bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of hormonal combined contraceptive in the onset of hidradenitis suppurativa: a retrospective cohort study
Authors: Molinelli Elisa , De Simoni Edoardo , Dragonetti Maria Luisa , Belleggia Sara , Maurizi Andrea , Gambini Daisy , Offidani Annamaria , Simonetti Oriana
Published: December 2024

Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disease characterized by recurrent painful nodules, abscesses and sinus tracts on the apocrine gland-bearing skin. The role of sex hormones in the pathogenesis as well as the use of hormonal treatment in the management of HS is still debated. We performed a retrospective cohort study, including 183 patients, to assess the influence of the combined oral contraceptive (oestrogen–progesterone COC) on HS onset and disease severity. Univariable and multivariable analyses highlighted that the patients undergoing COC therapy had a later onset of HS, more precisely 9.81 years after the patients who have not received COC, independently of body mass index, family history, smoking, acne, age of menarche and concomitant gynaecological disorders. This study suggests that COC use could influence the development and the progression of HS and supports the key role of sex hormones in the pathogenesis of the disease.
pH-sensitive liposomal curcumin with good biocompatibility for improving therapeutic efficacy by decreasing DNA methylation level in tumor cells
Authors: Wang Wanxue , Shao Mingzheng , Gong Changkai , Li Chengpeng , Yang Di , Liu Bingqian , Liu Yanqiong , Ma Haiou , Wang Zhenchao , Chen Danping
Published: December 2024

A new type of pH-sensitive liposome nanoparticles encapsulated with curcumin and doxorubicin was prepared and exhibited high specificity for tumor cells. The liposomal curcumin enables the endosome escape and decrease of the genomic methylation level and DNA methyltransferases expression in A549 and K562 cells for improving therapeutic efficacy.
Immunogenicity, Reactogenicity, and Safety of a Pentavalent Meningococcal ABCWY Vaccine in Adolescents and Young Adults Who Had Previously Received a Meningococcal ACWY Vaccine: A Phase 3, Randomized Controlled Clinical Study
Authors: Nolan Terry , Bhusal Chiranjiwi , Hoberman Alejandro , Llapur Conrado J , Voloshyna Olga , Fink Ezekiel , Gentile Angela , Wallace Garry , Richmond Peter C , Domachowske Joseph B , Mzolo Thembile , Lattanzi Maria , Toneatto Daniela ,   for the BOOST Study Group, Akinsola Adebayo , Ampajwala Madhavi , Arya Mark , Bartlett Andrew , Batra Divya , Bloch Mark Theo , Bordon Jose , Byars William , Carr Jeremy Peter James , Ceballos Ana , de Looze Ferdinandus , Deluca Mercedes , Domachowske Joseph , Farjo Rand , Fink Ezekiel , Gentile Angela , Gilsoul Jennifer , Gunner Elizabeth Anne , Gupta Anil K , Hoberman Alejandro , Hong Matthew , Kasarjian Julie , Llapur Conrado Juan , Mann Darvy , Marc Gonzalo Perez , Matherne Paul G , Mitchell Gretchen , Nolan Terry , Obed Mora Nair , OħMahony John , Richmond Peter , Riera Fernando Oscar , Rok Walter , Saravolatz Louis , Silas Peter , Soto Adriana Elvira , Sullivan Katherine , Surber Joseph , Teijeiro Ricardo Augusto , Tiong Florence , Voloshyna Olga , Wadia Ushma , Wallace Garry , Yut Clifford
Published: December 2024

Background

A MenABCWY vaccine containing 4CMenB and MenACWY-CRM vaccine components has been developed to protect against the 5 meningococcal serogroups that cause most invasive disease cases.

Methods

In this phase 3 study, healthy participants aged 15–25 years, who had received MenACWY vaccination ≥4 years previously, were randomized (1:1) to receive 2 MenABCWY doses 6 months apart or 1 MenACWY-CRM dose. Primary objectives were to demonstrate the noninferiority of MenABCWY 1 month postvaccination versus MenACWY-CRM, with a lower limit of 2-sided 95% confidence interval above −10% for group differences in 4-fold rise in human serum bactericidal antibody (hSBA) titers against serogroups ACWY, and to evaluate reactogenicity and safety. Secondary endpoints included percentages of participants with hSBA titers greater than or equal to the lower limit of quantitation (≥LLOQ) against serogroups ACWY and vaccine antigen-specific serogroup B (MenB) indicator strains.

Results

Noninferiority of MenABCWY versus MenACWY-CRM was demonstrated following each MenABCWY dose. Percentages of participants with hSBA titers ≥LLOQ for serogroups ACWY were 97.9%–98.9% and 99.5%–100% following 1 and 2 MenABCWY doses, respectively, and 96.8%–99.0% following 1 MenACWY-CRM dose. After 2 MenABCWY doses, 75.6%–96.3% of participants had hSBA titers ≥LLOQ against MenB indicator strains. The MenABCWY vaccine was well tolerated in MenACWY-primed individuals, with a favorable safety profile.

Conclusions

Immune responses against serogroups ACWY following 1 and 2 doses of investigational MenABCWY vaccine are noninferior to those following MenACWY-CRM in MenACWY-primed adolescents and young adults. Robust immune responses were observed against MenB indicator strains after 2 MenABCWY doses administered 6 months apart.

