bluuebunny/crossref_metadata_2025 huggingface dataset:
Does pay-for-performance design matter? Evidence from Brazil
Authors: Russo Letícia Xander , Powell-Jackson Timothy , Borghi Josephine , Sampaio Juliana , Gurgel Junior Garibaldi Dantas , Shimizu Helena Eri , Bezerra Adriana Falangola Benjamin , E Silva Keila Silene de Brito , Barreto Jorge Otávio Maia , de Carvalho André Luis Bonifácio , Kovacs Roxanne J , Gomes Luciano Bezerra , Fardousi Nasser , da Silva Everton Nunes
Published: April 2024

Pay-for-performance (P4P) schemes have been shown to have mixed effects on health care outcomes. A challenge in interpreting this evidence is that P4P is often considered a homogenous intervention, when in practice schemes vary widely in their design. Our study contributes to this literature by providing a detailed depiction of incentive design across municipalities within a national P4P scheme in Brazil [Primary Care Access and Quality (PMAQ)] and exploring the association of alternative design typologies with the performance of primary health care providers. We carried out a nation-wide survey of municipal health managers to characterize the scheme design, based on the size of the bonus, the providers incentivized and the frequency of payment. Using OLS regressions and controlling for municipality characteristics, we examined whether each design feature was associated with better family health team (FHT) performance. To capture potential interactions between design features, we used cluster analysis to group municipalities into five design typologies and then examined associations with quality of care. A majority of the municipalities included in our study used some of the PMAQ funds to provide bonuses to FHT workers, while the remaining municipalities spent the funds in the traditional way using input-based budgets. Frequent bonus payments (monthly) and higher size bonus allocations (share of 20–80%) were strongly associated with better team performance, while who within a team was eligible to receive bonuses did not in isolation appear to influence performance. The cluster analysis showed what combinations of design features were associated with better performance. The PMAQ score in the ‘large bonus/many workers/high-frequency’ cluster was 8.44 points higher than the ‘no bonus’ cluster, equivalent to a difference of 21.7% in the mean PMAQ score. Evidence from our study shows how design features can potentially influence health provider performance, informing the design of more effective P4P schemes.
Quadrivalent HPV Vaccine Effectiveness Against Cervical Intraepithelial Lesion Grade 2 or Worse in Norway: A Registry-Based Study of 0.9 Million Norwegian Women
Authors: Orumaa Madleen , Lahlum Elen Johanne , Gulla Marie , Tota Joseph E , Nygård Mari , Nygård Ståle
Published: April 2024

In Norway, single-cohort vaccination with quadrivalent human papillomavirus (qHPV) vaccine targeting 12-year-old girls took place in 2009–2016. In 2020, the oldest vaccinated cohort was 23 years old and had approached the age where risk of being diagnosed with cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increases rapidly. The aim of this cohort study was to assess direct qHPV vaccine effectiveness (VE) against CIN2+ among Norwegian women aged 16–30 years in 2007–2020. By using population-based health registries and individual-level data on vaccination status and potential subsequent CIN2+ incidence, we found 82% qHPV VE among women vaccinated before age 17 years.
From Confrontation to Cooperation: Describing Non-State Armed Group–UN Interactions in Peace Operations
Authors: Kotajoki Jenniina
Published: April 2024

