bluuebunny/crossref_metadata_2025 huggingface dataset:
Enoxaparin Failure in Patient With Cerebral Venous Sinus Thrombosis and Prothrombin G20210A Mutation
Authors: Polavarapu Adithya , Bhushan Anita , Duarte-Celada Walter , Windisch Thomas , Bhushan Bharat
Published: November 2024

Introduction:

Cerebral venous sinus thrombosis (CVST) is a rare, serious, and complex cerebrovascular disease. The prothrombin G20210A mutation is the second most common inherited thrombophilia and is considered to be one of the etiologies of CVST. The optimal heparinoid medication for treatment remains a topic of debate.

Case Report:

This case report describes a young woman with CVST who did not respond to low–molecular-weight heparin (LMWH). The patient was initially treated with LMWH; however, her symptoms and clot burden in the sagittal sinus worsened, and coagulation studies showed no evidence of therapeutic anticoagulation despite good compliance. Unfractionated heparin was then initiated, and the patient’s symptoms improved dramatically within 24 hours, along with the recanalization of the cerebral venous sinuses. Genetic testing revealed a heterozygous mutation in the prothrombin gene (G20210A). This mutation is a known risk factor for CVST. However, it is unclear why the patient did not respond to LMWH but responded appropriately to unfractionated heparin.

Conclusion:

This case report highlights the potential for LMWH resistance in patients with CVST and prothrombin gene mutations. These findings also emphasize the importance of close monitoring of coagulation parameters and clinical response in patients with CVST receiving LMWH.
Ensuring Iodine Adequacy in Pregnant and Lactating Vegan Women
Authors: Messina Virginia , Messina Mark
Published: November 2024

As a component of thyroid hormones, iodine is essential for brain development in the fetus and in young children. Some evidence suggests that pregnant and lactating women who consume a vegan diet may be at risk for iodine deficiency. Iodine sources for vegans include supplements, iodized salt, and seaweed. However, because the iodine content of seaweed is variable, with some types providing amounts that may lead to excessive intake, recommendations for consumption of these foods during pregnancy and breastfeeding should be specific regarding types and amounts. Pregnant and lactating women who choose a vegan diet should include a supplement of potassium iodide in their diet and should follow advice about the types of seaweed to avoid or limit.
Comparison of Pediatric and Adult Mandibular Fractures: Identifying Differences in Presentation and Management Using a National Trauma Database
Authors: Oxford Madison , Tucker Jacqueline , Goldenberg Dana , King Tonya S. , Ziai Kasra , Henry Cathy , Lighthall Jessyka G.
Published: November 2024

Background:

Facial fractures in children are less common than in adults but can lead to significant long-term complications, including growth abnormalities and functional issues. Mandibular fractures are the most common facial fractures in both age groups, yet there is no consensus on optimal management strategies. This study investigates the epidemiology, presentation, treatment, and outcomes of mandibular fractures in pediatric versus adult populations.

Methods:

The authors conducted a retrospective, population-based study using 2016 to 2019 data from the National Trauma Data Bank. Patients with mandibular fractures were categorized into pediatric (below 18 y) and adult (18 y or above) groups. The authors analyzed demographics, fracture mechanism, treatment modality, hospital outcome, and complication data.

Results:

Of the 42,866 patients with operative mandibular fractures, 3968 were pediatric (mean age: 13.3 y), and 38,898 were adult (mean age: 36.2 y). The primary fracture etiology for both groups was being struck, followed by motor vehicle incidents and falls. Pediatric patients were more frequently treated at level I trauma centers, had shorter times for surgical intervention, and were more frequently transferred to other facilities compared to adults. Antibiotic use was similar between groups, and hospital complications were infrequent, with low rates of infection and unplanned return to the operating room.

Conclusions:

Mandibular fractures in children, though less common than in adults, exhibit unique epidemiological and management characteristics. Children were more frequently transferred for care and received surgical intervention sooner than adults. Antibiotic use and complication rates were low and similar across both groups. Further research is needed to establish specific treatment guidelines for pediatric mandibular fractures.
Craniofacial Growth in Children With Unilateral Cleft Lip and Palate: Adopted From China Versus Born in Sweden
Authors: Sahlsten Schölin Johnna , Mark Hans , Rizell Sara
Published: November 2024

Objective:

In 2005, the number of internationally adopted children (IAC) with cleft lip and palate (CLP) from China increased globally, followed by an increase in the number of surgical complications. The aim was therefore to evaluate the craniofacial growth of children with unilateral CLP adopted from China and compare with non-adopted peers (NA).

Methods:

Cephalograms taken at 10 and 13 were analysed for the SNA, SNB, ANB, NAPg and NSBa angles. Surgical data were extracted from the medical records.

Results:

The rate of secondary cleft-related surgery including secondary alveolar bone grafting (SABG) was higher in the IAC group than in the native groups. At age 10, the IAC exhibited higher SNB and NAPg and lower ANB values than the NA-Mod group and a similar pattern was observed at age 13. The IAC group demonstrated significantly lower SNA and ANB and higher NAPg values than the NA-Orig group at age 10. At age 13, lower SNA and ANB and higher SNB, NAPg, and NSBa values were observed in the IAC group compared with the NA-Orig group.

Limitations:

Craniofacial growth is not finalized at age 13 years, why additional studies are needed to determine long-term outcomes.