Clinical Trials Registration. NCT04707391.
Virologic Failure and Emergent Integrase Strand Transfer Inhibitor Drug Resistance With Long-Acting Cabotegravir for HIV Treatment: A Meta-analysis
Authors: Perez Navarro Andrea , Nutt Cameron T , Siedner Mark J , McCluskey Suzanne M , Hill Andrew
Published: December 2024

Background

The long-acting injectable regimen of cabotegravir plus rilpivirine (CAB/RPV) emerged as an alternative to oral standard-of-care integrase strand transfer inhibitor (INSTI)–based regimens for individuals with adherence challenges or preference for reduced dosing schedules. Although oral INSTI regimens have a high barrier to emergent resistance, less is known about the potency and durability of CAB/RPV.

Methods

We reviewed clinical trial registries, PubMed, EMBASE, and conference abstract databases to identify reports of CAB/RPV for HIV therapy. We abstracted data on virologic failure (VF) and treatment-emergent INSTI resistance at 48 weeks (range: 24–52). We used single-proportion meta-analysis to summarize outcomes in 3 populations: antiretroviral therapy (ART)–naive individuals initiating CAB/RPV following suppression on oral ART, ART-experienced individuals switched to CAB/RPV with virologic suppression, and ART-experienced individuals switched to CAB/RPV with detectable viremia. Cochrane's RoB 2.0 and ROBINS-1 tools assessed risk of bias.

Results

Thirty-three studies (N = 9224) reported VF prevalence. Nineteen studies (N = 5662) reported resistance data. VF prevalence was 1% (95% CI: 1%–3%) in induction-maintenance studies, 1% (1%–2%) in switch-suppressed studies, and 5% (3%–10%) in switch-viremic studies. INSTI resistance prevalence among successfully genotyped participants at failure was 71% (25%–95%), 61% (44%–75%), and 41% (20%–65%) respectively. Dolutegravir cross-resistance was common (64% of those with emergent resistance).

Conclusions

Although VF rates with CAB/RPV were low, INSTI resistance emerged in approximately 40%–70% of individuals experiencing VF. These rates are significantly higher than those for oral INSTI-based regimens. Both individual-level and broader resistance surveillance may be warranted in populations with expanding CAB/RPV use.

Clinical Trials Registration. PROSPERO registration CRD42024543919.
Atrial Fibrillation After Respiratory Syncytial Virus Vaccination Among Older Adults
Authors: Birabaharan Morgan , Johns Scott T , Kaelber David C , Martin Thomas C S , Mehta Sanjay R
Published: December 2024

Respiratory syncytial virus (RSV) vaccine clinical trials reported higher frequencies of atrial fibrillation in intervention compared with control groups. In this large, population-based, propensity-matched study, we found that RSV vaccine was not associated with increased risk of new-onset or recurrent atrial fibrillation within 1–42 days, compared with influenza or tetanus, diphtheria, and pertussis (Tdap) vaccines.
The Application of Digital PCR as a Reference Measurement Procedure to Support the Accuracy of Quality Assurance for Infectious Disease Molecular Diagnostic Testing
Authors: Falak Samreen , O’Sullivan Denise M , Cleveland Megan H , Cowen Simon , Busby Eloise J , Devonshire Alison S , Valiente Esmeralda , Jones Gerwyn M , Kammel Martin , Milavec Mojca , Vierbaum Laura , Schellenberg Ingo , Zeichhardt Heinz , Kummrow Andreas , Vallone Peter M , Macdonald Rainer , Huggett Jim F
Published: December 2024

Background

Nucleic acid amplification tests (NAATs) assist in the diagnosis of numerous infectious diseases. They are typically sensitive and specific and can be quickly developed and adapted. Far more challenging is the development of standards to ensure NAATs are performing within specification; reference materials take time to develop and suitable reference measurement procedures (RMPs) have not been available. This study investigated digital PCR (dPCR) RMP delivery of traceability for NAAT external quality assessment (EQA).

Methods

Three National Metrology Institutes (NMIs) applied reverse transcription (RT)-dPCR as a candidate RMP to estimate the RNA quantity in 32 independent severe acute respiratory syndrome coronavirus 2 materials. The results were combined to value assign the respective materials: 21 materials were used in 6 rounds of EQA over 17 months for 61 laboratories for COVID-19 testing results compared with reference values.

Results

The agreement between the 3 NMIs showed <2-fold difference between laboratories. EQA laboratory reverse transcription quantitative PCR (RT-qPCR) values estimation of viral RNA quantity showed good median agreement with RT-dPCR reference value; however, RT-qPCR differences were generally between 10- and 50-fold between laboratories.

Conclusion

This work demonstrates how RT-dPCR can provide reference values for whole virus materials for NAAT quality assurance. RT-dPCR values guided EQA control material selection and provided EQA participants with traceability to RNA copy number delivered through the RMP. This approach can be used to support routine reference material use as well as to standardize quality assurance for NAATs where established reference materials are not available, such as in disease outbreaks.
Remnant Cholesterol: Quantification, Concentrations by Sex and Age, and Risk of Ischemic Heart Disease
Authors: Balling Mie , Afzal Shoaib , Varbo Anette , Nordestgaard Børge G , Langsted Anne
Published: December 2024

Background

Observational and genetic causal studies have shown an association between high concentrations of remnant cholesterol and increased risk of ischemic heart disease. However, findings from randomized intervention trials that reduced plasma triglycerides, a surrogate marker of remnant cholesterol, have been conflicting. The exact mechanisms by which remnant cholesterol contributes to atherosclerosis and, ultimately, ischemic heart disease remain incompletely understood. Additionally, insight on sex and age differences and the importance of measurement differences of remnant cholesterol in plasma concentrations and risk of ischemic heart disease are sparse.

