bluuebunny/crossref_metadata_2025 huggingface dataset:
Unravelling the complex pathogenesis of hidradenitis suppurativa
Authors: Frew John W
Published: February 2025

Hidradenitis suppurativa (HS) is a complex inflammatory disease, with rapid advances being made in our understanding of the complex immunological pathogenesis of the condition. New insights into the genomic landscape of HS have identified a number of genes that contribute to the development of HS in a polygenic manner, contributing to inflammatory dysregulation and alterations in epidermal stem cell fate in the follicular unit. These genomic variations can explain unique aspects of the disease such as the development and presence of epithelialized tunnels and abnormalities in wound healing. From genetic and translational studies, it is likely that these genetic alterations predispose to an innate immune dysregulation that can be triggered through sex hormone-responsive transcription factors with hormonal changes such as puberty, pregnancy and the menstrual cycle. The role of sex hormones in HS also has direct effects upon the development and maturation of inflammatory cells such as monocytes, which has the potential to explain differential patient response to treatments such as interleukin-23 antagonism. The role of adipose tissue as an active immunological organ also plays a role in the immune dysregulation seen in the disease. Fibrotic tissue and immunologically active fibroblasts play a significant role in the perpetuation of inflammation and development of adaptive immune dysfunction in the disease. The cutaneous and gut microbiomes play significant roles in the activation of innate immunity, although conflicting data exist as to their central or peripheral role in disease pathogenesis. Overall, our understanding of disease pathogenesis in HS is moving toward a more nuanced, complex paradigm in which patient heterogeneity in presentation and immunological characteristics are moving closer to the identification of therapeutic biomarkers to guide therapeutic modalities in the management of this burdensome condition.
2024 Anal Cancer Screening Guidelines: Analysis of Clinical Performance and Use of High-Resolution Anoscopy in a Large Cohort of Persons With Human Immunodeficiency Virus
Authors: Gaisa Michael , Deshmukh Ashish , Sigel Keith , Liu Yuxin
Published: February 2025

Recently published anal cancer screening guidelines recommend 5 strategies for high-risk populations using combinations of cytology and high-risk human papillomavirus testing. Based on data from 1223 persons with human immunodeficiency virus, all triage and cotesting strategies outperformed cytology alone. High-risk human papillomavirus testing improved specificity and reduced high-resolution anoscopy referrals, essential for guideline implementation.
The first comparative analysis of open and robotic tracheobronchoplasty for excessive Central airway collapse
Authors: Cho Jae M , Carpenter Sandra L , Mathew Fleming , Heidel Justin S , Kent Michael , Gangadharan Sidhu P , Wilson Jennifer L
Published: February 2025

OBJECTIVES

Tracheobronchoplasty is an operation to treat excessive central airway collapse by stabilizing the posterior tracheal membrane. In 2020, our institution transitioned from the traditional open approach to the robotic-assisted tracheobronchoplasty in select patients. This retrospective cohort study compares postoperative complications and short-term outcomes for patients undergoing open versus robotic tracheobronchoplasty at a high-volume complex airway center.

METHODS

A retrospective review of all patients who underwent open tracheobronchoplasty (2018–2020) and robotic tracheobronchoplasty (2020–2023) was conducted.

RESULTS

During the study period, 43 and 69 patients underwent robotic and open tracheobronchoplasty, respectively. Robotic tracheobronchoplasty had longer median operative times than open (8.4 vs 6.2 hours; p = <0.01). Both median ICU length of stay (1.0 vs 3.0 days, p = <0.01) and hospital length of stay (5.0 vs 7.0 days, p = <0.01) were shorter after robotic tracheobronchoplasty. There were no significant differences in major or minor complications, total Clavien-Dindo Score, estimated blood loss, discharge to home, and 30-day readmission. The robotic group had two reoperations during the index hospitalization and three conversions to open. There were no mortalities in either group. Short-term (3-month) functional and quality of life outcomes were equivalent between groups.

CONCLUSIONS

In selected patients with severe and symptomatic excessive central airway collapse, robotic tracheobronchoplasty is a safe and feasible alternative to the traditional open approach. Patients undergoing robotic tracheobronchoplasty have shorter ICU and total hospital stays with equivalent complication rates. As the robotic approach becomes more prevalent, further comparative outcomes are necessary with longer follow-up to ensure durability of the robotic-assisted repair.
Association of menopausal hormone therapy with risk of cardiovascular disease in Korean women
Authors: Yuk Jin-Sung , Kim Gwang Sil , Kim Dong-Gil , Byun Young Sup , Kim Myoung-Hwan , Yoon Sang-Hee , Han Gwan Hee , Kim Byung Gyu
Published: February 2025

Objective

To evaluate the association between various regimens and combinations of menopausal hormone therapy (MHT) and the risk of cardiovascular disease (CVD) in clinical practice.

Design

This was a population-based cohort study.

Methods

This population-based cohort study used data from the Health Insurance Review and Assessment Service. The data of women who reported entering menopause at ≥40 years of age with no history of CVD in the national health examination between 2011 and 2014 were extracted. A total of 134 298 pairs were included in the MHT and non-MHT groups after 1:1 propensity score matching. The participants were followed until December, 31, 2020.