Conclusions:

Results from this novel study present unfavorable craniofacial growth at age 10 and 13 years of age among IAC with UCLP and indicate an increased need for future orthognathic surgery compared with NA peers.
The always evolving diagnosis and management of Clostridioides difficile colitis: What you need to know
Authors: L'Huillier Joseph C. , Guo Weidun Alan
Published: November 2024

The diagnosis, pharmacologic management, and surgical options for Clostridioides difficile infection (CDI) are rapidly evolving, which presents a challenge for the busy surgeon to remain up to date on the latest clinical guidelines. This review provides an evidence-based practical guide for CDI management tailored to the needs of surgeons and surgical intensivists. Historically, the diagnosis of CDI relied on slow cell culture cytotoxicity neutralization assays, but now, the rapidly resulting nucleic acid amplification tests and enzyme immunoassays have become mainstream. In terms of antibiotic therapy, metronidazole and oral vancomycin were the main “workhorse” antibiotics in the early 2000s, but large randomized controlled trials have now demonstrated that fidaxomicin produces superior results. Regarding surgical intervention, total abdominal colectomy was once the only procedure of choice; however, diverting loop ileostomy with colonic lavage is emerging as a viable alternative. Finally, novel adjuncts such as fecal microbiota transplantation and targeted therapy against toxin B (bezlotoxumab) are playing an increasingly important role in the management of CDI.
Acute stroke care in low and middle-income countries
Authors: Martins Sheila Cristina Ouriques , Matuja Sarah Shali
Published: November 2024

Purpose of review

The purpose of this article is to discuss the global impact of stroke, the disparities and barriers to implement stroke care, and the global efforts to improve access to acute treatments in low and middle-income countries (LMICs).

Recent findings

Disparities in access to stroke care are influenced by socioeconomic inequalities, geographic disparities, and limited healthcare infrastructure, particularly in LMICs. Effective stroke care requires a coordinated approach involving emergency services, rapid diagnosis, timely treatment, and early rehabilitation. However, there are significant delays in implementing evidence-based practices, particularly in areas where stroke care resources are scarce.

Key barriers include geographic disparities, economic constraints, insufficient healthcare infrastructure, low public awareness, and weak policy frameworks. Addressing these challenges requires strengthening health systems, promoting universal health coverage, enhancing public and healthcare provider education, leveraging technology like telemedicine, and fostering international collaboration. Global efforts, including initiatives by the World Stroke Organization, focus on improving stroke care through infrastructure development, workforce training, and policy advocacy.

These recommended strategies aim to make stroke care accessible and effective for everyone, regardless of location or socioeconomic status, ultimately helping to reduce the global burden of stroke.
A bibliometric analysis of Mycobacterium bovis BCG research trends from 1990 to 2023.
Authors: Moswane Benjamin , Adelabu Olusesan Adeyemi , Musoke Jolly
Published: November 2024

Introduction

Mycobacterium bovis bacilli Calmette-Guèrin (BCG) vaccine is a live attenuated vaccine used against Tuberculosis (TB). BCG was produced from Mycobacterium bovis via the attenuation process by Albert Calmette and Camille Guèrin.

Aim

R-Bibliometrix was used for a bibliometric analysis on M. bovis BCG research from 1990 – 2023.

Methodology

Scopus database was used for the analysis and focused on terms related to the BCG vaccine. The data was processed and analysed through the Biblioshiny and Bibliometrix tools in R (version 4.3.3) and key metrics such as the most frequently cited papers, and author contributions were extracted. Figures were also generated for article output, citation averages, relevant keywords, and institution affiliations.

Results

The documents used totalled 1143 and were obtained from 519 sources. The most cited document was Behr 1999 with 1358 total citations (TCs), and the journal with the most publications in this field was the Vaccine Journal. The author with the most publications was Buddle BM (34 articles) and the most relevant institution was the University of Cape Town whilst the USA was the leading country in terms of single and multiple-country publications.

Conclusion

Considering that TB is still a public health problem, the current trends in M. bovis BCG research are warranted.
A comprehensive foundation model for cryo-EM image processing
Authors: Yan Yang , Fan Shiqi , Yuan Fajie , Shen Huaizong
Published: November 2024

Cryogenic electron microscopy (cryo-EM) has become a premier technique for high-resolution structural determination of biological macromolecules1–4. However, its widespread adoption is hampered by the need for specialized expertise. We introduce the Cryo-EM Image Evaluation Foundation (Cryo-IEF) model, pre-trained on an extensive dataset of approximately 65 million cryo-EM particle images using unsupervised learning. Cryo-IEF excels in various cryo-EM data processing tasks, such as classifying particles from different structures, clustering particles by pose, and assessing the quality of particle images. Upon fine-tuning, the model effectively ranks particle images by quality at high efficiency, enabling the creation of CryoWizard—a fully automated single-particle cryo-EM data processing pipeline. This pipeline has successfully resolved high-resolution structures of diverse properties and proven adept at mitigating the prevalent preferred orientation challenge in many cryo-EM samples. The Cryo-IEF model and CryoWizard pipeline collectively represent a significant advancement in rendering cryo-EM technology more accessible, efficient, and robust, with substantial implications for life sciences research.
TOP-DOWN CLIMATIC PROCESSES MODULATE BIODIVERSITY-FUNCTIONING RELATIONSHIPS ACROSS NORTH AMERICAN FORESTS
Authors: Maluquer Xavier Serra , Godoy Oscar , Ruiz-Benito Paloma , Astigarraga Julen , Rodríguez-Sánchez Francisco , Tijerín-Triviño Julián , Rueda Marta
Published: November 2024