Content

This review covers current knowledge regarding remnant cholesterol and its role in ischemic heart disease, with particular attention to measurement and sex- and age-specific differences.

Findings from observational, genetic, and mechanistic studies support the notion that higher remnant cholesterol may be an important cause of ischemic heart disease in both women and men. Concentrations of remnant cholesterol vary by age, with a sharp increase at early adulthood for men and around menopause for women. Remnant cholesterol can be calculated from a standard lipid profile and in addition measured directly using manual ultracentrifugation, automated assays, and nuclear magnetic resonance spectroscopy. Irrespective of the method used to assess plasma concentrations, high concentrations of remnant cholesterol are consistently associated with increased risk of myocardial infarction and ischemic heart disease in observational and genetic causal studies; cholesterol rather than triglycerides in remnants drive this risk. Importantly, results from ongoing randomized clinical trials aiming specifically at lowering remnant cholesterol and ischemic heart disease are eagerly awaited.
Local conditions drive interpopulation variation in field-based critical thermal maximum of brook trout
Authors: Stewart Erin M C , Bowman Jacob C , Wilson Chris C , Raby Graham D
Published: December 2024

Individual- and population-level responses to thermal change will be pivotal for species’ resilience and adaptive responses to climate change. Thermal tolerance of ectotherms has been extensively studied under laboratory conditions, but comparatively few studies have assessed intra- and interpopulation variation under natural conditions or in situ. We measured field critical thermal maximum (CTmax) of brook trout (Salvelinus fontinalis) populations at twenty sites across Ontario, Canada, to assess their thermal tolerance in situ and examine potential factors underlying intraspecific variation in thermal performance. We modelled CTmax as a function of acclimation using short-term stream temperature data to assess interpopulation variation, and used full-season stream temperatures to calculate thermal safety margins (TSM) for each population. CTmax ranged between 27.41 and 30.46°C and acclimation periods between 4 and 40 days were strong predictors of site CTmax, aligning closely with lab-based studies. Seasonal temperature profiles varied substantially among sites, with mean 30-day stream temperature accounting for 66% of the among-site variation in CTmax. TSMs ranged between 0.51 and 15.51°C and reflected differences among site thermal regimes. Streams in watersheds with more urban or agricultural development had the lowest TSMs in addition to those that were fed by lake surface water. This work emphasizes the importance of locally based conservation and management practices that act at or below the population level, as local factors beyond acclimation temperature were partly responsible for variation in thermal tolerance and thus dictate the resiliency of brook trout under climate change.
Ecological features of upriver migration in Kitakami River chum salmon and their connection to aerobic thermal performance
Authors: Abe Takaaki K , Kitagawa Takashi , Iino Yuki , Ito Motohiro , Sato Katsufumi
Published: December 2024

The physiological performance of ectotherms is influenced by temperature, raising concerns about the impact of global warming on ectotherms. Understanding the relationship between ecologically relevant temperatures and the physiological performance of ectotherms provides a basis for assessing their resilience to changing environments. Absolute aerobic scope (AAS) is a functional metric of the thermal performance of aquatic ectotherms. The thermal profile of chum salmon (Oncorhynchus keta) returning to the Kitakami River, Japan, in early October has already been explored in a previous study; however, the ecological aspects of their upriver migration (e.g. spawning site, migratory duration and experienced temperature) and their connection to AAS thermal profiles are not fully understood. To address this gap, we released 53 marked chum salmon throughout the spawning season (October–November), of which 48 were tracked using radio telemetry. Over 3 years, 18 were successfully tracked to their spawning sites, and 13 were tracked partway. The longest track was 93 km. The spawning sites of Kitakami River chum salmon depended on migration timing, with earlier run salmon tending towards upriver sites. Chum salmon returning in October spawned in the middle basin, typically requiring >5 days to reach the spawning sites, whereas those returning in November spawned in the lower sections in 1–3 days. Comparing the estimated thermal occupancy of migrating salmon with the published AAS profile, we found that Kitakami River chum salmon in early October spent almost all of their time within the optimal temperature window for AAS and tended to be below the peak temperature of AAS. Our findings provide a basis for the ecological features of migrating chum salmon in rivers and shed light on their aerobic thermal performance in the natural environment.
Diminished spinal cord perfusion despite distal aortic perfusion: an acute translational large animal experiment with occluded segmental arteries
Authors: Haunschild Josephina , Dietze Zara , Ossmann Susann , Von Aspern Konstantin , Naumann Jörg , Borger Michael A , Etz Christian D
Published: December 2024

OBJECTIVES

Neuroprotective measures have been established in open thoraco-abdominal aortic aneurysm repair to reduce the incidence of postoperative paraplegia. Distal aortic perfusion (DaP) is meant to increase blood flow to the abdominal organs and the spinal cord. Cerebrospinal fluid (CSF) drainage is part of peri- and postoperative clinical routine. We aimed to investigate the effect of both techniques on spinal cord perfusion in an acute large animal model with segmental artery occlusion.