Results

During a median follow-up of 7.9 (IQR 6.9-8.9) years, the incidences of CVD were 146 per 100 000 person/year and 179 per 100 000 person/year for the non-MHT and MHT groups, respectively. After adjusting for covariates, MHT use was associated with an increased CVD risk (hazard ratio [HR], 1.22 [1.14-1.31]) compared with the non-MHT group; the risk was based on an increased risk of stroke and coronary artery revascularization. Tibolone (HR, 1.38, [1.27-1.50]) was associated with increased CVD, but estrogen alone or combined estrogen/progestogen was not. There was no difference in CVD risk, regardless of the type of estrogen agent used. For combined estrogen/progestogen therapy, dydrogesterone was associated with reduced CVD risk.

Conclusions

There was an increased risk of CVD in MHT users. By regimen, tibolone use was associated with increased risk of CVD, whereas estrogen either alone or in combination with progestogen was not. There was no difference according to the type of estrogen. The type of progestogen seems to modify the results, since dydrogesterone was associated with reduced CVD risk.
The role of systemic inflammation in remnant cholesterol-associated cardiovascular risk: insights from the EPIC-Norfolk study
Authors: Kraaijenhof Jordan M , Kerkvliet Marije J , Nurmohamed Nick S , Grefhorst Aldo , Kroon Jeffrey , Wareham Nicholas J , Hovingh G Kees , Stroes Erik S G , Boekholdt S Matthijs , Reeskamp Laurens F
Published: February 2025

Aims

Both plasma levels of remnant cholesterol and low-density lipoprotein (LDL) cholesterol levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. In this study, we aimed to assess the extent to which inflammation mediates the effect of remnant and LDL cholesterol on (non)fatal major adverse cardiovascular events (MACE), comprising of coronary artery disease and ischaemic stroke.

Methods and results

This prospective study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk study, with a mean age of 58.8 ± 9.1 years, of which 9,357 (56.9%) were women. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher high-sensitivity C-reactive protein (hsCRP) levels [95% Confidence Interval (CI): 22.1, 37.4, P < 0.001], whereas LDL cholesterol was not significantly associated with hsCRP levels in the fully adjusted model. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a hazard ratio (HR) of 1.31 (95% CI: 1.14, 1.50, P < 0.001) for MACE, compared with an HR of 1.21 (95% CI: 1.13, 1.31, P < 0.001) for LDL cholesterol. Mediation analysis showed that hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, P < 0.001) of the effect of remnant cholesterol on MACE, whereas hsCRP did not mediate the effect of LDL cholesterol.

Conclusion

Plasma remnant cholesterol levels are independently associated with systemic inflammation and cardiovascular events. Inflammation, as measured with hsCRP, contributed minorly to the association between remnant cholesterol and MACE. This underscores the need to address both remnant cholesterol and systemic inflammation separately in the clinical management of cardiovascular disease.

Lay summary

This study finds that systemic inflammation does not influence the effect remnant cholesterol has on cardiovascular disease risk, suggesting the importance of addressing both remnant cholesterol and inflammation to manage cardiovascular health.
Towards a widely applicable earthquake detection algorithm for fibreoptic and hybrid fibreoptic-seismometer networks
Authors: Hudson T S , Klaasen S , Fontaine O , Bacon C A , Jónsdóttir K , Fichtner A
Published: February 2025

Distributed acoustic sensing (DAS) is a promising technology for providing dense (metre-scale) sampling of the seismic wavefield. However, harnessing this potential for earthquake detection with accurate phase picking and associated localization remains challenging. Single-channel algorithms are limited by individual channel noise, while machine learning and semblance methods are typically imited to specific geological settings, have no physically constrained phase association and/or require specific fibre geometries. Here, we present a method that seeks to detect seismicity for any geological setting, applicable for any fibre geometry, and combining both fibreoptic and conventional seismometer data to maximize the information used for detection and source localization. This method adapts a proven back-migration detection method to also include DAS observations, migrating energy from many receivers back in time to search for localized peaks in energy, corresponding to seismic sources. The strengths of this method are capitalizing on coherency over many channels to enhance detection sensitivity even in high-noise environments compared to single-channel algorithms, applicability to arbitrary fibre geometries, as well as built-in, physics-informed phase association and source localization. We explore the performance of the method using three geologically and geometrically diverse settings: a glacier, a volcanic eruption and a geothermal borehole. Our results evidence the effect of spatial-sampling extent and non-optimal fibreoptic geometries, accounting for P- and S-wave sensitivity, coupling effects and how the sensitivity of native fibreoptic strain measurements to shallow subsurface heterogeneities can affect detection. Finally, we attempt to also present a method-ambivalent overview of key challenges facing fibreoptic earthquake detection and possible avenues of future work to address them.
Artificial intelligence in global health: An unfair future for health in Sub-Saharan Africa?
Authors: Victor Audêncio
Published: February 2025

Artificial intelligence (AI) holds transformative potential for global health, particularly in underdeveloped regions like Africa. However, the integration of AI into healthcare systems raises significant concerns regarding equity and fairness. This debate paper explores the challenges and risks associated with implementing AI in healthcare in Africa, focusing on the lack of infrastructure, data quality issues, and inadequate governance frameworks. It also explores the geopolitical and economic dynamics that exacerbate these disparities, including the impact of global competition and weakened international institutions. While highlighting the risks, the paper acknowledges the potential benefits of AI, including improved healthcare access, standardization of care, and enhanced health communication. To ensure equitable outcomes, it advocates for targeted policy measures, including infrastructure investment, capacity building, regulatory frameworks, and international collaboration. This comprehensive approach is essential to mitigate risks, harness the benefits of AI, and promote social justice in global health.
Decomposing the genetic background of chronic back pain
Authors: Elgaeva Elizaveta E , Zorkoltseva Irina V , Nostaeva Arina V , Verzun Dmitrii A , Tiys Evgeny S , Timoshchuk Anna N , Kirichenko Anatoliy V , Svishcheva Gulnara R , Freidin Maxim B , Williams Frances M K , Suri Pradeep , Aulchenko Yurii S , Axenovich Tatiana I , Tsepilov Yakov A
Published: February 2025