Experimental evidence indicates that more diverse communities sustain higher levels of ecosystem functioning. Generally, bottom-up processes accounting for community selection and complementarity effects on biodiversity are used to explain biodiversity effects on ecosystem functioning. However, top-down macroecological processes can also influence the distribution of ecosystem functions across large environmental gradients and, importantly, biodiversity patterns. Here, we tested whether past climate instability, current climate, and climate-driven species abundance explain tree richness gradients, and therefore, determine the relationship between species richness and ecosystem functioning using 137,808 forest inventory plots across continental extents including forests of Canada, the US, and Mexico. Consistent with previous research, we found a positive monotonic relationship between species richness and biomass (measured as level stand basal area) across North American forests. However, structural equation models revealed that the indirect effect of past climate instability, current climate conditions, and climate-driven individuals’ abundance underlie species richness patterns and the positive covariation between species richness and biomass. The importance of top-down climatic processes varied from boreal to tropical regions, yet their significant effects were pervasive across all forest types, indicating that climate strongly modulates the strength of the relationships between species richness and basal area. Our results help to understand the assembly processes driving the ubiquitous positive monotonic relationship between species richness and basal area across continental extents. This knowledge, obtained from adopting a macroecological perspective, helps understanding biodiversity-functioning relationships, which are usually explained by mechanisms at the community level.

Significance statement

More biodiverse communities sustain higher levels of ecosystem functions (BEF hypothesis). The role of biotic interactions among trees within ecological communities determining BEF has been widely studied, but it is not well known how past climatic variability, current climate, and species abundance determine BEF. Using 137,808 forest inventory plots across North American forests located in Canada, the US, and Mexico, we document a positive relationship between tree species richness and stand basal area. Detailed analysis revealed that the positive BEF relationship is underlined by a strong and indirect effect of past and current climate. Our results highlight the importance of top-down climate processes operating at macroecological scales to understand biodiversity-functioning relationships.
Blocking SHP2 benefits FGFR2 inhibitor and overcomes its resistance in FGFR2-amplified gastric cancer
Authors: Zhang Yue , Wang Hanbing , Wei Yutao , Pan Yunfeng , Song Xueru , Shi Tao , Shao Jie , Yu Lixia , Liu Baorui , Wang Yue , Wei Jia
Published: November 2024

Fibroblast growth factor receptor 2 (FGFR2) is an important member of receptor tyrosine kinase (RTK) family. FGFR2 amplification occurs at a high frequency in gastric cancer (GC) and has been proven to be closely associated with poor prognosis and insensitivity to chemotherapy or immunotherapy. Current FGFR2-targeted therapies have limited efficacy. Hence, how to enhance efficacy and reverse resistance are urgent problems clinically. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) serves as the shared downstream mediator of all RTKs and a prominence immunosuppressive molecule. In this study, we identified FGFR2 amplification in 6.2% (10/161) of GC samples in our center. Then we showed that dual blocking SHP2 and FGFR2 enhanced the effects of FGFR2 inhibitor (FGFR2i) in FGFR2-amplified GC bothin vitroandin vivovia suppressing RAS/ERK and PI3K/AKT pathways. We further showed that it overcame FGFR2i resistance by reversing the feedback activation mediated by other RTKs and continuously suppressing FGFR2-initiated downstream pathways. Notably, SHP2 blockade could suppress PD-1 expression and promoted IFN-γ secretion of CD8+T cells, enhancing the cytotoxic functions of T cells in tumor immune microenvironment. Overall, our findings suggest that dual blocking SHP2 and FGFR2 is a compelling rationale with both targeted treatment and immune regulation for FGFR2-amplified GC.

Impact statement

Dual blocking SHP2 and FGFR2 can not only promote the targeted tumor-killing effects and overcome FGFR2 inhibitor resistance caused by feedback activation, but also activate T cell-mediated anti-tumor immunity by inhibiting PD-1 pathway in FGFR2-amplified GC.
Magnetotactic Bacteria Optimally Navigate Natural Pore Networks
Authors: Petroff Alexander P. , Kelin Vladislav , Radchenko-Hannafin Nina
Published: November 2024

Magnetotactic bacteria swim along geomagnetic field lines to navigate the pore spaces of water-saturated sediment. To understand the physical basis for efficient navigation in confined geometries, we observe the motion of Multicellular Magnetotactic Bacteria through an artificial pore space under an applied magnetic field. Magnetotaxis is fastest when bacteria swim a distance that is of order the pore size in the time required to align with the applied field. A model—in which bacteria deterministically align with the magnetic field and randomly scatter off boundaries—predicts the observed non-monotonic relationship between the drift velocity and applied magnetic field and the value of the maximum drift velocity. A comparison of diverse magnetotactic bacteria shows that the magnetic moments, swimming speeds, and hydrodynamic mobilities of different species covary such that the average speed of magnetotaxis for each species is close to optimal for its natural environment.
PAIRWISE: Deep Learning-based Prediction of Effective Personalized Drug Combinations in Cancer
Authors: Xu Chengqi , Us Ilkay , Cohen-Setton Jake , Milo Marta , Sidders Ben , Fitzgibbon Jude , Melnick Ari M. , Pan Heng , Elemento Olivier , Bulusu Krishna C.
Published: November 2024