METHODS

Eight pigs underwent minimally invasive segmental artery coil embolization prior to establishment of cardiopulmonary bypass with DaP. After initiation of DaP, CSF pressure was increased 3-fold by infusion of blood plasma. Collateral network near-infrared spectroscopy was used as an additional real-time monitoring method for indirect perfusion monitoring. Microspheres were injected for post-mortem regional spinal cord blood flow analysis.

RESULTS

DaP led to an increase in spinal cord perfusion limited to the very lower spinal cord (L3–S, up to 400% of baseline) and the corresponding paraspinous muscle area. The most vulnerable region between T8 and L2 was not reached by DaP (between 14% and 46% of baseline). After initiation of DaP, a 10% increase in oxygenation via collateral network near-infrared spectroscopy was observed for the low lumbar region. The increase in CSF pressure counteracted enhanced perfusion inflow leading to a decrease in net tissue perfusion.

CONCLUSIONS

DaP is effective in increasing blood flow to the distal spinal cord (effectively counteracting CSF pressure increase) and paraspinous muscles, despite occluded segmental arteries, resulting in hyperperfusion potentially leading to spinal cord oedema and delayed paraplegia postoperatively.
COCOA: A Framework for Fine-scale Mapping Cell-type-specific Chromatin Compartments with Epigenomic Information
Authors: Li Kai , Zhang Ping , Xu Jinsheng , Wen Zi , Zhang Junying , Zi Zhike , Li Li
Published: December 2024

Chromatin compartmentalization and epigenomic modification are crucial in cell differentiation and diseases development. However, precise mapping of chromatin compartmental patterns requires Hi-C or Micro-C data at high sequencing depth. Exploring the systematic relationship between epigenomic modifications and compartmental patterns remains challenging. To address these issues, we present COCOA, a deep neural network framework using convolution and attention mechanisms to infer fine-scale chromatin compartment patterns from six histone modification signals. COCOA extracts 1-D track features through bi-directional feature reconstruction after resolution-specific binning epigenomic signals. These track features are then cross-fused with contact features using an attention mechanism and transformed into chromatin compartment patterns through residual feature reduction. COCOA demonstrates accurate inference of chromatin compartmentalization at a fine-scale resolution and exhibits stable performance on test sets. Additionally, we explored the impact of histone modifications on chromatin compartmentalization prediction through in silico epigenomic perturbation experiments. Unlike obscure compartments observed with 1 kb resolution high-depth experimental data, COCOA generates clear and detailed compartmental patterns, highlighting its superior performance. Finally, we demonstrated that COCOA enables cell-type-specific prediction of unrevealed chromatin compartment patterns in various biological processes, making it an effective tool for gaining chromatin compartmentalization insights from epigenomics in diverse biological scenarios. The COCOA python code is publicly available at https://github.com/onlybugs/COCOA.
SCREEN: A Graph-based Contrastive Learning Tool to Infer Catalytic Residues and Assess Enzyme Mutations
Authors: Pan Tong , Bi Yue , Wang Xiaoyu , Zhang Ying , Webb Geoffrey I , Gasser Robin B , Kurgan Lukasz , Song Jiangning
Published: December 2024

The accurate identification of catalytic residues contributes to our understanding of enzyme functions in biological processes and pathways. The increasing number of protein sequences necessitates computational tools for the automated prediction of catalytic residues in enzymes. Here, we introduce SCREEN, a graph neural network for the high-throughput prediction of catalytic residues via the integration of enzyme functional and structural information. SCREEN constructs residue representations based on spatial arrangements and incorporates enzyme function priors into such representations through contrastive learning. We demonstrate that SCREEN (i) consistently outperforms currently-available predictors; (ii) provides accurate results when applied to inferred enzyme structures; and (iii) generalizes well to enzymes dissimilar from those in the training set. We also show that the putative catalytic residues predicted by SCREEN mimic key structural and biophysical characteristics of native catalytic residues. Moreover, using experimental data sets, we show that SCREEN’s predictions can be used to distinguish residues with a high mutation tolerance from those likely to cause functional loss when mutated, indicating that this tool might be used to infer disease-associated mutations. SCREEN is publicly available at https://github.com/BioColLab/SCREEN and https://ngdc.cncb.ac.cn/biocode/tool/7580.
Development of a core outcome set of quality indicators for enhanced recovery after surgery in minimally invasive cardiac heart valve surgery by interprofessional Delphi consensus
Authors: Klotz Susanne G R , Begerow Anke , Girdauskas Evaldas
Published: December 2024

OBJECTIVES

A core outcome set (COS) giving indicators of the quality of the process for minimally invasive valve surgery embedded into enhanced recovery after surgery (ERAS) protocols should be developed.

METHODS

Using web-based questionnaires, a Delphi process with three rounds was conducted from January to December 2022. Prior to the rounds, a systematic database search was performed identifying potential quality parameters. Experts for the panel were selected reflecting the interprofessional nature of the ERAS protocol. In the first round, participants could make suggestions of indicators in the pre-, intra- or postoperative and rehabilitative phase. These suggestions form together with the indicators of the literature a first indicator list. In the second round, participants could rate the relevance of the indicators resulting in a condensed indicator list. The third round was performed for further condensation based on importance ranking of the remaining indicators.