In various conflict contexts where the state is unable to maintain security and public order, non-state armed groups (NSAGs) and the United Nations (UN) conduct their activities alongside one another. While previous research has focused on hostile relations between the UN and NSAGs, less attention has been given to collaborative interactions. This paper aims to address this research gap by formulating a novel conceptual typology of NSAG–UN interactions in the context of a peace operation. The typological framework comprises two-dimensions: firstly, the thematic field of interaction including human rights, humanitarian needs and governance, security, and political processes and, secondly, the nature of interaction ranging from confrontation to cooperation. Based on the typology, interaction activities between the UN and NSAGs in two peacekeeping operations—the UN Operation in Côte d'Ivoire (UNOCI) and the UN Multidimensional Integrated Stabilization Mission in Mali (MINUSMA)—are systematically documented and described. While both cases show confrontation in the security field, UNOCI also commonly cooperated with NSAGs on security-related issues; MINUSMA instead cooperated with NSAGs primarily regarding the political process. The analysis further proposes factors that may explain such variation, including institutional arrangements and NSAG characteristics. The conceptual framework presented in this paper is crucial in advancing knowledge about an empirical phenomenon that we know little about and that has important implications for different forms of “local” engagement in peace operations and the effectiveness of UN policies and practices.
A rare case of carcino-sarcoma of the esophagus with huge intrathoracic metastasis
Authors: Alamassi Mohammad , Arabi Esraa Yaseen , Arabi Haitham , Saleh Waleed
Published: April 2024

Carcinosarcoma of the esophagus constitutes only 0.5%–2.8% of all malignant esophageal cancers. It is identified by the presence of both carcinomatous and sarcomatous components. A clear regimen of treatment has not been established due to the limited understanding of the disease. We present a case of carcinosarcoma of the esophagus with rapid recurrence and invasion to the intrathoracic cavity only 6 weeks after esophagectomy. Carcinosarcoma carries a poor prognosis, as it has a late tendency of hematogenous spread with a high growth rate.
Ultrasound-guided resection of cerebellar racemose neurocysticercosis: novel insights from a unique scenario
Authors: Rojas-Apaza Rolando V , Bocanegra-Becerra Jhon E , Ruiz-Garcia Henry , Rabanal-Palacios Jorge , Zambrano-Reyna Francisco
Published: April 2024

Racemose neurocysticercosis (RNC) is a malignant form of Taenia solium infection. It carries high mortality due to widespread intraparenchymal invasion, mass effect, and cyst rupture. Cerebellar RNC is unusual and constitutes a surgical challenge. Scarce applications of ultrasound (US) -guided resection have been reported for RNC of the posterior fossa. We report the case of a 66-year-old woman who presented with ataxia and dysmetria. Her past medical history was relevant for seizures and hydrocephalus secondary to neurocysticercosis. Because of the increasing cyst invasion and threatening mass effect in the posterior fossa, the patient underwent US-guided resection of lesions. Postoperative computed tomography (CT) demonstrated complete excision of cysts, and a 2-year follow-up magnetic resonance imaging (MRI) showed no recurrence. On neurological examination, the patient had persistent ataxia without new-onset neurological deficits. The present case study illustrates the feasibility and cost-effective approach of US-guided resection to provide enhanced operative visualization and achieve complete cyst resection.
Drug induced gingival enlargement - phenytoin: an overview and case report
Authors: Dhalla Nipun , Gopal Lipika , Palwankar Pooja
Published: April 2024

Gingival enlargement is a side effect of several different medication, including immunosuppressants, anticonvulsants, and calcium channel blockers. It is an inflammatory response that starts when plaque and calculus build up on the tooth surface. The most prevalent long-term neurological condition affecting people is epilepsy. In affluent nations, the prevalence of epilepsy is ~ 1%, whereas in less developed countries, it may >2%. The preferred medication for the condition, phenytoin, has major side effects include gingival enlargement. In addition to being visually disfiguring, this enlargement frequently affects speech, chewing and eating. Furthermore, those with poor dental hygiene, causes disabilities with motor coordination and muscular limitations leading to mental disability and physical impairments are more prone to periodontal disease. This article enlightened the mechanism of drug induced gingival enlargement clinically, microbiologically, and surgically.
Disrupting cell wall integrity impacts endomembrane trafficking to promote secretion over endocytic trafficking
Authors: Hoffmann Natalie , Mohammad Eskandar , McFarlane Heather E
Published: April 2024