Combination therapies offer promise for improving cancer treatment efficacy and preventing recurrence. However, identifying optimal drug combinations tailored to specific cancer subtypes and individual patients is extremely challenging due to the vast number of possible combinations and tumor heterogeneity. To address this gap, we take a machine learning approach combining deep learning with transfer learning to incorporate prior scientific knowledge and predict drug synergy based on tumor-specific transcriptome profiles. This approach, called PAIRWISE, explicitly modeled synergistic effects of drug combinations in cancer cell lines or individual tumor samples based on drug chemical structures, drug targets, and transcriptomes of inferred samples. PAIRWISE outperformed competing models with an area under the receiver operating characteristic curve (AUROC) of 0.85 on held-out cancer cell lines. When applied to an independent dataset of combinations with Bruton Tyrosine Kinase inhibitors (BTKi) in Diffuse Large B Cell Lymphoma (DLBCL) cell lines, PAIRWISE accurately predicted synergistic drug combinations with an AUROC of 0.72. To further confirm the robustness of PAIRWISE predictions, we performed an in silico, patient profile-directed screen for other compounds that would synergize with BTKi in DLBCL patients, and confirmed the synergy of the predictions using a panel of eight non-Hodgkin lymphoma cell lines. These findings demonstrate the ability of PAIRWISE to nominate effective personalized drug combinations, accelerating the development of precision oncology.
Rthoptera: standardised insect bioacoustics in R
Authors: Rivas Francisco , Buzzetti Filippo Maria , Brizio Cesare , Pijanowski Bryan C.
Published: November 2024

Crickets were the first study subjects at the dawn of bioacoustics, yet, almost 100 years later, freely available and robust analysis tools and protocols are still needed. We introduceRthoptera, a new open-source R package for the analysis of insect acoustic signals, offering accurate graphics and standardised temporal and spectral measurements through a streamlined workflow. Our package delivers results in a fraction of the time typically required by multi-software methods. Most of the functions have interactive versions (Shiny applications), facilitating their adoption by researchers with any level of experience. New acoustic metrics are introduced: Spectral Excursion, Pattern Complexity Index, Temporal Excursion, Dynamic Excursion, and Broadband Activity Index. Accompanied by an appropriate recording protocol, our tool can become the backbone of a standard analysis protocol for comparative insect bioacoustics.
Characterization of A Bronchoscopically Induced Transgenic Lung Cancer Pig Model for Human Translatability
Authors: Joshi Kirtan , Suvilesh Kanve N. , Natesh Nagabhishek Sirpu , Manjunath Yariswamy , Coberly Jared , Schlink Sarah , Kunin Jeffrey R. , Prather Randall S. , Whitworth Kristin , Nelson Benjamin , Bryan Jeffrey N. , Hoffman Timothy , Golzy Mojgan , Raju Murugesan , Teixeiro Emma , Telugu Bhanu P. , Kaifi Jussuf T. , Rachagani Satyanarayana
Published: November 2024

Background

There remains a need for animal models with human translatability in lung cancer (LC) research. Findings in pigs have high impact on humans due to similar anatomy and physiology. We present the characterization of a bronchoscopically-induced LC model in Oncopigs carrying inducible KRASG12Dand TP53R167Hmutations.

Methods

Twelve Oncopigs underwent 29 injections via flexible bronchoscopy. Eighteen Adenovirus-Cre recombinase gene (AdCre) inductions were performed endobronchially (n=6) and transbronchially with a needle (n=12). Eleven control injections were performed without AdCre. Oncopigs underwent serial contrast-enhanced chest CT with clinical follow-up for 29 weeks. Following autopsy, lung and organ tissues underwent histopathology, immunohistochemistry, and RNA-sequencing with comparative analysis with The Cancer Genome Atlas (TCGA) human LC data.

Results

All 18 sites of AdCre injections had lung consolidations on CT imaging. Transbronchial injections led to histopathologic invasive cancer and/or carcinoma in situ (CIS) in 11/12 (91.7%), and invasive cancer (excluding CIS) in 8/12 (66.6%). Endobronchial inductions led to invasive cancer in 3/6 (50%). A soft tissue metastasis was observed in one Oncopig. Immunohistochemistry confirmed expression of Pan-CK+/epithelial cancer cells, with macrophages and T cells infiltration in the tumor microenvironment. Transcriptome comparison showed 54.3% overlap with human LC (TCGA), in contrast to 29.88% overlap of KRAS-mutant mouse LC with human LC.

Conclusions

The transgenic and immunocompetent Oncopig model has a high rate of LC following bronchoscopic transbronchial induction. Overlap of the Oncopig LC transcriptome with human LC transcriptome was noted. This pig model is expected to have high clinical translatability to the human LC patient.
Evolution and functioning of an X-A balance sex determination system in hops
Authors: Akagi Takashi , Segawa Tenta , Uchida Rika , Tanaka Hiroyuki , Shirasawa Kenta , Yamagishi Noriko , Yaegashi Hajime , Natsume Satoshi , Takagi Hiroki , Abe Akira , Okuno Miki , Toyoda Atsushi , Sato Kyoko , Honniden Yuka , Zhang Cheng , Ushijima Koichiro , Patzak Josef , Horáková Lucie , Bačovský Václav , Hobza Roman , Charlesworth Deborah , Itoh Takehiko , Ono Eiichiro
Published: November 2024

Chromosomal sex determining systems with male heterogamety include actively male-determining-Y and X-A balance systems, both of which are found in animals and plants. The sex-determining genes have been identified in several active-Y plant systems, but the evolution and functioning of X-A balance systems remains mysterious. To study this, we sequenced and compared the genomes of two hop species. The evolution of the hop X-A balance system involved an ancient recombination suppression event across a large X chromosome region shared by both species. In one species, an autosome fused to this ancestral sex chromosome, and recombination was subsequently suppressed again. The two evolutionary strata created in this neo-X have degenerated to different degrees, and evolved correspondingly different dosage compensation levels that correlate with histone modification patterns. Finally, we identified an X-specific ETR1-like ethylene receptor in the ancestral X region. Its dosage may affect sex determination, as part of the counting mechanism of this X-A balance system.

