bluuebunny/crossref_metadata_2025 huggingface dataset:
Monstrous Moonshine for Integral Group Rings
Authors: Carnahan Scott , Urano Satoru
Published: March 2023

We propose a conjecture that is a substantial generalization of the genus zero assertions in both Monstrous Moonshine and Modular Moonshine. Our conjecture essentially asserts that if we are given any homomorphism to the complex numbers from a representation ring of a group ring for a subgroup of the Monster, we obtain a Hauptmodul by applying this homomorphism to a self-dual integral form of the Moonshine module. We reduce this conjecture to the genus-zero problem for “quasi-replicable” functions, by applying Borcherds’ integral form of the Goddard–Thorn no-ghost theorem together with some analysis of the Laplacian on an integral form of the Monster Lie algebra. We prove our conjecture for cyclic subgroups of the Monster generated by elements in class 4A, and we explicitly determine the multiplicities for a decomposition of the integral Moonshine Module into indecomposable modules of the integral group rings for these groups.
Genomic comparison of mecC-carrying methicillin-resistant Staphylococcus aureus from hedgehogs and humans in the Netherlands
Authors: Dierikx Cindy , Hengeveld Paul , Witteveen Sandra , van Hoek Angela , van Santen-Verheuvel Marga , Montizaan Margriet , Kik Marja , Maas Miriam , Schouls Leo , Hendrickx Antoni ,   the Dutch MRSA surveillance study group, Leversteijn-van Hall M A , van den Bijllaardt W , Van Mansfeld R , van Dijk K , Zwart B , Diederen B M W , Dorigo-Zetsma J W , Notermans D W , Ott A , Waar K , Ang W , Da Silvia J , Vlek A L M , Buiting A G M , Bode L G M , Paltansing S , van Griethuysen A J , den Reijer M , van Trijp M J C A , Wong M , Muller A E , van der Linden M P M , van Rijn M , Debast S B , Kolwijck E , al Naiemi N , Schulin T , Dinant S , van Mens S P , Melles D C , Cohen Stuart J W T , Gruteke P , Overdevest I T M A , van Dam A P , Maat I , Maraha B , Sinnige J C , Mattsson E E , van Meer M P A , Stam A , van Maarsenveen N , de Jong E , Vainio S , Heikens E , Steingrover R , Troelstra A , Bathoorn E , Trienekens T A M , van Dam D W , de Brauwer E I G B , van Duijkeren Engeline
Published: March 2023

Objectives

MRSA carrying the mecC gene (mecC-MRSA) have been found in humans and animals worldwide. A high carriage rate of mecC-MRSA has been described among hedgehogs in different countries. We performed genomic comparison of mecC-MRSA from hedgehogs and humans using next-generation sequencing (NGS) to investigate possible zoonotic transmission in the Netherlands.

Methods

Nasal swabs from hedgehogs (n = 105) were cultured using pre-enrichment and selective plates. Isolates were sequenced using Illumina NGS platforms. These data were compared with sequence data of mecC-MRSA (n = 62) from the Dutch national MRSA surveillance in humans.

Results

Fifty hedgehogs were found to be MRSA positive, of which 48 carried mecC. A total of 60 mecC-MRSA isolates derived from 50 hedgehogs were compared with the human isolates. Fifty-nine mecC-MRSA from hedgehogs and all but one isolate from humans belonged to clonal complexes CC130 and CC1943. The mecC gene was located within the SCCmec XI element. Most mecC-MRSA did not carry other resistance genes besides mecC and blaZ. Two human isolates carried erm(C). Isolates differed in the presence of various virulence genes, which were linked to distinct STs and clonal complexes. Some isolates had up to 17 virulence genes, which underlines their pathogenic potential. No genetic clusters of hedgehog and human isolates were found.

Conclusions

mecC-MRSA from hedgehogs and humans mainly belonged to the same two clonal complexes, indicating a common source. No firm evidence for recent zoonotic transmission was found. Further studies are needed to investigate the role of hedgehogs in the occurrence of mecC-MRSA in humans.
No change in avilamycin (Surmax® Premix) minimum inhibitory concentration for Clostridium perfringens isolates recovered from poultry up to 7 years post-approval in Canada
Authors: Simjee Shabbir , Gould George , Maduro Lila , Boulianne Martine , Pridmore Andrew , Parent Eric
Published: March 2023

Background

Clostridium perfringens, the causative agent of necrotic enteritis (NE) in chickens, has an enormous economic impact on global broiler production. The non-medically important antibiotic avilamycin was approved in Canada in 2014 to prevent and control NE in broiler chickens.

Objectives

To compare avilamycin susceptibility in C. perfringens isolates collected pre- and 7 years post-avilamycin approval in Canada and determine the avilamycin resistance mutation frequency rate in C. perfringens.

Methods

The MICs of avilamycin were determined for 89 strains of C. perfringens recovered from clinically relevant NE field cases pre-avilamycin approval between 2003 and 2013 (n = 50) and post-avilamycin approval between 2014 and 2021 (n = 39) across Canada. For determining the mutant prevention concentration (MPC) of avilamycin for C. perfringens strains, a strain with avilamycin MIC of 1 mg/L was randomly selected.

Results

MIC studies showed no difference in avilamycin susceptibility in pre-avilamycin and post-avilamycin isolates (MIC50/90: pre-avilamycin approval 2/2 mg/L and post-avilamycin approval 1/2 mg/L). The MPC was 8 × MIC (8 mg/L) for the selected strain.