The plant cell wall provides a strong yet flexible barrier to protect cells from the external environment. Modifications of the cell wall, either during development or under stress conditions, can induce cell wall integrity responses and ultimately lead to alterations in gene expression, hormone production, and cell wall composition. These changes in cell wall composition presumably require remodelling of the secretory pathway to facilitate synthesis and secretion of cell wall components and cell wall synthesis/remodelling enzymes from the Golgi apparatus. Here, we used a combination of live-cell confocal imaging and transmission electron microscopy to examine the short-term and constitutive impact of isoxaben, which reduces cellulose biosynthesis, and Driselase, a cocktail of cell-wall-degrading fungal enzymes, on cellular processes during cell wall integrity responses in Arabidopsis. We show that both treatments altered organelle morphology and triggered rebalancing of the secretory pathway to promote secretion while reducing endocytic trafficking. The actin cytoskeleton was less dynamic following cell wall modification, and organelle movement was reduced. These results demonstrate active remodelling of the endomembrane system and actin cytoskeleton following changes to the cell wall.
Stellar populations with optical spectra: deep learning versus popular spectrum fitting codes
Authors: Woo Joanna , Walters Dan , Archinuk Finn , Faber S M , Ellison Sara L , Teimoorinia Hossen , Iyer Kartheik
Published: April 2024

We compare the performance of several popular spectrum fitting codes (firefly, starlight, pypipe3d, and ppxf), and a deep-learning convolutional neural network (starnet), in recovering known stellar population properties (mean stellar age, stellar metallicity, stellar mass-to-light ratio M*/Lr and the internal E(B−V)) of simulated galaxy spectra in optical wavelengths. Our mock spectra are constructed from star-formation histories from the IllustrisTNG100-1 simulation. These spectra mimic the Sloan Digital Sky Survey (SDSS) through a novel method of including the noise, sky residuals, and emission lines taken directly from SDSS. We find that starnet vastly outperforms all conventional codes in both speed and recovery of stellar population properties (error scatter <0.08 dex, average biases <0.02 dex for all tested quantities), but it requires an appropriate training set. Of the non-machine-learning codes, ppxf was a factor of 3–4 times faster than the other codes, and was the best in recovering stellar population properties (error scatter of <0.11 dex, average biases <0.08 dex). However, the errors and biases are strongly dependent on both true and predicted values of stellar age and metallicity, and signal-to-noise ratio. The biases of all codes can approach 0.15 dex in stellar ages, metallicities and log M*/Lr, but remain ≲0.05 for E(B−V). Using unrealistic Gaussian noise in the construction of mock spectra will underestimate the errors in the metallicities by a factor of 2 or more, and mocks without emission lines will underestimate the errors in stellar age and M*/Lr by a factor of 2.
Systematic interrogation of CRISPR antimicrobials in Klebsiella pneumoniae reveals nuclease-, guide- and strain-dependent features influencing antimicrobial activity
Authors: Vialetto Elena , Miele Solange , Goren Moran G , Yu Jiaqi , Yu Yanying , Collias Daphne , Beamud Beatriz , Osbelt Lisa , Lourenço Marta , Strowig Till , Brisse Sylvain , Barquist Lars , Qimron Udi , Bikard David , Beisel Chase L
Published: April 2024