Chronic back pain (CBP) is a disabling condition with a lifetime prevalence of 40% and a substantial socioeconomic burden. Because of the high heterogeneity of CBP, subphenotyping may help to improve prediction and support personalized treatment of CBP. To investigate CBP subphenotypes, we decomposed its genetic background into a shared one common to other chronic pain conditions (back, neck, hip, knee, stomach, and head pain) and unshared genetic background specific to CBP. We identified and replicated 18 genes with shared impact across different chronic pain conditions and two genes that were specific for CBP. Among people with CBP, we demonstrated that polygenic risk scores accounting for the shared and unshared genetic backgrounds of CBP may underpin different CBP subphenotypes. These subphenotypes are characterized by varying genetic predisposition to diverse medical conditions and interventions such as diabetes mellitus, myocardial infarction, diagnostic endoscopic procedures, and surgery involving muscles, bones, and joints.
Systemic therapy for hepatocellular carcinoma, from the early to the advanced stage: a Japanese perspective
Authors: Ikeda Masafumi , Morizane Chigusa , Ueno Makoto , Okusaka Takuji , Ishii Hiroshi , Furuse Junji
Published: February 2025

Systemic therapy has now become mainstream for the treatment of hepatocellular carcinoma (HCC) and is also changing from molecular-targeted therapy, such as with sorafenib and lenvatinib, to immunotherapy, such as with the atezolizumab plus bevacizumab and durvalumab plus tremelimumab combination regimens. Molecular-targeted therapy is selected as the first-line treatment when immunotherapy is not indicated or as second- or later-line treatment when immunotherapy is ineffective. It is necessary to select the appropriate treatment taking into consideration the expected treatment efficacy and adverse events, as well as the hepatic reserve. Currently, newer agents and combination regimens as first-line/second-line treatment for advanced-stage HCC, combined therapy with transarterial chemoembolization for intermediate-stage HCC, and perioperative adjuvant therapy for curative treatment for early-stage HCC are being developed. Therefore, systemic therapy is now indicated for any stage of the disease. While local therapies were previously used as the main treatment strategy for HCC, systemic therapy in combination with local therapies is being actively attempted at present. Systemic therapy is currently the main focus of development of novel treatments for HCC.
Testosterone replacement therapy in men on active surveillance for prostate cancer
Authors: Applewhite James , McCarter Jacob , Saffati Gal , Kronstedt Shane , Hinojosa-Gonzalez David , La Troy , Diejomaoh Rioke M , Lipshultz Larry I , Khera Mohit
Published: February 2025

Background

While the use of testosterone replacement therapy (TRT) in men undergoing active surveillance (AS) for prostate cancer (PCa) has been historically contraindicated, recent studies have contributed to a paradigm shift to this approach.

Aim

To examine the impact of testosterone on prostate-specific antigen (PSA) levels and prostate biopsy progression in men with low testosterone on AS for PCa.

Methods

A retrospective single-center analysis was conducted on men undergoing AS for PCa who subsequently underwent TRT. Men previously treated for PCa were excluded. PSA and testosterone levels were recorded at regular intervals one year before and after the initiation of testosterone. ANOVA was used to analyze variance in PSA and testosterone levels, and paired t-tests and linear regression analysis were performed. Baseline and surveillance biopsies were documented.

Outcomes

The primary outcomes were changes in PSA levels and biopsy progression following initiation of testosterone therapy.

Results

Forty-three men met the inclusion criteria. Median (IQR) testosterone level before testosterone therapy was 272 (221.5–333.5) ng/dL and 578.5 (354.5–846.5) ng/dL after therapy (P < 0.01). No significant variation in mean PSA levels was observed (P = 0.87). Baseline biopsies were available for 27 patients, showing Gleason 3 + 3 = 6 in no more than three cores. Fifteen (55.6%) patients had one or more surveillance biopsies after starting testosterone therapy. Of these, 12 (80.0%) had no disease progression in biopsies over a mean of 44.3 months on testosterone. Three patients (20.0%) had a Gleason score 7 on biopsy after a mean of 79.5 months on testosterone therapy. No patients developed metastatic disease.

Clinical Implications

Testosterone therapy did not result in statistically significant changes in PSA levels in men with low testosterone on AS. Pathology changes were inconclusive, but the available data showed no apparent increase in PCa progression or disease worsening in the cohort.

Strengths and Limitations

The study’s strengths include a longitudinal follow-up design and use of multiple statistical analyses. Limitations include the retrospective design, small sample size which may limit generalizability, and lack of control group.

