bluuebunny/crossref_metadata_2025 huggingface dataset:
Methods for constructing and evaluating consensus genomic interval sets
Authors: Rymuza Julia , Sun Yuchen , Zheng Guangtao , LeRoy Nathan J , Murach Maria , Phan Neil , Zhang Aidong , Sheffield Nathan C
Published: August 2024

The amount of genomic region data continues to increase. Integrating across diverse genomic region sets requires consensus regions, which enable comparing regions across experiments, but also by necessity lose precision in region definitions. We require methods to assess this loss of precision and build optimal consensus region sets. Here, we introduce the concept of flexible intervals and propose three novel methods for building consensus region sets, or universes: a coverage cutoff method, a likelihood method, and a Hidden Markov Model. We then propose three novel measures for evaluating how well a proposed universe fits a collection of region sets: a base-level overlap score, a region boundary distance score, and a likelihood score. We apply our methods and evaluation approaches to several collections of region sets and show how these methods can be used to evaluate fit of universes and build optimal universes. We describe scenarios where the common approach of merging regions to create consensus leads to undesirable outcomes and provide principled alternatives that provide interoperability of interval data while minimizing loss of resolution.
Replication fork stalling in late S-phase elicits nascent strand degradation by DNA mismatch repair
Authors: Colicino-Murbach Erica , Hathaway Caitlin , Dungrawala Huzefa
Published: August 2024

Eukaryotic chromosomal replication occurs in a segmented, temporal manner wherein open euchromatin and compact heterochromatin replicate during early and late S-phase respectively. Using single molecule DNA fiber analyses coupled with cell synchronization, we find that newly synthesized strands remain stable at perturbed forks in early S-phase. Unexpectedly, stalled forks are susceptible to nucleolytic digestion during late replication resulting in defective fork restart. This inherent vulnerability to nascent strand degradation is dependent on fork reversal enzymes and resection nucleases MRE11, DNA2 and EXO1. Inducing chromatin compaction elicits digestion of nascent DNA in response to fork stalling due to reduced association of RAD51 with nascent DNA. Furthermore, RAD51 occupancy at stalled forks in late S-phase is diminished indicating that densely packed chromatin limits RAD51 accessibility to mediate replication fork protection. Genetic analyses reveal that susceptibility of late replicating forks to nascent DNA digestion is dependent on EXO1 via DNA mismatch repair (MMR) and that the BRCA2-mediated replication fork protection blocks MMR from degrading nascent DNA. Overall, our findings illustrate differential regulation of fork protection between early and late replication and demonstrate nascent strand degradation as a critical determinant of heterochromatin instability in response to replication stress.
A new method for network bioinformatics identifies novel drug targets for mucinous ovarian carcinoma
Authors: Craig Olivia , Lee Samuel , Pilcher Courtney , Saoud Rita , Abdirahman Suad , Salazar Carolina , Williams Nathan , Ascher David B , Vary Robert , Luu Jennii , Cowley Karla J , Ramm Susanne , Li Mark Xiang , Thio Niko , Li Jason , Semple Tim , Simpson Kaylene J , Gorringe Kylie L , Holien Jessica K
Published: August 2024

Mucinous ovarian carcinoma (MOC) is a subtype of ovarian cancer that is distinct from all other ovarian cancer subtypes and currently has no targeted therapies. To identify novel therapeutic targets, we developed and applied a new method of differential network analysis comparing MOC to benign mucinous tumours (in the absence of a known normal tissue of origin). This method mapped the protein-protein network in MOC and then utilised structural bioinformatics to prioritise the proteins identified as upregulated in the MOC network for their likelihood of being successfully drugged. Using this protein-protein interaction modelling, we identified the strongest 5 candidates, CDK1, CDC20, PRC1, CCNA2 and TRIP13, as structurally tractable to therapeutic targeting by small molecules. siRNA knockdown of these candidates performed in MOC and control normal fibroblast cell lines identified CDK1, CCNA2, PRC1 and CDC20, as potential drug targets in MOC. Three targets (TRIP13, CDC20, CDK1) were validated using known small molecule inhibitors. Our findings demonstrate the utility of our pipeline for identifying new targets and highlight potential new therapeutic options for MOC patients.
Synonymous rpsH variants: the common denominator in Escherichia coli adapting to ionizing radiation
Authors: Stemwedel Katharina , Haase Nadin , Christ Simon , Bogdanova Natalia V , Rudorf Sophia
Published: August 2024

Ionizing radiation (IR) in high doses is generally lethal to most organisms. Investigating mechanisms of radiation resistance is crucial for gaining insights into the underlying cellular responses and understanding the damaging effects of IR. In this study, we conducted a comprehensive analysis of sequencing data from an evolutionary experiment aimed at understanding the genetic adaptations to ionizing radiation in Escherichia coli. By including previously neglected synonymous mutations, we identified the rpsH c.294T > G variant, which emerged in all 17 examined isolates across four subpopulations. The identified variant is a synonymous mutation affecting the 30S ribosomal protein S8, and consistently exhibited high detection and low allele frequencies in all subpopulations. This variant, along with two additional rpsH variants, potentially influences translational control of the ribosomal spc operon. The early emergence and stability of these variants suggest their role in adapting to environmental stress, possibly contributing to radiation resistance. Our findings shed light on the dynamics of ribosomal variants during the evolutionary process and their potential role in stress adaptation, providing valuable implications for understanding clinical radiation sensitivity and improving radiotherapy.
Expeditious chemical synthesis of xylomannans disproves the proposed antifreeze activities
Authors: Zhu Qian , Nicolardi Simone , Wang Yuanguang , Liu Yasong , Xu Peng , Wang Jianjun , Zhu Dapeng , Yu Biao
Published: August 2024