CRISPR-Cas systems can be utilized as programmable-spectrum antimicrobials to combat bacterial infections. However, how CRISPR nucleases perform as antimicrobials across target sites and strains remains poorly explored. Here, we address this knowledge gap by systematically interrogating the use of CRISPR antimicrobials using multidrug-resistant and hypervirulent strains of Klebsiella pneumoniae as models. Comparing different Cas nucleases, DNA-targeting nucleases outperformed RNA-targeting nucleases based on the tested targets. Focusing on AsCas12a that exhibited robust targeting across different strains, we found that the elucidated modes of escape varied widely, restraining opportunities to enhance killing. We also encountered individual guide RNAs yielding different extents of clearance across strains, which were linked to an interplay between improper gRNA folding and strain-specific DNA repair and survival. To explore features that could improve targeting across strains, we performed a genome-wide screen in different K. pneumoniae strains that yielded guide design rules and trained an algorithm for predicting guide efficiency. Finally, we showed that Cas12a antimicrobials can be exploited to eliminate K. pneumoniae when encoded in phagemids delivered by T7-like phages. Altogether, our results highlight the importance of evaluating antimicrobial activity of CRISPR antimicrobials across relevant strains and define critical parameters for efficient CRISPR-based targeting.
Precise editing of pathogenic nucleotide repeat expansions in iPSCs using paired prime editor
Authors: Hwang Hye-Yeon , Gim Dongmin , Yi Hwalin , Jung Hyewon , Lee Jaecheol , Kim Daesik
Published: April 2024

Nucleotide repeat expansion disorders, a group of genetic diseases characterized by the expansion of specific DNA sequences, pose significant challenges to treatment and therapy development. Here, we present a precise and programmable method called prime editor–mediated correction of nucleotide repeat expansion (PE-CORE) for correcting pathogenic nucleotide repeat expansion. PE-CORE leverages a prime editor and paired pegRNAs to achieve targeted correction of repeat sequences. We demonstrate the effectiveness of PE-CORE in HEK293T cells and patient-derived induced pluripotent stem cells (iPSCs). Specifically, we focus on spinal and bulbar muscular atrophy and spinocerebellar ataxia type, two diseases associated with nucleotide repeat expansion. Our results demonstrate the successful correction of pathogenic expansions in iPSCs and subsequent differentiation into motor neurons. Specifically, we detect distinct downshifts in the size of both the mRNA and protein, confirming the functional correction of the iPSC-derived motor neurons. These findings highlight PE-CORE as a precision tool for addressing the intricate challenges of nucleotide repeat expansion disorders, paving the way for targeted therapies and potential clinical applications.
Epigenetic control of adaptive or homeostatic splicing during interval-training activities
Authors: Liu Ling , Nguyen Hai , Das Urmi , Ogunsola Samuel , Yu Jiankun , Lei Lei , Kung Matthew , Pejhan Shervin , Rastegar Mojgan , Xie Jiuyong
Published: April 2024

Interval-training activities induce adaptive cellular changes without altering their fundamental identity, but the precise underlying molecular mechanisms are not fully understood. In this study, we demonstrate that interval-training depolarization (ITD) of pituitary cells triggers distinct adaptive or homeostatic splicing responses of alternative exons. This occurs while preserving the steady-state expression of the Prolactin and other hormone genes. The nature of these splicing responses depends on the exon's DNA methylation status, the methyl-C-binding protein MeCP2 and its associated CA-rich motif-binding hnRNP L. Interestingly, the steady expression of the Prolactin gene is also reliant on MeCP2, whose disruption leads to exacerbated multi-exon aberrant splicing and overexpression of the hormone gene transcripts upon ITD, similar to the observed hyperprolactinemia or activity-dependent aberrant splicing in Rett Syndrome. Therefore, epigenetic control is crucial for both adaptive and homeostatic splicing and particularly the steady expression of the Prolactin hormone gene during ITD. Disruption in this regulation may have significant implications for the development of progressive diseases.
Proposing candidate genes under telomeric control based on cross-species position data
Authors: Projahn Elias F , Fuellen Georg , Walter Michael , Möller Steffen
Published: April 2024

