bluuebunny/crossref_metadata_2025 huggingface dataset:
The connection between the equatorial temperature bias and north–south helicity segregation in numerical simulations of the geodynamo
Authors: Davidson P A , Ranjan A
Published: February 2023

In recent numerical simulations of the geodynamo the dynamo action is driven, primarily, by the effects of helicity, with differential rotation playing only a secondary role. These dynamos display a number of robust features, such as: (i) thin convective columns outside the tangent cylinder whose azimuthally averaged helicity, $\langle h \rangle = \langle {{{\bf u}} \cdot \nabla \times {{\bf u}}} \rangle $, is left-handed in the north and right-handed in the south, (ii) approximately 2-D motion in the equatorial regions, with negligible axial velocity,$\langle {{u}_z} \rangle \approx 0$, (iii) positive radial current at mid-latitudes and negative radial current in the equatorial regions, (iv) a radial outflow in the equatorial regions and (v) elevated temperatures near the equator. We seek the relationship between all five of these observations. First, we note that $\langle {{u}_z} \rangle \approx 0$ near the equator follows from the skew-symmetric distribution of helicity, while a negative radial current at the equator is a generic feature of helicity-driven dynamos which have positive (negative) helicity in the south (north). Next, we confirm an earlier suggestion that the equatorial outflow is driven by Lorentz forces associated with the negative radial current. Crucially, however, this outflow does not account for the elevated equatorial temperatures. Rather, the high temperature near the equator is primarily a consequence of anisotropic turbulent diffusion, which preferentially carries heat radially outward along the equator, this anisotropy being a consequence of the (approximately) 2-D flow near the equator. In short, we show that the high equatorial temperatures are a direct consequence of the skew-symmetric distribution of helicity. Finally, we recall that the high equatorial temperatures can themselves explain the observed helicity distribution, as buoyant anomalies near the equator trigger inertial waves which carry negative helicity upward and positive helicity downward. Thus, there is a direct, two-way coupling between the high equatorial temperatures and the helicity distribution.
A finite-difference method for stress modelling based on wave propagation
Authors: Fan Zhuo , Cheng Fei , Liu Jiangping , Han Bingkai , Zheng Yunpeng
Published: February 2023

The determinations of detailed stress states are of great importance for various environmental and engineering investigations, which makes numerical stress modelling a key issue in many fields. We developed a new stress modelling method governed by elastic wave equations using finite-difference scheme. By introducing an artificial damping factor to the particle velocity in wave modelling, the proposed method is able to solve both the dynamic stress evolution and the static stress state of equilibrium. We validate the proposed method both in body force and surface force benchmarks in different scales. With the proposed method, we are able to substantially improve the modelling accuracy of models in unbounded domain by using the perfectly matched layer as the artificial boundary conditions. A 3-D concrete-faced rockfill dam model is further presented as a numerical example of practical investigation. The consistent results with the finite-element method further illustrate the proposed method's applicability. As a minor modification to wave modelling scheme, the proposed stress modelling method is not only accurate for geological models through different scales, but also physically reasonable and easy to implement for geophysicists.
Use of digital technologies to support cancer screening in community health promotion interventions: scoping review
Authors: Costantini Luigi , Del Riccio Marco , Piccoli Elisa , Lavecchia Vincenzo , Corradini Elena , Bonaccorsi Guglielmo , Martucci Gianfranco , Lavserack Glenn
Published: February 2023

The scoping review investigated how digital technologies have helped to increase cancer screening uptake in communities including adolescents, adults and elderly people during the COVID-19 outbreak between January 2020 and June 2021. Thirteen studies were identified as being relevant, mostly addressing underserved or minority communities with the purpose to increase screening uptake, delivering health education or investigating social and cultural barriers to cancer screening. The interventions effectively used digital technologies such as mobile apps and messengers mobile apps, messaging and Web platforms. The limitations imposed by COVID-19 on social interaction can be supported with digital solutions to ensure the continuity of cancer screening programs. However, more research is needed to clarify the exact nature of effectiveness, especially in large-scale interventions.
On a Conjecture of Bitoun and Schedler
Authors: Mustaţă Mircea , Olano Sebastián
Published: February 2023

Suppose that $X$ is a smooth complex algebraic variety of dimension $\geq 3$ and $f$ defines a hypersurface $Z$ in $X$, with a unique singular point $P$. Bitoun and Schedler conjectured that the ${\mathcal {D}}$-module generated by $\tfrac {1}{f}$ has length equal to $g_{P}(Z)+2$, where $g_{P}(Z)$ is the reduced genus of $Z$ at $P$. We prove that this length is always $\geq g_{P}(Z)+2$ and equality holds if and only if $\tfrac {1}{f}$ lies in the ${\mathcal {D}}$-module generated by $I_{0}(f)\tfrac {1}{f}$, where $I_{0}(f)$ is the multiplier ideal ${\mathcal {J}}(f^{1-\epsilon })$, with $0<\epsilon \ll 1$. In particular, we see that the conjecture holds if the pair $(X,Z)$ is log canonical. We can also recover, with an easy proof, the result of Bitoun and Schedler saying that the conjecture holds for weighted homogeneous isolated singularities. On the other hand, we give an example (a polynomial in $3$ variables with an ordinary singular point of multiplicity $4$) for which the conjecture does not hold.
A compilation of virulence-associated genes that are frequently reported in avian pathogenicEscherichia coli(APEC) compared to otherE. coli
Authors: Ovi Fozol , Zhang Li , Nabors Haley , Jia Linan , Adhikari Pratima
Published: February 2023

