bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell multi-omics analysis identifies context-specific gene regulatory gates and mechanisms
Authors: Malekpour Seyed Amir , Haghverdi Laleh , Sadeghi Mehdi
Published: April 2024

There is a growing interest in inferring context specific gene regulatory networks from single-cell RNA sequencing (scRNA-seq) data. This involves identifying the regulatory relationships between transcription factors (TFs) and genes in individual cells, and then characterizing these relationships at the level of specific cell types or cell states. In this study, we introduce scGATE (single-cell gene regulatory gate) as a novel computational tool for inferring TF–gene interaction networks and reconstructing Boolean logic gates involving regulatory TFs using scRNA-seq data. In contrast to current Boolean models, scGATE eliminates the need for individual formulations and likelihood calculations for each Boolean rule (e.g. AND, OR, XOR). By employing a Bayesian framework, scGATE infers the Boolean rule after fitting the model to the data, resulting in significant reductions in time-complexities for logic-based studies. We have applied assay for transposase-accessible chromatin with sequencing (scATAC-seq) data and TF DNA binding motifs to filter out non-relevant TFs in gene regulations. By integrating single-cell clustering with these external cues, scGATE is able to infer context specific networks. The performance of scGATE is evaluated using synthetic and real single-cell multi-omics data from mouse tissues and human blood, demonstrating its superiority over existing tools for reconstructing TF-gene networks. Additionally, scGATE provides a flexible framework for understanding the complex combinatorial and cooperative relationships among TFs regulating target genes by inferring Boolean logic gates among them.
CovEpiAb: a comprehensive database and analysis resource for immune epitopes and antibodies of human coronaviruses
Authors: Zhang Xue , Wu JingCheng , Luo Yuanyuan , Wang Yilin , Wu Yujie , Xu Xiaobin , Zhang Yufang , Kong Ruiying , Chi Ying , Sun Yisheng , Chen Shuqing , He Qiaojun , Zhu Feng , Zhou Zhan
Published: April 2024

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/.
New liquid chromatography tandem mass spectrometry reference data for estradiol show mini-puberty in both sexes and typical pre-pubertal and pubertal patterns
Authors: Kulle Alexandra E , Caliebe Amke , Lamprecht Tabea , Reinehr Thomas , Simic-Schleicher Gunter , Schulz Esther , Kleber Michaela , Rothermel Juliane , Heger Sabine , Hiort Olaf , Holterhus Paul-Martin
Published: April 2024

Context

Reliable estradiol (E2) reference intervals (RIs) are crucial in pediatric endocrinology.

Objectives

This study aims to develop a sensitive ultra-performance liquid chromatographic tandem mass spectrometry (UPLC-MS/MS) method for E2 in serum, to establish graphically represented RI percentiles and annual RIs for both sexes, and to perform a systematic literature comparison.

Methods

First, a UPLC-MS/MS method for E2 was developed. Second, graphically represented RI percentiles and annual RIs covering 0-18 years were computed (cohort of healthy children [1181 girls and 543 boys]). Subsequently, RIs were compared with published data by systematic searches.

Results

Lower limit of quantification was 11 pmol/L, indicating high sensitivity. Estradiol first peaked during mini-puberty in both sexes (girls up to 192 pmol/L; boys up to 225 pmol/L). As could be expected, girls showed higher pubertal E2 (up to 638 pmol/L). However, boys' RIs (up to 259 pmol/L) overlapped considerably. We found 4 studies in the literature that also used LC-MS/MS to determine E2 and published RIs for the complete pediatric age range. Reference intervals varied considerably. Pre-pubertal and pubertal phases were present in all studies. Higher E2 during the time of mini-puberty in both sexes was documented in 3 studies including ours.

Conclusions

Variability of RIs for E2 between studies illustrates the importance of laboratory-specific RIs despite using a LC-MS/MS reference method. In boys, the striking E2 peak during mini-puberty as well as high pubertal E2 without phenotypic estrogenization in regular male puberty indicates that the role of E2 in children and, especially in boys, requires better functional understanding.
MAB-5/Hox regulates the Q neuroblast transcriptome, including cwn-1/Wnt, to mediate posterior migration in Caenorhabditis elegans
Authors: Paolillo Vitoria K , Ochs Matthew E , Lundquist Erik A
Published: April 2024