Conclusion

No significant change in PSA level was observed after initiating testosterone therapy, despite an increase in testosterone levels. Despite limited biopsy data, our findings suggest similar rates of disease progression compared to the general AS population.
Weakest link, prioritized default logic and principles in argumentation
Authors: Pardo Pere , Yu Liuwen , Chen Chen , van der Torre Leendert
Published: February 2025

In this article, we study procedural and declarative logics for defaults in modular orders. Brewka’s prioritized default logic (PDL) and structured argumentation based on weakest link are compared to each other in different variants. This comparison takes place within the framework of attack relation assignments and the axioms (principles) recently proposed for them by Dung. To this end, we study which principles are satisfied by weakest link and disjoint weakest link attacks. With the aim of approximating PDL using argumentation, we identify an attack defined from PDL extensions, prove that each such PDL extension is a stable belief set under it and offer a similar principle-based analysis. We also prove an impossibility theorem for Dung’s axioms that covers PDL-inspired attack relation assignments. Finally, a novel variant of PDL with concurrent selection of defaults is also proposed, and compared to these argumentative approaches. In sum, our contributions fill an important gap in the literature created by Dung’s recent methods and open up new research questions on these methods.
BOWIE-ALIGN: JWST reveals hints of planetesimal accretion and complex sulphur chemistry in the atmosphere of the misaligned hot Jupiter WASP-15b
Authors: Kirk James , Ahrer Eva-Maria , Claringbold Alastair B , Zamyatina Maria , Fisher Chloe , McCormack Mason , Panwar Vatsal , Powell Diana , Taylor Jake , Thorngren Daniel P , Christie Duncan A , Esparza-Borges Emma , Tsai Shang-Min , Alderson Lili , Booth Richard A , Fairman Charlotte , López-Morales Mercedes , Mayne N J , Meech Annabella , Mollière Paul , Owen James E , Penzlin Anna B T , Sergeev Denis E , Valentine Daniel , Wakeford Hannah R , Wheatley Peter J
Published: February 2025

We present a transmission spectrum of the misaligned hot Jupiter WASP-15b from 2.8–5.2 microns observed with JWST’s NIRSpec/G395H grating. Our high signal-to-noise data, which has negligible red noise, reveals significant absorption by H$_2$O ($4.2\sigma$) and CO$_2$ ($8.9\sigma$). From independent data reduction and atmospheric retrieval approaches, we infer that WASP-15b’s atmospheric metallicity is supersolar ($\gtrsim 15\times$ solar) and its carbon-to-oxygen ratio is consistent with solar, that together imply planetesimal accretion. Our general circulation model simulations for WASP-15b suggest that the carbon-to-oxygen ratio we measure at the limb is likely representative of the entire photosphere due to the mostly uniform spatial distribution of ${\text{H}}_{2}{\text{O}}$, ${\text{CO}}_{2}$, and CO. We additionally see evidence for absorption by SO$_2$ and absorption at 4.9 $\mu$m, for which the current leading candidate is OCS (carbonyl sulphide), albeit with several caveats. If confirmed, this would be the first detection of OCS in an exoplanet atmosphere and point towards complex photochemistry of sulphur-bearing species in the upper atmosphere. These are the first observations from the BOWIE-ALIGN survey which is using JWST’s NIRSpec/G395H instrument to compare the atmospheric compositions of aligned/low-obliquity and misaligned/high-obliquity hot Jupiters around F stars above the Kraft break. The goal of our survey is to determine whether the atmospheric composition differs across two populations of planets that have likely undergone different migration histories (disc versus disc-free) as evidenced by their obliquities (aligned versus misaligned).
A recent confirmation of the wide binary gravitational anomaly
Authors: Hernandez X , Kroupa Pavel
Published: February 2025

Concerning recent published studies exploring the presence or otherwise of a gravitational anomaly at low accelerations in wide binary stars as observed by the Gaia satellite, the paper published by Cookson on the subject last year presents an interesting case. In that study, RMS values of binned relative internal one-dimensional velocities for wide binaries are compared to Newtonian predictions for that quantity, with the author concluding that the data presented show no indication of any inconsistency with Newtonian expectations. However, the comparison presented is critically flawed, as the Newtonian predictions used refer to wide binaries with mean total masses of 2.0 $\mathrm{M}_{\odot }$. This is larger than the 1.56 $\mathrm{M}_{\odot }$ value which applies to the data used in said paper. In this short note, we correct the error mentioned above and show that the data and error bars as given by Cookson are in fact inconsistent with Newtonian expectations. Contrary to the assertion in that study, the data presented there actually show a clear anomaly in the low acceleration gravitational regime, with the overall slope of the velocity-separation scaling being inconsistent with Newtonian expectations at a 3.3$\sigma$ level. Based on the data presented in the paper by Cookson, wide binary systems show a clear Milgromian deviation from Newtonian dynamics.
What do we gain when tolerating loss? The information bottleneck wrings out recombination
Authors: Narechania Apurva , Bobo Dean , DeSalle Rob , Mathema Barun , Kreiswirth Barry , Planet Paul J
Published: February 2025

Most microbes have the capacity to acquire genetic material from their environment. Recombination of foreign DNA yields genomes that are, at least in part, incongruent with the vertical history of their species. Dominant approaches for detecting these transfers are phylogenetic, requiring a painstaking series of analyses including alignment and tree reconstruction. But these methods do not scale. Here we propose an unsupervised, alignment-free and tree-free technique based on the sequential information bottleneck (SIB), an optimization procedure designed to extract some portion of relevant information from one random variable conditioned on another. In our case, this joint probability distribution tabulates occurrence counts of k-mers against their genomes of origin with the expectation that recombination will create a strong signal that unifies certain sets of co-occuring k-mers. We conceptualize the technique as a rate-distortion problem, measuring distortion in the relevance information as k-mers are compressed into clusters based on their co-occurrence in the source genomes. The result is fast, model-free, lossy compression of k-mers into learned groups of shared genome sequence, differentiating recombined elements from the vertically inherited core. We show that the technique yields a new recombination measure based purely on information, divorced from any biases and limitations inherent to alignment and phylogeny.
Genomic Signatures of Adaptation to Stress Reveal Shared Evolutionary Trends Between Tetrahymena utriculariae and Its Algal Endosymbiont, Micractinium tetrahymenae
Authors: Kelly Joseph B , Carlson David E , Reuter Manuela , Sommershof Annette , Adamec Lubomír , Becks Lutz
Published: February 2025

