2 Gyr after first pericentre, for 9 < log (M⋆/M⊙) < 10 and 10 < log (M⋆/M⊙) < 10.5 galaxies, respectively. By using MWAs, we break the degeneracy in time of quenching onset and time-scale of star formation rate (SFR) decline. We find that time of quenching onset relative to pericentre is $t_{\mathrm{delay}}=3.5^{+0.6}_{-0.9}$ Gyr and $t_{\mathrm{delay}}=-0.3^{+0.8}_{-1.0}$ Gyr for 9 < log (M⋆/M⊙) < 10 and 10 < log (M⋆/M⊙) < 10.5 galaxies, respectively, and exponential SFR suppression time-scales are τenv ≤ 1.0 Gyr for 9 < log (M⋆/M⊙) < 10 galaxies and τenv ∼ 2.3 Gyr for 10 < log (M⋆/M⊙) < 10.5 galaxies. Stochastic star formation histories remove the need for rapid infall quenching to maintain the bimodality in the SFR of cluster galaxies; the depth of the green valley prefers quenching onsets close to first pericentre and a longer quenching envelope, in slight tension with the MWA-driven results. Taken together these results suggest that quenching begins close to, or just after pericentre, but the time-scale for quenching to be fully complete is much longer and therefore ram-pressure stripping is not complete on first pericentric passage.
Formation of proto-globular cluster candidates in cosmological simulations of dwarf galaxies at z > 4
Authors: Sameie Omid , Boylan-Kolchin Michael , Hopkins Philip F , Wetzel Andrew , Ma Xiangcheng , Bullock James S , El-Badry Kareem , Quataert Eliot , Samuel Jenna , Schauer Anna T P , Weisz Daniel R
Published: April 2023

We perform cosmological hydrodynamical simulations to study the formation of proto-globular cluster candidates in progenitors of present-day dwarf galaxies $(M_{\rm vir} \approx 10^{10}\, {\rm M}_\odot$ at z = 0) as part of the ‘Feedback in Realistic Environment’ (FIRE) project. Compact (r1/2 < 30 pc), relatively massive (0.5 × 105 ≲ M⋆/M⊙ ≲ 5 × 105), self-bound stellar clusters form at 11 ≳ z ≳ 5 in progenitors with $M_{\rm vir} \approx 10^9\, \mathrm{M}_{\odot }$. Cluster formation is triggered when at least $10^7\, \mathrm{M}_{\odot }$ of dense, turbulent gas reaches $\Sigma _{\rm gas} \approx 10^4\, {\rm M}_\odot \, {\rm pc}^{-2}$ as a result of the compressive effects of supernova feedback or from cloud–cloud collisions. The clusters can survive for $2-3\, {\rm Gyr}$; absent numerical effects, they could possibly survive substantially longer, perhaps to z = 0. The longest lived clusters are those that form at significant distance – several hundreds of pc – from their host galaxy. We therefore predict that globular clusters forming in progenitors of present-day dwarf galaxies will be offset from any pre-existing stars within their host dark matter haloes as opposed to deeply embedded within a well-defined galaxy. Properties of the nascent clusters are consistent with observations of some of the faintest and most compact high-redshift sources in Hubble Space Telescope lensing fields and are at the edge of what will be detectable as point sources in deep imaging of non-lensed fields with JWST. By contrast, the star clusters’ host galaxies will remain undetectable.
Diagnosing the ejecta properties of engine-driven supernovae from observables in their initial phase
Authors: Maeda Keiichi , Suzuki Akihiro , Izzo Luca
Published: April 2023

Engine-driven explosions with continuous energy input from the central system have been suggested for supernovae (SNe) associated with a Gamma-Ray Burst (GRB), superluminous SNe (SLSNe), and at least a fraction of broad-lined SNe Ic (SNe Ic-BL) even without an associated GRB. In the present work, we investigate observational consequences in this scenario, focusing on the case where the energy injection is sufficiently brief, which has been suggested for GRB-SNe. We construct a simplified, spherical ejecta model sequence taking into account the major effects of the central engine; composition mixing, density structure, and the outermost ejecta velocity. Unlike most of the previous works for GRB-SNe, we solve the formation of the photosphere self-consistently, with which we can predict the photometric and spectroscopic observables. We find that these ejecta properties strongly affect their observational appearance in the initial phase (≲ a week since the explosion), highlighted by blended lines suffering from higher-velocity absorptions for the flatter density distribution and/or higher outermost ejeca velocity. This behaviour also affects the multiband light curves in a non-monotonic way. Prompt follow-up observations starting immediately after the explosion thus provides key diagnostics to unveil the nature of the central engine behind GRB-SNe and SNe Ic-BL. For SN 2017iuk associated with GRB 171205A these diagnosing observational data are available, and we show that the expected structure from the engine-driven explosion, i.e. a flat power-law density structure extending up to ≳100 000 km s−1, can explain the observed spectral evolution reasonably well.
The X-ray variation of M81* resolved by Chandra and NuSTAR
Authors: Niu Shu , Xie Fu-Guo , Wang Q Daniel , Ji Li , Yuan Feng , Long Min
Published: April 2023

