bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative effectiveness of pre-epiglottic baton plates and mandibular distraction in infants with Robin sequence
Authors: Resnick Cory M. , de Gijsel Jens , Jindal Snigdha , Quante Mirja , Poets Christian , Katz Eliot , Wiechers Cornelia 
Published: November 2024

Background:
Mandibular distraction osteogenesis (MDO) and pre-epiglottic baton plates (PEBP) are both effective for early management of upper airway obstruction (UAO) in infants with Robin sequence (RS), but have not been directly compared. The purpose of this study was to compare early airway, feeding and growth outcomes between these treatments.

Methods:
This is a bicentric retrospective cohort study from 2015-2021 including infants with RS treated with MDO or PEBP before 6 months-of-age with pre- and post-treatment sleep studies and follow-up at least through age 1-year. The primary outcome was immediate post-intervention UAO, measured as obstructive apnea-hypopnea index (oAHI) or obstructive apnea index (oAI), as available. Latest follow-up sleep studies, feeding and growth characteristics were also assessed.

Results:
114 subjects were included: MDO, n=31 and PEBP, n=83. Pre-treatment UAO was similar between groups (p=0.61). PEBP was initiated at a younger age (median [IQR] 31 [14,53] vs. 41 [28,84] days-of-life, p<0.05). Significant reduction of oAHI/oAI was achieved in both groups, but greater with MDO (98%) compared to PEBP (94%, p<0.05). PEBP demonstrated better early feeding and growth outcomes compared to MDO, with fewer surgical feeding tubes (p<0.001) and more rapid early growth (p=0.038). When stratified by pre-intervention UAO, infants starting with moderate UAO experienced similar airway outcomes with both treatments (p=0.11), while those with severe UAO had greater resolution with MDO (p<0.001).

Conclusion:
Both treatments effectively relieve moderate UAO in infants with RS, but MDO is more effective for infants with severe respiratory compromise.
The impact of transfusion kinetics on the inflammatory response following major injury
Authors: Carney Patrick R. , Zarzaur Ben L. , Holcomb John B. , Fox Erin E. , Wade Charles E. , Savage Stephanie A. 
Published: November 2024

BACKGROUND
The innate immune response is activated by tissue injury and may quickly become dysregulated in the setting of major trauma. Cytokines are a key component of this response and function to activate and mobilize neutrophils, macrophages, and natural killer cells. The purpose of this study was to understand how the kinetics of blood-based resuscitation may impact the cytokine response. Specifically, we hypothesize that transfusion kinetics make a fundamental contribution to the inflammatory response, beyond the volume of transfusion and injury severity.

METHODS
The Pragmatic, Randomized Optimal Platelet and Plasma Ratio data set was used in this retrospective analysis. Transfusion kinetics were quantified by calculating the total critical administration threshold episodes in three time periods, 1 to 2 hours following injury, 3 to 4 hours, and 5 to 6 hours following injury. The longitudinal response of key cytokines over 72 hours was assessed with a multivariable linear growth model, using critical administration threshold status as a time-varying covariate.

RESULTS
A total of 522 patients were included in this analysis. Pro-inflammatory cytokines interleukin (IL)-6 (p = 0.0354) and IL-8 (p < 0.0001) were significantly increased. Anti-inflammatory cytokines IL-1ra (p = 0.0001) and IL-10 (p < 0.0001) were significantly increased. Chemokines interferon-γ-inducible protein 10 (p = 0.0433), monocyte chemoattractant protein-1 (p = 0.0064), and macrophage inflammatory protein 1β (p = 0.0003) were significantly increased, while regulated up activation, normal T-cell expressed and secreted chemokine (p = 0.0216) was significantly decreased. Growth factors showed no significant response.

CONCLUSION
The kinetics of packed red blood cell transfusion demonstrate a potential association with the expression of cytokines following injury, beyond the total transfusion requirement or the severity of injury. Because cytokines activate and mobilize neutrophils, macrophages, and natural killer cells, these alterations may have a profound effect on degree and coordination of the immune response. As the contribution of various components of major resuscitation to inflammatory activation is clarified, such as types of blood product, tempo of transfusion, and operative care, targets for intervention should become more apparent.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Percutaneous and endoscopic transpapillary cholecystoduodenal stenting in acute cholecystitis—A viable long-term option in high-risk patients?
Authors: Argandykov Dias , El Moheb Mohamad , Nzenwa Ikemsinachi C. , Kalva Sanjeeva P. , Iqbal Shams , Smolinski-Zhao Sara , Krishnan Kumar , Velmahos George C. , Paranjape Charudutt 
Published: November 2024