Conclusions

These findings suggest that the susceptibility of C. perfringens strains to avilamycin was not impacted by its continued use in the 7 years following its approval in Canada. Avilamycin, a non-medically important antibiotic, poses no threat to human health regarding cross-resistance or co-selection of other medically important antibiotics. These factors make avilamycin an appropriate choice for continued use in broiler chickens to prevent and control NE without increased antimicrobial resistance concerns.
Inverse Associations between Measures of Adiposity and Glycated Albumin in US Adults, NHANES 1999–2004
Authors: Sullivan Valerie K , Wallace Amelia S , Rooney Mary R , Zhang Sui , Fang Michael , Christenson Robert H , Selvin Elizabeth
Published: March 2023

Background

Glycated albumin (GA) is a short-term measure of glycemic control. Several studies have demonstrated an inverse association between body mass index (BMI) and GA, which may affect its performance as a biomarker of hyperglycemia. We investigated cross-sectional associations between GA and multiple measures of adiposity, and compared its performance as a glycemic biomarker by obesity status, in a nationally representative sample of US adults.

Methods

We measured GA in adults from the 1999–2004 National Health and Nutrition Examination Survey. Separately in adults with and without diabetes, we assessed associations of GA with adiposity measures (BMI, waist circumference, trunk fat, total body fat, and fat mass index) in sex-stratified multivariable regression models. We compared sensitivity and specificity of GA to identify elevated hemoglobin A1c (HbA1c), by obesity status.

Results

In covariate-adjusted regression models, all adiposity measures were inversely associated with GA in adults without diabetes (β=−0.48 to −0.22%-point GA per 1 SD adiposity measure; n = 9750) and with diabetes (β=−1.73 to −0.92%-point GA per SD). Comparing adults with vs without obesity, GA exhibited lower sensitivity (43% vs 54%) with equivalent specificity (99%) to detect undiagnosed diabetes (HbA1c ≥ 6.5%). Among adults with diagnosed diabetes (n = 1085), GA performed well to identify above-target glycemia (HbA1c ≥ 7.0%), with high specificity (>80%) overall but lower sensitivity in those with vs without obesity (81% vs 93%).

Conclusions

Inverse associations between GA and adiposity were present in people with and without diabetes. GA is highly specific but may not be sufficiently sensitive for diabetes screening in adults with obesity.
Artificial Intelligence as Supporting Reader in Breast Screening: A Novel Workflow to Preserve Quality and Reduce Workload
Authors: Ng Annie Y , Glocker Ben , Oberije Cary , Fox Georgia , Sharma Nisha , James Jonathan J , Ambrózay Éva , Nash Jonathan , Karpati Edith , Kerruish Sarah , Kecskemethy Peter D
Published: March 2023

Objective

To evaluate the effectiveness of a new strategy for using artificial intelligence (AI) as supporting reader for the detection of breast cancer in mammography-based double reading screening practice.

Methods

Large-scale multi-site, multi-vendor data were used to retrospectively evaluate a new paradigm of AI-supported reading. Here, the AI served as the second reader only if it agrees with the recall/no-recall decision of the first human reader. Otherwise, a second human reader made an assessment followed by the standard clinical workflow. The data included 280 594 cases from 180 542 female participants screened for breast cancer at seven screening sites in two countries and using equipment from four hardware vendors. The statistical analysis included non-inferiority and superiority testing of cancer screening performance and evaluation of the reduction in workload, measured as arbitration rate and number of cases requiring second human reading.

Results

Artificial intelligence as a supporting reader was found to be superior or noninferior on all screening metrics compared with human double reading while reducing the number of cases requiring second human reading by up to 87% (245 395/280 594). Compared with AI as an independent reader, the number of cases referred to arbitration was reduced from 13% (35 199/280 594) to 2% (5056/280 594).

Conclusion

The simulation indicates that the proposed workflow retains screening performance of human double reading while substantially reducing the workload. Further research should study the impact on the second human reader because they would only assess cases in which the AI prediction and first human reader disagree.
A comparison of exposure uncertainty propagation models used in epidemiological studies
Authors: Huang Guowen , Liu Feng
Published: March 2023

In the field of ecological epidemiological studies, accurate estimation of the long-term health effects of air pollution is crucial. Two-step models that involve exposure assessment and health effects estimation are often used for this purpose. However, the accuracy of exposure assessment is uncertain and may not accurately reflect true exposure. Despite several proposed methods to manage this uncertainty, the impact of different approaches on air pollution inferences remains uncertain. In this study, we conduct a simulation study to compare the inferences of air pollution impact from various exposure uncertainty propagation models while investigating their health effects. The results suggest that the Without-uncertainty model and the Multi-set method are preferable to the prior method and pollution-health jointly model (without cut-off). Moreover, a case study further reinforces the evidence of a link between mortality and PM2.5 concentrations, showing that an increase of 1 μg⋅m−3 in PM2.5 concentration is likely to increase all-cause deaths in Scotland by 4.51% [95% credible interval (CI), 3.42%, 5.49%] to 7.51% (95% CI, 6.28%, 8.80%). These findings have important implications for policymakers and public health officials seeking to mitigate the harmful effects of air pollution.
Proximal causal inference for complex longitudinal studies
Authors: Ying Andrew , Miao Wang , Shi Xu , Tchetgen Tchetgen Eric J
Published: March 2023