Escherichia coli survive in various hosts and environments due to their highly diversified genome. These bacteria have coevolved with humans, colonized a broad range of hosts, and survive as a commensal organism or pathogen. Escherichia coli that adopted a pathogenic lifecycle in avian hosts typically belong to phylogroups B2 and D. Phylogenic investigations discovered these E. coli are noticeably overlapped with the phylogroup of E. coli infecting humans. This overlapping is possibly due to a parallel evolution in both hosts from a common ancestor, which indicates a high zoonotic potential of avian pathogenic E. coli (APEC). However, some contrasting evidence of other phylogroups infecting the avian host has also been reported in recent studies indicating phylogroups of E. coli are not definitive, only suggestive to their virulence in chickens. Furthermore, virulence-associated genes that contribute to bacterial features necessary to establish APEC infection, are predominantly located in plasmids. Therefore, phylogenetic classification based on chromosomal markers is often inadequate to identify APEC. Moreover, E. coli can obtain virulent plasmids from other bacteria, which further complicates the link between phylogenetic classification and pathotype. Previous research has reported an array of virulence-associated genes highly prevalent only in APEC isolates. Function of these genes are possibly a prerequisite to establishing APEC infections in chickens. Consequently, these genes can be used to distinguish APEC from environmental, commensal, intestinal, and other extraintestinal E. coli. Therefore, we have extensively reviewed previous literature to compile the virulence-associated genes that are highly prevalent in APEC compared to other E. coli. From this review, we have identified 10 key virulence-associated genes (iss,tsh,iroN, episomal/chromosomal ompT,iutA,cvaC,hlyF,iucD,papG allel(II/III), and papC) that are frequently reported in APEC isolates than nonpathogenic E. coli. A compilation of these research findings can be crucial to the molecular identification of APEC. Furthermore, it can serve as a guideline for future investigation and aid in formulation of intervention strategies.
HER2-low status may predict poor neoadjuvant chemotherapy response in HR-negative breast cancer: a real-world multicenter study
Authors: Xu Weiwei , Jiang Yunshan , Xu Lingyun , Li Changwen , Wang Ji , Liu Zhao , Xue Dandan , Gu Yanlin , Zhong Zhaoyun , He Shiqing , Wang Shui , Zhou Wenbin , Pan Hong
Published: February 2023

Objective

We aimed to investigate the impact of human epidermal growth factor receptor 2 status (human epidermal growth factor receptor 2-low versus human epidermal growth factor receptor 2-zero) on pathological response to neoadjuvant chemotherapy and survival outcomes in early-stage breast cancer.

Methods

Patients with primary invasive breast cancer received neoadjuvant chemotherapy between July 2018 and July 2021 were identified from six hospitals. The primary efficacy end-point was total pathological complete response. The second short-term efficacy end-points include breast pathological complete response, axillary lymph nodes pathological complete response and the score of Miller-Payne grade. Long-term efficacy end-point was disease-free survival.

Results

429 patients with human epidermal growth factor receptor 2 negative invasive tumors were included, 267 (62.24%) had human epidermal growth factor receptor 2-low tumors. Hormone receptor-positive patients had a higher percentage of human epidermal growth factor receptor 2-low tumors compared to hormone receptor-negative patients (71.97% versus 42.14%). The pathological response rate was significantly lower in human epidermal growth factor receptor 2-low tumors than in human epidermal growth factor receptor 2-zero tumors for total patients in univariate analysis, including the rates of total pathological complete response (5.2% versus 14.2%), breast pathological complete response (6.4% versus 17.3%), nodes pathological complete response (26.3% versus 37.7%) and MP4–5 (21.2% versus 33.8%). Subgroup analysis showed that the rates of total pathological complete response, breast pathological complete response and MP4–5 were also significantly lower in human epidermal growth factor receptor 2-low tumors versus human epidermal growth factor receptor 2-zero tumors in both univariate and multivariate analysis in hormone receptor-negative subgroup. With the median follow-up of 24 months, disease-free survival was comparable between these two subgroups (P = 0.816).

Conclusions

Our results demonstrate that human epidermal growth factor receptor 2-low tumors achieved a significantly lower pathological complete response rate with conventional chemotherapy than those with human epidermal growth factor receptor 2-zero tumors, especially for hormone receptor-negative group. Large, randomized, prospective studies are needed to confirm our data and further evaluate the prognostic value of human epidermal growth factor receptor 2-low expression.
Defining rurality: an evaluation of rural definitions and the impact on survival estimates
Authors: Franks Jeffrey A , Davis Elizabeth S , Bhatia Smita , Kenzik Kelly M
Published: February 2023

Background

Patients with cancer living in rural areas have inferior cancer outcomes; however, studies examining this association use varying definitions of “rural,” complicating comparisons and limiting the utility of the results for policy makers and future researchers.

Methods

Surveillance, Epidemiology, and End Results data (2000-2016) were used to assess risk of cancer mortality and mortality from any cause across 4 definitions of rurality: Urban Influence codes (UIC), National Center for Health Statistics (NCHS), Rural-Urban continuum codes (RUCC), and Index of Relative Rurality. Binary (urban vs rural) and ternary (urban, micropolitan, rural) definitions were evaluated. Multivariable parametric survival models estimated hazards of mortality overall and among 3 cancer groupings: screening related, obesity related, and tobacco related. Definition agreement was also assessed.