BACKGROUND
The prolonged use of percutaneous cholecystostomy tubes (PCTs) in patients with acute cholecystitis, deemed inoperable, is fraught with complications. Transpapillary cholecystoduodenal stenting (TCDS) is an alternative technique that restores the physiologic outflow of bile, avoiding the need for an external drain. However, the long-term safety and efficacy of this approach remain unclear. We sought to prospectively assess the safety and efficacy of this procedure, performed via percutaneous or endoscopic approach, in high-risk patients presenting with acute cholecystitis.

METHODS
This prospective study included consecutive patients with acute cholecystitis and long-lasting, prohibitive surgical risk, in whom TCDS was offered at two partnering tertiary care centers between August 1, 2018, and December 31, 2022. Patients with a need for endoscopic retrograde cholangiopancreatography (ERCP) underwent ERCP-guided TCDS. In patients without a need for ERCP, a temporary PCT was followed by fluoroscopic-guided TCDS 4 weeks to 6 weeks later. Interval cholecystectomy was performed in patients who became surgical candidates later. All patients were followed up until January 1, 2023.

RESULTS
Transpapillary cholecystoduodenal stenting was successful in 67 (percutaneous in 45/50; endoscopic in 22/23) of 73 patients (92%) attempted. Over a median follow-up period of 17 months (7, 26), 10 patients (15%) developed stent blockage or migration; all but two had their stent successfully replaced. Five patients (7%) developed mild, self-limited pancreatitis. Five (7%) patients underwent interval cholecystectomy at a median time of 7 months.

CONCLUSION
Transpapillary cholecystoduodenal stenting is a safe and promising definitive alternative to chronic PCT in high-risk patients with acute cholecystitis that eliminates the discomfort and complications of long-term external drainage.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level II.
Broadening indications: A descriptive and comparative in-depth analysis of venovenous extracorporeal membrane oxygenation outcomes in trauma and nontrauma patients
Authors: Spivak Holden , Rao Appajosula , Haase Daniel , Galvagno Samuel , Kundi Rishi , O'Connor James , Stein Deborah , Scalea Thomas , Powell Elizabeth 
Published: November 2024

BACKGROUND
Venovenous extracorporeal membrane oxygenation (VV ECMO) has been used for medical etiologies of acute respiratory distress syndrome refractory to conventional management. More recently, VV ECMO has been used to stabilize trauma patients with acute lung injury. We hypothesize that patients with traumatic injuries requiring VV ECMO have similar survival outcomes and describe the characteristics between the two populations.

METHODS
This single-center, retrospective cohort study included all trauma and nontrauma patients in an 8-year period who were placed on VV ECMO. Cannulation decisions were made via multidisciplinary discussions between two intensivists and a trauma surgeon. Data were analyzed with descriptive statistics and regression analysis. After testing for normality, significance was defined as a p < 0.05.

RESULTS
A total of 516 patients were identified (438 nontrauma and 78 trauma VV ECMO patients). The trauma patient, defined as undergoing cannulation during initial trauma admission, had a median age of 29 years with 81% of patients being male, while the nontrauma patient had a median age of 41 years with 64% being males. Trauma VV ECMO patients had shorter ECMO courses (216 hours vs. 372 hours, p < 0.001), earlier cannulation (8 hours vs. 120 hours, p < 0.001), higher lactic acid levels precannulation (4.2 mmol/L vs. 2.3 mmol/L, p < 0.001), higher Sequential Organ Failure Assessment scores (13 vs. 11, p = 0.001), and higher Simplified Acute Physiology Scores II (63 vs. 48, p < 0.001). There was no difference in bleeding complications. Survival to discharge rates were similar between trauma and nontrauma VV ECMO groups (69% vs. 71%, p = 0.81).