A standard assumption for causal inference about the joint effects of time-varying treatment is that one has measured sufficient covariates to ensure that within covariate strata, subjects are exchangeable across observed treatment values, also known as ‘sequential randomization assumption (SRA)’. SRA is often criticized as it requires one to accurately measure all confounders. Realistically, measured covariates can rarely capture all confounders with certainty. Often covariate measurements are at best proxies of confounders, thus invalidating inferences under SRA. In this paper, we extend the proximal causal inference (PCI) framework of Miao, Geng, et al. (2018. Identifying causal effects with proxy variables of an unmeasured confounder. Biometrika, 105(4), 987–993. https://doi.org/10.1093/biomet/asy038) to the longitudinal setting under a semiparametric marginal structural mean model (MSMM). PCI offers an opportunity to learn about joint causal effects in settings where SRA based on measured time-varying covariates fails, by formally accounting for the covariate measurements as imperfect proxies of underlying confounding mechanisms. We establish nonparametric identification with a pair of time-varying proxies and provide a corresponding characterization of regular and asymptotically linear estimators of the parameter indexing the MSMM, including a rich class of doubly robust estimators, and establish the corresponding semiparametric efficiency bound for the MSMM. Extensive simulation studies and a data application illustrate the finite sample behaviour of proposed methods.
The Suicidal Crisis
Authors: Galynker Igor
Published: March 2023

An enduring suicide epidemic in the United States calls for urgent action aimed at suicide prevention. However, conventional suicide assessment and prediction methods continue to fall short in identifying individuals at high risk for imminent suicide. Decades of suicide research provide an understanding of who is at lifetime risk for suicide, yet determining when an individual will attempt suicide remains a challenge. The second edition of the Suicidal Crisis aims to tackle the dire need for improved identification of whether any given individual is at risk for near-term suicide. The empirically validated suicide-specific diagnosis, suicide crisis syndrome (SCS), which is under consideration by the APA for addition to the DSM-5-TR, describes an acute pre-suicidal state with specific diagnostic criteria that clinicians can identify during the clinical interview, Objectively diagnosed SCS, which does not include suicidal ideation, warrants immediate clinical intervention to save the life. The narrative-crisis model of suicide (NCM) integrates SCS and long-term suicide risk factors into a multistage framework explaining how stressful life events can contribute to a distorted view of self, others, and the future and trigger a suicidal crisis among individuals with a heightened vulnerability for suicide. The book contains over 50 clinical cases of acutely suicidal individuals, comprehensive instructions for how to conduct clinical assessment of suicide risk, and a chapter dedicated to how clinicians’ emotional responses to suicidal patients can be used to assess suicide risk. Using the NCM as a guiding framework, clinical interventions are discussed, emphasizing targeted symptom relief for acutely suicidal individuals.
Characterization of Anomalous Grains in FeCo Magnetic Alloys
Authors: Deitz Julia I , Ruggles Timothy J , Noell Philip J , Susan Donald F , Kustas Andrew B , Kotula Paul G , Michael Joseph R
Published: March 2023

Heat-treated FeCo-based magnetic alloys were characterized using a suite of electron microscopy techniques to gain insight into their structural properties. Electron channeling contrast imaging (ECCI) in the scanning electron microscope (SEM) found unique grains towards the outer edge of a FeCo sample with nonuniform background contrast. High-magnification ECCI imaging of these nonuniform grains revealed a weblike network of defects that were not observed in standard uniform background contrast grains. High-resolution electron backscattered diffraction (HR-EBSD) confirmed these defect structures to be dislocation networks and additionally found subgrain boundaries within the nonuniform contrast grains. The defect content within these grains suggests that they are unrecrystallized grains, and ECCI can be used as a rapid method to quantify unrecrystallized grains. To demonstrate the insight that can be garnered via ECCI on these unique grains, the sample was imaged before and after micro indentation. This experiment showed that slip bands propagate throughout the material until interacting with the dislocation networks, suggesting that these specific defects provide a barrier to plastic deformation. Taken together, these results show how ECCI can be used to better understand failure mechanisms in alloys and provides further evidence that dislocation networks play a critical role in the brittle failure of FeCo alloys.
Histological and Immunohistochemical Investigation of the Cerebellum in Porcupine and Guinea Pig
Authors: Goodarzi Nader , Nowrozi Masoumeh , Baharan Omid
Published: March 2023