Despite advances in our understanding of low-luminosity active galactic nuclei (LLAGNs), the fundamental details about the mechanisms of radiation and flare/outburst in hot accretion flow are still largely missing. We have systematically analysed the archival Chandra and NuSTAR X-ray data of the nearby LLAGN M81*, whose Lbol ∼ 10−5LEdd. Through a detailed study of X-ray light curve and spectral properties, we find that the X-ray continuum emission of the power-law shape more likely originates from inverse Compton scattering within the hot accretion flow. In contrast to Sgr A*, flares are rare in M81*. Low-amplitude variation can only be observed in soft X-ray band (amplitude usually ≲2). Several simple models are tested, including sinusoidal-like and quasi-periodical. Based on a comparison of the dramatic differences of flare properties among Sgr A*, M31*, and M81*, we find that, when the differences in both the accretion rate and the black hole mass are considered, the flares in LLAGNs can be understood universally in a magnetohydrodynamical model.
Structural gray matter alterations in glioblastoma and high-grade glioma—A potential biomarker of survival
Authors: Lamichhane Bidhan , Luckett Patrick H , Dierker Donna , Yun Park Ki , Burton Harold , Olufawo Michael , Trevino Gabriel , Lee John J , Daniel Andy G S , Hacker Carl D , Marcus Daniel S , Shimony Joshua S , Leuthardt Eric C
Published: April 2023

Background

Patients with glioblastoma (GBM) and high-grade glioma (HGG, World Health Organization [WHO] grade IV glioma) have a poor prognosis. Consequently, there is an unmet clinical need for accessible and noninvasively acquired predictive biomarkers of overall survival in patients. This study evaluated morphological changes in the brain separated from the tumor invasion site (ie, contralateral hemisphere). Specifically, we examined the prognostic value of widespread alterations of cortical thickness (CT) in GBM/HGG patients.

Methods

We used FreeSurfer, applied with high-resolution T1-weighted MRI, to examine CT, evaluated prior to standard treatment with surgery and chemoradiation in patients (GBM/HGG, N = 162, mean age 61.3 years) and 127 healthy controls (HC; 61.9 years mean age). We then compared CT in patients to HC and studied patients’ associated changes in CT as a potential biomarker of overall survival.

Results

Compared to HC cases, patients had thinner gray matter in the contralesional hemisphere at the time of tumor diagnosis. patients had significant cortical thinning in parietal, temporal, and occipital lobes. Fourteen cortical parcels showed reduced CT, whereas in 5, it was thicker in patients’ cases. Notably, CT in the contralesional hemisphere, various lobes, and parcels was predictive of overall survival. A machine learning classification algorithm showed that CT could differentiate short- and long-term survival patients with an accuracy of 83.3%.

Conclusions

These findings identify previously unnoticed structural changes in the cortex located in the hemisphere contralateral to the primary tumor mass. Observed changes in CT may have prognostic value, which could influence care and treatment planning for individual patients.
An Automated, Online Feasibility Randomized Controlled Trial of a Just-In-Time Adaptive Intervention for Smoking Cessation (Quit Sense)
Authors: Naughton Felix , Hope Aimie , Siegele-Brown Chloë , Grant Kelly , Barton Garry , Notley Caitlin , Mascolo Cecilia , Coleman Tim , Shepstone Lee , Sutton Stephen , Prevost A Toby , Crane David , Greaves Felix , High Juliet
Published: April 2023

Introduction

Learned smoking cues from a smoker’s environment are a major cause of lapse and relapse. Quit Sense, a theory-guided Just-In-Time Adaptive Intervention smartphone app, aims to help smokers learn about their situational smoking cues and provide in-the-moment support to help manage these when quitting.