CONCLUSION
This study demonstrates that trauma VV ECMO patients have higher markers of severe illness/injury when compared with their nontrauma VV ECMO counterparts yet have similar survival rates and shorter ECMO runs. Venovenous extracorporeal membrane oxygenation in trauma patients is a useful treatment modality for refractory hypoxemia, respiratory acidosis, and stabilization because of acute lung and thoracic injury.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level IV.
Combining functional annotation and multi-trait fine-mapping methods improves fine-mapping resolution at glycaemic trait loci
Authors: Soenksen Jana , Chen Ji , Varshney Arushi , Martin Susan ,   MAGIC, Parker Stephen C. J. , Morris Andrew P. , Asimit Jennifer L. , Barroso Inês 
Published: November 2024

AbstractThe Meta-Analysis of Glucose and Insulin-related traits Consortium (MAGIC) identified 242 loci associated with glycaemic traits fasting insulin (FI), fasting glucose (FG), 2h-Glucose (2hGlu), and glycated haemoglobin (HbA1c). However, most causal variants remain unknown. We investigated whether combining multi-trait fine-mapping with functional information would improve fine-mapping resolution.Using single-trait fine-mapping results (FINEMAP) as input, we performed multi-trait fine-mapping (flashfm) at 50 loci significantly associated with >1 glycaemic trait. We considered 32 cell-type specific and 28 static annotations to build enrichment models with fGWAS. We performed annotation-informed fine-mapping, using FINEMAP and flashfm, with resulting prior probabilities.Compared to annotation-agnostic single-trait fine-mapping, multi-trait fine-mapping reduced median 99% credible set sizes (99% CS) from 58 to 17.5 (p=5.75 × 10−18). Annotation information reduced 99% CS from 67 to 50.5 (p=1.57×10−7) in single-trait, and to 14.5 (p=2.69×10−18) in multi-trait fine-mapping.In conclusion, multi-trait and annotation-informed fine-mapping narrow down likely causal variants, separately and combined.
IMMClock reveals immune aging and T cell function at single-cell resolution
Authors: Schmidt Yael Gurevich , Wu Di , Madan Sanna , Sinha Sanju , Sahni Sahil , Gopalan Vishaka , Wang Binbin , Dhruba Saugato Rahman , Schäffer Alejandro A. , Weng Nan-ping , Restifo Nicholas P. , Wang Kun , Ruppin Eytan 
Published: November 2024

AbstractThe aging of the immune system substantially impacts individual immune responses, yet accurately quantifying immune age remains a complex challenge. Here we developedIMMClock, a novel immune aging clock that uses gene expression data to predict the biological age of individual CD8⁺ T cells, CD4⁺ T cells, and NK cells. The accuracy of IMMClock is first validated across multiple independent datasets, demonstrating its robustness. Second, utilizing the IMMClock, we find that intrinsic cellular aging processes are more strongly altered during immune aging than differentiation processes. Thirdly, our analysis confirms the strong associations between immune aging and established processes such as cellular senescence, exhaustion, and telomere length at the single cell level. Furthermore, immune aging is accelerated under several disease conditions such as type 2 diabetes, heart disease, and cancer. Finally, we apply IMMClock to analyze a perturb-seq gene activation screen of T cell functionality. We find that the post-perturbation immune age of individual T cells is strongly correlated with their pre-perturbation immune age. Furthermore, the immune age at resting state of individual T cells is strongly predictive of their post-stimulation activation state. Overall, IMMClock advances our understanding of immune aging by providing precise, single-cell level age estimations. Its future applications hold promise for identifying interventions that concomitantly rejuvenate and activate T cells, potentially enhancing efforts to counteract age-related immune decline.
Identification of Ephrin type-B receptor 4 as a critical mediator of tissue fibrosis
Authors: Wu Brian , Lively Starlee S. , Fine Noah , Pastrello Chiara , Maglaviceanu Anca , Espin-Garcia Osvaldo , Pollock-Tahiri Evan , Nakamura Sayaka , Kaur Paramvir , Rockel Jason S. , Potla Pratibha , Gupta Himanshi , Datta Poulami , Tang Laura , Vohra Shabana , Nakamura Akihiro , Gandhi Rajiv , Wu Jiangping , Hinz Boris , Jurisica Igor , Kapoor Mohit 
Published: November 2024