The present study was designed to investigate the cerebellum histology and immunohistochemistry in porcupine (Hystrix cristata) and guinea pig (Cavia porcellus). Two adult porcupines and two adult guinea pigs were used. For general histology, crystal violet and Luxol fast blue stains were applied. For immunohistochemistry, myelin-associated glycoprotein (MAG), neurofilament 200 (NF200), calbindin D-28K, and glial fibrillary-associated protein (GFAP) were investigated. The cerebellar cortex in both species was composed of three cellular layers: molecular, granular, and Purkinje cell (PC) layers. Purkinje cells in the porcupine showed a purple-colored and dark blue-colored cytoplasm in reaction to the crystal violet and Luxol fast blue staining, respectively. In the guinea pig, PC has a uniform reaction to the Luxol fast blue with dark-blue–colored cytoplasm. However, in response to the crystal violet, some PC with dark-purple cytoplasm showed stronger reaction than other PC which showed light-purple cytoplasm. The PC layer in some folia of the porcupine cerebellum was composed of 2–3 layers. The expression rates of calbindin D-28K, MAG, GFAP, and NF200 in the porcupine cerebellum were determined to be 19%, 42.5%, 62%, and 30%, respectively. These values were determined to be 27%, 34%, 43.5%, and 31.5%, respectively, in the guinea pig cerebellum.
The clumpy structure of ϵ Eridani’s debris disc revisited by ALMA
Authors: Booth Mark , Pearce Tim D , Krivov Alexander V , Wyatt Mark C , Dent William R F , Hales Antonio S , Lestrade Jean-François , Cruz-Sáenz de Miera Fernando , Faramaz Virginie C , Löhne Torsten , Chavez-Dagostino Miguel
Published: March 2023

ϵ Eridani is the closest star to our Sun known to host a debris disc. Prior observations in the (sub-)millimetre regime have potentially detected clumpy structure in the disc and attributed this to interactions with an (as yet) undetected planet. However, the prior observations were unable to distinguish between structure in the disc and background confusion. Here, we present the first ALMA image of the entire disc, which has a resolution of 1.6 × 1.2 arcsec2. We clearly detect the star, the main belt, and two-point sources. The resolution and sensitivity of this data allow us to clearly distinguish background galaxies (that show up as point sources) from the disc emission. We show that the two-point sources are consistent with background galaxies. After taking account of these, we find that resolved residuals are still present in the main belt, including two clumps with a >3σ significance – one to the east of the star and the other to the north-west. We perform N-body simulations to demonstrate that a migrating planet can form structures similar to those observed by trapping planetesimals in resonances. We find that the observed features can be reproduced by a migrating planet trapping planetesimals in the 2:1 mean motion resonance and the symmetry of the most prominent clumps means that the planet should have a position angle of either ∼10° or ∼190°. Observations over multiple epochs are necessary to test whether the observed features rotate around the star.
Forecasting the precipitable water vapour along lines of sight in the Chajnantor region from a WRF simulation
Authors: Marín Julio C , Ortiz Felipe , Curé Michel
Published: March 2023

The water vapour in the atmosphere is the main factor affecting ground-based astronomical observations at IR and submillimetre/millimetre wavelengths. Precipitable water vapour (PWV) forecasts over astronomical sites are usually provided at the zenith. However, better observational scheduling could be carried out if PWV forecasts were provided along lines of sight from an observing position. In this study, we implemented a methodology to provide PWV forecasts along all lines of sight at the APEX observatory from a regional numerical weather model. Results show that the best observing conditions are located between -10° and 150° of azimuth, from the zenith to 50° elevation and approximately between 00 and 10 LT (4 and 14 UTC). The Chajnantor region shows a large homogeneity over the sky during each observing time, with half the time showing standard deviation (SD) values below 0.26 mm and less than 15 per cent of the time showing SD values larger than 0.5 mm, when considering all azimuth and elevation angles from the zenith to 15° elevation. The PWV along lines of sight over this region may differ from the PWV calculated at the zenith. Thus, PWV forecasts along lines of sight should be better used in everyday operations at observatories rather than regular PWV visualizations at the zenith. This will allow better observational planning in specific directions, depending on the objects that want to be observed. In addition, site testing studies can be benefited from using this numerical methodology when searching the best sites for IR and submillimetre/millimetre observations.
The most luminous, merger-free AGNs show only marginal correlation with bar presence
Authors: Garland Izzy L , Fahey Matthew J , Simmons Brooke D , Smethurst Rebecca J , Lintott Chris J , Shanahan Jesse , Silcock Maddie S , Smith Joshua , Keel William C , Coil Alison , Géron Tobias , Kruk Sandor , Masters Karen L , O’Ryan David , Thorne Matthew R , Wiersema Klaas
Published: March 2023

The role of large-scale bars in the fuelling of active galactic nuclei (AGNs) is still debated, even as evidence mounts that black hole growth in the absence of galaxy mergers cumulatively dominates and may substantially influence disc (i.e. merger-free) galaxy evolution. We investigate whether large-scale galactic bars are a good candidate for merger-free AGN fuelling. Specifically, we combine slit spectroscopy and Hubble Space Telescope imagery to characterize star formation rates (SFRs) and stellar masses of the unambiguously disc-dominated host galaxies of a sample of luminous, Type-1 AGN with 0.02 < z < 0.24. After carefully correcting for AGN signal, we find no clear difference in SFRs between AGN hosts and a stellar mass-matched sample of galaxies lacking an AGN (0.013 < z < 0.19), although this could be due to small sample size (nAGN = 34). We correct for SFR and stellar mass to minimize selection biases, and compare the bar fraction in the two samples. We find that AGNs are marginally (∼1.7σ) more likely to host a bar than inactive galaxies, with AGN hosts having a bar fraction, $f_{\mathrm{bar}}=0.59^{+0.08}_{-0.09}$ and inactive galaxies having a bar fraction, $f_{\mathrm{bar}}=0.44^{+0.08}_{-0.09}$. However, we find no further differences between SFR- and mass-matched AGNs and inactive samples. While bars could potentially trigger AGN activity, they appear to have no further, unique effect on a galaxy’s stellar mass or SFR.
Gravitational radiation from thermal mountains on accreting neutron stars: sources of temperature non-axisymmetry
Authors: Hutchins T J , Jones D I
Published: March 2023