Neurogenesis involves the precisely coordinated action of genetic programs controlling large-scale neuronal fate specification down to terminal events of neuronal differentiation. The Q neuroblasts in Caenorhabditis elegans, QL on the left and QR on the right, divide, differentiate, and migrate in a similar pattern to produce three neurons each. However, QL on the left migrates posteriorly, and QR on the right migrates anteriorly. The MAB-5/Hox transcription factor is necessary and sufficient for posterior Q lineage migration and is normally expressed only in the QL lineage. To define genes controlled by MAB-5 in the Q cells, fluorescence-activated cell sorting was utilized to isolate populations of Q cells at a time in early L1 larvae when MAB-5 first becomes active. Sorted Q cells from wild-type, mab-5 loss-of-function (lof), and mab-5 gain-of-function (gof) mutants were subject to RNA-seq and differential expression analysis. Genes enriched in Q cells included those involved in cell division, DNA replication, and DNA repair, consist with the neuroblast stem cell identity of the Q cells at this stage. Genes affected by mab-5 included those involved in neurogenesis, neural development, and interaction with the extracellular matrix. cwn-1, which encodes a Wnt signaling molecule, showed a paired response to mab-5 in the Q cells: cwn-1 expression was reduced in mab-5(lof) and increased in mab-5(gof), suggesting that MAB-5 is required for cwn-1 expression in Q cells. MAB-5 is required to prevent anterior migration of the Q lineage while it transcriptionally reprograms the Q lineage for posterior migration. Functional genetic analysis revealed that CWN-1 is required downstream of MAB-5 to inhibit anterior migration of the QL lineage, likely in parallel to EGL-20/Wnt in a noncanonical Wnt pathway. In sum, work here describes a Q cell transcriptome, and a set of genes regulated by MAB-5 in the QL lineage. One of these genes, cwn-1, acts downstream of mab-5 in QL migration, indicating that this gene set includes other genes utilized by MAB-5 to facilitate posterior neuroblast migration.
Ploidy inference from single-cell data: application to human and mouse cell atlases
Authors: Takeuchi Fumihiko , Kato Norihiro
Published: April 2024

Ploidy is relevant to numerous biological phenomena, including development, metabolism, and tissue regeneration. Single-cell RNA-seq and other omics studies are revolutionizing our understanding of biology, yet they have largely overlooked ploidy. This is likely due to the additional assay step required for ploidy measurement. Here, we developed a statistical method to infer ploidy from single-cell ATAC-seq data, addressing this gap. When applied to data from human and mouse cell atlases, our method enabled systematic detection of polyploidy across diverse cell types. This method allows for the integration of ploidy analysis into single-cell studies. Additionally, this method can be adapted to detect the proliferating stage in the cell cycle and copy number variations in cancer cells. The software is implemented as the scPloidy package of the R software and is freely available from CRAN.
Serca Uncoupling May Facilitate Cold Acclimation in Dark-Eyed Juncos (Junco hyemalis) without Regulation by Sarcolipin or Phospholamban
Authors: Elowe Cory R , Stager Maria
Published: April 2024

Synopsis

Homeothermic endotherms defend their body temperature in cold environments using a number of behavioral and physiological mechanisms. Maintaining a stable body temperature primarily requires heat production through shivering or non-shivering thermogenesis (NST). Although the use of NST is well established in mammalian systems, the mechanisms and extent to which NST is used in birds are poorly understood. In mammals, one well-characterized mechanism of NST is through uncoupling of Ca2+ transport from ATP hydrolysis by sarco/endoplasmic reticulum ATPase (SERCA) in the skeletal muscle, which generates heat and may contribute to Ca2+ signaling for fatigue resistance and mitochondrial biogenesis. Two small proteins—sarcolipin (SLN) and phospholamban (PLN)—are known to regulate SERCA in mammals, but recent work shows inconsistent responses of SLN to cold acclimation in birds. In this study, we measured SERCA uncoupling in the pectoralis flight muscle of control (18°C) and cold-acclimated (−8°C) dark-eyed juncos (Junco hyemalis) that exhibited suppressed SLN transcription in the cold. We measured SERCA activity and Ca2+ uptake rates for the first time in cold-acclimated birds and found greater SERCA uncoupling in the muscle of juncos in the cold. However, SERCA uncoupling was not related to SLN or PLN transcription or measures of mitochondrial biogenesis. Nonetheless, SERCA uncoupling reduced an individual’s risk of hypothermia in the cold. Therefore, while SERCA uncoupling in the cold could be indicative of NST, it does not appear to be mediated by known regulatory proteins in these birds. These results prompt interesting questions about the significance of SLN and PLN in birds and the role of SERCA uncoupling in response to environmental conditions.
Immune-pineal-ocular Axis in Amphibians: Unveiling A Novel Connection
Authors: Titon Stefanny C M , Neto Patrício G Garcia , Titon Braz , de Figueiredo Aymam C , Markus Regina P , Gomes Fernando R , Assis Vania R
Published: April 2024

Synopsis

Melatonin is a hormone known as an endogenous temporal marker signaling the dark phase of the day. Although the eyes seem to be the main site of melatonin production in amphibians, little information is available about the natural variation in ocular melatonin levels and its modulation following immune stimulation. We investigated the daily variation of plasma and ocular melatonin levels in bullfrogs (Lithobates catesbeianus) and their modulation following an immune stimulation with lipopolysaccharide (LPS) in yellow cururu toads (Rhinella icterica). For the daily variation, bullfrogs were bled and then euthanized for eye collection every 3 h over 24 h to determine plasma and ocular melatonin levels. We found a positive correlation between ocular and plasma melatonin levels, with maximum values at night (22 h) for both plasma and the eyes. For immune stimulation, yellow cururu toads received an intraperitoneal injection of LPS or saline solution during the day (10 h) or at night (22 h). Two hours after injection, toads were bled and euthanized for eye collection to obtain plasma and ocular melatonin levels. In addition, the liver and bone marrow were collected to investigate local melatonin modulation. Our results demonstrate that retinal light-controlled rhythmic melatonin production is suppressed while liver and bone marrow melatonin levels increase during the inflammatory assemblage in anurans. Interestingly, the LPS injection decreased only ocular melatonin levels, reinforcing the central role of the eyes (i.e., retina) as an essential organ of melatonin production, and a similar role to the pineal gland during the inflammatory response in amphibians. Together, these results point to a possible immune-pineal-ocular axis in amphibians, yet to be fully described in this group.
Contestation and Resilience in the Liberal International Order: The Case of Climate Change
Authors: Thompson Alexander
Published: April 2024