Results

Overall, 3 788 273 patients with an incident cancer representing 605 counties were identified. There was little discordance between binary definitions of rural vs urban and moderate agreement at the 3 levels. Adjusted models using binary definitions revealed 15% to 17% greater hazard of cancer mortality in rural compared with urban. At the 3 levels when comparing rural with metropolitan, RUCC and NCHS saw similarly increased hazard ratios; however, Index of Relative Rurality did not. Screening-related cancers saw the highest hazards of mortality and the largest divergence between definitions. Obesity-related and tobacco-related cancers saw similarly increased hazards of mortality at the binary and ternary levels.

Conclusions

Hazard of death is similar across binary definitions; however, this differed when categorized as ternary or continuous, especially among screening-related cancers. Results suggest that study purpose should direct choice of definitions and categorization.
Aggregated functional data model applied on clustering and disaggregation of UK electrical load profiles
Authors: Franco Gabriel , P. E. de Souza Camila , Garcia Nancy L
Published: February 2023

Understanding electrical energy demand at the consumer level plays an important role in planning the distribution of electrical networks and offering of off-peak tariffs, but observing individual consumption patterns is still expensive. On the other hand, aggregated load curves are normally available at the substation level. The proposed methodology separates substation aggregated loads into estimated mean consumption curves, called typical curves, including information given by explanatory variables. In addition, a model-based clustering approach for substations is proposed based on the similarity of their consumers’ typical curves and covariance structures. The methodology is applied to a real substation load monitoring dataset from the UK and tested in eight simulated scenarios.
Sexual function among women with vaginismus: a biopsychosocial approach
Authors: Banaei Mojdeh , Kariman Nourossadat , Ozgoli Giti , Nasiri Maliheh , Roozbeh Nasibeh , Zare Fatemeh
Published: February 2023

Background

Vaginismus is known as a type of sexual pain disorder. Regarding the multifactorial nature of vaginismus, the biopsychosocial model is one of the best models to describe this sexual disorder.

Aim

The present research was conducted to study the determinants of sexual function in women with and without vaginismus based on the biopsychosocial model.

Methods

This case-control study was conducted in Iran on 420 women with and without primary vaginismus who met the inclusion criteria. All eligible people were included in the research once their eligibility was verified and their informed permission was acquired; convenience and purposive sampling techniques were used continually. Data collection tools included the demographic and obstetric information form and multiple published scales and questionnaires. Structural equation modeling with LISREL 9.2 software (Scientific Software International) was used to evaluate the determinants of the sexual function of vaginismus.

Outcomes

Participants rated their determinants of sexual function based on the biopsychosocial model.

Results

The mean ages of the case and control groups were 27.67 and 28.44 years, respectively. The direct, indirect, and total effects of the dimensions of sexual health on sexual function and the diagnostic score of vaginismus of the women with vaginismus were significant (P < .001). Furthermore, based on the results, the diagnostic score of vaginismus in women with vaginismus was significantly affected by the direct, indirect, and cumulative impacts of vaginal penetration cognition and fear of sex (P = .016, P = .005). Women with and without vaginismus were able to accept the models’ excellent fit.

Clinical Implications

This study helps inform health planners and policy makers about the sexual function of women with vaginismus, the factors related to this disorder, and the multidimensional nature of this sexual problem.

Strengths and Limitations

This study attempted to offer a more comprehensive and complete view of present knowledge via surveying different aspects of sexual health and by means of valid and reliable tools and path analysis. The study’s merits include the use of the biopsychosocial model to evaluate sexual function in women with vaginismus, the use of a variety of questionnaires to compare women with and without vaginismus, and the size of the sample. The research was limited by the fact that electronic sampling was conducted because of the COVID-19 epidemic.

Conclusion

Based on the findings of the present study for the group of women with vaginismus, the direct, indirect, and overall effects of the majority of dimensions of sexual health were significantly correlated with sexual function and vaginismus.
Understanding the high-mass binary black hole population from stable mass transfer and super-Eddington accretion in bpass
Authors: Briel M M , Stevance H F , Eldridge J J
Published: February 2023

With the remarkable success of the Ligo-Virgo-Kagra consortium in detecting binary black hole mergers, it has become possible to use the population properties to constrain our understanding of the progenitor stars’ evolution. The most striking features of the observed primary black hole mass distributions are the extended tail up to 100 M⊙ and an excess of masses at 35 M⊙. Currently, isolated binary population synthesis have difficulty explaining these features. Using the well-tested bpass detailed stellar binary evolution models to determine mass transfer stability, accretion rates, and remnant masses, we postulate that stable mass transfer with super-Eddington accretion is responsible for the extended tail. These systems are able to merge within the Hubble time due to more stable mass transfer at higher donor masses with higher mass ratios and spin-orbit coupling, allowing the orbits to shrink sufficiently. Furthermore, we find that in bpass the 35 M⊙ excess is not due to pulsational pair-instability, as previously thought, but a feature caused by stable mass transfer, whose regime is limited by the mass transfer stability, quasi-homogeneous evolution, and stellar winds. These findings are at odds with those from other population synthesis codes but in agreement with other recent studies using detailed binary evolution models.
Star formation histories of dwarf spheroidal and dwarf elliptical galaxies in the local Universe
Authors: Seo Mira , Ann Hong Bae
Published: February 2023