Cold-adapted species are able to generate cryoprotective proteins and glycoproteins to prevent freezing damage. The [→4)-β-D-Manp-(1→4)-β-D-Xylp-(1→]n xylomannan from the Alaska beetle Upis ceramboides was disclosed by Walters and co-workers in 2009 as the first glycan-based antifreeze agent, which was later reported to be found in diverse taxa. Here, we report the rapid synthesis of four types of xylomannans, including the proposed antifreeze xylomannan up to a 64-mer (Type I), the regioisomeric [→3)-β-D-Manp-(1→4)-β-D-Xylp-(1→]n 16-mer (Type II), the diastereomeric [→4)-β-L-Manp-(1→4)-β-D-Xylp-(1→]n 16-mer (Type III) and the block-wise [→4)-β-D-Manp-(1→]m[→4)-β-D-Xylp-(1→]n 32-mer (Type IV), by employing a strategic iterative exponential glycan growth (IEGG) process. The nuclear magnetic resonance spectral data of the alleged natural xylomannan are in accordance only to those of the block-wise Type IV glycan and none of these synthetic xylomannans has been found to be capable of inducing thermal hysteresis. These results disprove the previous reports about the natural occurrence of antifreeze xylomannans.
Time-series satellite remote sensing reveals gradually increasing war damage in the Gaza Strip
Authors: Holail Shimaa , Saleh Tamer , Xiao Xiongwu , Xiao Jing , Xia Gui-Song , Shao Zhenfeng , Wang Mi , Gong Jianya , Li Deren
Published: August 2024

War-related urban destruction is a significant global concern, impacting national security, social stability, people’s survival and economic development. The effects of urban geomorphology and complex geological contexts during conflicts, characterized by different levels of structural damage, are not yet fully understood globally. Here we report how integrating deep learning with data from the independently developed LuoJia3-01 satellite enables near real-time detection of explosions and assessment of different building damage levels in the Israel–Palestine conflict. We found that the damage continually increased from 17 October 2023 to 2 March 2024. We found 3747 missile craters with precision positions and sizes, and timing on vital infrastructure across five governorates in the Gaza Strip on 2 March 2024, providing accurate estimates of potential unexploded ordnance locations and assisting in demining and chemical decontamination. Our findings reveal a significant increase in damage to residential and educational structures, accounting for 58.4% of the total—15.4% destroyed, 18.7% severely damaged, 11.8% moderately damaged and 12.5% slightly damaged—which exacerbates the housing crisis and potential population displacement. Additionally, there is a 34.1% decline in the cultivated area of agricultural land, posing a risk to food security. The LuoJia3-01 satellite data are crucial for impartial conflict monitoring, and our innovative methodology offers a cost-effective, scalable approach to assess future conflicts in various global contexts. These first-time findings highlight the urgent need for an immediate ceasefire to prevent further damage and support the release of hostages and subsequent reconstruction efforts.
Every Crisis Is an Opportunity: Advancing Blood Culture Stewardship During a Blood Culture Bottle Shortage
Authors: Ryder Jonathan H , Van Schooneveld Trevor C , Diekema Daniel J , Fabre Valeria
Published: August 2024

The current manufacturing disruption of BACTEC blood culture bottles has drawn attention to diagnostic stewardship around blood culture utilization. In this perspective, we offer strategies for implementing blood culture stewardship using a graded approach based on a hospital's blood culture bottle supply. These strategies should inform plans to mitigate the impact of the shortage on patient care and reinforce fundamental principles of blood culture stewardship.
Pulmonary embolism with thrombus in transit across a patent foramen ovale
Authors: Iyengar Sumedh , Stolear Anton , Dulgher Maxim , Ahmed Ashraf , Shkolnik Evgeny , Zarich Stuart
Published: August 2024

Thromboembolism-in-transit, specifically impending paradoxical embolism (IPDE), is a rare and life-threatening condition with limited reported cases. We present a case of a 51-year-old male with obstructive sleep apnea, initially diagnosed with deep vein thrombosis and pulmonary embolism. Further evaluation revealed a saddle pulmonary embolus extending into the right atrium, straddling a patent foramen ovale (PFO), confirmed by transesophageal echocardiogram. Despite a critical left anterior descending coronary artery stenosis, surgical thrombectomy, PFO closure, and coronary artery bypass grafting were successfully performed. Thromboembolism-in-transit poses diagnostic challenges, and there is a lack of consensus on the optimal treatment strategy. Surgical interventions, including embolectomy and PFO closure, have shown promise, while thrombolytic therapy remains controversial. This case underscores the importance of tailored management in the absence of standardized guidelines, emphasizing the need for further research to establish evidence-based protocols for this uncommon but potentially fatal condition.
Spatial survival analysis accounts for female-biased breeding dispersal and provides realistic estimates of true annual survival in migratory warblers
Authors: Mumme Ronald L
Published: August 2024