This article examines contestation and change in the global climate change regime, considered as a suborder of the broader Liberal International Order (LIO). The extensive literature on the LIO has overlooked the important case of climate institutions. The article begins by establishing that the climate regime is indeed part of the LIO, considering both its institutional and ideational features. I then outline the most important episodes of contestation against the regime, led at different times by the United States and emerging powers in the developing world, and note that the sources of contestation were partly endogenous to the regime itself. Despite persistent political challenges and the slow progress of global climate cooperation, the climate regime has remained largely intact and resilient. I explain this outcome by pointing to institutional design features and strategies that allowed the suborder to absorb and accommodate contestation before it escalated, including the nonbinding approach to commitments reflected in the Paris Agreement. The article concludes with a discussion of broader lessons for the LIO and for the design and effectiveness of climate institutions.
An efficiency-improved GPU algorithm for the 2 + 2 + 1 method in nonlinear beamforming
Authors: Sun Yimin , Silvestrov Ilya , Bakulin Andrey
Published: April 2024

Nonlinear beamforming (NLBF) has emerged as a highly effective technology for enhancing seismic data quality. The crux of NLBF's success lies in its ability to robustly estimate local traveltime operators directly from input data, a process that entails solving millions or even billions of nonlinear optimization problems per input gather. Among the solvers used for estimating these operators is the 2 + 2 + 1 method, for which we have previously introduced algorithmic implementations on both the CPU and GPU platforms. In this paper, we present an efficiency-improved GPU algorithm for the 2 + 2 + 1 method, particularly beneficial when dealing with small data apertures in NLBF. Our enhanced GPU algorithm brings significant improvements in computation efficiency through several strategic measures, which include leveraging Horner's method to minimize the mathematical overhead of traveltime calculation, implementing a GPU-friendly data reduction algorithm to exploit GPU computational power, and optimizing shared GPU memory usage as the primary workspace whenever feasible. To demonstrate the tangible efficiency enhancement achieved by our new GPU algorithm, via two illustrative examples, we compare its performance with that of our previous implementation.
Comprehensive analysis of immune signatures in primary biliary cholangitis and autoimmune hepatitis
Authors: Yang Xiaoxue , Li Jiawei , Ren Meiling , Pan Xuemei , Liu Huiling , Jiang Jie , Li Man , Yang Zhe , Han Bingyu , Ma Lina , Hao Jianlei , Duan Yuanyuan , Yin Zhinan , Xu Yan , Xiang Zheng , Wu Bin
Published: April 2024

Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are autoimmune diseases that target hepatocytes and bile duct cells, respectively. Despite their shared autoimmune nature, the differences in immunologic characteristics between them remain largely unexplored. This study seeks to elucidate the unique immunological profiles of PBC and AIH and to identify key differences. We comprehensively analyzed various T cell subsets and their receptor expression in a cohort of 45 patients, including 27 PBC and 18 AIH cases. Both diseases exhibited T cell exhaustion and senescence along with a surge in inflammatory cytokines. Significantly increased CD38+HLA-DR+CD8+ T cell populations were observed in both diseases. AIH was characterized by an upregulation of CD8+ terminally differentiated T, CD4+ effector memory T, and CD4+ terminally differentiated T cells, and a concurrent reduction in regulatory T cells. In contrast, PBC displayed a pronounced presence of T follicular helper (Tfh) cells and a contraction of CD4−CD8− T cell populations. Correlation analysis revealed that NKP46+ natural killer frequency was closely tied to alanine aminotransferase and aspartate aminotransferase levels, and TIGIT expression on T cells was associated with globulin level in AIH. In PBC, there is a significant correlation between Tfh cells and ALP levels. Moreover, the identified immune landscapes in both diseases strongly related to disease severity. Through logistic regression analysis, γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies emerged as distinct markers capable of differentiating PBC from AIH. In conclusion, our analyses reveal that PBC and AIH share similarities and differences regarding to immune profiles. γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies are potential noninvasive immunological markers that can differentiate PBC from AIH.
Shikonin in breast cancer treatment: a comprehensive review of molecular pathways and innovative strategies
Authors: Iranzadeh Saeid , Dalil Davood , Kohansal Soroush , Isakhani Mahdi
Published: April 2024

Objectives

Breast cancer is a prevalent disease that has a substantial impact on women’s mortality rates. Shikonin, a naphthoquinone derived from Lithospermum erythrorhizon, has demonstrated substantial anticancer effects. This study aims to conduct a comprehensive review of the latest research findings regarding the therapeutic efficacy of shikonin in the context of breast cancer treatment, with a specific emphasis on elucidating the underlying molecular mechanisms.

Methods

A comprehensive literature review was conducted on shikonin and breast cancer by searching PubMed, Scopus, Web of Science, and Google Scholar databases.