We present the star formation histories (SFHs) of early-type dwarf galaxies, dSphs and dEs, in the local Universe within z  = 0.01. The SFHs of early-type dwarf galaxies are characterized by pre-enriched, metal-poor old stellar populations, absence of moderately old stars that have ages of a few Gyr. There are some differences in the SFHs of dSphs and dEs. In particular, dSphs formed old (≳ 10 Gyr old) metal-poor stars ∼2 times more than dEs. The effects of reionization and feedback from supernova explosions are thought to be strong enough to remove the gas left, which prevent moderately old stellar populations in dSphs. In contrast, the ejected gases are not completely removed from dEs and fall back to ignite burst of star formation at a few Gyr after the first period of violent bursts of star formation, showing a suppression of star formation at lookback time ≈9.6 Gyr. The second peak of star formation at lookback time ≈4.5 Gyr in dEs produces moderately old stellar populations. Distinction between dSphs and dEs is useful to examine the SFHS of the early-type dwarfs since the cumulative SFHs are most closely related to their morphology. The stellar mass plays an important role in the SFHs of the early-type dwarfs as a driver of star formation, especially in galaxies with primordial origin.
SUPER VII. morphology and kinematics of H α emission in AGN host galaxies at cosmic noon using SINFONI
Authors: Kakkad D , Mainieri V , Vietri G , Lamperti I , Carniani S , Cresci G , Harrison C , Marconi A , Bischetti M , Cicone C , Circosta C , Husemann B , Man A , Mannucci F , Netzer H , Padovani P , Perna M , Puglisi A , Scholtz J , Tozzi G , Vignali C , Zappacosta L
Published: February 2023

We present spatially resolved H α properties of 21 type 1 AGN host galaxies at z ∼ 2 derived from the SUPER survey. These targets were observed with the adaptive optics capabilities of the SINFONI spectrograph, a near-infrared integral field spectrograph, that provided a median spatial resolution of 0.3 arcsec (∼2 kpc). We model the H α emission line profile in each pixel to investigate whether it traces gas in the narrow line region or if it is associated with star formation. To do this, we first investigate the presence of resolved H α emission after subtracting the AGN PSF. We find extended H α emission in 16 out of the 21 type 1 AGN host galaxies (76 per cent). Based on the BPT diagnostics, optical line flux ratios and line widths (FWHM), we show that the H α emission in five galaxies is ionized by the AGN (30 per cent), in four galaxies by star formation (25 per cent) and for the rest (45 per cent), the ionization source is unconstrained. Two galaxies show extended H α FWHM >600 km s−1, which is interpreted as a part of an AGN-driven outflow. Morphological and kinematic maps of H α emission in targets with sufficient signal-to-noise ratio suggest the presence of rotationally supported discs in six galaxies and possible presence of companions in four galaxies. In two galaxies, we find an anticorrelation between the locations of extended H α emission and [O iii]-based ionized outflows, indicating possible negative feedback at play. However, in the majority of galaxies, we do not find evidence of outflows impacting H α-based star formation.
Precession and polar alignment of accretion discs in triple (or multiple) stellar systems
Authors: Ceppi Simone , Longarini Cristiano , Lodato Giuseppe , Cuello Nicolás , Lubow Stephen H
Published: February 2023

We investigate the mechanism of polar alignment for accretion discs in hierarchical systems (HSs) with more than two stars. In eccentric binary systems, low-mass discs that are sufficiently tilted to the binary orbit align in a polar configuration with respect to the binary plane by aligning their angular momentum to the binary eccentricity vector. In HSs, secular evolution of the orbital parameters makes the eccentricity vector of the system precess with time. This precession undermines the stability of the polar orbit for accretion discs hosted in HSs. We analytically show that the binary criteria for polar alignment derived in the literature are necessary but not sufficient conditions for polar alignment in HSs. Then, we derive an analytical criterion for polar alignment in HSs. In general, we find that discs orbiting the innermost level of an HS can go polar. Conversely, radially extended discs orbiting the outer levels of an HS cannot polarly align and evolve as orbiting around a circular binary. We confirm our findings through detailed numerical simulations. Also, our results are compatible with the observed distribution of disc–orbit mutual inclination. Finally, we compare the observed distribution of disc inclinations in the binary and in the HS populations. Binaries host mainly coplanar discs, while HSs show a wide range of disc inclinations. We suggest that the wider range of inclinations in HSs results from the secular oscillation of their orbital parameters (such as Kozai–Lidov oscillations), rather than from a different initial condition or evolution between HSs and binaries.
Expanding the application of anti-CRISPR proteins in plants for tunable genome editing
Authors: Liu Yang , Yuan Guoliang , Hyden Brennan , Tuskan Gerald A , Abraham Paul E , Yang Xiaohan
Published: February 2023

Anti-CRISPR proteins are very efficient for inhibiting CRISPR/Cas9-based genome editing tools in both herbaceous and woody plant species.
Edge fracture of thixotropic elastoviscoplastic liquid bridges
Authors: Chan San To , Varchanis Stylianos , Shen Amy Q , Haward Simon J
Published: February 2023

It has recently been shown that torsion can break liquid bridges of viscoelastic fluids, with potential application to their clean and rapid dispensing. However, many commonplace fluids (paints, adhesives, pastes, and foodstuffs like chocolate) have more complex thixotropic elastoviscoplastic (TEVP) properties that depend on the imposed stress and the timescale of deformation. Using a commercial thermal paste, we show that liquid bridges of TEVP fluids can also be broken by torsion, demonstrating the applicability of the technique for improved dispensing of real industrial fluids. The liquid bridge breaking mechanism is an elastic instability known as “edge fracture.” Dimensional analysis predicts that the effects of thixotropy and plasticity can be neglected during edge fracture. Simulation using a nonlinear, phenomenological TEVP constitutive model confirms such a prediction. Our work yields new insight into the free-surface flows of TEVP fluids, which may be important to processes such as electronic packaging, additive manufacturing, and food engineering.
Pulmonary Rehabilitation Using Minimal Equipment for People With Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis
Authors: Cheng Sonia Wing Mei , McKeough Zoe J , McNamara Renae J , Alison Jennifer A
Published: February 2023

Objective

Pulmonary rehabilitation programs that use minimal equipment for exercise training, rather than gymnasium equipment, would enable delivery of pulmonary rehabilitation to a greater number of people with chronic obstructive pulmonary disease (COPD). The effectiveness of minimal equipment programs in people with COPD is unclear. This systematic review and meta-analysis aimed to determine the effects of pulmonary rehabilitation using minimal equipment for aerobic and/or resistance training in people with COPD.