One sentence summary

Based on whole genome sequences of the cultivated hop,Humulus lupulus, and its wild relativeH. japonicus, we describe the evolution of sex chromosomal regions, three of which that evolved region-specific dosage compensation, and identify a candidate gene involved in their X-A balance sex determining system.
Inducible FAK Deletion but not FAK Inhibition in Endothelial Cells Activates p53 to Suppress Tumor Growth in PYK2-null Mice
Authors: Chen Xiao Lei , Ojalill Marjaana , Jean Christine , Tancioni Isabelle , Jiang Shulin , Boyer Antonia , Ozmadenci Duygu , Uryu Sean , Tarin David , Schlessinger Joseph , Stupack Dwayne G. , Schlaepfer David D.
Published: November 2024

Focal adhesion kinase (FAK) functions as a signaling and scaffolding protein within endothelial cells (ECs) impacting blood vessel function and tumor growth. Interpretations of EC FAK-null phenotypes are complicated by related PYK2 (protein tyrosine kinase 2) expression, and to test this, we created PYK2-/-FAKfl/flmice with tamoxifen-inducible EC-specific Cre recombinase expression. At 11 weeks of age, EC FAK inactivation resulted in increased heart and lung mass and vascular leakage only on a PYK2-/-background. Surprisingly, ∼90% of PYK2-/-EC FAK-/-mice survived to 75 weeks of age. Syngeneic melanoma, breast, or lung carcinoma tumors did not grow in PYK2-/-EC FAK-/-mice, but tumors grew normally in PYK2-/-EC FAKfl/flmice lacking Cre. This tumor inhibitory phenotype was associated with abortive EC vessel sprouting, enhanced EC p53 tumor suppressor and p21CIP1 (cyclin-dependent inhibitor 1) expression, and alterations in serum cytokine levels. To discern the role of FAK kinase versus scaffolding activity in ECs, we generated kinase defective (FAK K454R, KD) PYK2-/-EC FAKfl/KDand PYK2-/-EC FAKfl/WT(WT, wildtype) mice. Hemizygous EC FAK-/KDexpression supported primary tumor growth but not metastasis, implicating EC FAK activity in tumor dissemination.In vitro, hemizygous expression of either WT or KD FAK suppressed EC p21CIP1 levels and cell death observed in primary PYK2-/-EC FAK-/-ECs. Combined FAK and PYK2 knockdown in tumor cells also increased p21CIP1 and PARP1 (poly ADP-ribose polymerase 1) levels in a p53-associated manner impacting anchorage-independent growth. Together, these results underscore the linkage between PYK2 and FAK loss with p53 activation impacting tumor growth.

Impact Statement

PYK2-null combined with endothelial cell-specific FAK transgenic mouse models show that loss of FAK activity limits tumor spread and that genetic or chemical degradation preventing combined FAK-PYK2 expression may be an approach to induce a p53-associated anti-tumor response.
Factors Associated with Failure of Fecal Microbiota Transplant for RecurrentClostridioides difficileInfection
Authors: Nguyen Joseph D. K. , Yohannes Kibret G. , Setiady Initha , Phillips Emma C. , Hays R. Ann , Behm Brian W. , Warren Cirle A. , Shin Jae Hyun
Published: November 2024

Background

Clostridioides difficileinfection (CDI) has emerged as a prevalent and recurrent antibiotic-associated infection. Fecal microbiota transplantation (FMT) is the most effective treatment for recurrent CDI (rCDI). Despite high success rates, FMT is ineffective in 5-20% of cases. Factors associated with failure have not been clearly defined. We seek to better understand factors predictive of FMT failure.

Methods

A retrospective chart review was conducted on adult patients who were screened at the ComplicatedC. difficileClinic at the University of Virginia Health System and received FMT for rCDI between 2013 and 2022. Primary outcome was failure of FMT, defined as either rCDI or all-cause death within one year.

Results

240 patients underwent FMT: 70.4% were female, median age was 68, and median episodes of CDI was 4. 24.6% experienced failure within the year (18.3% had rCDI and 7.1% died). Age 70 or older (p=0.007), male sex (p=0.013), ≥4 episodes of CDI (p=0.010), hypertension (p=0.010), diabetes mellitus (p=0.002), malignancy (p=0.034), high thyroid-stimulating hormone (p=2.696×10−5), anemia (p=0.002), and low zinc (p=0.025) were significantly associated with FMT failure on univariate analysis; age 70 or older (OR=2.66 [1.29-5.67]), ≥4 episodes of CDI (OR=3.13 [1.47-7.09]), and diabetes mellitus (OR=2.82 [1.25-6.50]) persisted to be associated with failure on multivariate analysis.

Conclusions

Our study shows that FMT remains an effective treatment for rCDI. We highlight several factors associated with FMT failure, such as older age, ≥4 episodes of CDI, anemia, elevated TSH, and low zinc, and the need for additional research to clearly define causality.
Increasing access to certified nurse-midwives prevents use of medical interventions during labor: an application of g-computation and target trial emulation
Authors: Simmons Elizabeth , Austin Anna , Wood Mollie , Mansfield Alyssa J. , Sheffield-Abdullah Karen , Singh Kavita
Published: November 2024

Background

Prenatal care (PNC) led by a certified nurse-midwife (CNM) may reduce medical interventions and complications during labor and delivery, compared to physician-led care. We estimated the prevalence of six outcomes if we intervened to increase the number of low-risk pregnant people enrolled in PNC with a CNM.