The evolution of intracellular endosymbiosis marks a major transition in the biology of the host and endosymbiont. Yet, how adaptation manifests in the genomes of the participants remains relatively understudied. We investigated this question by sequencing the genomes of Tetrahymena utriculariae, a commensal of the aquatic carnivorous bladderwort Utricularia reflexa, and its intracellular algae, Micractinium tetrahymenae. We discovered an expansion in copy number and negative selection in a TLD domain-bearing gene family in the genome of T. utriculariae, identifying it as a candidate for being an adaptive response to oxidative stress resulting from the physiology of its endosymbionts. We found that the M. tetrahymenae genome is larger than those of other Micractinium and Chlorella and contains a greater number of rapidly expanding orthogroups. These were enriched for Gene Ontology terms relevant to the regulation of intracellular signal transduction and cellular responses to stress and stimulus. Single-exon tandem repeats were overrepresented in paralogs belonging to these rapidly expanding orthogroups, which implicates long terminal repeat retrotransposons (LTRs) as potential agents of adaptation. We additionally performed a comparative transcriptomic analysis of M. tetrahymenae in a free-living state and in endosymbiosis with T. utriculariae and discovered that the genes that are differentially expressed were enriched for pathways that evidence shifts in energy generation and storage and in cellular protection strategies. Together, our results elucidate the axes along which the participants must adapt in this young endosymbiosis and highlight evolutionary responses to stress as a shared trend.
mRNA-LM: full-length integrated SLM for mRNA analysis
Authors: Li Sizhen , Noroozizadeh Shahriar , Moayedpour Saeed , Kogler-Anele Lorenzo , Xue Zexin , Zheng Dinghai , Montoya Fernando Ulloa , Agarwal Vikram , Bar-Joseph Ziv , Jager Sven
Published: February 2025

The success of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) messenger RNA (mRNA) vaccine has led to increased interest in the design and use of mRNA for vaccines and therapeutics. Still, selecting the most appropriate mRNA sequence for a protein remains a challenge. Several recent studies have shown that the specific mRNA sequence can have a significant impact on the translation efficiency, half-life, degradation rates, and other issues that play a major role in determining vaccine efficiency. To enable the selection of the most appropriate sequence, we developed mRNA-LM, an integrated small language model for modeling the entire mRNA sequence. mRNA-LM uses the contrastive language–image pretraining integration technology to combine three separate language models for the different mRNA segments. We trained mRNA-LM on millions of diverse mRNA sequences from several different species. The unsupervised model was able to learn meaningful biology related to evolution and host–pathogen interactions. Fine-tuning of mRNA-LM allowed us to use it in several mRNA property prediction tasks. As we show, using the full-length integrated model led to accurate predictions, improving on prior methods proposed for this task.
The membrane-targeting-sequence motif is required for exhibition of recessive resurrection in Escherichia coli RNase E
Authors: Basak Papri , Ekka Manjula , Pandiyan Apuratha , Tandon Smriti , Gowrishankar Jayaraman
Published: February 2025

The essential homotetrameric endoribonuclease RNase E of Escherichia coli participates in global RNA turnover as well as stable RNA maturation. The protomer’s N-terminal half (residues 1–529) bears the catalytic, allosteric, and tetramerization domains, including the active site residues D303 and D346. The C-terminal half (CTH, residues 530–1061) is dispensable for viability. We have previously described a phenomenon of recessive resurrection in RNase E that requires the CTH, wherein the wild-type homotetramer apparently displays nearly identical activity in vivo as a heterotetramer comprising three catalytically dead subunits (with D303A or D346A substitutions) and one wild-type subunit. Here, we show that recessive resurrection is exhibited even in dimeric RNase E with the CTH, and that it is largely dependent on the presence of a membrane-targeting-sequence motif (residues 565–582). A single F575E substitution also impaired recessive resurrection, whereas other CTH motifs (such as those for binding of RNA or of partner proteins) were dispensable. The phenomenon was independent of RNA 5′-monophosphate sensing by the enzyme. We propose that membrane-anchoring of RNase E renders it processive for endoribonucleolytic action, and that recessive resurrection and dominant negativity associated with mutant protomers are mutually exclusive manifestations of, respectively, processive and distributive catalytic mechanisms in a homo-oligomeric enzyme.
Structural and mechanistic insights into the activation of a short prokaryotic argonaute system from archaeon Sulfolobus islandicus
Authors: Dai Zhikang , Chen Yu , Guan Zeyuan , Chen Xueting , Tan Keyi , Yang Kaiyue , Yan Xuhui , Liu Yidong , Gong Zhou , Han Wenyuan , Zou Tingting
Published: February 2025