RESULTS

Three studies could be included in the systematic literature search providing a list of 22 indicators. Twenty-one experts participated in the Delphi survey. The experts named 315 indicators in the first round. After condensation in two further rounds, the final COS consisted of 24 indicators in the categories structure, process, outcome and complications.

CONCLUSIONS

A consensual minimum set of quality measurements during pre-, intra- and postoperative and rehabilitation phase for patients with minimally invasive heart surgery is now available for enhancing the quality of clinical practice and facilitating comparisons across different ERAS programs.
Parametric finite-element discretization of the surface Stokes equations: inf-sup stability and discretization error analysis
Authors: Hardering Hanne , Praetorius Simon
Published: December 2024

We study a higher-order surface finite-element penalty-based discretization of the tangential surface Stokes problem. Several discrete formulations are investigated, which are equivalent in the continuous setting. The impact of the choice of discretization of the diffusion term and of the divergence term on numerical accuracy and convergence, as well as on implementation advantages, is discussed. We analyse the inf-sup stability of the discrete scheme in a generic approach by lifting stable finite-element pairs known from the literature. A discretization error analysis in tangential norms then shows optimal order convergence of an isogeometric setting that requires only geometric knowledge of the discrete surface.
Plasma Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers of Cognitive Decline in People With Human Immunodeficiency Virus
Authors: Mukerji Shibani S , Bachanová Petra , Park Hemi , Rosen Linzy V , Kashlan Rommi , Kivisäkk Pia , Anderson Albert M , Chow Felicia C , Wu Kunling , Dastgheyb Raha M , Rubin Leah H , Tassiopoulos Katherine , Parker Robert A , Hyle Emily P
Published: December 2024

Background

We examined the relationship between neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and cognition in people with human immunodeficiency virus (HIV) at baseline and longitudinally.

Methods

Plasma and clinical data were available from virally suppressed people with HIV (PWH) aged ≥45 years in the AIDS Clinical Trials Group HAILO study. Four neuropsychological assessments standardized and averaged (NPZ-4) represented cognition. Plasma collection date marked baseline; slope summarized longitudinal NPZ-4 changes. Linear regressions examined biomarkers associations with baseline NPZ-4 and longitudinal change.

Results

The study included 503 participants with a median age of 52 (interquartile range [IQR, 48–57]) years and observation of 6 (IQR, 5–7) years, and 26% had baseline cognitive impairment defined by HAILO. Cross-sectionally, higher NfL (β = −.76, P < .01) and GFAP (β = −.44, P = .02) were associated with worse NPZ-4. Longitudinally, the median NPZ-4 slope was 0.003 (IQR, −0.06 to 0.06) units/year with 48% demonstrating cognitive decline. Higher NfL (β = −.08, P < .01), but not GFAP (β = −.03, P = .08), was associated with cognitive decline.

Conclusions

NfL and GFAP were associated with worse cognition cross-sectionally; only NfL was associated with cognitive decline. Their clinical utility remains uncertain given small effect sizes and should be studied in populations with more rapid decline.
Pharmacokinetic/pharmacodynamic analysis of meropenem and fosfomycin combinations in in vitro time–kill and hollow-fibre infection models against multidrug-resistant and carbapenemase-producing Klebsiella pneumoniae
Authors: Farooq Aneeq , Martens Miklas , Kroemer Niklas , Pfaffendorf Christoph , Decousser Jean-Winoc , Nordmann Patrice , Wicha Sebastian G
Published: December 2024

Background

MDR Gram-negative bacteria, such as ESBL-producing and carbapenemase-producing Klebsiella pneumoniae, represent major global health threats. Treatment options are limited due to increasing resistance and slowed development of novel antimicrobials, making it necessary to apply effective combination therapies based on approved antibiotics.

Objectives

To quantitatively evaluate the synergistic potential of meropenem and fosfomycin against carbapenem-resistant K. pneumoniae strains isolated from clinics.

Methods

We evaluated four MDR K. pneumoniae strains, each expressing KPC-2 or KPC-3, using static time–kill assays that accounted for measured meropenem degradation. This was followed by pharmacokinetic/pharmacodynamic (PK/PD) interaction modelling, which estimated meropenem degradation rate constants and identified perpetrator–victim relationships in PD interactions. Dynamic hollow-fibre infection model (HFIM) experiments were used to confirm synergy.

Results

Static time–kill assays demonstrated high killing effects and suppressed regrowth for the combination of meropenem and fosfomycin, compared with the failure of monotherapy. Meropenem degradation was significantly higher in the presence of bacteria, attributable to carbapenemase activity. Pharmacometric models indicated a synergistic interaction primarily driven by meropenem as the perpetrator, enhancing the potency of fosfomycin. HFIM experiments confirmed in vitro synergy, demonstrating continuous bacterial suppression of the combination therapy.

Conclusions

Meropenem and fosfomycin exhibited additive or synergistic potential against carbapenemase-expressing single- or double-resistant K. pneumoniae at clinically achievable concentrations. This combination therapy may offer a strategy against MDR infections, possibly improving clinical treatment outcomes. Further in vivo research is needed to translate these findings into clinical practice, emphasizing the importance of PK/PD modelling in rationalizing antibiotic use.
Analysis of eligibility criteria clusters based on large language models for clinical trial design
Authors: Bornet Alban , Khlebnikov Philipp , Meer Florian , Haas Quentin , Yazdani Anthony , Zhang Boya , Amini Poorya , Teodoro Douglas
Published: December 2024

Objectives

Clinical trials (CTs) are essential for improving patient care by evaluating new treatments’ safety and efficacy. A key component in CT protocols is the study population defined by the eligibility criteria. This study aims to evaluate the effectiveness of large language models (LLMs) in encoding eligibility criterion information to support CT-protocol design.