Methods

Literature databases were searched up to September 2022 for randomized controlled trials (RCTs) comparing the effect of minimal equipment programs with usual care or with exercise equipment-based programs for exercise capacity, health-related quality of life (HRQoL), and strength.

Results

Nineteen RCTs were included in the review and 14 RCTs were included in the meta-analyses, which reported low to moderate certainty of evidence. Compared with usual care, minimal equipment programs increased 6-minute walk distance (6MWD) by 85 m (95% CI = 37 to 132 m). No difference in 6MWD was observed between minimal equipment and exercise equipment-based programs (14 m, 95% CI = −27 to 56 m). Minimal equipment programs were more effective than usual care for improving HRQoL (standardized mean difference = 0.99, 95% CI = 0.31 to 1.67) and were not different from exercise equipment-based programs for improving upper limb strength (6 N, 95% CI = −2 to 13 N) or lower limb strength (20 N, 95% CI = −30 to 71 N).

Conclusion

In people with COPD, pulmonary rehabilitation programs using minimal equipment elicit clinically significant improvements in 6MWD and HRQoL and are comparable with exercise equipment–based programs for improving 6MWD and strength.

Impact

Pulmonary rehabilitation programs using minimal equipment may be a suitable alternative in settings where access to gymnasium equipment is limited. Delivery of pulmonary rehabilitation programs using minimal equipment may improve access to pulmonary rehabilitation worldwide, particularly in rural and remote areas and in developing countries.
A Seventeenth-Century Manuscript of the Academic Drama Lingua
Authors: Challinor Jennie
Published: February 2023

This article explores a previously unknown manuscript of the anonymous academic drama Lingua. Housed in the Bridgeman family archives in Staffordshire Record Office, the manuscript is similar but by no means identical to the 1607 printed edition. I examine the manuscript’s possible provenance, its distinctive features and key variants (including its attention to act music), before focusing on two substantial original passages. Both of these episodes demonstrate a clear satirical interest in Wales, recycling as they do various Welsh stereotypes common in professional drama of the early seventeenth century. I argue that these sections—which also bear the mark of an engagement with Spenser and Rabelais—enrich our understanding not only of Lingua but of the links between university drama and wider literary and theatrical cultures. I conclude that these sections are likely authorial, and that Thomas Tomkis (to whom the play is usually attributed) may well have contributed to or overseen the production of the manuscript.
Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals
Authors: Ng Cheng Han , Tang Ansel Shao Pin , Xiao Jieling , Wong Zhen Yu , Yong Jie Ning , Fu Clarissa E. , Zeng Rebecca W. , Tan Caitlyn , Wong Gabriel Hong Zhe , Teng Margaret , Chee Douglas , Tan Darren Jun Hao , Chan Kai En , Huang Daniel Q. , Chew Nicholas W.S. , Nah Benjamin , Siddqui Mohammad S. , Sanyal Arun J. , Noureddin Mazen , Muthiah Mark
Published: February 2023

Background and Aims:

Obeticholic acid (OCA) is a farnesoid X receptor agonist used in primary biliary cholangitis (PBC) treatment. Recent studies have expanded OCA use for NASH treatment and results from phase 3 clinical trial have shown beneficial reduction of ≥1 stage of fibrosis with no NASH worsening. However, safety concerns still preside, thus we systematically examine the safety profile of OCA in chronic liver disease.

Materials and Methods:

A search was conducted in Medline and Embase databases for OCA randomized controlled trials in chronic liver disease. Binary events were pooled with Paule-Mandel random effects model and proportional events were examined in a generalized linear mixed model with Clopper-Pearson intervals.

Results:

A total of 8 studies and 1878 patients were analyzed. There was a 75% [risk ratio (RR): 1.75, 95% CI: 1.43–2.15, p < 0.01] increased pruritis risk. OCA increased constipation incidence (RR: 1.88, 95% CI: 1.45–2.43, p < 0.01), decreased diarrhea (RR: 0.62, 95% CI: 0.50–0.77, p < 0.01), and increased development of hyperlipidemia (RR: 2.69, 95% CI: 1.85–3.92, p < 0.01) relative to placebo. Sensitivity analysis in NASH-only studies found a dose-dependent effect with pruritis which increases to RR: 3.07 (95% CI: 1.74–5.41) at 25 mg. However, up to 9.98% (95% CI: 5.01%–18.89%) of NAFLD patients with placebo similarly experience pruritis events. Overall, 16.55% (95% CI: 6.47%–36.24%) of patients with NAFLD on OCA experienced pruritis. There was no significant increase in cardiovascular events.