Key findings

Shikonin significantly reduces tumor cell viability, proliferation, migration, invasion, and metastasis in both in vivo and in vitro across all breast cancer subtypes. Additionally, when combined with other pharmaceutical agents, it exhibits synergistic effects. Shikonin stimulates immunogenic cell death, resulting in apoptosis and necroptosis. The induction of immunogenic cell death by shikonin enhances the immunogenicity of breast cancer cells, leading to its involvement in the development of dendritic cell-based tumor vaccines against breast cancer.

Conclusion

Shikonin exhibits potent anti-breast cancer properties and shows significant potential for the advancement of immunotherapeutic approaches against breast cancer, as well as enhancing the efficacy of conventional treatment strategies.
Fulminant Heterotopic Ossification of the Lower Extremity After Gunshot Injury and Blunt Trauma: A Case Report
Authors: Estel Katharina , Back David Alexander , Scheuermann-Poley Catharina , Willy Christian
Published: April 2024

Traumatic heterotopic ossification (HO) of the lower extremity is relatively rare but is of major importance in clinical practice. They are defined as posttraumatic abnormal formations of bone within soft tissue outside of the skeletal system. This article describes the clinical case of a 31-year-old male patient who suffered 2 traumatic events within 12 months—a gunshot wound in the lumbar spine/gluteal region followed by a severe traumatic brain injury with intracranial hemorrhage in a traffic accident as a pedestrian. Clinically, the patient was bedridden because of complete stiffening of the lumbar spine, both hip joints, and the left knee joint. After preoperative diagnosis, 3 surgical ablations of the HO were performed on both the hip joints and the left knee joint. In addition, physiotherapeutic exercise, postoperative nonsteroidal anti-inflammatory drug administration (25 mg of indomethazine for 6 weeks, 3 times a day), and perioperative radiation with 7 Gy for each operation were advised. After 4 years of follow-up, the patient showed significant improvement. In HO treatment, prophylactic local radiotherapy (pre- and postoperative radiation with a local single dose of 7 Gy) and postoperative administration of nonsteroidal anti-inflammatory drugs are often recommended. For therapeutic purposes, surgical resection is still indicated for pronounced cases.
SDSS J222428.53+261423.2: unique emission lines properties unveil a sub-kiloparsec dual AGN candidate
Authors: Zheng Qi , Zhang XueGuang , Yuan QiRong , Severgnini Paola , Vignali Cristian
Published: April 2024

In this paper, we presented a detailed analysis of the Sloan Digital Sky Survey optical spectrum of a new sub-kpc scale dual AGN candidate SDSS J222428.53+261423.2 (=SDSS J2224). The target is one of the few AGNs with all the optical narrow emission lines characterized by double-peaked profiles and with peak separations in velocity units of about 930 km s−1. If the double-peaked narrow emission lines (DPNELs) are due to a dual AGN in SDSS J2224, the estimated physical separation between the two cores is about 500 pc. Meanwhile, three alternative explanations are also discussed in this paper, however, we can not find solid evidence to completely rule them out. Our results support the presence of a sub-kpc dual AGN with DPNELs in all lines, indicating a key episode of galaxy merging evolution at sub-kpc scale.
Co-repressors AtSDR4L and DIG1 interact with transcription factor VAL2 and promote Arabidopsis seed-to-seedling transition
Authors: Lu Bailan , Alizadeh Milad , Hoy Ryan , Zheng Renwei , Go Dongeun , Song Liang
Published: April 2024

Two transcriptional co-repressors physically interact with a transcription factor that is known to recruit a multi-protein complex, which promotes the repression of seed maturation genes by depositing trimethylation marks on lysine 27 of the histone 3 tails.
A Comprehensive Study of the Phase Transitions of the Frustrated J1-J2 Ising Model on the Square Lattice
Authors: Li Shang-Wei , Jiang Fu-Jiun
Published: April 2024

We study the phase transitions of the two-dimensional (2D) frustrated J1-J2 Ising model on the square lattice with Monte Carlo simulations. Here J1 < 0 and J2 > 0 are the couplings for the nearest and next nearest neighbor Ising spins, respectively. In addition, we consider J1 = −1 and J2/|J1| ≡ g = 0.56, 0.58, 0.60, 0.62, 0.64, and 0.7 in our investigation. Several physical quantities including the Binder ratio U, the specific heat Cv, and the energy density E are obtained. The analyses of these calculated observables indicate that the considered phase transitions for g ≥ 0.58 are likely second order, and the nature of the phase transition associated with g = 0.56 needs further investigation. A comparison between the histograms of E for the phase transitions considered here and the one associated with the five-state ferromagnetic Potts model on the square lattice is conducted. The outcomes imply that if the studied phase transitions are weakly first order, then they have much larger correlation lengths than that of the five-state Potts model.
Universities in less developed regions: analyzing their local research impact
Authors: Papazoglou Michalis E , Daglis Theodoros , Constantelou Anastasia , Drivaliaris Dimosthenis , Vassiliou Evangelos E
Published: April 2024