Breeding dispersal—between-season change in breeding location—is usually female-biased in birds and creates problems in accurately estimating annual survival, as conventional Cormack-Jolly-Seber (CJS) survival models cannot discriminate between mortality and undetected emigration. Recently, spatial CJS (s-CJS) models have been developed that use data on breeding dispersal within a population to account for undetected emigration and provide corrected estimates of true annual survival, a development that promises to advance avian conservation initiatives that require accurate estimates of annual survival. Using a 14-year dataset on a color-banded population of Setophaga citrina (Hooded Warbler) in northwest Pennsylvania, I examined female-biased breeding dispersal and performance of an s-CJS model in estimating true annual survival of females and males. I also compared my findings to published literature on other migratory North American warblers, a group with many species of high conservation concern. Breeding dispersal in the S. citrina study population is strongly female-biased, with median dispersal distances of 151 m for females (n = 227) and 51 m (n = 336) for males. Although most individuals disperse short distances, the observed pattern of breeding dispersal within the study site was best modeled using a heavy-tailed Cauchy dispersal kernel, a model that indicates the presence of a substantial tail of undetected long-distance dispersal, particularly in females. Using the Cauchy model, s-CJS analysis yielded realistic estimates of S. citrina true annual survival, 0.61 for both sexes, and resolved ambiguities evident in much lower estimates of apparent annual survival, 0.45 for females and 0.54 for males, derived from conventional CJS analysis. Because long-distance breeding dispersal is widespread in migratory warblers and especially frequent in females, analyses of warbler survival should employ s-CJS methods whenever possible, as estimates of apparent annual survival derived from conventional CJS methods will in most cases poorly approximate true annual survival.
It is good to be average: Ecological correlates of breeding phenology in an Arctic seabird, Alle alle (Dovekie)
Authors: Ribeiro Léa , Devogel Marion , Grissot Antoine , Kidawa Dorota , Jakubas Dariusz , Syposz Martyna , Wojczulanis-Jakubas Katarzyna
Published: August 2024

Recognizing the deviation in an animal’s behavior from a population mean is not only necessary to understand the evolution and stability of the whole system but also to predict the future of a population in a changing environment. Arctic seabirds are expected to exhibit high synchronization in timing of breeding at the population level, due to highly seasonal and harsh environmental conditions. Nevertheless, even in such a highly synchronized system, there are always some earlier and later breeders, and the drivers of inter-pair variation remain largely unknown. Using an 8-year dataset on Alle alle (Dovekie), a small Arctic seabird, we examined potential drivers of breeding phenology. We found that A. alle pairs were quite repeatable in their phenology, and preserved their phenological status, with their chicks hatching consistently before, during, or after the population median date for hatching, despite that the calendar position of the median shifted between years. This would suggest that timing of breeding is associated with some pair characteristics, either via properties of the nest and/or some partner’s traits. However, breeding phenology of the pair was not dependent on nest location, pair bond duration or morphological similarity of the partners. Importantly, timing of breeding was negatively associated with chick growth rate, indicating fitness consequences of phenology. A simulation in our study further suggests that the chance of fledgling survival in the context of predation may be the highest for the chicks that hatched during the peak of the hatching period. While our results suggest that the timing of the breeding is important for the reproductive outcome, further research is required to determine the drivers of the consistent breeding phenology within A. alle pairs.
Linnebo on Analyticity and Thin Existence
Authors: Povich Mark
Published: August 2024

In his groundbreaking book, Thin Objects, Øystein Linnebo argues for an account of neo-Fregean abstraction principles and thin existence that does not rely on analyticity or conceptual rules. It instead relies on a metaphysical notion he calls “sufficiency”. In this short discussion, I defend the analytic or conceptual-rule account of thin existence.
An energy and information analysis method of logic gates based on stochastic thermodynamics
Authors: Ge Xiaohu , Ruan Muyao , Peng Xiaoxuan , Xiao Yong , Yang Yang
Published: August 2024

To reduce the energy consumption of logic gates in digital circuits, the size of transistors approaches the mesoscopic scale, e.g. sub-7 nanometers. However, existing energy consumption analysis methods exhibit various deviation for logic gates when the nonequilibrium information processing of mesoscopic scale transistors with ultra-low voltages is analyzed. Based on the stochastic thermodynamics theory, an information energy ratio method is proposed for the energy consumption estimation of XOR gates composed of mesoscopic scale transistors. The proposed method provides a new insight to quantify the transformation between the information capacity and energy consumption for XOR gates and extending to other logic gates. Utilizing the proposed analysis method, the supply voltage of the parity check circuit can be optimized by numerical simulations without expensive and complex practical measurements. The information energy ratio is the first analytical method to quantify the energy and information transformation of logic gates at the mesoscopic scale.
The impact of immunity on the risk of coronary artery disease: insights from a multiomics study
Authors: Bian Rutao , Li Dongyu , Xu Xuegong , Zhang Li
Published: August 2024

Background

Immune inflammation is intricately associated with coronary artery disease (CAD) progression, necessitating the pursuit of more efficacious therapeutic strategies. This study aimed to uncover potential therapeutic targets for CAD and myocardial infarction (MI) by elucidating the causal connection between regulatory immune-related genes (RIRGs) and these disorders.

Methodology

We performed summary data-based Mendelian randomization analysis to assess the therapeutic targets linked to expression quantitative trait loci and methylation quantitative trait loci of RIRGs in relation to CAD and MI. Independent validation cohorts and datasets from coronary artery and left ventricular heart tissue were analyzed. To strengthen causal inference, colocalization analysis and PhenoScanner phenotype scans were employed.

Results

Utilizing multiomics integration, we pinpointed EIF2B2, FCHO1, and DDT as CAD risk genes. Notably, EIF2B2 and FCHO1 displayed significant associations with MI. High EIF2B2 expression, regulated by cg16144293, heightened CAD and MI risk at rs175438. In contrast, enhanced FCHO1 expression, modulated by cg18329931, reduced CAD and MI risk at rs13382133. DDT upregulation influenced by cg11060661 and cg09664220 was associated with decreased CAD risk at rs5760120. Colocalization analysis firmly established these relationships.