Conclusions:

OCA may represent the first pharmacological treatment approved for NASH. However, pruritis, constipation, diarrhea, and hyperlipidemia were major events with evident dose-dependent effect that affect tolerability in NASH. Future long-term studies for longitudinal safety events are required.
Canagliflozin ameliorates the development of NAFLD by preventing NLRP3-mediated pyroptosis through FGF21-ERK1/2 pathway
Authors: Huang Shaohan , Wu Beibei , He Yingzi , Qiu Ruojun , Yang Tian , Wang Shuo , Lei Yongzhen , Li Hong , Zheng Fenping
Published: February 2023

Recent studies have suggested that sodium-glucose co-transporter2 inhibitors go beyond their glycemic advantages to ameliorate the development of NAFLD. However, little research has been done on the underlying mechanisms. Here, we took deep insight into the effect of canagliflozin (CANA), one of the sodium-glucose co-transporter2 inhibitor, on the progression of NAFLD, and explored the molecular mechanisms. Our findings showed that CANA-treated ob/ob and diabetic mice developed improved glucose and insulin tolerance, although their body weights were comparable or even increased compared with the controls. The CANA treatment ameliorated hepatic steatosis and lipid accumulation of free fatty acid–treated AML12 cells, accompanied by decreased lipogenic gene expression and increased fatty acid β oxidation–related gene expression. Furthermore, inflammation and fibrosis genes decreased in the livers of CANA-treated ob/ob and diabetic mice mice. FGF21 and its downstream ERK1/2/AMPK signaling decreased, whereas NLRP3-mediated pyroptosis increased in the livers of the ob/ob and diabetic mice mice, which was reversed by the CANA treatment. In addition, blocking FGF21 or ERK1/2 activity antagonized the effects of CANA on NLRP3-mediated pyroptosis in lipopolysaccharide plus nigericin-treated J774A.1 cells. We conclude that CANA treatment alleviated insulin resistance and the progression of NAFLD in ob/ob and diabetic mice mice independent of the body weight change. CANA protected against the progression of NAFLD by inhibiting NLRP3-mediated pyroptosis and enhancing FGF21-ERK1/2 pathway activity in the liver. These findings suggest the therapeutic potential of sodium-glucose co-transporter2 inhibitors in the treatment of NAFLD.
Heart rate variability is associated with disease severity and portal hypertension in cirrhosis
Authors: Miceli Giuseppe , Calvaruso Vincenza , Casuccio Alessandra , Pennisi Grazia , Licata Massimo , Pintus Chiara , Basso Maria G. , Velardo Mariachiara , Daidone Mario , Amodio Emanuele , Petta Salvatore , Simone Fabio , Cabibbo Giuseppe , Di Raimondo Domenico , Craxì Antonio , Pinto Antonio , Tuttolomondo Antonino
Published: February 2023

Introduction:

Autonomic nervous system activity in cirrhotic portal hypertension is linked to hyperdynamic circulation. Heart rate variability (HRV) is a validated noninvasive method to assess the sympathovagal balance. To investigate the correlation between HRV parameters and degree of portal hypertension, we studied a cohort of patients with cirrhosis accounting for etiology and treatments.

Patients and Methods:

In this cross-sectional, observational cohort study, 157 outpatients of both sex with nonalcoholic cirrhosis were assessed by upper gastrointestinal endoscopy to search for esophagogastric varices. Twenty-four-hour electrocardiogram Holter monitoring with 3 HRV parameters measurement [SD of the NN intervals, root mean square successive difference of NN intervals, and SD of the averages of NN intervals (SDANN)] according to time-domain analysis were performed in all patients. Sixteen patients with large esophagogastric varices underwent measurements of the HVPG and assessment of HRV parameters at baseline and after 45 days on carvedilol.

Results:

The liver dysfunction, expressed by Child-Pugh class or MELD score, was directly related to root mean square successive difference of NN intervals and inversely related to SDANN. Presence of ascites was inversely related to SDANN and to SD of the NN intervals. Treatment with carvedilol had an inverse relation with SDANN. Presence and size of esophagogastric varices had an inverse relation to SDANN and SD of the NN intervals. Upon multivariate analysis the associations between SDANN and Child-Pugh class, size of varices and ascites were confirmed. In the subgroup of 16 patients undergoing HVPG measurement, pressure gradient was unrelated to heart rate and HRV parameters.

Conclusions:

Time-domain HRV parameters in patients with cirrhosis, confirm the autonomic nervous system alteration, and their correlation to the degree of portal hypertension suggesting a role of the ANS in hepatic decompensation.
mTORC1 inhibition uncouples lipolysis and thermogenesis in white adipose tissue to contribute to alcoholic liver disease
Authors: Song Qing , Chen Yingli , Ding Qinchao , Griffiths Alexandra , Liu Lifeng , Park Jooman , Liew Chong Wee , Nieto Natalia , Li Songtao , Dou Xiaobing , Jiang Yuwei , Song Zhenyuan
Published: February 2023

Background:

Adipose tissue thermogenic activities use fatty acids from lipolysis for heat generation. Therefore, a tight coupling between lipolysis and thermogenesis is physiologically imperative in maintaining not only body temperature but also lipids homeostasis. Adipose tissue dysfunction contributes to alcoholic liver disease (ALD). Here, studies were conducted to examine how alcohol intake affects adipose tissue thermogenic activities and whether altered adipose tissue thermogenesis contributes to ALD.

Methods:

Both the Lieber-DeCarli and the NIAAA mouse models of ALD were used. Denervation surgery in epididymal fat pads was performed. CL316,243, a selective β3-adrenoceptor agonist, SR59230A, a selective β3 adrenoceptor (ADRB3) antagonist, and rapamycin, a selective mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, were administrated through i.p. injection. Adipocyte-specific Prdm16 knockout mice were subjected to alcohol-containing diet chronically.