Materials and Methods

We extracted eligibility criterion sections, phases, conditions, and interventions from CT protocols available in the ClinicalTrials.gov registry. Eligibility sections were split into individual rules using a criterion tokenizer and embedded using LLMs. The obtained representations were clustered. The quality and relevance of the clusters for protocol design was evaluated through 3 experiments: intrinsic alignment with protocol information and human expert cluster coherence assessment, extrinsic evaluation through CT-level classification tasks, and eligibility section generation.

Results

Sentence embeddings fine-tuned using biomedical corpora produce clusters with the highest alignment to CT-level information. Human expert evaluation confirms that clusters are well structured and coherent. Despite the high information compression, clusters retain significant CT information, up to 97% of the classification performance obtained with raw embeddings. Finally, eligibility sections automatically generated using clusters achieve 95% of the ROUGE scores obtained with a generative LLM prompted with CT-protocol details, suggesting that clusters encapsulate information useful to CT-protocol design.

Discussion

Clusters derived from sentence-level LLM embeddings effectively summarize complex eligibility criterion data while retaining relevant CT-protocol details. Clustering-based approaches provide a scalable enhancement in CT design that balances information compression with accuracy.

Conclusions

Clustering eligibility criteria using LLM embeddings provides a practical and efficient method to summarize critical protocol information. We provide an interactive visualization of the pipeline here.
Morphological and biological characterization of Spermophagus niger (Motschulsky, 1866) (Coleoptera: Chrysomelidae) from four West African countries
Authors: Kabore Emmanuel , Koussoube Jean Christophe , Kam Koï Wenceslas , Sanon Antoine , Ilboudo Zakaria
Published: December 2024

In Burkina Faso and many West African countries, Spermophagus niger (L.) is the main insect pest of Hibiscus sabdariffa seeds stored with considerable damage. Variations in bioclimatic conditions can lead to significant changes in the morphology and biology of populations of the same insect species, leading to strains that are morphologically and biologically different and that would react differently to a given control method. In this study, strains of S. niger from Niger (Niamey), Ghana (Navrongo), Benin (Parakou) and five localities in Burkina Faso (Diébougou, Banfora, Saaba, Mani, and Manga) are studied under controlled conditions (32 °C ± 0.1, 43% ± 1 r.h., L: D 12:12). The results showed that males from Niamey and Parakou lived longer, while females from Niamey and Diébougou had a statistically high longevity.

The larval survival rate of the Niamey strain was significantly lower than Manga, Parakou, and Navrongo. The Niamey strain recorded adults compared to the other strains. In terms of weight, the females and males from Banfora and Niamey were statistically heavier than other strains. At the end of the study, S. niger’ strains showed different morphologies in terms of weight. Furthermore, adult longevity, larval survival rate, and emergence rate were strain dependent.
The p-Frobenius number for the triple of certain quadratic numbers
Authors: Komatsu Takao , Yilmaz Fatih
Published: December 2024

In this paper, we give closed-form expressions of the $p$-Frobenius number for the triple of the numbers $a n(n-1)+r$ for an integer $a\ge 4$ and $r$ is odd. For the set of given positive integers $A:=\{a_{1},a_{2},\dots ,a_{k}\}$, the $p$-Frobenius number is the largest integer whose nonnegative integral linear combinations of given positive integers in $A$ are expressed in at most $p$ ways. When $p=0$, the $0$-Frobenius number is the classical Frobenius number, which is the central topic of the famous linear Diophantine problem of Frobenius.
Insights into the emerging immune checkpoint NR2F6 in cancer immunity
Authors: Miftah Hayat , Benthami Hamza , Badou Abdallah
Published: December 2024

NR2F6 has emerged as a key player in immune regulation, especially in cancer immunity. It has indeed been reported that NR2F6 could suppress the anti-tumor immune response, and has therefore been suggested as possible target in cancer immunotherapy. In this review, we will start by describing the complex structure of the NR2F6 gene and its multifaceted biological functions. Then we will examine its expression in distinct immune cells and cancer cells, elucidating its role in cancer progression. Subsequently, we will highlight the predictive significance of NR2F6 for cancer patient outcome, suggesting its possible use as a prognostic biomarker. Finally, we will discuss the emerging potential of NR2F6 as a therapeutic target, presenting novel opportunities for the development of effective cancer immunotherapy strategies.
A machine learning approach to automate microinfarct and microhemorrhage screening in hematoxylin and eosin-stained human brain tissues
Authors: Cerny Oliveira Luca , Chauhan Joohi , Chaudhari Ajinkya , Cheung Sen-ching S , Patel Viharkumar , Villablanca Amparo C , Jin Lee-Way , DeCarli Charles , Chuah Chen-Nee , Dugger Brittany N
Published: December 2024