Conclusion

EIF2B2, FCHO1, and DDT represent risk loci for CAD progression within RIRGs. Our identification of these genes enhances understanding of CAD pathogenesis and directs future drug development efforts.
Maternal Health Disparities in Acute Care Rehabilitation
Authors: Segraves Rebeca , Segraves Jenna , Parr Rebecca , Samel Erin , Smith-Aldrick Vivian
Published: August 2024

Patients with a high-risk pregnancy or who immediately give birth are often not provided access to acute care occupational and physical therapy during their hospital admission. The greatest potential for health care crises, including maternal mortality, occurs during the first 6 weeks after birth. Maternal mortality and morbidity, which continue to rise in the United States, are considered indicators of the overall population health of a country. It is estimated that over 80% of pregnancy-related deaths are preventable. The leading causes of death within the first 6 weeks after birth are hemorrhage, hypertensive disorders, and infection. Implicit biases about childbearing individuals who are perceived to be relatively young, independent, active, and healthy may unintentionally contribute to areas of substandard care that adversely impact maternal health outcomes. It is a professional and ethical imperative that health providers, including occupational and physical therapists, establish themselves as allies to patient groups at high risk for disparate treatment. The Acute Care OB Rehab Implicit Bias Self-Reflection Tool is an instrument designed for health providers to identify stereotypes that may contribute to inequitable access to rehabilitation in the hospital after birth. Including rehabilitation services for the perinatal population in the hospital setting can play a pivotal role in early detection of adverse events with activity that may directly impact the increasing maternal mortality rate in the United States.
Progressive improvement in time to diagnosis in axial spondyloarthritis through an integrated referral and education system
Authors: Chan Antoni , Rigler Kathryn , Ahmad Nadia , Lafont Tanguy
Published: August 2024

Objectives

To assess the delay in the diagnosis of axial SpA (axSpA) in a real-world cohort over a 16-year period and to evaluate factors associated with this delay. We implemented a service improvement project and evaluated its effectiveness in improving time to diagnosis of axSpA.

Methods

A cohort of axSpA patients newly diagnosed between January 2008 and December 2023 were studied. Surveys were carried out in 2013, 2017, 2019 and 2023 to assess time to diagnosis, which was divided into four periods from onset of inflammatory back pain to year of axSpA diagnosis. The time to diagnosis over the study period was analysed using a statistical process control chart.

Results

Over the study period, 988 referrals were received and 366 (37%) had axSpA. There was a progressive increase in the number of females with axSpA. The mean time to diagnosis significantly decreased from 9.8 years (s.d. 1.2) in 2008 to 1.0 years (s.d. 1.0) in 2023. The greatest delay was from the onset of back pain to first seeing their general practitioners (GPs; mean 3.2 years). There was a significant improvement in the mean time to diagnosis across the time periods through the service improvement interventions.

Conclusion

Structural and organizational change in triage, referral and clinic pathways has led to earlier recognition of axSpA. This is further enhanced through an integrated education program and awareness campaign for the public, GPs and healthcare professionals, including physiotherapists. With continuous quality improvement cycles, we achieved our aim of reducing the mean time to diagnosis to 1 year.
Balancing functions of antifouling, nitric oxide release and vascular cell selectivity for enhanced endothelialization of assembled multilayers
Authors: Zhang Sulei , Sun Jun , Guo Shuaihang , Wang Yichen , Zhang Yuheng , Lei Jiao , Liu Xiaoli , Chen Hong
Published: August 2024

Surface endothelialization is a promising way to improve the hemocompatibility of biomaterials. However, current surface endothelialization strategies have limitations. For example, various surface functions are not well balanced, leading to undesirable results, especially when multiple functional components are introduced. In this work, a multifunctional surface was constructed by balancing the functions of antifouling, nitric oxide (NO) release and endothelial cell promotion via layer-by-layer (LBL) self-assembly. Poly(sodium p-styrenesulfonate-co-oligo(ethylene glycol) methacrylate) (negatively charged) and polyethyleneimine (positively charged) were deposited on silicon substrates to construct multilayers by LBL self-assembly. Then, organic selenium, which has a NO-releasing function, and the cell-adhesive peptide Gly-Arg-Glu-Asp-Val-Tyr, which selectively promotes endothelial cells, were introduced on the assembled multilayers. Poly(oligo(ethylene glycol) methacrylate) is a hydrophilic component for antifouling properties, and poly(sodium p-styrenesulfonate) is a heparin analog that provides negative charges. By modulating the contents of poly(oligo(ethylene glycol) methacrylate) and poly(sodium p-styrenesulfonate) in the copolymers, the NO release rates catalyzed by the modified surfaces were regulated. Moreover, the behaviors of endothelial cells and smooth muscle cells on modified surfaces were well controlled. The optimized surface strongly promoted endothelial cells and inhibited smooth muscle cells to achieve endothelialization effectively.
Rapid fabrication of biomimetic PLGA microsphere incorporated with natural porcine dermal aECM for bone regeneration
Authors: Zhou Xiaosong , Guo Min , Wang Zongliang , Wang Yu , Zhang Peibiao
Published: August 2024