Prokaryotic Argonaute proteins (pAgos) defend the host against invading nucleic acids, including plasmids and viruses. Short pAgo systems confer immunity by inducing cell death upon detecting invading nucleic acids. However, the activation mechanism of the SiAgo system, comprising a short pAgo from the archaeon Sulfolobus islandicus and its associated proteins SiAga1 and SiAga2, remains largely unknown. Here, we determined the cryo-electron microscopy structures of the SiAgo–Aga1 apo complex and the RNA–DNA-bound SiAgo–Aga1 complex at resolutions of 2.7 and 3.0 Å, respectively. Our results revealed that a positively charged pocket is generated from the interaction between SiAgo and SiAga1, exhibiting an architecture similar to APAZ-pAgo of short pAgo systems and accommodating the nucleic acids. Further investigation elucidated the conserved mechanism of nucleic acid recognition by SiAgo–Aga1. Both the SiAgo–Aga1 interaction and nucleic acid recognition by the complex are essential for antiviral defense. Biochemical and structural analyses demonstrated that SiAgo–Aga1 undergoes extensive conformational changes upon binding to the RNA–DNA duplex, thereby licensing its interaction with the effector SiAga2 to trigger the immune response. Overall, our findings highlight the evolutionary conservation of Agos across phylogenetic clades and provide structural insights into the activation mechanism of the SiAgo system.
Screening for brain metastases in patients with advanced non-small cell lung cancer and an actionable genomic alteration: a structured literature review
Authors: Huijs Jarno W J , Bortolot Martina , Berghoff Anna S , Brastianos Priscilla K , Degens Juliette H R J , De Ruysscher Dirk K M , Compter Annette , Hendriks Lizza E L
Published: February 2025

Background

Brain metastases (BM) frequently occur in patients with non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGA). Targeted therapies (TTs) improve outcomes, but differences in BM screening and eligibility criteria across trials make comparisons challenging. While stage IV NSCLC guidelines recommend BM screening, it is not mandatory, and imaging techniques vary.

Methods

Registrational and phase II/III trials of FDA/EMA-approved TTs for advanced NSCLC with AGA, published since 2012, were included. Main focus of the review was evaluation of baseline brain screening practices across trials. Information on BM follow-up, BM incidence, and BM-related outcomes was retrieved.

Results

Of 51 trials, 71% mandated baseline BM screening, and 27% mandated follow-up imaging for all patients. MRI was specified for BM assessment in 31% of the trials. BM incidence at baseline was high, up to 40% in the first-line setting. While most trials included patients with BM, eligibility criteria varied, and 43% of trials pre-specified BM-related outcomes; 56% of phase III trials used BM as a stratification factor.

Conclusion

This review highlights the increasing attention to BM screening in NSCLC TT trials. However, substantial heterogeneity remains in BM eligibility, screening, outcomes, and follow-up. Standardizing these aspects in future trials is essential.
Oseltamivir Reduces 30-Day Mortality in Older Adults With Influenza: A Pooled Analysis From the 2012–2019 Serious Outcomes Surveillance Network of the Canadian Immunization Research Network
Authors: Pott Henrique , Andrew Melissa K , Shaffelburg Zachary , Nichols Michaela K , Ye Lingyun , ElSherif May , Hatchette Todd F , LeBlanc Jason J , Ambrose Ardith , Boivin Guy , Bowie William , Johnstone Jennie , Katz Kevin , Lagacé-Wiens Phillipe , Loeb Mark , McCarthy Anne , McGeer Allison , Poirier Andre , Powis Jeff , Richardson David , Semret Makeda , Smith Stephanie , Smyth Daniel , Stiver Grant , Trottier Sylvie , Valiquette Louis , Webster Duncan , McNeil Shelly A
Published: February 2025

Background

Oseltamivir is recommended for the treatment of adults hospitalized with influenza, but adherence is often suboptimal. This may be due to doubts about the reliability of the evidence supporting its benefits, particularly when initiation is delayed. We aimed to assess the effectiveness of oseltamivir in reducing mortality in older adults hospitalized with influenza, with a focus on the timing of initiation.

Methods

The CIRN-SOS Network gathered data on severe respiratory illnesses across 5 Canadian provinces during the influenza seasons 2012–2019. Individuals aged ≥65 years with confirmed influenza and available antiviral prescription data were included. We compared the 30-day survival rates of hospitalized patients based on oseltamivir prescription status. Kaplan-Meier estimated survival probability and inverse probability of treatment (IPT)–weighted Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. The analyses considered the time to antiviral initiation (>48 vs ≤48 hours).

Results

Among the 8135 influenza patients studied, 2126 did not receive antiviral treatment, whereas 6009 were treated with oseltamivir. A total of 395 patients were hospitalized for >30 days. The overall mortality rate was 8.32 per 1000 person-days, with 53.9% of the deaths occurring within the first week. Oseltamivir recipients had a 18% lower risk of 30-day mortality (IPT-weighted HR, 0.82 [95% CI, .69–.98]). The benefit was significant for influenza A (IPT-weighted HR, 0.74 [95% CI, .61–.91]) but not for influenza B (IPT-weighted HR, 1.12 [95% CI, .81–1.56]). Oseltamivir remained effective even when initiated after 48 hours (IPT-weighted HR, 0.66 [95% CI, .49–.90]). Influenza vaccination did not mediate the effectiveness of oseltamivir in reducing mortality.

Conclusions

Oseltamivir significantly reduces mortality risk in older adults hospitalized with influenza, even when administered after 48 hours, independent of vaccination status.