In this paper, we present a comprehensive computational framework aimed at suggesting genes whose transcriptional regulation is likely to be influenced by their chromosomal position. This framework provides a user-friendly web interface, enabling researchers to explore the positional properties of all human genes and their orthologs across species, with a focus on their relation to the telomeres. Our approach involves multiple scoring methods, each adjustable by users, representing different features of the genes' positional variation across species. The resulting rankings can be combined to identify candidate genes that may be subject to position effects. Furthermore, the ranking can be tailored to a specific set of reference genes. We evaluate the method within the context of TPE-OLD, a mechanism where telomeres can exert a direct influence on gene expression across considerable genomic distances, and empower researchers to delve deeper into genes of interest, analyzing their position across species and estimating their susceptibility to position effects like TPE-OLD. We also provide simple enrichment analyses of user-provided gene lists in relation to top-ranking candidate genes.
CWGCNA: an R package to perform causal inference from the WGCNA framework
Authors: Liu Yu
Published: April 2024

WGCNA (weighted gene co-expression network analysis) is a very useful tool for identifying co-expressed gene modules and detecting their correlations to phenotypic traits. Here, we explored more possibilities about it and developed the R package CWGCNA (causal WGCNA), which works from the traditional WGCNA pipeline but mines more information. It couples a mediation model with WGCNA, so the causal relationships among WGCNA modules, module features, and phenotypes can be found, demonstrating whether the module change causes the phenotype change or vice versa. After that, when annotating the module gene set functions, it uses a novel network-based method, considering the modules' topological structures and capturing their influence on the gene set functions. In addition to conducting these biological explorations, CWGCNA also contains a machine learning section to perform clustering and classification on multi-omics data, given the increasing popularity of this data type. Some basic functions, such as differential feature identification, are also available in our package. Its effectiveness is proved by the performance on three single or multi-omics datasets, showing better performance than existing methods. CWGCNA is available at: https://github.com/yuabrahamliu/CWGCNA.
Frequent Disengagement and Subsequent Mortality Among People With HIV and Hepatitis C in Canada: A Prospective Cohort Study
Authors: Saeed Sahar , Thomas Tyler , Dinh Duy A , Moodie Erica , Cox Joseph , Cooper Curtis , Gill John , Martel-Laferriere Valerie , Panagiotoglou Dimitra , Walmsley Sharon , Wong Alexander , Klein Marina B
Published: April 2024

Background

The cascade of care, commonly used to assess HIV and hepatitis C (HCV) health service delivery, has limitations in capturing the complexity of individuals’ engagement patterns. This study examines the dynamic nature of engagement and mortality trajectories among people with HIV and HCV.

Methods

We used data from the Canadian HIV-HCV Co-Infection Cohort, which prospectively follows 2098 participants from 18 centers biannually. Markov multistate models were used to evaluate sociodemographic and clinical factors associated with transitioning between the following states: (1) lost-to-follow-up (LTFU), defined as no visit for 18 months; (2) reengaged (reentry into cohort after being LTFU); (3) withdrawn from the study (ie, moved); (4) death; otherwise remained (5) engaged-in-care.

Results

A total of 1809 participants met the eligibility criteria and contributed 12 591 person-years from 2003 to 2022. LTFU was common, with 46% experiencing at least 1 episode, of whom only 57% reengaged. One in 5 (n = 383) participants died during the study. Participants who transitioned to LTFU were twice as likely to die as those who were consistently engaged. Factors associated with transitioning to LTFU included detectable HCV RNA (adjusted hazards ratio [aHR], 1.37; 95% confidence interval [CI], 1.13–1.67), evidence of HCV treatment but no sustained virologic response result (aHR, 1.99; 95% CI, 1.56–2.53), and recent incarceration (aHR, 1.94; 95% CI, 1.58–2.40). Being Indigenous was a significant predictor of death across all engagement trajectories.