Bioactive microspheres coated with acellular extracellular matrix (aECM) have received extensive attention in bone tissue engineering. In this work, biomimetic microspheres with different aECM ratios, uniform size and controllable size were prepared easily by blending natural porcine dermal aECM and poly (lactic-co-glycolic acid) (PLGA) using electrohydrodynamic spraying and solidification actuated by solvent extraction method. In this work, the appropriate polymer concentration and preparation voltage were investigated, and the surface morphology of the microspheres was observed by scanning electron microscope. Sirius red was used to visualize aECM exposure on the surface of the microspheres. The in vitro and in vivo experiments were carried out to evaluate the bioactivity and osteogenic properties of the microspheres. The results showed that the morphology and size of PLGA microspheres had little influence on the aECM blending. In vitro experiments showed that the higher the content of aECM, the better the cell adhesion performance. In vivo, rat calvarial defect models were observed and characterized at 4 and 8 weeks postoperatively, and the values of BV/TV of 50aECM/PLGA were 47.57 ± 1.14% and 72.92 ± 2.19%, respectively. The results showed that the skull healing effect was better in aECM-containing microspheres. In conclusion, aECM/PLGA composite microspheres can increase cell adhesion performance through the addition of aECM. Moreover, in vivo experiments have proved that aECM/PLGA microspheres are beneficial to bone repair, which means the aECM/PLGA microspheres are a promising bone tissue engineering material.
Constructing a highly efficient multifunctional carbon quantum dot platform for the treatment of infectious wounds
Authors: Zhang Hangzhen , Bai Jiafan , Chen Xiangli , Wang Linyu , Peng Wenzhen , Zhao Yuancong , Weng Jie , Zhi Wei , Wang Jianxin , Zhang Kai , Zhang Xingdong
Published: August 2024

Antibiotic resistance poses a huge threat to public health, which has increased the difficulty and transmission of disease treatment, as well as the burden and cost of medical institutions. In response to the current problems and challenges in inflammation control and treatment of bacterial infected wounds, inspired by antibacterial mechanisms based on active elements such as N, S, Cu and tannic acid (TA), a highly efficient multifunctional carbon quantum dot platform was proposed in this study and constructed through their special assembly in a solvothermal reaction system for the treatment of infected wounds. By introducing active elements such as N, S and Cu, this carbon quantum dot platform is endowed with antibacterial properties, while also achieving good angiogenesis promoting performance through the use of ion Cu. Meanwhile, the good antioxidant activity of TA (one of the precursors used) enables this platform to have better immunomodulatory performance in vivo. The research results on the treatment of bacterial infection models indicate that the multifunctional carbon quantum dots obtained can accelerate the healing of infected wounds by inhibiting bacterial infection, regulating immunoreaction, accelerating collagen deposition and promoting angiogenesis. This multifunctional carbon quantum dot platform shows good clinical application prospects in treating bacterial infected wounds. Additionally, the fluorescence characteristics of such carbon dots can be expected to realize visual therapy in the future.
Serine protease inhibitor E2 protects against cartilage tissue destruction and inflammation in osteoarthritis by targeting NF-κB signalling
Authors: Wang Linzhu , Chen Shuangshuang , Zhang Huizhen , Wei Guozhao , Ma Fenghua , Zhang Mingxiu , Zhang Boyang , Yang Sen , Cheng Hongyi , Yang Ruonan , Wang Ruifeng , Liu Mengyuan , Song Yang , Li Xuelian , E Xiaoqiang
Published: August 2024

Objective

OA is a chronic disease characterized by cartilage degeneration and inflammation, with no approved disease-modifying drugs. This study aimed to identify pathogenic genes and elucidate their mechanism in OA.

Methods

We systematically identified pathogenic genes combined sing-cell and bulk transcriptome profiles of cartilage tissues in OA. Adenovirus carrying the serpin peptidase inhibitor clade E member 2 (serpinE2) or exogenous serpinE2 was injected into monosodium iodoacetate (MIA)-induced OA-model rats. Histological analysis, immunohistochemistry and Alcian blue staining were performed. In vitro, immunofluorescence, quantitative real-time PCR (RT-qPCR), ELISA and western blot assays were performed.

Results

serpinE2 exhibited elevated expression and hypomethylation, showing a positive association with collagen pathway activities in patients with OA. Silencing serpinE2 aggravated MIA-induced knee cartilage degeneration in OA-model rats. Conversely, the intra-articular injection of exogenous serpinE2 ameliorated articular cartilage degeneration, reduced pain-related behavioural responses and relieve synovitis in MIA-induced OA-model rats. Exogenous serpinE2 not only attenuated the elevation of NLRP3, IL-1β and caspase1 expression levels but also restored the reduction in cell viability induced by lipopolysaccharide (LPS) in chondrocytes. Mechanistically, we found that exogenous serpinE2 inhibited LPS-induced reactive oxygen species (ROS) release and NF-κB signalling activation.

Conclusions

serpinE2 plays a protective role in cartilage and synovium tissues, suggesting that serpinE2 gene transfer or molecules that upregulate serpinE2 expression could be therapeutic candidates for OA.
The use of intravenous methylprednisolone in giant cell arteritis: a population-based study
Authors: Henningson Hampus , Hammar Björn , Mohammad Aladdin J
Published: August 2024

Objectives

To determine clinical characteristics, outcome and occurrence of comorbidities in patients with biopsy-confirmed giant cell arteritis (GCA) treated with intravenous methylprednisolone (IVMP) vs those receiving oral glucocorticoids (OGC) only.

Methods

A retrospective study included patients with GCA diagnosed from 2004 through 2019. Clinical and laboratory characteristics, and cumulative GC dose were compared in patients receiving IVMP vs OGCs. Changes in visual acuity (VA), occurrence of comorbidities after GCA diagnosis, and mortality were analysed.