The spin distribution of accreting neutron stars in low-mass X-ray binary systems shows a concentration of pulsars well below the Keplerian break-up limit. It has been suggested that their spin frequencies may be limited by the emission of gravitational waves, due to the presence of large-scale asymmetries in the internal temperature profile of the star. These temperature asymmetries have been demonstrated to lead to a non-axisymmetric mass distribution, or ‘mountain’, that generates gravitational waves at twice the spin frequency. The presence of a toroidal magnetic field in the interior of accreting neutron stars has been shown to introduce such anisotropies in the star’s thermal conductivity, by restricting the flow of heat orthogonal to the magnetic field and establishing a non-axisymmetric temperature distribution within the star. We revisit this mechanism, extending the computational domain from (only) the crust to the entire star, incorporating more realistic microphysics, and exploring different choices of outer boundary condition. By allowing a magnetic field to permeate the core of the neutron star, we find that the likely level of temperature asymmetry in the inner crust (ρ ∼ 1013 g cm−3) can be up to 3 orders of magnitude greater than the previous estimate, improving prospects for one day detecting continuous gravitational radiation. We also show that temperature asymmetries sufficiently large to be interesting for gravitational wave emission can be generated in strongly accreting neutron stars if crustal magnetic fields can reach ∼1012 G.
Oocytes can repair DNA damage during meiosis via a microtubule-dependent recruitment of CIP2A–MDC1–TOPBP1 complex from spindle pole to chromosomes
Authors: Leem Jiyeon , Kim Jae-Sung , Oh Jeong Su
Published: March 2023

Because DNA double-strand breaks (DSBs) greatly threaten genomic integrity, effective DNA damage sensing and repair are essential for cellular survival in all organisms. However, DSB repair mainly occurs during interphase and is repressed during mitosis. Here, we show that, unlike mitotic cells, oocytes can repair DSBs during meiosis I through microtubule-dependent chromosomal recruitment of the CIP2A–MDC1–TOPBP1 complex from spindle poles. After DSB induction, we observed spindle shrinkage and stabilization, as well as BRCA1 and 53BP1 recruitment to chromosomes and subsequent DSB repair during meiosis I. Moreover, p-MDC1 and p-TOPBP1 were recruited from spindle poles to chromosomes in a CIP2A-dependent manner. This pole-to-chromosome relocation of the CIP2A–MDC1–TOPBP1 complex was impaired not only by depolymerizing microtubules but also by depleting CENP-A or HEC1, indicating that the kinetochore/centromere serves as a structural hub for microtubule-dependent transport of the CIP2A–MDC1–TOPBP1 complex. Mechanistically, DSB-induced CIP2A–MDC1–TOPBP1 relocation is regulated by PLK1 but not by ATM activity. Our data provide new insights into the critical crosstalk between chromosomes and spindle microtubules in response to DNA damage to maintain genomic stability during oocyte meiosis.
Structural basis for guide RNA selection by the RESC1–RESC2 complex
Authors: Dolce Luciano G , Nesterenko Yevheniia , Walther Leon , Weis Félix , Kowalinski Eva
Published: March 2023

Kinetoplastid parasites, such as trypanosomes or leishmania, rely on RNA-templated RNA editing to mature mitochondrial cryptic pre-mRNAs into functional protein-coding transcripts. Processive pan-editing of multiple editing blocks within a single transcript is dependent on the 20-subunit RNA editing substrate binding complex (RESC) that serves as a platform to orchestrate the interactions between pre-mRNA, guide RNAs (gRNAs), the catalytic RNA editing complex (RECC), and a set of RNA helicases. Due to the lack of molecular structures and biochemical studies with purified components, neither the spacio-temporal interplay of these factors nor the selection mechanism for the different RNA components is understood. Here we report the cryo-EM structure of Trypanosoma brucei RESC1–RESC2, a central hub module of the RESC complex. The structure reveals that RESC1 and RESC2 form an obligatory domain-swapped dimer. Although the tertiary structures of both subunits closely resemble each other, only RESC2 selectively binds 5′-triphosphate-nucleosides, a defining characteristic of gRNAs. We therefore propose RESC2 as the protective 5′-end binding site for gRNAs within the RESC complex. Overall, our structure provides a starting point for the study of the assembly and function of larger RNA-bound kinetoplast RNA editing modules and might aid in the design of anti-parasite drugs.
Investigating RNA–RNA interactions through computational and biophysical analysis
Authors: Mrozowich Tyler , Park Sean M , Waldl Maria , Henrickson Amy , Tersteeg Scott , Nelson Corey R , De Klerk Anneke , Demeler Borries , Hofacker Ivo L , Wolfinger Michael T , Patel Trushar R
Published: March 2023