Methods

A two-arm feasibility randomized controlled trial (N = 209) to estimate parameters to inform a definitive evaluation. Smoker’s willing to make a quit attempt were recruited using online paid-for adverts and randomized to “usual care” (text message referral to NHS SmokeFree website) or “usual care” plus a text message invitation to install Quit Sense. Procedures, excluding manual follow-up for nonresponders, were automated. Follow-up at 6 weeks and 6 months included feasibility, intervention engagement, smoking-related, and economic outcomes. Abstinence was verified using cotinine assessment from posted saliva samples.

Results

Self-reported smoking outcome completion rates at 6 months were 77% (95% CI 71%, 82%), viable saliva sample return rate was 39% (95% CI 24%, 54%), and health economic data 70% (95% CI 64%, 77%). Among Quit Sense participants, 75% (95% CI 67%, 83%) installed the app and set a quit date and, of those, 51% engaged for more than one week. The 6-month biochemically verified sustained abstinence rate (anticipated primary outcome for definitive trial), was 11.5% (12/104) among Quit Sense participants and 2.9% (3/105) for usual care (adjusted odds ratio = 4.57, 95% CIs 1.23, 16.94). No evidence of between-group differences in hypothesized mechanisms of action was found.

Conclusions

Evaluation feasibility was demonstrated alongside evidence supporting the effectiveness potential of Quit Sense.

Implications

Running a primarily automated trial to initially evaluate Quit Sense was feasible, resulting in modest recruitment costs and researcher time, and high trial engagement. When invited, as part of trial participation, to install a smoking cessation app, most participants are likely to do so, and, for those using Quit Sense, an estimated one-half will engage with it for more than 1 week. Evidence that Quit Sense may increase verified abstinence at 6-month follow-up, relative to usual care, was generated, although low saliva return rates to verify smoking status contributed to considerable imprecision in the effect size estimate.
Effect of Messaging Content on Engagement With a Short Messaging Service for Perioperative Smoking Cessation
Authors: Jose Thulasee , Cha Sarah , Graham Amanda L , Amato Michael S , Schroeder Darrell R , Warner David O
Published: April 2023

Introduction

We determined whether a tobacco cessation intervention targeting brief perioperative abstinence (“quit for a bit”) increased engagement of surgical patients with treatment compared with an intervention targeting long-term postoperative abstinence (“quit for good”).

Aims and Methods

Surgical patients who smoke were stratified according to intended duration of postoperative abstinence, and then randomized within strata to receive either a “quit for a bit” or a “quit for good” intervention. Both employed initial brief counseling and short message service (SMS) to deliver treatment up to 30 days after surgery. The primary outcome of treatment engagement was defined as the rate at which subjects actively responded to system requests delivered via SMS.

Results

The engagement index did not differ between intervention groups (median [25th, 75th] of 23.7% [8.8, 46.0] for “quit for a bit” group (n = 48) and 22.2% [4.8, 46.0] for “quit for good” group (n = 50), p = .74), nor did the proportion of patients continuing SMS use after study completion (33% and 28%, respectively). Exploratory abstinence outcomes on the morning of surgery and 7 and 30 days after surgery did not differ between groups. Program satisfaction was high in both groups and did not differ. There was no significant interaction between intended abstinence duration and any outcome, ie, alignment of intent with intervention did not affect engagement.

Conclusions

Tobacco cessation treatment delivered via SMS was well accepted by surgical patients. Tailoring an SMS intervention to focus on the benefits of short-term abstinence for surgical patients did not increase engagement in treatment or perioperative abstinence rates.

Implications

Treatment of surgical patients for tobacco use is efficacious and reduces postoperative complications. However, implementation in clinical practice has proved challenging, and new methods of engaging these patients in cessation treatment are needed. We found that tobacco use treatment delivered via SMS was feasible and well utilized by surgical patients. Tailoring an SMS intervention to focus on the benefits of short-term abstinence for surgical patients did not increase engagement in treatment or perioperative abstinence rates.

Clinical Trial Number

NCT03839043. Registry URL: https://clinicaltrials.gov/ct2/show/NCT03839043
Ostrogradsky mode in scalar–tensor theories with higher-order derivative couplings to matter
Authors: Naruko Atsushi , Saito Ryo , Tanahashi Norihiro , Yamauchi Daisuke
Published: April 2023