Results

A total of 419 patients (69% female) were included. In total, 111 patients were initially treated with IVMP, 104 (94%) of whom showed visual manifestations at onset and 308 received OGCs only. Ninety patients (21.5%) exhibited visual involvement at onset, verified by an ophthalmologist. Compared with OGC, patients receiving IVMP exhibited lower inflammatory response at presentation. There was a tendency for improvement in VA with the use of IVMP, but the results were not statistically significant (OR 1.19, 95% CI 0.35–4.01). Patients treated with IVMP had a higher risk of newly diagnosed diabetes mellitus within a year of GCA diagnosis (OR 2.59, 95% CI 1.19–5.63). This risk remained elevated after adjusting for cumulative OGC dose at three months (adjusted OR 3.30, 95% CI 1.29–8.43). There was no difference in survival between treatment groups.

Conclusions

Our study found no evidence supporting any benefit of using IVMP in improving VA or survival. IVMP may increase diabetes risk within a year of GCA diagnosis. Further studies are needed to evaluate the value of IVMP in GCA.
What Lies Beneath: Critical Contexts in Medical Education Research
Authors: Colbert-Getz Jorie M. , Ryan Michael S. , Ortega Pilar
Published: August 2024

Medical education is a complex field involving interacting contexts of settings, individuals, and institutional culture. Understanding how contexts interact is important for the applicability of research findings. In this article, the authors describe contexts highlighted in this year’s Research in Medical Education articles related to being and belonging, the definition of medical education, assessment and feedback, and learning and climate. The authors summarize the various contexts and examine implications for the medical education research community.
Redefining Management in Hypertrophic Cardiomyopathy: The Role and Challenges of Exercise Rehabilitation
Authors: Verma Amogh , Anand Ayush , Patel Vaishnavi Akshay , Singh Ajeet , Ahsan Areeba , Kanagala Sai Gautham , Jain Hritvik , Dey Rohit Chandra , Khatib Mahalaqua Nazli , Zahiruddin Quazi Syed , Gaidhane Abhay M , Sharma Divya , Rustagi Sarvesh , Satapathy Prakasini
Published: August 2024

Hypertrophic cardiomyopathy (HCM), a common genetic heart condition, is characterized by thickening of the left ventricle, which can result in a range of health issues, such as arrhythmias, heart failure, and sudden death. Despite traditional cautions against exercise in HCM patients due to potential exacerbation of symptoms and risk of sudden death, recent evidence suggests a paradigm shift toward the benefits of structured exercise rehabilitation. The pathogenesis of HCM, the physical and psychological effects of the illness on patients, and changing views on exercise as a therapeutic intervention are all covered in this review. Recent research shows that modest physical activity can considerably enhance functional ability, psychological health, and overall quality of life in individuals with heart failure without increasing the risk of unfavorable cardiac events, challenging earlier recommendations. Moreover, exercise rehabilitation has been shown to induce favorable myocardial remodeling and enhance cardiovascular fitness, suggesting a revaluation of exercise prescriptions tailored to individual patient profiles. Despite the promising role of exercise in managing HCM, this review also acknowledges the complexities of implementing rehabilitation programs, including the need for comprehensive patient assessment, personalized exercise regimens, and monitoring for potential complications. Future research should focus on optimizing exercise recommendations, understanding long-term outcomes, and integrating exercise rehabilitation into standard care protocols for HCM to foster a more holistic approach to patient management. Underscoring the necessity of a multidisciplinary strategy that balances the benefits of physical activity with the unique risks associated with HCM with the aim of improving patient outcomes through evidence-based, patient-centered care.
Incidence of liver complications with hemochromatosis-associated HFE p.C282Y homozygosity: The role of central adiposity
Authors: Lucas Mitchell R. , Pilling Luke C. , Atkins Janice L. , Melzer David
Published: August 2024

Background and Aims:

The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but the combined effects are unclear. We estimated waist-to-hip ratio (WHR) associations with incident clinical outcomes in routine care in p.C282Y+/+ participants in the UK Biobank community cohort.

Approach and Results:

Baseline WHR data available in 1297 male and 1602 female p.C282Y+/+ with 13.3-year mean follow-up for diagnoses. Spline regressions and Cox proportional hazard models were adjusted for age and genetic principal components. Cumulative incidence was from age 40 to 80 years. In p.C282Y+/+ males, there were positive linear WHR relationships for hospital inpatient–diagnosed liver fibrosis/cirrhosis (p = 2.4 × 10−5), liver cancer (p = 0.007), non-alcoholic fatty liver disease (p = 7.7 × 10−11), and type 2 diabetes (p = 5.1 × 10−16). The hazard ratio for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was 4.13 for liver fibrosis/cirrhosis (95% CI: 2.04–8.39, p = 8.4 × 10−5 vs. normal WHR); cumulative age 80 incidence 15.0% (95% CI: 9.8%–22.6%) versus 3.9% (95% CI: 1.9%–7.6%); for liver cancer, cumulative incidence was 9.2% (95% CI: 5.7%–14.6%) versus 3.6% (95% CI: 1.9%–6.6%). Hemochromatosis was diagnosed in 23 (96%) of the 24 high WHR p.C282Y+/+ males with incident fibrosis/cirrhosis. High WHR (≥0.85; 30.0%) p.C282Y+/+ females had raised hazards for liver fibrosis/cirrhosis (hazard ratio = 9.17, 95% CI: 2.51–33.50, p = 3.8 × 10−7) and Non-alcoholic fatty liver disease (hazard ratio = 5.17, 95% CI: 2.48–10.78, p = 1.2 × 10−5). Fibrosis/cirrhosis associations were similar in the subset with additional primary care diagnoses.