It is not uncommon to encounter overoptimistic views among policy-makers concerning the extent to which the research outcome of a university can have an impact on the innovation and economic performance of a local economy. Policies and expectations are usually influenced by optimal cases of top-ranked universities in highly innovative geographies. However, most universities do not function in such contexts, but in regions of weak innovation and economic development, often characterized as less developed regions (LDRs). To enrich our understanding about universities within LDRs, this study attempts to provide insights into the local research impact of a young university located within an LDR by analyzing bibliometric data. Findings show that although the university’s research output grows, there is hardly any evidence of an impact on local organizations, suggesting that the expected universities’ roles and related innovation policies should always consider the characteristics of the place within which they function.
Acquisition of 2C-like totipotency through defined maternal-effect factors
Authors: Gui Liming , Zhong Qin , Yang Jue , Sun Jiajia , Lu Jianping , Picton Helen M , Li Changzhong
Published: April 2024

Fully grown oocytes have the natural ability to transform 2 terminally differentiated gametes into a totipotent zygote representing the acquisition of totipotency. This process wholly depends on maternal-effect factors (MFs). MFs stored in the eggs are therefore likely to be able to induce cellular reprogramming to a totipotency state. Here we report the generation of totipotent-like stem cells from mESCs using 4MFs Hsf1, Zar1, Padi6, and Npm2, designated as MFiTLSCs. MFiTLSCs exhibited a unique and inherent capability to differentiate into embryonic and extraembryonic derivatives. Transcriptomic analysis revealed that MFiTLSCs are enriched with 2-cell-specific genes that appear to synergistically induce a transcriptional repressive state, in that parental genomes are remodeled to a poised transcriptional repression state while totipotency is established following fertilization. This method to derive MFiTLSCs could help advance the understanding of fate determinations of totipotent stem cells in a physiological context and establish a foundation for the development of oocyte biology-based reprogramming technology.
Non-Operative Versus Operative Treatment of Z-Type Comminuted Clavicle Fractures in Adolescents: A Prospective Sub-Stratified Cohort Analysis
Authors: Sabatini Coleen S. , Edmonds Eric W. , Nepple Jeffrey J. , Liotta Elizabeth S. , Hergott Katelyn , Perkins Crystal A. , Wilson Philip L. , Li Ying , Ellis Henry B. , Pandya Nirav K. , Pennock Andrew T. , Spence David D. , Willimon Samuel C. , Bae Donald S. , Kocher Mininder S. , Busch Michael T. , Williams David N. , Heyworth Benton E.
Published: April 2024

Objectives:

To compare the clinical, radiographic, and patient-reported outcomes of non-operative and operative treatment of adolescents with comminuted ‘Z-type’ mid-shaft clavicle fractures.

Methods:

Design: Prospective observational cohort

Setting:

Eight tertiary-care pediatric centers

Patient Selection Criteria:

Patients 10 to 18 years-old who were treated either operatively or non-operatively for a diaphyseal clavicle fracture between 2013 and 2017 were screened/enrolled at the time of injury. The current sub-cohort analysis was derived from a larger adolescent clavicle study population of 907 patients.

Outcome Measurements and Comparisons:

Complications and validated patient-reported outcome measures (PROs):(ASES, QuickDASH, Marx Shoulder Activity Score, EQ-5D, EQ-VAS, and patient satisfaction score) were compared between operative and non-operative cohorts.

Results:

Eighty-one patients (69 male (85.2%), 12 female; average age 15 years (11.1-18.7); 78 with sports participation (96.2%)), were followed through bony healing and return to sports, while 59 patients (73%) completed two-year follow-up with patient-reported outcomes (PROs), 26 of whom were treated non-operatively and 33 treated operatively. All demographic and fracture characteristics were similar (p>0.05) between the two-year follow-up cohorts except for fracture shortening, which was greater in the operative cohort (23 mm vs 29 mm, p=0.01). After controlling for this potential confounder through both regression and propensity matched sub-group analysis, non-operative versus operative cohorts showed no difference in rates of nonunion (0%), delayed union (0% vs. 2.3%, p=1.0), symptomatic malunion (2.7% vs 0%, p=0.4), refracture (2.7% vs 2.2%, p=1.0), unexpected subsequent surgery (5.4% vs. 11.4%, p=0.45), or clinically significant complications (5.4% vs. 16%, p=0.17). There were no differences in any PROs between cohorts, both before and after controlling for the difference in fracture shortening (all p-values >0.05).

Conclusions:

In this prospective comparison of complications and two-year PROs in adolescents with comminuted Z-type clavicle fractures, non-operative and operative treatment yielded similar outcomes.

Level of Evidence:

Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
Primary Closure of External Fixator Pin Sites Is Safe After Orthopaedic Trauma Surgery
Authors: Brodell James D. , Haws Brittany , Shroff Jeffrey B. , Karnyski Steven T. , Hoffman Samantha , Soin Sandeep P. , Humphrey Catherine A. , Gorczyca John T. , Ketz John P.
Published: April 2024

OBJECTIVES:

To determine if rates of pin site infection and surgical site infection among patients managed with primary closure after external fixator removal were similar to those allowed to heal secondarily.

METHODS:

Design:

Retrospective cohort.

Setting:

Urban/Suburban Academic Level I Trauma Center.

Patient Selection Criteria:

Patients who had received a lower extremity external fixator for provisional management before definitive fixation of lower extremity fractures were included with pin site wounds closed primarily or allowed to heal by secondary intention.