Metric transformation is a tool to find a new theory of gravity beyond general relativity. The gravity action is guaranteed to be free from the dangerous Ostrogradsky mode as long as the metric transformation is regular and invertible. Various degenerate higher-order scalar–tensor theories without extra degrees of freedom have been found through the metric transformation with a scalar field and its derivatives. In this work, we examine how a matter coupling changes the degeneracy for a theory generated from the Horndeski theory through the metric transformation with the second derivative of a scalar field, taking a minimally coupled free scalar field as the matter field. When the transformation is invertible, this theory is equivalent to the Horndeski theory with a higher-order derivative coupling to the matter scalar field. Working in this Horndeski frame and the unitary gauge, we find that the degeneracy conditions are solvable and the matter metric must have a certain structure to remove the Ostrogradsky mode.
An update on pathogenesis of inflammatory disorders with its management
Authors: Bansal Palak , Verma Diksha , Singh Tamber Sukhbir , Sharma Ramica
Published: April 2023

Objectives

Pathogenesis of inflammation has been linked to a variety of diseases, so exploring the cause of inflammation is very much crucial. Once the cause is predicted then the treatment of the inflammation and related disorders become predictable.

Key findings

An inflammatory response is the immune system’s response to harmful stimuli that can be triggered by pathogens, damaged cells, and toxic compounds. Inflammation and the diseases associated with it are becoming more popular. There are several complications that arise due to inflammation, such as cardiovascular disease, rheumatoid arthritis, gout, asthma, etc. Inflammation results in plethora of events characterised by release of inflammatory cytokines activation of nuclear factor kappa-B, mitogen-activated protein kinase, Janus kinase signalling, and the activator of transcription (signal transducer and activator of transcription) pathway, facilitate the process of inflammation. Hence with this review, it will open the vista for new interventions used in the management of inflammatory disorders.

This review deals with the various inflammatory disorder and pathogenesis associated with them. This article opens a window to explore more relevant pharmacological treatment for the benefit of the society. Till date the medication that is available for the management of inflammatory diseases/disorders provides only symptomatic treatment and that is only to a limit. The medication such as steroids posses a serious adverse drug reactions and other option like disease modifying anti-rheumatic drugs/slow-acting anti-rheumatic drugs are not economical or budget friendly. Hence, with this review we can look for various targets that are beneficial in the management of inflammatory-related disorders.
Effect of a surgical skills month on intern performance in the orthopaedic in-training examination
Authors: Samade Richard , Scharschmidt Thomas J.
Published: April 2023

Background:

The orthopaedic in-training examination (OITE) is an annual national assessment of knowledge in orthopaedic surgery residents. Our primary aim was to determine if intern performance in the OITE (measured by correct answers) differed before and after the adoption of a formal surgical skills month (SSM) in the residency curriculum. A secondary aim was to evaluate the relationship between intern OITE and post-graduate year two (PGY-2) scores.

Methods:

A single institution retrospective cohort study was performed, comparing orthopaedic surgery interns who took the OITE before (15 residents) and after (16 residents) the year 2013 (when an SSM was introduced). De-identified OITE raw and percentage correct scores were obtained from all resident records. Statistical testing included independent sample t test and linear regression, with a significance level of 0.05.

Results:

Comparison of OITE percentage of correct answers overall, between interns before and after 2013, showed a significant increase after initiating the SSM (44.8%±4.13% vs. 49.9%±8.44%, P=0.0414). In addition, regression analysis demonstrated a positive linear relationship between intern and PGY-2 OITE scores after the SSM was implemented (R
2=0.380, P=0.011, β=0.424, CI: 0.1135341 –1.190913).

Conclusion:

Implementation of an SSM led to increased intern OITE scores. Moreover, intern OITE scores were more predictive of PGY-2 scores after SSM implementation. Earlier education (such as a surgical skills month) for orthopaedic surgery interns can aid knowledge acquisition and career development at the beginning of their training.

Level of Evidence:

Level III.
Myxoinflammatory Fibroblastic Sarcoma of the Hand
Authors: Alhumaidan Mohammed I. , Bin Makhashen Maraei , Bassas Abdulelah F. , Mater Mohammed E. , Alsufayan Faris A. , Alfaqeeh Faisal A.
Published: April 2023