Clinical Trials Registration. NCT01517191.
Can Pollution Markets Work in Developing Countries? Experimental Evidence from India
Authors: Greenstone Michael , Pande Rohini , Ryan Nicholas , Sudarshan Anant
Published: February 2025

Market-based environmental regulations are seldom used in low-income countries, where pollution is highest but state capacity is often low. We collaborated with the Gujarat Pollution Control Board (GPCB) to design and experimentally evaluate the world’s first particulate matter emissions market, which covered industrial plants in a large Indian city. There are three main findings. First, the market functioned well. Treatment plants, randomly assigned to the emissions market, traded permits to become significant net sellers or buyers. After trading, treatment plants held enough permits to cover their emissions 99% of the time, compared to just 66% compliance with standards under the command-and-control status quo. Second, treatment plants reduced pollution emissions, relative to control plants, by 20% to 30%. Third, the market reduced abatement costs by an estimated 11%, holding constant emissions. This cost-savings estimate is based on plant-specific marginal cost curves that we estimate from the universe of bids to buy and sell permits in the market. The combination of pollution reductions and low costs imply that the emissions market has mortality benefits that exceed its costs by at least twenty-five times.
Teledidactic peer-tutored musculoskeletal ultrasound training for medical students—the TELMUS study
Authors: Neubauer Ricarda , Recker Florian , Bauer Claus-Juergen , Petzinna Simon , Karakostas Pantelis , Behning Charlotte , Schäfer Valentin Sebastian
Published: February 2025

Objectives

Despite growing interest in musculoskeletal ultrasound (MSUS), training opportunities are often limited due to staff shortages and disbalances of expertise between rural and urban areas. Teledidactic approaches have the potential to expand access to training opportunities. This study aims to compare the effectiveness of teledidactic peer-tutored MSUS training to a conventional approach.

Methods

A teledidactic course was held by a student tutor following a validated MSUS curriculum. An on-campus MSUS training taught by physician lecturers served as a control. Students were randomly assigned to one of both study groups. Objective structured clinical examinations (OSCE) were conducted before and after the training to objectively measure the learning outcome of the participants. Handheld ultrasound devices (ButterflyIQ®) and iPads (Apple Inc., eighth generation) were provided to the students for the MSUS course.

Results

Thirty medical students participated in the study. Prior to the course, baseline OSCE scores were recorded as 13.03/63 (SD ± 4.20) for the on-campus cohort and 13.00/63 (SD ± 6.04) for the teledidactic group. In the post-training OSCE evaluation, the on-campus cohort attained an average score of 56.80/63 (SD ± 4.22), while the TELMUS group averagely achieved 58.53/63 points (SD ± 3.52). While all students’ skills increased over time, there was no significant difference between the two cohorts either before or after the course.

Conclusion

Peer-tutored, teledidactic MSUS training showed to be non-inferior to the conventional approach and is a promising approach to reduce local and global disparities in educational opportunities regarding MSUS.
Association between large vessel vasculitis and inflammatory bowel disease: a case-control study
Authors: Maillet François , Nguyen Yann , Espitia Olivier , Perard Laurent , Salvarani Carlo , Rivière Etienne , Ndiaye Dieynaba , Durel Cécile-Audrey , Guilpain Philippe , Mouthon Luc , Kernder Anna , Loricera Javier , Cohen Pascal , Melki Isabelle , de Moreuil Claire , Limal Nicolas , Mékinian Arsène , Costedoat-Chalumeau Nathalie , Morel Nathalie , Boutemy Jonathan , Raffray Loïc , Allain Jean-Sébastien , Devauchelle Valérie , Kone-Paut Isabelle , Fabre Marc , Durel Marie , Dossier Antoine , Abad Sébastien , Visentini Marcella , Bigot Adrien , Yildiz Halil , Fain Olivier , Samson Maxime , Gondran Guillaume , Abitbol Vered , Terrier Benjamin
Published: February 2025

Objectives

To describe the characteristics and outcome of patients with the association of large vessel vasculitis (LVV, Takayasu arteritis [TA] or GCA) and IBD.

Methods

An observational, multicentre, retrospective case-control study. Cases were LVV-IBD patients from European countries, whereas controls had isolated LVV (iLVV).

Results

A total of 39 TA-IBD and 12 GCA-IBD cases were enrolled, compared with 52 isolated GCA (iGCA) and 93 isolated TA (iTA) controls. LVV occurred after IBD in 56% in TA-IBD and 75% in GCA-IBD, with a median interval of 1 year (interquartile range [IQR] 1–7) in TA-IBD and 8.6 years (IQR 1–17.7) in GCA-IBD. Crohn’s disease was more common in TA-IBD (67%), whereas ulcerative colitis was more common in GCA-IBD (58%). Compared with iTA, TA-IBD were significantly younger at diagnosis of TA (median age 27 vs 37 years, P < 0.001) and had more upper limb claudication (36% vs 12%, P = 0.006). GCA-IBD patients had more frequent arterial thickening or stenosis than controls (75% vs 30%, respectively, P = 0.044) and tended to more frequently involve gastrointestinal arteries (20% vs 0%, respectively, P = 0.06). LVV occurred in IBD patients despite treatment with glucocorticoids (36%), azathioprine (25%) or TNF-alpha blockers (29%). The presence of the IBD was not associated with a higher LVV relapse rate in multivariate analysis (adjusted hazard ratio [aHR] 0.62 [0.13–2.83] for GCA and aHR 0.92 [0.44–1.89] for TA).