Methods

We used 2014-2019 Pregnancy to Early Life Longitudinal data. The study population comprised people aged 18-55 with a low-risk pregnancy who initiated PNC with a physician or CNM at <13 weeks gestation and had a live birth. We used g-computation to estimate the prevalence and prevalence difference of cesarean sections, labor inductions, epidural use, postpartum hemorrhage, maternal infection and obstetric trauma under hypothetical scenarios where 10%, 20% and 50% more people and 100% more people with government-funded insurance had CNM-led PNC. We adjusted for payer of delivery, maternal age, education, race, and estimated 95% confidence intervals (CI) using bootstrap resampling.

Results

Among 130,835 pregnant people, one-fourth had CNM-led PNC. A 10% increase in CNM-led PNC resulted in a reduction in the prevalence of cesarean sections of -0.39 percentage-points (95% CI: 0.41 to -0.35), in labor inductions of -0.21 percentage-points (95% CI: -0.25 to -0.17), in epidural use of -0.85 percentage-points (95% CI: -0.89 to -0.80), and in maternal infections of-0.08 percentage-points (95% CI: -0.11 to -0.06), but an increase in prevalence of postpartum hemorrhage of 0.03 percentage-points (95% CI: 0.01 to 0.05) and no change in prevalence of obstetric trauma (0.00 percentage-points; 95% CI: -0.02 to 0.03). The effect estimates were larger for 20% and 50% increases.

Conclusions

A scale-up of CNM-led care contributes to a decrease in use of some medical interventions and complications during labor and delivery.

Key Points

Our results suggest that interventions to increase the number of low-risk pregnancies attended by CNMs versus physicians could reduce the use of some medical interventions and complications during labor and delivery.

With 10% more low-risk pregnant individuals enrolled in prenatal care with a CNM, the prevalence of cesarean sections, labor inductions, epidural analgesia, and maternal infection decreased, while the prevalence of postpartum hemorrhage increased slightly, and the prevalence of obstetric trauma did not change.

As barriers to accessing care with a CNM still exist for low-risk pregnant populations, policy makers and clinical providers should help to reduce barriers to access to CNMs to help improve clinical outcomes.
An Optimal Mass Transport Model for the Analysis of DCE-MRI and its Application to Breast Cancer Treatment Response
Authors: Chen Xinan , Huang Wei , Shukla-Dave Amita , Paudyal Ramesh , Gullo Roberto Lo , Perez Marcelina , Pinker Katja , Deasy Joseph O.
Published: November 2024

Purpose

Dynamic contrast-enhanced MR imaging (DCE-MRI) is widely deployed in cancer care and research, but the methods conventionally used to quantify contrast agent kinetics do not account the cross-voxel movement characterized by advection and diffusion. We hypothesized that unbalanced optimal mass transport could be used to quantify and visualize such contrast agent flows across tumor volumes.

Methods

We developed a computational fluid dynamics model termed the unbalanced regularized optimal mass transport (urOMT) model. We tested the urOMT on a multi-institutional dataset of 153 longitudinal DCE-MRI scans from 39 breast cancer patients treated with neoadjuvant chemotherapy (NACT.)

Results

The urOMT model can quantify dynamic fluid transport properties such as net speed, flux and rates of contrast entering and leaving the tumor (influx and efflux). The urOMT model can also visualize the trajectories and directions of net fluid flows. Quantitative metrics from urOMT exhibited distinct patterns that may be relevant to predicting pathological complete response (pCR) to NACT.

Conclusion

The urOMT model can be used to estimate and visualize local fluid flow in DCE-MRI breast cancer images. Model-based estimates of flux, influx and efflux should be tested as potential predictive imaging biomarkers to measure treatment effectiveness in patients treated with NACT. The urOMT model in principle has applicability to other cancer imaging use cases, but this will require further testing.
Novel wheat germ agglutinin-based mass cytometry cell barcoding reagent for heterogeneous, live or fixed sample
Authors: Hannan Riley T , Barker Dayton , Cox Brendan P , Roosa Colleen A , Harper Taylor A. , Solga Michael D. , Griffin Donald R. , Sturek Jeffrey M.
Published: November 2024

Sample multiplexing in flow cytometry is a powerful technique which allows for reduction of error, inclusion of control samples for batch effect correction, and reduction in both time and consumable usage. Current industry standard for barcoding in mass cytometry is an intracellular reagent, which requires fixation and permeabilization of sample prior to barcoding. We developed a barcode using the ubiquitous and well-tolerated membrane labeling lectin, wheat germ agglutinin. This barcode effectively labels all tested cell types, both live and fixed. We determine that barcode yields, or the ratio of debarcoded cells to total input cells, is stable in live pooled sample for at least an hour. This barcode does not show differential performance across major PBMC lineages. Thus, this universal wheat germ agglutinin-based barcode represents an advance in gentle, non-reactive cell surface barcoding for live cells.
Biases in the Parsortix® system observed with pancreatic cancer cell lines
Authors: Vandenbussche Nele , Imschoot Renske , Lintermans Béatrice , Denolf Lode , Taminau Joachim , Fieuws Charlotte , Berx Geert , Gevaert Kris , Claes Kathleen B.M.
Published: November 2024