Myxoinflammatory fibroblastic sarcoma is an ultra-rare tumor type with a prevalence of fewer than two per 100,000 people. The tumor poses a challenge because it can be misdiagnosed as a benign lesion in clinical and radiological investigations, causing serious morbidity in patients. We present the case of a 33-year-old patient who presented with painless hand swelling that was misdiagnosed as lymphaticovenous malformation based on magnetic resonance imaging. The patient underwent surgical excision, and myxoinflammatory fibroblastic sarcoma was diagnosed postoperatively. All surgical interventions failed to achieve negative margin. A decision to start radiotherapy was made, and tissue convergence was done temporally using acellular dermal matrix and split-thickness skin graft. On patient follow-up, the graft had taken well, and the patient was undergoing radiotherapy sessions with a plan for permanent hand reconstruction after negative margins are achieved. Based on this case report, we identified that magnetic resonance imaging is not yet a reliable method to diagnose myxoinflammatory fibroblastic sarcoma. Therefore, implementing a multidisciplinary team approach, a preoperative core needle biopsy, planned surgical intervention, and early involvement of radiotherapy is recommended to minimize morbidity. We strongly urge establishing a sarcoma specialized treatment center in the region to limit patient morbidity.
Farnesoid X receptor alpha ligands inhibit HDV in vitro replication and virion infectivity
Authors: Legrand Anne-Flore , Lucifora Julie , Lacombe Benoît , Ménard Camille , Michelet Maud , Foca Adrien , Abrial Pauline , Salvetti Anna , Rivoire Michel , Lotteau Vincent , Durantel David , André Patrice , Ramière Christophe
Published: April 2023

Background and Aims:

HDV, a satellite of HBV, is responsible for the most severe form of human viral hepatitis, for which curative therapy is still awaited. Both HBV and HDV use the hepatic transporter of bile acids (ie, Na+-taurocholate cotransporting polypeptide) to enter hepatocytes. We have previously shown that ligands of the farnesoid-X-receptor alpha (FXR), a master regulator of bile acids metabolism, inhibit HBV replication. Here we asked whether FXR ligands can also control HDV infection.

Approach and Results:

In vitro HDV monoinfections or HDV/HBV coinfections and superinfections were performed in differentiated HepaRG cells (dHepaRG) and primary human hepatocytes. Following treatment with FXR ligands, HDV RNAs and antigens were analyzed by RT-qPCR, northern blot, immunofluorescence, and western blot. Virus secretion was studied by RNA quantification in supernatants, and the infectivity of secreted HDV particles was measured by reinfection of naive HuH7.5-Na+-taurocholate cotransporting polypeptide cells. In HDV/HBV superinfection models, a 10-day treatment with FXR ligand GW4064 decreased intracellular HDV RNAs by 60% and 40% in dHepaRG cells and primary human hepatocytes, respectively. Both HDV genomic and antigenomic RNAs were affected by treatment, which also reduced the amount of intracellular delta antigen. This antiviral effect was also observed in HDV monoinfected dHepaRG cells, abolished by FXR loss of function, and reproduced with other FXR ligands. In HBV/HDV coinfected dHepaRG cells, HDV secretion was decreased by 60% and virion-specific infectivity by >95%.

Conclusions:

FXR ligands both inhibit directly (ie, independently of anti-HBV activity) and indirectly (ie, dependently of anti-HBV activity) the replication, secretion, and infectivity of HDV. The overall anti-HDV activity was superior to that obtained with interferon-α, highlighting the therapeutic potential of FXR ligands in HDV-infected patients.
Toll-like receptor 2 activation in monocytes contributes to systemic inflammation and alcohol-associated liver disease in humans
Authors: Maccioni Luca , Kasavuli Joyce , Leclercq Sophie , Pirlot Boris , Laloux Géraldine , Horsmans Yves , Leclercq Isabelle , Schnabl Bernd , Stärkel Peter
Published: April 2023

Background and Rationale:

In the context of gut leakiness and translocation of microbial products in alcohol-associated liver disease (ALD), it is possible that systemic and liver inflammation involve the activation of circulating monocyte through gut-derived factors. We explored the association between monocytes, microbial translocation, systemic inflammation, and ALD.

Methods:

Patients with alcohol use disorder following a rehabilitation program were compared with healthy controls. We determined the circulating number and proportion of monocyte subsets by FACS. The activation of signaling pathways by gut-derived microbes was analyzed by quantitative PCR in isolated monocytes. Cytokines secretion by monocytes and phagocytosis were assessed in vitro. Serum microbial translocation markers and cytokines were measured by ELISA and multiplex assay, respectively. ALD severity and liver inflammatory responses were analyzed in liver biopsies by various methods.

Results:

In patients with alcohol use disorder, the number of blood monocytes increased compared with controls. Monocytes from patients with alcohol use disorder upregulated IL-1β and IL-8 together with toll-like receptor 2 and downstream AP-1, while fungal sensor CARD9 was downregulated. IL-1β and IL-8 were actively secreted upon stimulation in vitro with the toll-like receptor 2 ligand peptidoglycan. Exposure with Escherichia coli confirmed preserved bacterial phagocytic activity. In contrast, Candida albicans stimulation leads to downregulation of IL-1β and TNFα compared with controls. Systemic cytokines and monocyte changes correlated with microbial translocation. Hepatic IL-1β and IL-8 increased with ALD severity together with liver macrophage activation and upregulation of chemokines involved in monocyte attraction.