ABSTRACTPulmonary fibrosis (PF) is a pathology associated with interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF). Fibrosis promotes continual secretion of extracellular matrix (ECM), producing non-functional scar tissue and causing organ failure. This study investigated the tyrosine kinase receptor Ephrin type-B receptor 4 (EphB4) as a mediator of PF. To this end, we generated mice with conditionalCol1a2-driven deletion ofEphb4and used a preclinical mouse model of PF, total and single nuclei RNA sequencing, NanoString, publicly available single cell data, computational analysis, and functional assays of mouse and human healthy control and IPF lung fibroblasts.Col1a2-CreERT-drivenEphb4deletion, or EphB4 inhibition via NVP-BHG712, markedly protected against bleomycin-induced PF. Total RNA-sequencing of fibroblasts isolated fromEphb4-deficient fibrotic mouse lungs exhibited reduced expression of ECM, ER Cargo, and protein trafficking-related genes. NVP-BHG712 reduced expression of these identified genes in mouse lung fibroblasts under fibrotic conditionsin vitro. Single nuclei RNA sequencing of mouse lungs treated with NVP-BHG712 identified transcriptomic changes of ECM genes in specific fibroblast subpopulations. Total RNA sequencing, computational, and functional assays using mouse and human IPF fibroblasts identified elastin as a key mediator involved in EphB4 signaling. Overall, we identified EphB4 as a crucial mediator of PF.
Large-Scale Quantitative Cross-Linking and Mass Spectrometry Provides New Insight on Protein Conformational Plasticity within Organelles, Cells, and Tissues
Authors: Keller Andrew , Bakhtina Anna , Bruce James E. 
Published: November 2024

AbstractMany proteins can exist in multiple conformational statesin vivoto achieve distinct functional roles. These states include alternative conformations, variable PTMs, and association with interacting protein, nucleotide, and ligand partners. Quantitative chemical cross-linking of live cells, organelles, or tissues together with mass spectrometry provides the relative abundance of cross-link levels formed in two or more compared samples, which depends both on the relative levels of existent protein conformational states in the compared samples as well as the relative likelihood of the cross-link originating from each. Because cross-link conformational state preferences can vary widely, one expects intra-protein cross-link levels from proteins with high conformational plasticity to display divergent quantitation among samples with differing conformational ensembles. Here we use the large volume of quantitative cross-linking data available on the public XLinkDB database to cluster intra-protein cross-links according to their quantitation in many diverse compared samples to provide the first widescale glimpse of cross-links grouped according to the protein conformational state(s) from which they predominantly originate. We further demonstrate how cluster cross-links can be aligned with any protein structure to assess the likelihood that they were derived from it.
Integrating Nanopore MinION Sequencing into National Animal Health AMR Surveillance Programs: An Indonesian Pilot Study of Chicken Slaughterhouse Effluent and Rivers
Authors: Telussa Rallya , Rahayu Puji , Yunindika Thufeil , Kapsak Curtis , Rahayu Kanti Puji , Susanti Oli , Suandy Imron , Triwijayanti Nuraini , Niasono Aji B. , Ma’arif Syamsul , Wibawa Hendra , Lestari  , Utomo Gunawan B. , Zenal Farida C. , Schoonman Luuk , Voth-Gaeddert Lee E. 
Published: November 2024

AbstractAntimicrobial resistance (AMR) poses significant risks to human and animal health while the environment can contribute to its spread. National AMR surveillance programs are pivotal for assessing AMR prevalence, trends, and intervention outcomes, however, integrating advanced surveillance tools can be difficult. This pilot study, conducted by FAO ECTAD Indonesia and DGLAHS, Indonesian Ministry of Agriculture, evaluated the costs and benefits of integrating the Nanopore MinION, Illumina MiSeq, and Sensititre system into a culture-based slaughterhouse-river surveillance system. Water samples were collected from six chicken slaughterhouses and adjacent rivers (pre- and post-treatment effluent, upstream, downstream). Culture-based ESBL and generalE. coliconcentrations were estimated via the WHO Tricycle Protocol, while isolates (n=42) were sequenced (MinION, MiSeq) and antimicrobial susceptibility testing conducted (Sensititre). The Tricycle Protocol results provided estimates of effluent and river concentrations of ESBL and generalE. coliidentifying ESBL-to-generalE. coliratios of 13.8% and 6.2%, respectively. Compared to hybrid sequencing assemblies, MinION had a higher concordance than MiSeq for ARG identification (98%), virulence genes (96%), and locations for both (predominately plasmids). Furthermore, MinION concordance with Sensititre AST was 91%. Cost-benefit comparisons suggest sequencing can complement culture-based methods but is dependent on the value placed on the additional information gained.Highlights:This study demonstrates the integration of Nanopore MinION sequencing into a national AMR surveillance program, highlighting its potential for monitoring antibiotic-resistantE. coliin slaughterhouse effluent and rivers.Our findings show that Nanopore MinION sequencing exhibits high concordance with hybrid sequencing assemblies, validating its effectiveness for genomic surveillance in decentralized settings.The study evaluates the cost-benefit of using Nanopore MinION, Illumina MiSeq, and Sensititre AST, comparing information gained with cost.Graphical Abstract
Negative regulation of miRNAs sorting in EVs: the RNA-binding protein PCBP2 impairs SYNCRIP-mediated miRNAs EVs loading
Authors: Marocco Francesco , Garbo Sabrina , Montaldo Claudia , Colantoni Alessio , Quattrocchi Luca , Gaboardi Gioele , Cicchini Carla , Tartaglia Gian Gaetano , Battistelli Cecilia , Tripodi Marco 
Published: November 2024