Pancreatic cancer has a 5-year survival rate of merely 12%. The high rate of late-stage diagnoses underscores the need for reliable biomarkers for early detection and disease monitoring. Circulating tumor cells (CTCs) have emerged as a promising biomarker, yet their detection remains challenging due to their rarity and phenotypic diversity. This study evaluates the Parsortix® system, a microfluidic device designed to enrich CTCs based on size and deformability, using pancreatic cancer cell lines. As increasing evidence indicates that during epithelial to mesenchymal transition (EMT) a cell’s deformability increases, we evaluated to what extent the Parsortix® system was biased towards epithelial cancer cells. First, the EMT stage of three pancreatic cancer cell lines, CAPAN-1, PANC-1 and MIA PaCa-2, was assessed using immunocytochemistry, flow cytometry and proteomics. CAPAN-1 cells were classified as epithelial, MIA PaCa-2 cells exhibited a mesenchymal-like phenotype, and PANC-1 cells demonstrated a hybrid phenotype. Then, by spiking these cells into blood samples, we determined the Parsortix® system’s ability to recover the cancer cells. Our results indicated that epithelial and hybrid phenotypes are more efficiently captured (62.6 ± 18.5% and 65.4 ± 11.1%) than mesenchymal cancer cells (32.8 ± 10.2%). To confirm these findings, spike-in experiments were repeated using an EMT inducible cell line. Again, significantly lower recovery rates were found for the cells in a mesenchymal-like state (31.5 ± 6.4%) compared to those in an epithelial state (47.56 ± 7.2%). In conclusion, the Parsortix® system may underestimate the presence of mesenchymal CTCs.
L-lactic acid induces short- and long-term cardioprotective effects through MCT1 transport, induction of metabolic reprogramming, and gene expression modulation
Authors: Cler Marina , Pérez-Amodio Soledad , Valls-Lacalle Laura , Martínez-Fraiz Elena , Barba Ignasi , Ganse Freddy G. , Nicastro Laura , Terracciano Cesare M. , Rodríguez-Sinovas Antonio , Engel Elisabeth
Published: November 2024

Lactic acid is recognized as an alternative fuel source for various tissues and is acknowledged for its protective effects in the brain. However, its potential as a cardioprotective agent remains controversial. Here, we aimed to (1) evaluate the impact of acute L-lactic acid administration, given at the onset of reperfusion, on myocardial infarct size in isolated mouse hearts submitted to transient global ischemia, (2) assess the effects of chronic L-lactic acid exposure in living myocardial slices (LMS) from human hearts, and (3) elucidate the underlying mechanisms. Isolated mouse hearts were submitted to global ischaemia (35 min) followed by reperfusion (60 min), with L-lactic acid being or not administered during the first 15 min of reperfusion. L-lactic acid reduced infarct size by 23% at 20 mmol/L. An acidic Krebs induced less protection, and monocarboxylate transporter 1 (MCT1) inhibition with AR-C 141990 attenuated L-lactic acid’s protection to the level of acidic Krebs.1H NMR spectroscopy revealed significant metabolic changes in L-lactic acid-treated hearts, with pathway enrichment analysis showing a nearly a 3-fold enrichment in pyruvate metabolism, fatty acid biosynthesis, and gluconeogenesis, suggesting a metabolic shift. Moreover, electrically stimulated human LMS treated with L-lactic acid for 48 h exhibited improved contractility and upregulation of structural and functional cardiomyocyte components, stemness-related markers, and pro-angiogenic proteins. These findings support a cardioprotective role for L-lactic acid in both short- and long-term contexts, mediated in part by its uptake through the MCT1 transporter, induction of metabolic reprogramming, and gene expression modulation.
Discovery of A Chimeric Polyketide Family as Cancer Immunogenic Chemotherapeutic Leads
Authors: Xue Dan , Xu Mingming , Madden Michael D. , Lian Xiaoying , Older Ethan A. , Pulliam Conor , Hui Yvonne , Shang Zhuo , Gupta Gourab , Raja Manikanda K. , Wang Yuzhen , Sardi Armando , Long Yaoling , Chen Hexin , Fan Daping , Bugni Tim S. , Testerman Traci L. , Wu Qihao , Li Jie
Published: November 2024

Discovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for cancer treatment that uses a chemical drug to achieve the efficacy of both chemotherapy and immunotherapy. Herein we report a high-throughput screening platform and the subsequent discovery of a new class of cancer immunogenic chemotherapeutic leads. Our platform integrates informatics-based activity metabolomics for rapid identification of microbial natural products with both novel structures and potent activities. Additionally, we demonstrate the use of microcrystal electron diffraction (MicroED) for direct structure elucidation of the lead compounds from partially purified mixtures. Using this strategy to screen geographically and phylogenetically diverse microbial metabolites against pseudomyxoma peritonei, a rare and severe cancer, we discovered a new class of leads, aspercyclicins. The aspercyclicins feature an unprecedented tightly packed polycyclic polyketide scaffold that comprises continuous fused, bridged, and spiro rings. The biogenesis of aspercyclicins involves two distinct biosynthetic pathways, leading to formation of chimeric compounds that cannot be predicted by bottom-up approaches mining natural products biosynthetic genes. With comparable potency to some clinically used anticancer drugs, aspercyclicins are active against multiple cancer cell types by inducing immunogenic cell death (ICD), including the release of damage-associated molecular patterns and subsequent phagocytosis of cancer cells. The broad-spectrum ICD-inducing activity of aspercyclicins, combined with their low toxicity to normal cells, represents a new class of potential cancer immunogenic chemotherapeutics and particularly the first drug lead for pseudomyxoma peritonei treatment.
NOLC1 Suppresses Immuno-chemotherapy by Inhibiting p53-mediated Ferroptosis in Gastric Cancer
Authors: Zhao Shengsheng , Lin Ji , Zhu Bingzi , Jin Yin , Dong Qiantong , Ruan Xiaojiao , Jin Dan , Yi Yongdong , Bai Binglong , Li Hongzheng , Liang Danna , Lu Jianhua , Meng Letian , Wang Xiang , Cui Yuekai , Gu Yuyang , Shen Xian , Lu Xufeng , Rao Shangrui , Sun Weijian
Published: November 2024