Conclusions:

Our results point to the contribution of activated monocytes to systemic inflammation and ALD. Monocytes likely infiltrate the liver, transform into monocyte-derived macrophages and release IL-1β and IL-8 in response to peptidoglycan and toll-like receptor 2 activation.
The role of natural experiments in hepatology research: filling the gap between clinical trials and service evaluations
Authors: Buchanan Ryan M. , Smith Alex , Rowe Ian
Published: April 2023

Research developing and testing interventions that address the social determinants of liver disease are urgently needed; however, this cannot be achieved using conventional clinical research designs. A different approach is needed to conduct widely applicable, inclusive, and community-based research that addresses upstream factors driving liver morbidity. Natural experimental studies encompass a well-established field of research methodology that is less familiar to clinical hepatologists than conventional research methods such as the randomized control trial. The key strength of natural experiments is that, when robustly designed, they can be used to imply causality from routinely collected data. As such, they are well placed to test the impact of community interventions that aim to address social determinants of liver disease that cannot feasibly be assessed in a randomized control trial. In this review, we define natural experiments and their potential utility. We then work through examples of where they have already been used in clinical hepatology to highlight a range of research designs, analytical approaches, and best practices regarding their conduct and reporting. In doing so, we hope to equip clinical hepatologists with another tool to ensure the hepatology community can meet the global liver disease epidemic with evidence-based interventions.
Low vitamin A levels are associated with liver-related mortality: a nationally representative cohort study
Authors: Song Jiunn , Jiang Z. Gordon
Published: April 2023

Introduction:

Vitamin A, a fat-soluble vitamin that includes retinol and carotenoids, is implicated in liver fibrosis, whereas its deficiency has been associated with various liver diseases and higher overall mortality. This study aims to determine the relationship between levels of vitamin A species and liver fibrosis, as well as liver-related mortality in the population of the US.

Methods:

A total of 12,299 participants from the National Health and Nutrition Examination Survey III (NHANES III) were analyzed to provide nationally representative estimates of the relationship between the levels of vitamin A species and liver fibrosis measured by Fibrosis-4 (FIB-4) index and liver-related mortality.

Results:

A low blood level of retinol, but not other retinoid derivatives, was associated with significant liver fibrosis after adjustment for demographics, anthropometric measurements, medical history, retinol, and carotene intakes. Compared with vitamin D and E, retinol deficiency demonstrated much stronger associations with a high FIB-4 score. Individuals with known risks of chronic liver disease (CLD) and the lowest pentile of retinol levels had ORs of 3.12 (95% CI, 1.64–5.91) for possible fibrosis and 19.7 (95% CI, 5.71–67.7) for likely fibrosis, and an HR of 7.76 (95% CI, 1.19–50.5) for liver-related mortality compared with those in the highest retinol-level pentile. These relationships were more pronounced among individuals with known risks of chronic liver disease than without.

Conclusions:

A low circulating retinol level is associated with liver fibrosis and liver-related mortality in chronic liver disease. This relationship is potentially driven by a mechanistic link rather than the malabsorption of fat-soluble vitamins and may be leveraged for disease prognostication and have therapeutic implications.
Patient survey augments detection of harmful alcohol relapse after liver transplant for alcohol-associated cirrhosis
Authors: Rice Brooke A. , Mehta Neil , Grab Joshua , Dodge Jennifer L. , Sherman Courtney B.
Published: April 2023

Background:

Predicting the risk of alcohol relapse after a liver transplant for alcohol-associated liver disease is critical to guide candidate selection and optimize alcohol use disorder management. We aimed to use patient survey to augment the detection of alcohol relapse and its risk factors and to understand patient perceptions of the importance of alcohol abstinence.

Methods:

In this retrospective cohort study, we used a telephone survey and chart review to assess the incidence of post-transplant harmful alcohol relapse, risk factors, and long-term outcomes for patients transplanted for alcohol-associated cirrhosis at our center from 2002 to 2016.