ABSTRACTWhile it is accepted that Extracellular Vesicles (EVs)-mediated transfer of microRNAs contributes to intercellular communication, the knowledge about molecular mechanisms controlling the selective and dynamic miRNA-loading in EVs is still limited to few specific RNA-binding proteins interacting with sequence determinants. Moreover, although mutagenesis analysis demonstrated the presence/function of specific intracellular retention motifs, the interacting protein/s remained unknown.Here, PCBP2 was identified as a direct interactor of an intracellular retention motif: RIP coupled to RNA pull down and proteomic analysis demonstrated that it binds to miRNAs embedding this motif and mutagenesis proved the binding specificity. Notably, PCBP2 binding requires SYNCRIP, a previously characterized miRNA EV-loader as indicated by SYNCRIP knock-down.SYNCRIP and PCBP2 may contemporarily bind to miRNAs as demonstrated by EMSA assays and PCBP2 knock-down causes EV-loading of intracellular microRNAs.This evidence highlights that multiple proteins/miRNA interactions govern miRNA compartmentalization and identifies PCBP2 as a dominant inhibitor of SYNCRIP function.
Multi-omic analyses of a twin pair with mirror image cleft lip identifies pathogenic variant inFGF20modified by differential methylation upstream ofZFP57
Authors: Awotoye Waheed , Machado-Paula Ligiane A , Hovey Luke , Keen Henry , Chimenti Michael , Darbro Benjamin , Dabdoub Shareef , Thomas James C , Murray Jeff , Rengasamy Venugopalan Shankar , Moreno-Uribe Lina , Petrin Aline L 
Published: November 2024

AbstractBackgroundDisturbances in the intricate processes that control craniofacial morphogenesis can result in birth defects, most common of which are orofacial clefts (OFCs). Nonsyndromic cleft lip (nsCL), one of the phenotypic forms amongst OFCs, has a non-random laterality presentation with the left side being affected twice as often compared to the right side. This study investigates the etiology of nsCL and the factors contributing to its laterality using a pair of monozygotic twins with mirror-image cleft lip.MethodsWe conducted whole-genome sequencing (WGS) analyses in a female twin pair with mirror image nsCL, their affected mother and unaffected father to identify etiopathogenic variants. Additionally, to identify possible cleft lip laterality modifiers, DNA-methylome analysis was conducted to test for differential methylation patterns between the mirror twins. Lastly, DNA methylation patterns were also analyzed on an independent cohort of female cases with unilateral cleft lip (left=22; right=17) for replication purposes.ResultsWe identified a protein-altering variant inFGF20(p.Ile79Val) within the fibroblast growth factor interacting family domain segregating with the nsCL in this family. Concurrently, DNA-methylome analysis identified differential methylation regions (DMRs) upstream of Zinc-finger transcription factorZFP57(Δβ > 5%). Replication of these results on an independent cohort, confirmed these DMRs, emphasizing their biological significance (p<0.05). Enrichment analysis indicated that these DMRs are involved in DNA methylation during early embryo development (FDR adjusted p-value = 1.3241E-13). Further bioinformatics analyses showed one of these DMRs acting as a binding site for transcription factorAP2A(TFAP2A), a key player in craniofacial development. Interactome analysis also suggested a potential role forZFP57in left/right axis specification, thus emphasizing its significance in cleft laterality.ConclusionThis study provides novel insights into the etiology of nsCL and its laterality, suggesting an interplay between etiopathogenic variants and DNA methylation in cleft laterality. Our findings elucidate the intricate mechanisms underlying OFCs development. Understanding these factors may offer new tools for prevention and management of OFCs, alleviating the burden on affected individuals, their families and global health.