Numerous viruses utilize essential long-range RNA–RNA genome interactions, specifically flaviviruses. Using Japanese encephalitis virus (JEV) as a model system, we computationally predicted and then biophysically validated and characterized its long-range RNA–RNA genomic interaction. Using multiple RNA computation assessment programs, we determine the primary RNA–RNA interacting site among JEV isolates and numerous related viruses. Following in vitro transcription of RNA, we provide, for the first time, characterization of an RNA–RNA interaction using size-exclusion chromatography coupled with multi-angle light scattering and analytical ultracentrifugation. Next, we demonstrate that the 5′ and 3′ terminal regions of JEV interact with nM affinity using microscale thermophoresis, and this affinity is significantly reduced when the conserved cyclization sequence is not present. Furthermore, we perform computational kinetic analyses validating the cyclization sequence as the primary driver of this RNA–RNA interaction. Finally, we examined the 3D structure of the interaction using small-angle X-ray scattering, revealing a flexible yet stable interaction. This pathway can be adapted and utilized to study various viral and human long-non-coding RNA–RNA interactions and determine their binding affinities, a critical pharmacological property of designing potential therapeutics.
POSTRE: a tool to predict the pathological effects of human structural variants
Authors: Sánchez-Gaya Víctor , Rada-Iglesias Alvaro
Published: March 2023

Understanding the pathological impact of non-coding genetic variation is a major challenge in medical genetics. Accumulating evidences indicate that a significant fraction of genetic alterations, including structural variants (SVs), can cause human disease by altering the function of non-coding regulatory elements, such as enhancers. In the case of SVs, described pathomechanisms include changes in enhancer dosage and long-range enhancer-gene communication. However, there is still a clear gap between the need to predict and interpret the medical impact of non-coding variants, and the existence of tools to properly perform these tasks. To reduce this gap, we have developed POSTRE (Prediction Of STRuctural variant Effects), a computational tool to predict the pathogenicity of SVs implicated in a broad range of human congenital disorders. By considering disease-relevant cellular contexts, POSTRE identifies SVs with either coding or long-range pathological consequences with high specificity and sensitivity. Furthermore, POSTRE not only identifies pathogenic SVs, but also predicts the disease-causative genes and the underlying pathological mechanism (e.g, gene deletion, enhancer disconnection, enhancer adoption, etc.). POSTRE is available at https://github.com/vicsanga/Postre.
Risk management under climate change and its implication on technical efficiency: Evidence from Senegal
Authors: Collins-Sowah Peron A , Adjin Kougblenou C , Henning Christian H C A , Kanu Edmond A
Published: March 2023

Using empirical data from a nationally representative farm household survey in Senegal, this study evaluated the impact of different risk management strategies employed by farm households on technical efficiency (TE). The findings of the study suggest that risk management has implications for TE. We find that the use of ex-post risk management strategies is associated with relatively higher technical efficiencies with respect to the meta-frontier compared to other risk management strategies. Households employing only ex-ante risk management strategies were observed to be the least technically efficient in comparison to households employing other risk management strategies. The findings also suggest that managing production risks using multiple strategies does not necessarily result in the highest TE gain compared to the use of single strategies. The findings underscore the need to evaluate the trade-offs and likely consequences of risk management approaches used by farm households to provide countermeasures to deal with any adverse related effects.
Multifunctional LPxTG‐motif surface protein derived from Limosilactobacillus reuteri SH 23 in DSS‐induced ulcerative colitis of mice
Authors: Zong Manli , Chang Chun , Anjum Rameesha , Xu Hai , Guo Yuxing , Pan Daodong , Wu Zhen
Published: March 2023

Lactobacillus species is one of the most commonly used probiotics with a wide range of health‐promoting effects, and beneficial effects of the surface protein of the lactobacillus could potentially be involved in the action of probiotics in the gastrointestinal tract. In this study, the anti‐inflammatory effect of LPxTG‐motif surface protein (LMP) derived from Limosilactobacillus reuteri SH 23 was assessed using a mouse model of colitis induced by dextran sodium sulfate (DSS). The results showed that LMP has the inhibition properties upon the DSS‐induced ulcerative colitis of mice via the MAPK‐dependent NF‐κB pathway. The inflammatory factors TNF‐α and IL‐6 were inhibited, and the IL‐10 secretion was enhanced in the LMP‐treated DSS mice model. Furthermore, the diversity of the intestinal microbiota bacteria in this treated group was also influenced, including the increase in the abundance of Lactobacillus and Akkermansia genus in the LMP‐treated mice groups, and there is a positive correlation between the IL‐10 cytokines with the changes in the intestinal microbiota Lactobacillus and Akkermansia. Therefore, LMP derived from the Limosilactobacillus reuteri SH 23 has the potential to alleviate inflammatory diseases through the balance of the intestinal flora with the inhibition of the inflammatory factors in the NF‐κB pathway.
Awareness, Adjustment, Assistance, Alignment, and Advocacy: Operationalizing Social Determinants of Health Topics in Undergraduate Medical Education Curricula
Authors: Sandhu Sahil , Solomon Loel , Gottlieb Laura M.
Published: March 2023