Microinfarcts and microhemorrhages are characteristic lesions of cerebrovascular disease. Although multiple studies have been published, there is no one universal standard criteria for the neuropathological assessment of cerebrovascular disease. In this study, we propose a novel application of machine learning in the automated screening of microinfarcts and microhemorrhages. Utilizing whole slide images (WSIs) from postmortem human brain samples, we adapted a patch-based pipeline with convolutional neural networks. Our cohort consisted of 22 cases from the University of California Davis Alzheimer’s Disease Research Center brain bank with hematoxylin and eosin-stained formalin-fixed, paraffin-embedded sections across 3 anatomical areas: frontal, parietal, and occipital lobes (40 WSIs with microinfarcts and/or microhemorrhages, 26 without). We propose a multiple field-of-view prediction step to mitigate false positives. We report screening performance (ie, the ability to distinguish microinfarct/microhemorrhage-positive from microinfarct/microhemorrhage-negative WSIs), and detection performance (ie, the ability to localize the affected regions within a WSI). Our proposed approach improved detection precision and screening accuracy by reducing false positives thereby achieving 100% screening accuracy. Although this sample size is small, this pipeline provides a proof-of-concept for high efficacy in screening for characteristic brain changes of cerebrovascular disease to aid in screening of microinfarcts/microhemorrhages at the WSI level.
REMEDIES IN EU ANTITRUST LAW
Authors: Ibáñez Colomo Pablo
Published: December 2024

Remedies are central in contemporary EU antitrust enforcement. However, they remain relatively misunderstood. Against this background, this article has three main objectives. It seeks, first, to shed light on the nature and purpose of remedial action under Articles 101 and 102 TFEU, with a focus on the European Commission’s activity. The point of intervention, the case law shows, is to bring an infringement effectively to an end. As a matter of positive law, it is unclear that there is room for restorative remedies (that is, remedies that seek to recreate the conditions of competition as they would have existed in the absence of the practice). Second, the article takes a critical perspective on the practice of the past decade. It appears, in particular, that a ‘principles-based approach’ to the administration of remedies is likely to lead to suboptimal outcomes. Finally, some recommendations are outlined so that the letter of the law matches the demands and ambitions of the sort of regulatory-like intervention that is necessary in digital markets and other industries presenting similar features.
Spatiotemporal modelling with dynamic deformation for nonstationary covariance structures
Authors: Morales Fidel Ernesto Castro , Paez Marina Silva
Published: December 2024

In this paper, we present an innovative spatiotemporal model that allows dynamic variation in the spatial correlation structure over time through dynamic deformation. We propose that temporal deformation occurs smoothly relative to that in the original region. To incorporate this idea, we employ state space models to model dynamic deformation. Generalizing this class of models based on spatial deformation was driven by the need to model monthly average temperature data in the southern region of Brazil. The distinctive traits of this region, characterized by plateaus and mountain ranges and close proximity to the Atlantic Ocean, provide notable geographic diversity. This diversity, in addition to different meteorological phenomena over time, may influence the spatial correlation function. The model parameters are estimated via a Bayesian approach, which requires the use of Markov chain Monte Carlo methods to approximate the posterior distributions of parameters. The model is applied to 15 years of monthly average temperature data from the southern region of Brazil. The primary result of this analysis reveals a significant improvement in temperature modelling when the proposed model is used compared with that when versions that employ static deformation are used.
Colo-cutaneous fistula in the setting of complicated sigmoid diverticulitis previously managed with percutaneous drainage: a case report
Authors: Correa Natalia
Published: December 2024

Colo-cutaneous fistulas are a rare complication of diverticular disease. Percutaneous drainage offers a promising alternative to surgical intervention in the management of complicated diverticular disease with abscess formation. Recent case studies and literature reviews support its efficacy in achieving abscess resolution and reducing the need for surgery. However, careful patient selection, technical proficiency, and multidisciplinary management are critical to optimizing outcomes. As the body of evidence grows, percutaneous drainage is likely to play an increasingly important role in the therapeutic arsenal against complicated diverticular disease; however, the risk of complications, particularly fistula formation, must be carefully considered. Our case presents a rare incident of a colo-cutaneous fistula occurring after CT-guided percutaneous drainage of a pericolic abscess secondary to perforated sigmoid diverticulitis that failed medical management. The patient ultimately underwent Hartmann’s procedure where the diseased sigmoid colon, adhered small bowel, and fistula tract were excised with an end colostomy creation.
Thoracoscopic segmentectomy for lung tumour with displaced B1 + 2
Authors: Miyajima Masahiro , Ogura Keishi , Mishina Taijirou , Watanabe Atsushi
Published: December 2024

The frequency of bronchial branching abnormalities is about 0.6%, of which about 75% are related to the right upper lobe. The frequency of left B1 + 2 transition bronchus is even rarer, but a few cases have been reported. A 43-year-old man, who presented with an abnormal pulmonary nodule suspected to be lung cancer in the left S4 segment, underwent video-assisted thoracoscopic segmentectomy of S3 plus lingular segment. Preoperative three-dimensional contrast-enhanced computed tomography (CT) revealed a displaced B1 + 2 bronchus arising from the left main bronchus, which ascends behind the main pulmonary artery. Video-assisted thoracic surgery was performed successfully, and the nodule was pathologically diagnosed as a lymphoma. Preoperative three-dimensional contrast-enhanced CT was very useful to detect this rare bronchial abnormality. In the present case, three-dimensional CT allowed us to safely operate on a patient with a rare B1 + 2 displaced bronchus in the left upper lobe.
Genitourinary tuberculosis presenting as treatment resistant dysuria in a young patient: a case report
Authors: Woodward Louis , Sahin Ali , Almpanis Stefanos
Published: December 2024