Results:

Chronic alcohol consumption, which enhances adipose tissue lipolysis, inhibits thermogenic activities of beige adipocytes in inguinal white adipose tissue (WAT), leading to an uncoupling status between lipolysis and thermogenesis in WAT at both basal and ADRB3 stimulation states. CL316,243 administration exacerbates liver pathologies of ALD. Alcohol intake inhibits mTORC1 activities in WAT. In mice, mTORC1 inhibition by rapamycin inhibits the thermogenesis of iWAT, whereas enhancing WAT lipolysis. Further investigations using adipocyte-specific Prdm16 knockout mice revealed that functional deficiency of beige adipocytes aggravates liver pathologies of ALD, suggesting that the inhibitory effect of alcohol on WAT browning/thermogenesis contributes to ALD pathogenesis.

Conclusion:

Chronic alcohol consumption induces an “uncoupling status” between lipolysis and browning/thermogenesis in WAT by inhibiting mTORC1 activation. Diminished WAT browning/thermogenesis, concomitant with enhanced lipolysis, contributes to ALD pathogenesis.
Diagnostic performance of Ga-68 FAPI 04 PET/CT in colorectal malignancies
Authors: Prashanth Arun , Kumar Ravichander Senthil , Eswaran Prasad , Kalyan Suman , Maheswari Babu Sridev
Published: February 2023

Aim

To evaluate the role of Ga-68 fibroblast activation protein inhibitor 04 PET/computed tomography (FAPI) in colorectal cancers (CRCs) in terms of diagnostic accuracy and impact on clinical management. FAPI is compared with FDG PET/CT and conventional imaging in staging, restaging, recurrence detection, and response evaluation of CRC.

Methods

Twenty-nine consecutive patients of histopathologically confirmed primary or relapsed CRC were included in the study. Patients who underwent FAPI PET/CT along with either FDG PET/CT or conventional imaging were included. Primary lesions, recurrence sites, lymph nodes, and metastatic lesions were recorded on all the scans. Maximum standardized uptake value (SUVmax) was measured from both primary and metastatic lesions.

Results

The sensitivity of FAPI in primary and recurrence detection is 100% compared to 88% for FDG/conventional imaging. The overall sensitivity of FAPI stands at 98% with accuracy at 95% whereas for FDG/conventional imaging the sensitivity and accuracy are 78% and 77%, respectively, with P < 0.002. Significant difference was noted in the detection of peritoneal metastasis (96% vs. 66%).

Conclusion

FAPI PET/CT shows better sensitivity and accuracy in the evaluation of CRCs, especially in peritoneal disease compared to FDG PET/CT and conventional imaging. FAPI has the potential to replace FDG in CRCs.
Assessing Disease Activity in Pediatric Crohn’s Disease Using Ultrasound: The Pediatric Crohn Disease Intestinal Ultrasound Score
Authors: van Wassenaer Elsa A. , van Rijn Rick R. , de Voogd Floris A.E. , van Schuppen Joost , Kindermann Angelika , de Meij Tim G.J. , van Limbergen Johan E. , Gecse K.B. , D’Haens Geert R. , Benninga Marc A. , Koot Bart G.P. ,   on behalf of the RAINBOW group
Published: February 2023

Objectives:

Currently, there is no consensus on how to score Crohn disease (CD) activity assessed by intestinal ultrasound (IUS) in children. This study aimed to design an easy-to-use IUS score for disease activity in pediatric CD.

Methods:

Children undergoing ileo-colonoscopy for CD assessment underwent IUS the day before ileo-colonoscopy, assessed with simple endoscopic score for CD (SES-CD). IUS features were compared to the SES-CD on segmental level. Multiple regression analyses, separately for terminal ileum (TI) and colon, were done to assess predictors of disease activity and to develop a model.

Results:

In 74 CD patients (median 15 years, 48% female), 67 TI and 364 colon segments were assessed. Based on receiver operating characteristics curves, bowel wall thickness (BWT) was categorized into low [1 point: 2–3 mm (TI) and 1.6–2 mm (colon)], medium [2 points: 3.0–3.7 mm (TI) and 2.0–2.7 mm (colon)], and high [3 points: >3.7 mm (TI) and >2.7 mm (colon)]. In TI, only BWT was retained in the model [high BWT: odds ratio (OR) 11.50, P < 0.001]. In colon, BWT (high BWT: OR 8.63, P < 0.001) and mesenteric fat (1 point: OR 3.02, P < 0.001) were independent predictors. A pediatric Crohn disease IUS score (PCD-US) cut-off of 1 resulted in a sensitivity of 82% (95% confidence interval, CI: 65%–93%) and 85% (95% CI: 80%–89%) and a cut-off of 3 in a specificity of 88% (72%–97%) and 92% (87%–96%) for TI and colon, respectively. Inter-observer agreement was moderate for TI and colon (K: 0.42, K: 0.49, respectively).

Conclusions:

The PCD-US score is an easy-to-use and reliable score to detect or rule out CD activity on segmental level in children. External validation is needed before applying this score in clinical practice.
The Effectiveness and Safety of Methotrexate as the First-Line Immunomodulator of Maintenance Therapy in Pediatric Crohn Disease
Authors: Choi Young Min , Kim Jeong Min , Moon Jin Soo , Ko Jae Sung , Yang Hye Ran
Published: February 2023

Objectives:

Methotrexate (MTX) has been used as maintenance therapy for Crohn disease (CD) in adults and children. However, there are only a few studies on the MTX’s effectiveness in thiopurine-naïve CD adult patients and children. This study aimed to evaluate the MTX’s effectiveness and safety as first immunomodulator for maintenance therapy in pediatric CD.