Social and economic factors, such as those related to food, housing, and transportation, are major drivers of health and health inequities. Multiple national professional organizations have articulated roles for physicians in identifying and addressing social determinants of health (SDOH) and the need to include SDOH in all stages of physician education. Despite encouragement from these professional organizations, medical schools still do not routinely offer SDOH education alongside basic and clinical sciences curricula. A recent national expert consensus process identified priority SDOH knowledge domains and professional skills for medical students but lacked an organizing schema and specific pedagogical examples to help translate prioritized skills into routine pedagogical practice. One such schema is the 5As framework developed by the National Academies of Sciences, Engineering, and Medicine, which elaborates on 5 strategies to strengthen social care: awareness, adjustment, assistance, alignment, and advocacy. In this article, the authors highlight and provide examples of how mapping SDOH skills to the 5As framework can help educators meaningfully operationalize SDOH topics into specific curricular activities during the preclinical and clinical stages of undergraduate medical education. As a foundational first step in this direction, medical schools should conduct an internal curricular review of social care content (ideally mapped to the 5As framework) and identify opportunities to integrate these topics into existing courses when relevant (e.g., in social medicine, population health, and health systems science courses). Given that health and social care integration is highly context dependent, each medical school will likely need to tailor curricular changes based on their own institutional needs, mission, patient populations, and ties to the community. To increase interinstitutional alignment, medical schools might consider using or adapting peer-reviewed materials and assessments curated and centralized by the National Collaborative for Education to Address the Social Determinants of Health.
Outcomes of Growth-friendly Instrumentation in Osteogenesis Imperfecta: A Preliminary Report
Authors: Badin Daniel , Mun Frederick , Akbarnia Behrooz A. , Perez-Grueso Francisco , Sponseller Paul D. ,   Pediatric Spine Study Group
Published: March 2023

Background:

There is limited literature on the outcomes in patients with osteogenesis imperfecta (OI) undergoing growth-friendly instrumentation (GFI). The purpose of this study was to report the outcomes of GFI in patients with early-onset scoliosis (EOS) and OI. We hypothesized that similar trunk elongation could be obtained in OI patients, but with higher complication rates.

Methods:

A multicenter database was studied for patients with EOS and OI etiology who had GFI from 2005 to 2020, with a minimum 2-year follow-up. Demographic, radiographic, clinical, and patient-reported outcomes data were collected and compared with an idiopathic EOS cohort matched 2:1 for age, follow-up duration, and curve magnitude.

Results:

Fifteen OI patients underwent GFI at a mean age of 7.3±3.0 years, with an average follow-up of 7.3±3.9 years. OI patients had a mean preoperative coronal curve of 78.1±14.5 and achieved 35% correction after index surgery. There were no differences in major coronal curves and coronal percent correction between the OI and idiopathic groups at all time points. T1-S1 length (cm) was lower for the OI group at baseline (23.3±4.6 vs. 27.7±7.0; P=0.028) but both groups had similar growth (mm) per month (1.0±0.6 vs. 1.2±1.1; P=0.491). OI patients had a significantly increased risk of proximal anchor failure, which occurred in 8 OI patients (53%) versus 6 idiopathic patients (20%) (P=0.039). OI patients who underwent preoperative halo-traction (N=4) had greater T1-S1 length gain (11.8±3.2 vs. 7.3±2.8; P=0.022) and greater percent major coronal curve correction (45±11 vs. 23±17; P=0.042) at final follow-up versus patients with no halo-traction (N=11). Staged foundation fusion was performed in 2 cases.

Conclusion:

Compared with matched idiopathic EOS patients, OI patients undergoing GFI achieved similar radiographic outcomes but sustained greater rates of anchor failures, likely due to weakened bone. Preoperative halo-traction was a useful adjunct and may improve final correction. Staged foundation fusion is an idea to consider for difficult cases.

Level of Evidence:

Therapeutic—III
Cellulite: Clinical Challenges and Future Perspectives
Authors: Shridharani Sachin M. , Moradi Amir , Khalifian Saami , LaTowsky Brenda , Petraki Chrysi , Bass Lawrence S.
Published: March 2023

BACKGROUND

Existing cellulite interventions pose various clinical challenges related mostly to ecchymosis and recovery time.

OBJECTIVE

To discuss the current treatment options for minimizing recovery time, efficacy of these options, and investigations into possible future approaches.

METHODS

A roundtable meeting was convened to discuss and share views on the clinical challenges seen in the present practice of cellulite treatments along with future approaches and mitigation strategies. The participants' views helped guide a narrative review on this topic.

RESULTS

Cosmetic clinicians have a range of new interventions to choose from for cellulite improvement, each with different benefits and safety aspects. Bruising is a typical side effect that is seen with treatments targeting the fibrous septa, such as subcision and injectable treatments, and in some cases may produce long-lasting hyperpigmentation from postinflammatory hyperpigmentation or hemosiderin staining. Various strategies that could potentially mitigate bruising and other adverse effects of cellulite treatment are under clinical investigation, including, but not limited to, different injection techniques and dilutions, compression garments, cold packs, arnica gel, pulsed dye laser treatment, intralesional epinephrine, and tranexamic acid.

CONCLUSION

Clinical challenges including varying treatment outcomes and certain treatment sequelae remain, and further research is needed to prevent side effects and improve treatment outcomes.
Correlation of elevated serum uric acid with coronary artery disease in Xinjiang, China: A retrospective case-control study
Authors: Li Hua-Yin , Ji Hong-Yu , Maimaitituersun Gulinigaer , Ma Yi-Tong , Fu Zhen-Yan
Published: March 2023