Results:

Over the median follow-up of 5.9 years, 20.4% relapsed, with 9.3% harmful relapse after median of 4.0 years. The survey response rate was 44.0% (n=110). Of survey responders, 44.3% did not recall discussing alcohol in post-transplant clinics, and 17.6% of relapses were identified by the survey alone. In univariate analysis, shorter pretransplant sobriety (OR: 0.96 per month, p=0.02) and history of pretransplant relapse (OR: 2.99, p=0.02) were associated with post-transplant harmful relapse. After adjusting for these factors, High-risk Alcoholism Relapse score ≥4 predicted harmful relapse (OR: 3.43, p=0.049). A total of 27.3% of patients with both pretransplant relapse and High-risk Alcoholism Relapse score ≥4 relapsed to harmful use compared with 5.2% of those with 1 or neither risk factor (p < 0.001). Harmful relapse was associated with increased graft loss (30.4% vs. 17.4%) and inferior 10-year post–liver transplant survival (61.5% vs. 80.7%).

Conclusions:

Incorporating patient survey data allowed the detection of relapses otherwise unreported to clinicians, highlighting the need for novel strategies to detect relapse. Utilizing this augmented data, we identified pretransplant sobriety length, pretransplant relapse, and High-risk Alcoholism Relapse score ≥4 as risk factors that should be evaluated pretransplant to guide candidate selection and peritransplant alcohol use disorder management.
FXR and NASH: an avenue for tissue-specific regulation
Authors: Henry Zakiyah , Meadows Vik , Guo Grace L.
Published: April 2023

NASH is within the spectrum of NAFLD, a liver condition encompassing liver steatosis, inflammation, hepatocyte injury, and fibrosis. The prevalence of NASH-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. There is no Food and Drug Administration (FDA)-approved pharmacological intervention for NASH. The farnesoid X receptor (FXR) is essential in regulating bile acid homeostasis, and dysregulation of bile acids has been implicated in the pathogenesis of NASH. As a result, modulators of FXR that show desirable effects in mitigating key characteristics of NASH have been developed as promising therapeutic approaches. However, global FXR activation causes adverse effects such as cholesterol homeostasis imbalance and pruritus. The development of targeted FXR modulation is necessary for ideal NASH therapeutics, but information regarding tissue-specific and cell-specific FXR functionality is limited. In this review, we highlight FXR activation in the regulation of bile acid homeostasis and NASH development, examine the current literature on tissue-specific regulation of nuclear receptors, and speculate on how FXR regulation will be beneficial in the treatment of NASH.
Single-cell transcriptome analysis revealed the immune profile of PD-1 blockade in gallbladder carcinoma liver metastasis
Authors: Xie Lin , Ning Zhouyu , Hua Yongqiang , Wang Peng , Meng Zhiqiang
Published: April 2023

Background:

Gallbladder carcinoma is the most common cancer of the biliary tract, and the immune checkpoint blockade showed promising efficacy in the treatment of advanced gallbladder carcinoma. However, the underlying mechanisms remain unknown.

Methods:

Single-cell RNA sequencing was used to reveal immune cell dynamics in an anti-PD-1 responder with gallbladder carcinoma liver metastases. Gene set variation analysis, pseudotime analysis, single-cell regulatory network inference and clustering analysis, and CellChat analysis were used to identify the functions of each cell cluster. Immunohistochemistry and multicolored immunohistochemistry analysis were applied to confirm the intratumoral cell types, and the prognostic value of CXCL13+CD8+T cells in patients with gallbladder carcinoma liver metastases with immunotherapy was evaluated. Four biliary tract carcinoma and 3 immunotherapy bulk RNA-seq datasets were analyzed to investigate the prognostic value of CXCL13+CD8+T cells and SPP1+TAMs.

Result:

A total of 19,648 high-quality single-cell transcriptome data were obtained from liver metastasis before and after aPD-1 therapy. We discovered improved cytotoxic activity in CD8+T cells and enhanced proinflammatory phenotypes in myeloid cells. The identified SPP1+TAMs were related to poor prognosis. The increased effector/memory T cells represented characteristics similar to exhausted T cells in transitory status after aPD-1therapy, which may play a crucial role in the antitumor immune response. We further revealed that CXCL13+T cells in a high subtype of biliary tract carcinoma were characterized as a ‘hot tumor’ profile with high immune scores, correlated to the immunostimulatory context with favorable survival, and can predict effective responses to immunotherapy.