Conclusions:

In p.C282Y+/+ males and females, increasing WHR is associated with substantially higher risks of liver complications. Interventions to reduce central adiposity to improve these outcomes should be tested.
A Novel Symptomatic Lecithin-Cholesterol Acyltransferase Gene Mutation With Corneal Amyloidosis
Authors: Abu Dail Yaser , Flockerzi Elias , Flockerzi Fidelis , Matthaei Mario , Cursiefen Claus , Seitz Berthold
Published: August 2024

Purpose:

To present ocular clinical, histological, systemic, and genetic findings of a patient with familial lecithin-cholesterol acyltransferase (LCAT) deficiency caused by a novel genetic variant of the LCAT gene associated with secondary corneal amyloidosis.

Methods:

Case report.

Results:

A 74-year-old woman presented with decreased visual acuity (VA), sensitivity to light, and progressive whitening of both corneas for approximately 20 years. The patient had undergone penetrating keratoplasty (PKP) on the right eye 6 years ago. Ophthalmologic examination revealed decreased VA in both eyes (OD: 0.05, OS: 0.3), and even further reduced glare VA (OD: 0.05, OS: 0.1), diffuse whitish corneal opacity involving the total thickness of the corneal stroma without crystalline deposits, and a marked peripheral diffuse arcus. Systemic examination revealed severely reduced plasma high-density lipoprotein cholesterol levels, target cells in blood smear, and chronic normochromic anemia. Clinically, LCAT deficiency was the most likely diagnosis. Further genetic analysis confirmed the diagnosis. The patient is homozygous for the novel variant c.943T>C (p.Trp315Arg) in the LCAT gene. Histologic examination of the cornea removed during the first keratoplasty revealed amyloid deposits. The cornea removed at the second keratoplasty had small vacuoles in the anterior stroma, indicating recurrence of lipid deposition.

Conclusions:

LCAT deficiency is a rare genetic disorder that can cause corneal opacities because of lipid deposition in the cornea. Systemic manifestations may help in the differential diagnosis to other diseases associated with severe high-density lipoprotein cholesterol reduction. Genetic analysis is employed to confirm the diagnosis. Some mutations in the LCAT gene seem to be associated with secondary corneal amyloidosis. Further investigation of this association is warranted. A recurrence of corneal opacity after PKP seems to occur mainly in the anterior corneal stroma.
Corneal Sensitivity and Neuropathy in Patients With Ocular Graft-Versus-Host Disease
Authors: Surico Pier Luigi , Yavuz Saricay Leyla , Singh Rohan Bir , Kahale Francesca , Romano Francesco , Dana Reza
Published: August 2024

Purpose:

To assess corneal sensitivity changes in patients with ocular graft-versus-host disease using a non-contact and Cochet–Bonnet esthesiometer. In addition, we evaluate the association between corneal sensitivity and subbasal nerve changes and epitheliopathy in these patients.

Methods:

In this retrospective study, the clinical data and images were evaluated for 36 patients (19 female, 17 male) who fulfilled the inclusion criteria. The analyzed data included demographic and ocular surface parameters, including best-corrected visual acuity, corneal sensitivity with non-contact (mbar) and Cochet–Bonnet (cm) esthesiometer, corneal fluorescein staining (CFS) and symptoms scores, tear volume (Schirmer-I test, mm/5′), and subbasal nerve density (μm/mm2; assessed with in vivo confocal microscopy).

Results:

The mean age of the study cohort was 59.9 ± 10.5 years. The mean corneal sensitivity assessed by Cochet–Bonnet and non-contact esthesiometer was 5.9 ± 0.3 cm and 7.3 ± 2.0 mbar, respectively. The ocular surface parameters included a corneal fluorescein staining (CFS) score, as per the National Eye Institute grading scheme, of 6.9 ± 3.5, and a Schirmer-I test result of 7.5 ± 6.2 mm/5 minutes.. Total corneal subbasal nerve density was inversely associated with CFS scores (r = −0.74; P < 0.001). Moreover, similar correlations between CFS scores and main trunk (r = −0.62; P < 0.001) and branch (r = −0.59; P < 0.001) nerve densities were observed. A significant correlation was found between reduced corneal sensitivity and higher CFS scores (r = 0.66; P < 0.001). Higher pressures were correlated with lower total (r = −0.83; P < 0.001), main trunk (r = −0.62; P < 0.001), and branch (r = −0.72; P < 0.001) nerve densities. The univariate analysis showed that corneal sensitivity loss (assessed with non-contact esthesiometer) was correlated with advanced age of the patients (P = 0.049) and inversely associated with total (P < 0.001), main trunk (P < 0.001), and branch (P < 0.001) nerve densities. In addition, sensitivity loss was inversely associated with punctal occlusion (cauterization (P = 0.001) or plug placement (P < 0.001). The multivariate analysis adjusted for age and punctal occlusion confirmed the associations in the univariate analysis.

Conclusions:

In this study, we observed that corneal sensitivity loss was associated with reduced main trunk, branch, and total nerve density in patients with ocular graft-versus-host disease. In addition, a significant correlation was observed between reduced corneal nerve density, corneal sensitivity, and severity of epitheliopathy.
Hospital readmission for acute kidney injury is independently associated with de novo end-stage renal disease after liver transplantation
Authors: Bittermann Therese , Kathawate Ranganath G. , Schaubel Douglas E. , Lewis James D. , Goldberg David S.
Published: August 2024