Elevated serum uric acid (SUA) levels are associated with coronary artery disease (CAD). However, whether this association is independent of traditional cardiovascular risk factors remains controversial. Our study aimed to determine the concentration of SUA in the presence and severity of CAD in multi-ethnic patients in Xinjiang, China. For this study, 412 consecutive patients with percutaneous coronary intervention (PCI) and 845 individuals with normal coronary angiograms were included in the study. CAD severity was evaluated using the Gensini score index. The SUA concentrations and the levels of various cardiometabolic risk factors were investigated. We assessed the relationship between SUA levels and other cardiometabolic risk factors. Logistic regression was used to evaluate risk factors for PCI patients. SUA levels were significantly elevated in PCI patients compared to those in control subjects (P < .01). With increased UA levels, we found that the risk factors for CAD increased. SUA concentration had a significant positive relationship with total cholesterol (P < .01), triglycerides (P < .01), low-density lipoprotein cholesterol (P < .01), and creatinine (P < .01) in both sexes. In the PCI group, there was no significant correlation between UA levels. SUA levels are not an independent risk factor for CAD. It can be concluded that in Xinjiang, China, SUA is related to multiple risk factors for CAD, but not related to the severity of CAD.
Immune checkpoint inhibitors are effective in the treatment of Epstein-Barr virus-associated gastric cancer: A case report
Authors: An Gaili , He Xin Cheng , Bai Jun , Wang Jianhua
Published: March 2023

Rationale:

Gastric cancer (GC) is one of the most common malignancies globally, and its occurrence and development are associated with genetic, dietary, biological, and immune factors. Epstein-Barr virus-associated gastric cancer (EBVaGC), as a special subtype of GC, has become a research hotspot in recent years. In patients with advanced GC, Epstein-Barr virus infection is closely related to lymph node metastasis, depth of tumor invasion, and poor prognosis. There is great clinical need for a new treatment modality for EBVaGC. Advances in molecular biology and cancer genetics have led to the development of immune checkpoint inhibitors (ICIs); patients treated with ICIs experience clinical benefit and few adverse effects.

Patient concerns and Diagnoses:

We report a 31-year-old male with advanced EBVaGC and multiple sites of lymph node metastasis who was intolerant to multiple lines of chemotherapy.

Interventions and outcome:

After immune checkpoint inhibitor treatment, both primary and metastatic tumors shrank significantly without noticeable adverse reactions. After 21 months of progression-free status, the patient underwent R0 resection.

Lessons:

This case report provides evidence for the use of ICIs in treating EBVaGC. It also shows that detection of Epstein-Barr virus-encoded small nuclear RNA may be a prognostic factor in gastric cancer.
Meaningful Improvement and Worsening in Patients Who Do Not Achieve Low Disease Activity and Switch Therapy to a New Biologic or Targeted Disease-Modifying Antirheumatic Drug
Authors: Curtis Jeffrey R. , Fiore Stefano , Ford Kerri , Janak Jud C. , Chang Hong , Pappas Dimitrios A. , Blachley Taylor , Emeanuru Kelechi , Bykerk Vivian P.
Published: March 2023

Objective

The aim of this study was to assess the change in disease activity associated with switching from 1 biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) to another in patients with rheumatoid arthritis who did not achieve low disease activity (LDA) after 6 to 12 months of their initial treatment.

Methods

This observational study included patients from the CorEvitas Rheumatoid Arthritis Registry, who initiated a b/tsDMARD at the index visit (prebaseline), had any clinical disease activity index (CDAI) improvement but did not achieve LDA/remission at the subsequent visit (baseline), and switched therapy at baseline or between baseline and follow-up visits. Regardless of the preswitch CDAI value, 2 thresholds of CDAI change were used to define meaningful improvement and worsening for all patients: ≥6 units and ≥12 units; no meaningful change was defined as any change between −6 to +6 units and −12 to +12 units, based on respective thresholds.

Results

Of 1226 patients fulfilling the inclusion criteria, 93 (7.6%) switched therapy at baseline or between baseline and follow-up, after an inadequate response at the baseline visit. At follow-up, meaningful worsening occurred in 30.1% and 12.9% of switchers, whereas the remaining switchers achieved meaningful improvement (34.4% and 20.4%) or had no meaningful change (35.5% and 66.7%), based on the thresholds of ≥6 and ≥12 units, respectively.

Conclusions

Rheumatoid arthritis patients, who had not achieved LDA and switched b/tsDMARD, were more likely to have meaningful improvement or no change, rather than meaningful worsening. These data may help some patients overcome their hesitancy to switch therapy, potentially improving clinical outcomes.
Prolonged COVID-19 PCR positivity and molnupravir treatment experience in a late-stage AIDS case with Kaposi sarcoma
Authors: Sarlak Konya Petek , Demirtürk Neşe
Published: March 2023

In this case report, we describe the treatment of a young patient with end-stage AIDS, disseminated kaposi sarcoma and COVID-19 infection with molnupravir. With a positive SARS-CoV-2 test, a woman who had never received antiretroviral therapy was admitted to our hospital. On physical examination, multiple small purple maculopapular lesions were present on the body. In the laboratory findings HIV RNA was 255.000 copies, CD4:7 u/L. Tenofovir+ emtricitabine/dolutegravir was started for HIV treatment. Skin biopsy was found to be compatible with Kaposi's sarcoma. The patient's swab every other day was examined for COVID-PCR and remained positive for 63 days. Due to the necessity of oncological treatment, antiviral molnupiravir 2*800 mg treatment was started  for 5 days. COVID-PCR performed 4 days after molnupravir treatment and it was negative. We think that early initiation of antiviral treatment is important for PCR negativity and early access to oncological treatment especially in end-stage COVID-positive AIDS cases.