Outcome Measures and Comparisons:

The rate of pin tract infection and surgical site infection following primary closure of external fixator pin sites relative to patients whose pin sites were allowed to heal through secondary intention.

RESULTS:

In total, 256 patients were evaluated: 143 patients (406 pin sites) in the primary closure group and 113 patients (340 in sites) in the secondary closure group. The average age was 49 ± 16 years. Sixty-five percent of included patients were male. There was no difference in pin tract infections between cohorts (primary = 0.5%, secondary = 1.5%, P = 0.26). External fixator duration in the primary closure group was 11.5 ± 8.4 days and 13.0 ± 8.1 days in the secondary closure group (P = 0.15). There was a greater rate of surgical site infections in the secondary intention cohort (15.9% vs. 7.7%, P = 0.047).

CONCLUSIONS:

There was no difference in pin site infection rate after primary pin site closure relative to patients who were allowed to heal through secondary intention. Furthermore, there was a lower rate of surgical site infection after primary closure. These results challenge the dogma of secondary closure for ex fix pin sites, suggesting that debridement and primary closure is a safe option for management of external fixator pin sites and may impart benefit in decreasing infection risk.

LEVEL OF EVIDENCE:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Biomechanical Comparison of Anterior Cervical Plate Fixation Versus Integrated Fixation Cage for Anterior Cervical Discectomy and Fusion
Authors: Murphy Timothy P. , Tran Jeremy D. , Colantonio Donald F. , Le Anthony H. , Fredericks Donald R. , Roach William B. , Chung Joon , Pisano Alfred J. , Wagner Scott C. , Helgeson Melvin D.
Published: April 2024

Study Design:

Cadaveric, biomechanic study.

Objective:

To compare the range of motion profiles of the cervical spine following one-level anterior cervical discectomy and fusion (ACDF) constructs instrumented with either an interbody cage and anterior plate or integrated fixation cage in a cadaveric model.

Summary of Background Data:

While anterior plates with interbody cages are the most common construct of fixation in ACDF, newer integrated cage-plate devices seek to provide similar stability with a decreased implant profile. However, differences in postoperative cervical range of motion between the 2 constructs remain unclear.

Methods:

Six cadaveric spines were segmented into 2 functional spine units (FSUs): C2-C5 and C6-T2. Each FSU was nondestructively bent in flexion-extension (FE), right-left lateral bending (LB), and right-left axial rotation (AR) at a rate of 0.5°/s under a constant axial load until a limit of 2-Nm was reached to evaluate baseline range of motion (ROM). Matched pairs were then randomly assigned to undergo instrumentation with either the standard anterior cage and plate (CP) or the integrated fixation cage (IF). Following instrumentation, ROM was then remeasured as previously described.

Results:

For CP fixation, ROM increased by 61.2±31.7% for FE, 36.3±20.4% for LB, and 31.7±19.1% for AR. For IF fixation, ROM increased by 64.2±15.5% for FE, 56.7±39.8% for LB, and 94.5±65.1% for AR. There was no significant difference in motion between each group across FE, LB, and AR.

Conclusion:

This biomechanical study demonstrated increased motion in both the CP and IF groups relative to the intact, un-instrumented state. However, our model showed no differences in ROM between CP and IF constructs in any direction of motion. These results suggest that either method of instrumentation is a suitable option for ACDF with respect to constructing stiffness at time zero.
Immunization with a low dose of zymosan A confers resistance to depression-like behavior and neuroinflammatory responses in chronically stressed mice
Authors: Liu Huijun , Zhu Tao , Zhang Linlin , Li Fu , Zheng Meng , Chen Bingran , Zhu Haojie , Ren Jie , Lu Xu , Huang Chao
Published: April 2024