Methods:

This retrospective cohort study recruited 64 pediatric CD patients treated with MTX as a first-line immunomodulator. Clinical remission (CR) was assessed at weeks 14, 26, and 52. Mucosal healing (MH) was assessed at weeks 26 and 52.

Results:

Of 64 patients who received MTX, CR was noted in 60.9% at week 14, 29.7% with MH in 68.0% at week 26, and 27.8% with MH in 81.8% at week 52. When comparing age subtypes according to the Paris classification, the CR rate was higher in A1a than in the other subtypes at week 26 (60.0% in A1a, 26.5% in A1b, 0% in A2;P= 0.038). There were no differences in disease location, behavior, or perianal involvement. Adverse effects were noted in 30 of 64 (46.9%) patients, including 1 patient who stopped MTX before 26 weeks owing to side effects; increased liver enzymes in 25 (39.0%) patients, leukopenia in 5 (7.8%), nausea in 5 (7.8%), skin erosion in 1 (1.6%), and headache in 1 (1.6%).

Conclusion:

MTX as a first-line immunomodulator may be an effective and safe maintenance therapy for pediatric CD patients.
Lateral Malleolar Bursitis in a Competitive In-Line Rollerblade Speed Skater – A Case Report
Authors: Koistinen Brendan , Herman Daniel C.
Published: February 2023

A 10-year-old nationally-competitive female in-line rollerblade speed skater presented to a sports medicine clinic with bilateral lateral ankle pain and swelling over 2 months. Patient had tenderness to palpation and focal swelling at the lateral malleoli. Ultrasound examination confirmed a diagnosis of lateral adventitial malleolar bursitis, potentially due to repetitive shear forces across the lateral malleoli. Inspection of the patient's carbon-fiber boots revealed millimeters of discrepancy in fit around the patient's lateral malleoli. Following brief relative rest from sport, the patient had custom-molded boots made and was able to return to high-level competition and shortly thereafter was pain free. This case is the first known report of lateral malleolar bursitis in an athlete and highlights the role of equipment evaluation which may be necessary in these athletes.
Transmission of Bias in the Medical Record Among Physical Medicine and Rehabilitation Trainees
Authors: Qin Evelyn , Seeds Alicia , Wallingford Allison , Copley Michelle , Humbert Andrew , Junn Cherry , Starosta Amy
Published: February 2023

Stigmatizing language can negatively influence providers’ attitudes and care toward patients, but this has not been studied among physiatrists. An online survey was created to assess whether stigmatizing language can impact physical medicine and rehabilitation (PM&R) trainees’ attitudes toward patients. We hypothesized stigmatizing language would negatively impact trainees’ attitudes. Participants were randomized to a stigmatizing or neutral language vignette describing the same hypothetical spinal cord injury patient. Questions were asked about attitudes and assumptions towards the patient, pain management based on the vignette, and general views regarding individuals with disabilities. Between August 2021 to January 2022, 75 U.S. PM&R residency trainees participated. Thirty-seven (49.3%) identified as women; 52 (69.3%) were white, and half (50.6%) received the stigmatized vignette. Participants exposed to stigmatizing language scored 4.8 points lower (p < 0.01) on the provider attitude toward patient scale compared to those exposed to neutral language. There were no significant differences in the disability attitude scores between the two groups (p = 0.81). These findings may indicate that stigmatizing language in the medical record may negatively affect PM&R trainees’ attitudes toward patients. Further exploration is needed to identify the best way to educate trainees and reduce the propagation of bias in the medical record.
Increased 68Ga-FAPI Activity in Benign Pulmonary Nodules
Authors: Su Dan , Li Zhuoyuan , Deng Jia , Qiu Chen , Chen Yue
Published: February 2023

A 68-year-old man who had recently been diagnosed with pulmonary nodules underwent both 18F-FDG and 68Ga-FAPI PET/CT. Both studies showed increased uptake in pulmonary nodules, which are suspected to be malignant. However, based on the histopathological findings after surgery, this is ultimately diagnosed as a benign pulmonary nodule. Our case suggests that pulmonary nodules with intense 68Ga-FAPI uptake may be benign as well.
Are We Approaching a Change in Paradigm in PET/CT Imaging of Solid Gastrointestinal (or Digestive) Tract Tumors With the Clinical Application of FAPI Imaging?
Authors: Delgado Bolton Roberto C. , Calapaquí Terán Adriana K. , Herrmann Ken , Fanti Stefano , Giammarile Francesco
Published: February 2023

Studies with [68Ga]Ga-labeled or [18F]F-labeled fibroblast activation protein inhibitor compounds have demonstrated favorable characteristics for PET/CT imaging, making them especially interesting for digestive tumors. In this review, the recent evidence in this field and its potential clinical applications are discussed.
A Case Study of Hidradenitis Suppurativa
Authors: Bort Nicole L.
Published: February 2023

Hidradenitis suppurativa (HS) is a complex, chronic, inflammatory skin disease that is often unrecognized or misdiagnosed. Patients frequently present to with painful nodules, inflammatory papules, sinus tracts, and scarring to intertriginous areas seeking care to alleviate symptoms. There is a paucity of information available specifically aimed to educate emergency nurse practitioners on how to recognize, diagnose, and treat this population. The article highlights the main diagnostic criteria and treatment options available for HS patients to help expand disease awareness.