Gastric cancer (GC) is one of the most malignant cancers, and cisplatin (Cis)-based chemotherapy remains the main clinical treatment for GC. However, Cis resistance often occurs, largely limiting its therapeutic efficacy in tumors. Therefore, a better understanding of the drug resistance mechanism could reveal new approaches for improving GC treatment efficacy. Here, we define the integrative role of nucleolar and coiled-body phosphoprotein 1 (NOLC1), a molecular chaperone that is significantly upregulated in GC tissues and Cis-resistant GC cells. Knocking down NOLC1 increased GC sensitivity to Cis by regulating ferroptosis. Mechanistically, NOLC1 binds to the p53 DNA binding domain (DBD), decreasing p53 nuclear translocation stimulated by Cis and suppressing p53 transcriptional functions. Then, the p53-mediated ferroptosis is suppressed. Furthermore, the silence of NOLC1 promoted ferroptosis-induced immunogenic cell death (ICD) and reprogrammed the immunosuppressive tumor microenvironment, thereby increasing sensitivity to anti-programmed cell death-1 (PD-1) therapy plus Cis. The combination of anti-PD-1 plus Cis effectively inhibited GC growth without significant side effects. In summary, our findings reveal that targeting NOLC1 may be a novel therapeutic strategy for GC and may increase the efficacy of chemotherapy combined with immune checkpoint inhibitor (ICI) therapy.
Maximizing meiotic crossover rate reveals the map of Crossover Potential
Authors: Jing Juli , Lian Qichao , Durand Stephanie , Mercier Raphael
Published: November 2024

Meiotic crossovers are limited in number and unevenly distributed along chromosomes, both features often differing between sexes. The mechanisms imposing a different crossover landscape in female and male meiosis remain elusive. Here, we simultaneously disrupted multiple anti-crossover mechanisms in Arabidopsis and analyzed the whole genome sequence of thousands of female- and male-derived progenies. The largest crossover increase was reached inzyp1 recq4, with 12-fold in females and a 4.5-fold increase in males. Despite this unprecedented level of crossovers, fertility is marginally affected, opening new possibilities for plant breeding. Manipulating additional crossover regulators inzyp1 recq4did not further elevate the frequency of crossovers, but modified the relative contributions of the two known crossover pathways. This suggests an upper limit was reached and the two pathways compete for a large but limited set of recombination intermediates. Remarkably, while wild-type crossover distribution differs markedly between sexes, the crossover landscapes of diverse mutants in both females and males converge to a single novel profile, which we termed Crossover Potential (COP). The COPprofile, which we defined using 49,482 crossovers, can be accurately predicted using only sequence divergence and chromatin features. We propose that the COPrepresents the density of eligible recombination precursors, which is determined by genomic features and is thus identical in females and males. It suggests that the sexual dimorphism in the crossover landscape results exclusively from differential regulation of the likeness of precursors to mature into crossovers.
The Impact of Brain-Derived Neurotrophic Factor Polymorphism and Stimulation Parameters on the Response to Repetitive Transcranial Magnetic Stimulation: A Systematic Review
Authors: Kuo Yi-Ling , Lin Gracy , Glatt Stephen J.
Published: November 2024

Introduction

TMS has been a common technique used to stimulate neuromodulatory changes, which can have therapeutic effects. The underlying mechanism is still unknown, however it is thought to cause neuroplastic changes via LTD or LTP. However, the effects are highly variable, with demographics and baseline physiology thought to be playing a role.

Objectives

The purposes of this systematic review were to 1) examine how BDNF polymorphisms are related to the after-effects of rTMS in humans and 2) investigate the association between BDNF polymorphism and rTMS stimulation parameters as contributing factors to the response to rTMS.

Materials and Methods

Studies identified from PubMed, The Cochrane Library, and Embase were screened for eligibility. Data were extracted from the selected studies by one reviewer and verified by another reviewer. Risk of Bias was assessed using the Cochrane Collaboration’s tool. Results were synthesized narratively.

Results

Of the 224 initial studies, 35 were included in this systematic review. 33 out of 35 studies had at least one domain of high or unclear risk of bias. 53% of the studies in healthy individuals showed differences in TMS-derived or behavioral measures between Val/Val homozygotes and Met allele carriers. The neuromodulatory effects were more reliable in Val/Val homozygotes than Met allele carriers. In stroke, neuromodulatory effects on corticospinal excitability and motor deficits were more evident in Val/Val homozygotes than Met allele carriers. Similarly, in depression, Val/Val homozygotes demonstrated more improvement in depression symptoms compared with Met allele carriers following rTMS. The role of BDNF polymorphism in other disorders remained unclear.

Conclusion

It remains inconclusive whether and how BDNF genotype impacts the effects of rTMS. Methodological heterogeneity in the stimulation parameters, such as dosage and excitatory or inhibitory protocols, interact with BDNF polymorphism and contribute to the response to rTMS.