Stimulation of the innate immune system prior to stress exposure is a possible strategy to prevent depression under stressful conditions. Based on the innate immune system stimulating activities of zymosan A, we hypothesize that zymosan A may prevent the development of chronic stress-induced depression-like behavior. Our results showed that a single injection of zymosan A 1 day before stress exposure at a dose of 2 or 4 mg/kg, but not at a dose of 1 mg/kg, prevented the development of depression-like behaviors in mice treated with chronic social defeat stress (CSDS). The prophylactic effect of a single zymosan A injection (2 mg/kg) on CSDS-induced depression-like behaviors disappeared when the time interval between zymosan A and stress exposure was extended from 1 day or 5 days to 10 days, which was rescued by a second zymosan A injection 10 days after the first zymosan A injection and 4 days (4×, once daily) of zymosan A injections 10 days before stress exposure. Further analysis showed that a single zymosan A injection (2 mg/kg) 1 day before stress exposure could prevent the CSDS-induced increase in pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Inhibition of the innate immune system by pretreatment with minocycline (40 mg/kg) abolished the preventive effect of zymosan A on CSDS-induced depression-like behaviors and CSDS-induced increase in pro-inflammatory cytokines in the brain. These results suggest that activation of the innate immune system triggered by zymosan A prevents the depression-like behaviors and neuroinflammatory responses in the brain induced by chronic stress.
A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis
Authors: Hitomi Yuki , Ueno Kazuko , Aiba Yoshihiro , Nishida Nao , Kono Michihiro , Sugihara Mitsuki , Kawai Yosuke , Kawashima Minae , Khor Seik-Soon , Sugi Kazuhiro , Kouno Hirotaka , Kohno Hiroshi , Naganuma Atsushi , Iwamoto Satoru , Katsushima Shinji , Furuta Kiyoshi , Nikami Toshiki , Mannami Tomohiko , Yamashita Tsutomu , Ario Keisuke , Komatsu Tatsuji , Makita Fujio , Shimada Masaaki , Hirashima Noboru , Yokohama Shiro , Nishimura Hideo , Sugimoto Rie , Komura Takuya , Ota Hajime , Kojima Motoyuki , Nakamuta Makoto , Fujimori Naoyuki , Yoshizawa Kaname , Mano Yutaka , Takahashi Hironao , Hirooka Kana , Tsuruta Satoru , Sato Takeaki , Yamasaki Kazumi , Kugiyama Yuki , Motoyoshi Yasuhide , Suehiro Tomoyuki , Saeki Akira , Matsumoto Kosuke , Nagaoka Shinya , Abiru Seigo , Yatsuhashi Hiroshi , Ito Masahiro , Kawata Kazuhito , Takaki Akinobu , Arai Kuniaki , Arinaga-Hino Teruko , Abe Masanori , Harada Masaru , Taniai Makiko , Zeniya Mikio , Ohira Hiromasa , Shimoda Shinji , Komori Atsumasa , Tanaka Atsushi , Ishigaki Kazuyoshi , Nagasaki Masao , Tokunaga Katsushi , Nakamura Minoru
Published: April 2024

Background and Aims:

Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC.

Approach and Results:

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10-8). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758.

Conclusions:

PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.
Age Suppresses the Association Between Traumatic Brain Injury Severity and Functional Outcomes: A Study Using the NIDILRR TBIMS Dataset
Authors: Winter Laraine , Moriarty Helene , Robinson Keith M. , Leiby Benjamin E. , Schmidt Krista , Whitehouse Christina R. , Swanson Randel L.
Published: April 2024

Objectives:

Recovery from traumatic brain injury (TBI) is extremely difficult to predict, with TBI severity usually demonstrating weak predictive validity for functional or other outcomes. A possible explanation may lie in the statistical phenomenon called suppression, according to which a third variable masks the true association between predictor and outcome, making it appear weaker than it actually is. Age at injury is a strong candidate as a suppressor because of its well-established main and moderating effects on TBI outcomes. We tested age at injury as a possible suppressor in the predictive chain of effects between TBI severity and functional disability, up to 10 years post-TBI.

Setting:

Follow-up interviews were conducted during telephone interviews.

Participants:

We used data from the 2020 NDILRR Model Systems National Dataset for 4 successive follow-up interviews: year 1 (n = 10,734), year 2 (n = 9174), year 5 (n = 6,201), and year 10 (n = 3027).

Design:

Successive cross-sectional multiple regression analyses.

Main Measures:

Injury severity was operationalized using a categorical variable representing duration of posttrauma amnesia. The Glasgow Outcomes Scale—Extended (GOS-E) operationally defined functioning. Sociodemographic characteristics having significant bivariate correlations with GOS-E were included.

Results:

Entry of age at injury into the regression models significantly increases the association between TBI severity and functioning up to 10 years post-TBI.

Conclusions:

Age at injury is a suppressor variable, masking the true effect of injury severity on functional outcomes. Identifying the mediators of this suppression effect is an important direction for TBI rehabilitation research.
Risk factors of transient and permanent hypoparathyroidism after thyroidectomy: a systematic review and meta-analysis
Authors: Ning Kang , Yu Yongchao , Zheng Xinyi , Luo Zhenyu , Jiao Zan , Liu Xinyu , Wang Yiyao , Liang Yarong , Zhang Zhuoqi , Ye Xianglin , Wu Weirui , Bu Jian , Chen Qiaorong , Cheng Fuxiang , Liu Lizhen , Jiang Mingjie , Yang Ankui , Wu Tong , Yang Zhongyuan
Published: April 2024

Background:

Postoperative hypoparathyroidism (hypoPT) is a common complication following thyroid surgery. However, current research findings on the risk factors for post-thyroid surgery hypoPT are not entirely consistent, and the same risk factors may have different impacts on transient and permanent hypoPT. Therefore, there is a need for a comprehensive study to summarize and explore the risk factors for both transient and permanent hypoPT after thyroid surgery.

Materials and methods:

Two databases (PubMed and Embase) were searched from inception to 2024. The Newcastle–Ottawa Scale was used to rate study quality. Pooled odds ratios were used to calculate the relationship of each risk factor with transient and permanent hypoPT. Subgroup analyses were conducted for hypoPT with different definition-time (6 or 12 months). Publication bias was assessed using Begg’s test and Egger’s test.