Conclusion

This study identifies specific clinical and imaging characteristics of LVV-IBD patients, in particular a more severe vascular presentation of GCA-IBD patients compared with iGCA patients.
Generational variations in wellbeing: suicide rates, cohort characteristics, and national socio-political context over seven decades
Authors: Stockard Jean
Published: February 2025

Over recent decades, the relative wellbeing of younger birth cohorts declined in many western countries, indicating growing generational inequality. Building on Durkheimian theory, this paper examines explanations for these changes, hypothesizing that differences in cohort wellbeing are related to variations in social integration associated with birth cohorts and national socio-political contexts. Age–period-specific suicide rates of men and women from 1950 to 2020 in 19 highly developed western nations, including 26 birth cohorts, born from 1875 to 2004, are examined using estimable function analysis and age–period–cohort characteristic (APCC) models. Cohort variations in wellbeing are significantly greater in English-speaking nations, which have traditionally provided less institutionalized support and social integration than continental European nations. Age-specific suicide rates are larger for cohorts with childhood demographic characteristics associated with less social integration (relative cohort size and family structure). Major historical events associated with social integration in formative years of late adolescence and young adulthood also influence cohort wellbeing, with higher age-specific rates for cohorts experiencing the Great Depression of the 1930s and health pandemics of the early 20th and 21st centuries and lower rates for those experiencing periods of war and national conflict. However, the magnitude of these associations is strongly influenced by socio-political context. Negative effects of cohort characteristics are muted and positive effects are enhanced in the continental nations. In addition, patterns of associations vary by age and gender. Results remain with strong controls for the pace of change, additional measures of national context, and sensitivity analyses.
New branch on the tree of life of Gastrotricha: establishment of a new genus for limno-terrestrial species
Authors: Minowa Axell Kou , Kieneke Alexander , Campos Ariane , Balsamo Maria , Plewka Michael , Guidi Loretta , Araújo Thiago Quintão , Garraffoni André RinaldoSenna
Published: February 2025

Gastrotricha encompass a diversity of free-living micrometazoans typically associated with aquatic or semi-aquatic environments. The discovery of a gastrotrich species in limno-terrestrial habitats challenges existing taxonomic classifications and expands our understanding of their ecological diversity. This study describes Dendroichthydium ibyrapora gen. et sp. nov., a new gastrotrich from epiphytic mosses found in Atlantic rainforest within Serra do Japi biological reserve, and establishes its taxonomic status through morphological and molecular analyses. Morphological characterization was conducted using light microscopy, scanning electron microscopy, and confocal laser scanning microscopy, revealing that D. ibyrapora exhibits distinctive adaptations suited to limno-terrestrial environments, including unique cuticular adaptations and rearrangement of locomotory cilia. Molecular phylogenetics, using 18S and 28S ribosomal DNA sequences, supports the recognition of Dendroichthydium as a new genus, distinctly separated from known genera within Paucitubulatina. Furthermore, we propose reclassifying Chaetonotus (Chaetonotus) silvaticus to Dendroichthydium silvaticus comb. nov. based on shared morphological traits. The establishment of the genus Dendroichthydium reflects the ongoing need to re-evaluate gastrotrich diversity and taxonomy, highlighting the role of underexplored limno-terrestrial habitats in hosting unique life forms. This study underscores the importance of integrating morphology and genetics to improve our understanding of phylogenetics and the evolutionary dynamics of Gastrotricha.
Quantitative Analysis of Relationship between Paraspinal Muscle Degeneration and Degree of Degenerative Lumbar Spondylolisthesis
Authors: Da Weiwei , Jian Qiang , Evan Joiner , Chan Andrew K. , McCormick Paul C. , Mandigo Christopher E. , Neira Justin Anthony , Angevine Peter D. , Li Xiaofeng , Chou Dean
Published: February 2025

Study Design.

Clinical retrospective study.

Objective.

The authors aim to analyze the relationship between paraspinal muscle degeneration and degree of L4-5 Degenerative lumbar spondylolisthesis (DLS).

Summary of Background Data.

While paraspinal muscle degeneration is thought to contribute to spondylolisthesis severity, this relationship has yet to be fully characterized.

Methods.

A retrospective analysis was performed of all neurosurgical patients admitted to the Columbia Neurosurgery Spine Division for treatment of L4-5 DLS between January 2018 and March 2024. Preoperative lumbopelvic parameters and slip percentage (SP) were calculated from standing radiographs; paraspinal muscle volume (MV), fatty volume (FV) and fatty infiltration (FI) of posterior paraspinal muscle were derived from MRI images using 3D Slicer (Earth, TX). Correlation and multiple linear regression analyses were used to assess the relationship between SP and paraspinal MV, FV, FI, and spinopelvic parameters.

Results.

221 patients with average SP of 23.74±0.09% were included. The female patients had higher SP, lumbar lordosis (LL), pelvic incidence (PI) and lower IVA than the male patients. However, paraspinal MV was lower and FI was higher in the Meyerding Grade II and female groups compared to the Grade I and male groups (P<0.01). There was a positive correlation between SP and metrics of fat replacement (P<0.01) and a negative correlation between SP and metrics of paraspinal muscles volume (P<0.01) at the L4-5 level. A stepwise multivariate regression ultimately included MFI, IVA, and LL and accounted for 15.2% of the variance in SP.

Conclusion.

In this single center retrospective study, greater degree of spondylolisthesis was modestly associated with lower MV and increased FI of the lumbar paraspinal muscles, suggesting that paraspinal muscle degeneration may be one of several important factors in the development of spondylolisthesis.