End-stage renal disease (ESRD) after liver transplantation (LT) is associated with high morbidity and mortality. The consequences of hospitalizations for post-LT acute kidney injury (AKI) are poorly understood. Using linked Medicare claims and transplant registry data, we analyzed adult liver alone recipients not receiving pretransplant dialysis between January 1, 2007, and December 31, 2016. Covariate-adjusted Cox proportional hazards models stratified by center evaluated factors associated with AKI readmission during the first post-LT year, and whether AKI readmission was associated with de novo early (<1 y) or late (≥1 y) ESRD post-LT. The cohort included 10,559 patients and was 64.5% male, 72.5% White, 8.1% Black, and 14.0% Hispanic with median age 62 years. Overall, 2875 (27.2%) patients had ≥1 AKI hospitalization during the first year. Estimated glomerular filtration rate at LT was associated with AKI readmission (adjusted HR: 1.16 per 10 mL/min/1.73m2 decrease; p<0.001). The adjusted HR for early ESRD in patients with ≥1 AKI readmission <90 days post-LT was 1.90 (p<0.001). The adjusted HRs for late ESRD with 1 and ≥2 prior AKI readmissions were 1.57 and 2.80, respectively (p<0.001). AKI readmissions in the first post-LT year impact over one-quarter of recipients. These increase the risk of subsequent ESRD, but may represent an opportunity to intervene and mitigate further renal dysfunction.
Omalizumab for Treatment of Anti-GD2 Antibody-related Urticaria
Authors: Glincher Rachel , Lentini-Rivera Angela , Andre Jones Latisha , D’Andrea Linda , Durney Christina , Kasper Christine , Lin Yichih , Shrager Leslie , Markova Alina , Lacouture Mario , Modak Shakeel
Published: August 2024

Outcomes for high-risk neuroblastoma have improved with the addition of antidisialoganglioside (GD2) antibody-mediated immunotherapy to multimodality therapy. Urticaria is an expected side effect of anti-GD2 immunotherapy. Rarely, despite maximal use of antihistamines and H2 receptor antagonists, refractory urticaria can result in impaired quality of life, and delays or discontinuation of immunotherapy. The anti-IgE monoclonal antibody, omalizumab, is approved for the treatment of asthma and chronic spontaneous urticaria. We successfully managed grade 3, naxitamab-related urticaria refractory to standard management in 2 patients using omalizumab, allowing for continued anti-GD2 immunotherapy. Omalizumab did not impact antitumor activity or immunogenicity of naxitamab.
Concurrent Osteonecrosis of the Jaw and Hip in a Child With Severe Aplastic Anemia Undergoing Transplant
Authors: Kaya Zühre , Kirkiz Kayali Serap , Topuz Türkcan Büşra , Yilmaz Metin , Boyunağa Öznur , Koçak Ülker
Published: August 2024

We present the first case of concomitant hip and jaw osteonecrosis in a 10-year-old child with aplastic anemia undergoing a transplant. Biphosphonate treatment may be beneficial for hip osteonecrosis but harmful for jaw osteonecrosis. Our experience suggests that clinicians should be cautious when prescribing bisphosphonate to children with simultaneous hip and jaw osteonecrosis. They should be aware of the osteonecrosis locations and treatment choices.
Severe Pneumonia in PICU Admissions: The Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) Observational Cohort Study, 2020–2022*
Authors: Wong Judith Ju Ming , Abbas Qalab , Wang Justin Qi Yuee , Xu Wei , Dang Hongxing , Phan Phuc Huu , Guo Liang , Lee Pei Chuen , Zhu Xuemei , Angurana Suresh Kumar , Pukdeetraipop Minchaya , Efar Pustika , Yuliarto Saptadi , Choi Insu , Fan Lijia , Hui Alvin Wun Fung , Gan Chin Seng , Liu Chunfeng , Samransamruajkit Rujipat , Cho Hwa Jin , Ong Jacqueline Soo May , Lee Jan Hau ,   on behalf of the Pediatric Acute and Critical Care Asian Network (PACCMAN)
Published: August 2024

OBJECTIVES:

Mortality from pneumonia is three times higher in Asia compared with industrialized countries. We aimed to determine the epidemiology, microbiology, and outcome of severe pneumonia in PICUs across the Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN).

DESIGN:

Prospective multicenter observational study from June 2020 to September 2022.

SETTING:

Fifteen PICUs in PACCMAN.

PATIENTS:

All children younger than 18 years old diagnosed with pneumonia and admitted to the PICU.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Clinical, microbiologic, and outcome data were recorded. The primary outcome was PICU mortality. Univariate and multivariable logistic regression was performed to investigate associations between PICU mortality and explanatory risk factors on presentation to the PICU. Among patients screened, 846 of 11,778 PICU patients (7.2%) with a median age of 1.2 years (interquartile range, 0.4–3.7 yr) had pneumonia. Respiratory syncytial virus was detected in 111 of 846 cases (13.1%). The most common bacteria were Staphylococcus species (71/846 [8.4%]) followed by Pseudomonas species (60/846 [7.1%]). Second-generation cephalosporins (322/846 [38.1%]) were the most common broad-spectrum antibiotics prescribed, followed by carbapenems (174/846 [20.6%]). Invasive mechanical ventilation and noninvasive respiratory support was provided in 438 of 846 (51.8%) and 500 of 846 (59.1%) patients, respectively. PICU mortality was 65 of 846 (7.7%). In the multivariable logistic regression model, age (adjusted odds ratio [aOR], 1.08; 95% CI, 1.00–1.16), Pediatric Index of Mortality 3 score (aOR, 1.03; 95% CI, 1.02–1.05), and drowsiness (aOR, 2.73; 95% CI, 1.24–6.00) were associated with greater odds of mortality.

CONCLUSIONS:

In the PACCMAN contributing PICUs, pneumonia is a frequent cause for admission (7%) and is associated with a greater odds of mortality.