Results:

A total of 19 risk factors from the 93 studies were included in the analysis. Among them, sex and parathyroid autotransplantation were the most frequently reported risk factors. Meta-analysis demonstrated that sex (female vs. male), cN stage, central neck dissection, lateral neck dissection, extent of central neck dissection (bilateral vs. unilateral), surgery [total thyroidectomy (TT) vs. lobectomy], surgery type (TT vs. sub-TT), incidental parathyroidectomy, and pathology (cancer vs. benign) were significantly associated with transient and permanent hypoPT. Preoperative calcium and parathyroid autotransplantation were only identified as risk factors for transient hypoPT, while preoperative PTH was a protective factor. Additionally, node metastasis and parathyroid in specimen were associated with permanent hypoPT.

Conclusion:

The highest risk of hypoPT occurs in female thyroid cancer patients with lymph node metastasis undergoing TT combined with neck dissection. The key to preventing postoperative hypoPT lies in the selection of surgical approach and intraoperative protection.
Comparative investigation of neoadjuvant immunotherapy versus adjuvant immunotherapy in perioperative patients with cancer: a global-scale, cross-sectional, and large-sample informatics study
Authors: Guo Song-Bin , Hu Le-Sheng , Huang Wei-Juan , Zhou Zhen-Zhong , Luo Hui-Yan , Tian Xiao-Peng
Published: April 2024

Background:

Neoadjuvant and adjuvant immunotherapies for cancer have evolved through a series of remarkable and critical research advances; however, addressing their similarities and differences is imperative in clinical practice. Therefore, this study aimed to examine their similarities and differences from the perspective of informatics analysis.

Methods:

This cross-sectional study retrospectively analyzed extensive relevant studies published between 2014 and 2023 using stringent search criteria, excluding nonpeer-reviewed and non-English documents. The main outcome variables are publication volume, citation volume, connection strength, occurrence frequency, relevance percentage, and development percentage. Furthermore, an integrated comparative analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression statistics, and Walktrap algorithm analysis.

Results:

This analysis included 1373 relevant studies. Advancements in neoadjuvant and adjuvant immunotherapies have been promising over the last decade, with an annual growth rate of 25.18 vs. 6.52% and global collaboration (International Co-authorships) of 19.93 vs. 19.84%. Respectively, five dominant research clusters were identified through unsupervised hierarchical clustering based on machine learning, among which Cluster 4 (Balance of neoadjuvant immunotherapy efficacy and safety) and Cluster 2 (Adjuvant immunotherapy clinical trials) [Average Publication Year (APY): 2021.70±0.70 vs. 2017.54±4.59] are emerging research populations. Burst and regression curve analyses uncovered domain pivotal research signatures, including microsatellite instability (R2=0.7500, P=0.0025) and biomarkers (R2=0.6505, P=0.0086) in neoadjuvant scenarios, and the tumor microenvironment (R2=0.5571, P=0.0209) in adjuvant scenarios. The Walktrap algorithm further revealed that ‘neoadjuvant immunotherapy, nonsmall cell lung cancer (NSCLC), immune checkpoint inhibitors, melanoma’ and ‘adjuvant immunotherapy, melanoma, hepatocellular carcinoma, dendritic cells’ (Relevance Percentage: 100 vs. 100%, Development Percentage: 37.5 vs. 17.1%) are extremely relevant to this field but remain underdeveloped, highlighting the need for further investigation.

Conclusion:

This study identified pivotal research signatures and provided substantial predictions for neoadjuvant and adjuvant cancer immunotherapies. In addition, comprehensive quantitative comparisons revealed a notable shift in focus within this field, with neoadjuvant immunotherapy taking precedence over adjuvant immunotherapy after 2020; such a qualitative finding facilitate proper decision-making for subsequent research and mitigate the wastage of healthcare resources.
A quality improvement project to improve treatment of severe hypertriglyceridemia in veterans
Authors: Wool Caroline R. , Shaw Kathy , Saxon David R.
Published: April 2024

Background:

Severe hypertriglyceridemia (sHTG) is associated with an increased risk of acute pancreatitis. Prompt recognition and treatment of sHTG is key for prevention of acute pancreatitis and its associated life-threatening complications.

Local problem:

Patients with sHTG at a primary care clinic within the Veterans Affairs Eastern Colorado Health Care System were receiving suboptimal treatment that did not align with evidence-based guidelines.

Methods:

We initiated a quality improvement (QI) project to improve the management of sHTG in an outpatient primary care clinic. Veterans with a triglyceride level between 500 and 1,500 mg/dl were included in the project.

Interventions:

Project interventions included provider education, patient education, and targeted electronic consultations (e-consults) with treatment recommendations. The primary outcome was to decrease the percentage of patients with triglycerides ≥500 mg/dl by 25%. The secondary outcome was to decrease the mean triglyceride level of the patient population by 15%.

Results:

Education on evaluation and treatment of sHTG was given to 100% (n = 21) of primary care clinicians. Overall, 72.8% (95% CI [62.6–81.6%]) of patients (n = 67) received appropriate written education materials, and 72.8% (95% CI [62.6–81.6%]) of patients (n = 67) received a targeted e-consult. The percentage of patients with sHTG decreased by 47%. Average triglyceride level decreased from 651 to 483 mg/dl (25.8% decrease).

Conclusion:

A multipronged QI project consisting of provider education, patient education, and targeted e-consults resulted in decreased triglyceride levels and improved access to specialist expertise. Clinical implications include decreased prevalence of sHTG and risk of acute pancreatitis among patients in the project.