Genitourinary tuberculosis is the second most common form of extrapulmonary tuberculosis. We present the case of a male patient in his late 20s who presented to his general practitioner with symptoms of recurrent urinary tract infection (UTI). Upon investigation his estimated glomerular filtration rate was found to be 61 ml/min/1.75 m2 and an ultrasound scan of the kidney, ureters, and bladder revealed a left sided hydronephrosis. A computerized tomography urogram confirmed upper and lower pole lesions of the left kidney with ureteric changes and lymphadenopathy consistent with chronic atypical infection. A urine acid-fast bacilli culture was positive for urinary tuberculosis (TB). The patient’s disseminated TB was treated with conventional anti-TB medications. Our case report highlights the value in considering genitourinary tuberculosis amongst the list of differential diagnoses in younger patients presenting with symptoms of recurrent UTI.
Unusual intravesical findings: a case report on foreign body in the bladder of an adolescent female
Authors: Alabassi Kholoud , Ata Yaser M , Alshahwani Noora , Elkadhi Abdelrahman
Published: December 2024

Bladder foreign bodies (BFB) are uncommon in the pediatric population. They typically arise from self-insertion, iatrogenic factors, or trauma. Cystoscopy is the preferred intervention. A 16-year-old female presented with a [2-]day history of dysuria, suprapubic pain, and a palpable rectal foreign body. Imaging revealed an 8.2 cm radiopaque object in the bladder. Diagnostic laparoscopy confirmed no perforation. Cystoscopy identified and removed a lead pencil from the bladder. A small bladder perforation was noted post-removal. The patient had a smooth recovery and was discharged with a Foley catheter, which was later removed following normal postoperative imaging results. Prompt diagnosis and intervention are crucial for managing pediatric BFBs to prevent complications. Imaging and cystoscopy play key roles in treatment.
Millets for a sustainable future
Authors: Ghatak Arindam , Pierides Iro , Singh Roshan Kumar , Srivastava Rakesh K , Varshney Rajeev K , Prasad Manoj , Chaturvedi Palak , Weckwerth Wolfram
Published: December 2024

Our current agricultural system faces a perfect storm—climate change, a burgeoning population, and unpredictable outbreaks such as COVID-19 which disrupt food production, particularly for vulnerable populations in developing countries. A paradigm shift in agriculture practices is needed to tackle these issues. One solution is the diversification of crop production. While ~56% of the plant-based protein stems from  three major cereal crops (rice, wheat, and maize), underutilized crops such as millets, legumes, and other cereals are highly neglected by farmers and the research community. Millets are one of the most ancient and versatile orphan crops with attributes such as fast growing, high yielding, withstanding harsh environments, and rich in micronutrients such as iron and zinc, making them appealing to achieve agronomic sustainability. Here, we highlight the contribution of millet to agriculture and focus on the genetic diversity of millet, genomic resources, and next-generation omics and their applications under various stress conditions. Additionally, integrative omics technologies could identify and develop millets with desirable phenotypes having high agronomic value and mitigating climate change. We emphasize that biotechnological interventions, such as genome-wide association, genomic selection, genome editing, and artificial intelligence/machine learning, can improve and breed millets more effectively.
Future challenges for UK regulation of brain organoid research
Authors: Jackson Emily
Published: December 2024

One of this century’s most dramatic scientific developments is the reprogramming of stem cells in order to create organoids, that is, self-organizing 3D models that mimic the structure and function of human organs. This article considers whether brain organoids in particular might raise any new questions for law, now or in the near future. If complex human brain organoids were to become capable of consciousness or sentience, the current regulation of human tissue research, which protects the interests of tissue donors, might need to be supplemented in order to protect the interests of the tissue itself. Human brain organoids can also be implanted into animal hosts, and if this were to result in animals with significantly enhanced cognitive abilities, additional protective measures might become necessary.
Conscious Nutrition to Improve Survival Prognosis of Donor Kidney Recipients: A Narrative Review
Authors: Zulkhash Nargiz , Shanazarov Nasrulla , Kissikova Saule , Turebekov Duman , Ismagulova Elnara
Published: December 2024

Kidney transplantation is the optimal treatment for end-stage chronic kidney disease, increasing survival rates and improving quality of life. Diet affects patient weight and well-being, can trigger certain diseases, and influences post-surgery outcomes. The purpose of the study was to investigate dietary strategies in patients with chronic kidney disease, in early and long-term donor kidney recipients, and to formulate specific nutritional recommendations. For this purpose, a narrative review of the available information in both the Republic of Kazakhstan and the world’s scientific literature over the last 10 years was carried out. The following evidence-based resources were used: Scopus, PubMed, Embase, Cochrane Library, and Web of Knowledge. The study provides the latest statistical data on kidney transplantation and risk factors, and a comparative analysis between countries. Existing data on basic nutrition and the possibility of using it after transplantation are examined in detail. In addition, the recommendations for daily intake of salt, potassium, sodium, vitamin D, and calcium were analyzed. The energy value of the diet and its association with overweight, obesity, and the development of diabetes mellitus were studied. Using DASH (Dietary Approaches to Stop Hypertension) and low-protein diets as examples, the potential risks and their applicability for this patient category are analyzed. The article's materials and conclusions can serve as a training manual for nephrologists, therapists, and surgeons.