Conclusions:

Our study provided an overview of immune cell dynamics in gallbladder carcinoma liver metastases after aPD-1 treatment and highlighted the importance of CXCL13+T cells in biliary tract carcinoma and effective responses to immunotherapy, which would advance the understanding and treatment of the disease.
Organelle stress and alterations in interorganelle crosstalk during liver fibrosis
Authors: Sinha Saloni , Hassan Nora , Schwartz Robert E.
Published: April 2023

The synchronous functioning and quality control of organelles ensure cell survival and function and are essential for maintaining homeostasis. Prolonged exposure to stressors (viruses, bacteria, parasitic infections, alcohol, drugs) or genetic mutations often disrupt the functional integrity of organelles which plays a critical role in the initiation and progression of several diseases including chronic liver diseases. One of the most important pathologic consequences of chronic liver diseases is liver fibrosis, characterized by tissue scarring due to the progressive accumulation of extracellular matrix components. Left untreated, fibrosis may advance to life-threatening complications such as cirrhosis, hepatic decompensation, and HCC, which collectively accounts for ∼1 million deaths per year worldwide. Owing to the lack of treatment options that can regress or reverse cirrhosis, liver transplantation is currently the only available treatment for end-stage liver disease. However, the limited supply of usable donor organs, adverse effects of lifelong immunosuppressive regimes, and financial considerations pose major challenges and limit its application. Hence, effective therapeutic strategies are urgently needed. An improved understanding of the organelle-level regulation of fibrosis can help devise effective antifibrotic therapies focused on reducing organelle stress, limiting organelle damage, improving interorganelle crosstalk, and restoring organelle homeostasis; and could be a potential clinical option to avoid transplantation. This review provides a timely update on the recent findings and mechanisms covering organelle-specific dysfunctions in liver fibrosis, highlights how correction of organelle functions opens new treatment avenues and discusses the potential challenges to clinical application.
SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment
Authors: Wang Shuai , Wang Rui , Xu Nan , Wei Xuyong , Yang Yijie , Lian Zhengxing , Cen Beini , Shen Chenchen , Li Wangyao , Wang Jianguo , Zhang Zhensheng , Tang Linsong , Wei Qiang , Lu Di , Xu Xiao
Published: April 2023

Background and Aims:

HCC is a malignant disease. Compared with tyrosine kinase inhibitors (the classical therapy), immune checkpoint inhibitors are more effective in the treatment of HCC, despite their limited efficacy. Among these restricted factors, exhaustion of tumor-infiltrated lymphocytes, especially CD8+ T cells, is a core event. We aimed to determine the key factors contributing to CD8+ T-cell infiltration in HCC and investigate the underlying mechanisms.

Approach and Results:

Using machine learning and multiplex immunohistochemistry analysis, we showed that dedicator of cytokinesis protein 2 (DOCK2) was a potential indicator of infiltrated CD8+ T cells in HCC. Using RNA sequencing, flow cytometry analysis, and mouse HCC models, we demonstrated that DOCK2 inactivation accounted for infiltrated CD8+ T-cell exhaustion in tumors. Using quasi-targeted metabolomics, mass spectrum, and mass cytometry by time of flight analysis, we found that cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells suppressed DOCK2 enzymatic activity of T cells. Through virtual screening, molecular docking simulation, and experiments validation, we demonstrated that tolazamide reversed DOCK2 inactivation-mediated CD8+ T-cell exhaustion and enhanced anti–programmed death-ligand 1 antibody+apatinib immunotherapeutic effects on HCC.

Conclusions:

This study indicates that DOCK2 controls CD8+ T-cell infiltration in HCC, and cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells promotes effector T-cell exhaustion. The findings suggest that the usage of conventional drugs affects immunotherapy efficacy in HCC patients.
Intermittent fasting—the future treatment in NASH patients?
Authors: Minciuna Iulia , Gallage Suchira , Heikenwalder Mathias , Zelber-Sagi Shira , Dufour Jean-François
Published: April 2023

NASH is one of the leading causes of chronic liver disease with the potential of evolving towards end-stage liver disease and HCC, even in the absence of cirrhosis. Apart from becoming an increasingly prevalent indication for liver transplantation in cirrhotic and HCC patients, its burden on the healthcare system is also exerted by the increased number of noncirrhotic NASH patients. Intermittent fasting has recently gained more interest in the scientific community as a possible treatment approach for different components of metabolic syndrome. Basic science and clinical studies have shown that apart from inducing body weight loss, improving cardiometabolic parameters, namely blood pressure, cholesterol, and triglyceride levels; insulin and glucose metabolism; intermittent fasting can reduce inflammatory markers, endoplasmic reticulum stress, oxidative stress, autophagy, and endothelial dysfunction, as well as modulate gut microbiota. This review aims to further explore the main NASH pathogenetic metabolic drivers on which intermittent fasting can act upon and improve the prognosis of the disease, and summarize the current clinical evidence.