Interpretation

Disengagement from clinical care was common and resulted in higher death rates. People LTFU were more likely to require HCV treatment highlighting a priority population for elimination strategies.
Application of machine learning and grey Taguchi technique for the development and optimization of a natural fiber hybrid reinforced polymer composite for aircraft body manufacture
Authors: Esangbedo Moses Olabhele , Samuel Bassey Okon
Published: April 2024

The rapid expansion of the air transport industry raises significant sustainability concerns due to its substantial carbon emissions and contribution to global climate change. These emissions are closely linked to fuel consumption, which in turn is influenced by the weight of materials used in aircraft systems. This study extensively applied machine learning tools for the optimization of natural fiber-reinforced composite material production parameters for aircraft body application. The Taguchi optimization technique was used to study the effect of sisal fibers, glass fibers, fiber length, and NaOH treatment concentration on the performance of the materials. Multi-objective optimization methods like the grey relational analysis and genetic algorithm (using the MATLAB programming interface) were employed to obtain the best combination of the studied factors for low fuel consumption (low carbon emission) and high-reliability structural applications of aircraft. The models developed from regressional analysis had high accuracy of prediction, with R-Square values all >80%. Optimization of the grey relational analysis of the developed composite using the genetic algorithm showed the best process parameter to achieve low weight material for aircraft application to be 40% sisal, 5% glass fiber at 35 mm fiber length, and 5% NaOH concentration with grey relational analysis at the highest possible level, which is unity.
VND Genes Redundantly Regulate Cell Wall Thickening during Parasitic Nematode Infection
Authors: Gushino Saki , Tsai Allen Yi-Lun , Otani Misato , Demura Taku , Sawa Shinichiro
Published: April 2024

Plant parasitic root-knot nematodes are major agricultural pests worldwide, as they infect plant roots and cause substantial damages to crop plants. Root-knot nematodes induce specialized feeding cells known as giant cells (GCs) in the root vasculature, which serve as nutrient reservoirs for the infecting nematodes. Here, we show that the cell walls of GCs thicken to form pitted patterns that superficially resemble metaxylem cells. Interestingly, VASCULAR-RELATED NAC-DOMAIN1 (VND1) was found to be upregulated, while the xylem-type programmed cell death marker XYLEM CYSTEINE PEPTIDASE 1 was downregulated upon nematode infection. The vnd2 and vnd3 mutants showed reduced secondary cell wall pore size, while the vnd1 vnd2 vnd3 triple mutant produced significantly fewer nematode egg masses when compared with the wild type. These results suggest that the GC development pathway likely shares common signaling modules with the metaxylem differentiation pathway and VND1, VND2, and VND3 redundantly regulate plant–nematode interaction through secondary cell wall formation.
Cell type-specific adaptation of the SARS-CoV-2 spike
Authors: Carrascosa-Sàez Marc , Marqués María-Carmen , Geller Ron , Elena Santiago F , Rahmeh Amal , Dufloo Jérémy , Sanjuán Rafael
Published: April 2024

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can infect various human tissues and cell types, principally via interaction with its cognate receptor angiotensin-converting enzyme-2 (ACE2). However, how the virus evolves in different cellular environments is poorly understood. Here, we used experimental evolution to study the adaptation of the SARS-CoV-2 spike to four human cell lines expressing different levels of key entry factors. After twenty passages of a spike-expressing recombinant vesicular stomatitis virus (VSV), cell-type-specific phenotypic changes were observed and sequencing allowed the identification of sixteen adaptive spike mutations. We used VSV pseudotyping to measure the entry efficiency, ACE2 affinity, spike processing, TMPRSS2 usage, and entry pathway usage of all the mutants, alone or in combination. The fusogenicity of the mutant spikes was assessed with a cell–cell fusion assay. Finally, mutant recombinant VSVs were used to measure the fitness advantage associated with selected mutations. We found that the effects of these mutations varied across cell types, both in terms of viral entry and replicative fitness. Interestingly, two spike mutations (L48S and A372T) that emerged in cells expressing low ACE2 levels increased receptor affinity, syncytia induction, and entry efficiency under low-ACE2 conditions. Our results demonstrate specific adaptation of the SARS-CoV-2 spike to different cell types and have implications for understanding SARS-CoV-2 tissue tropism and evolution.
Within-host influenza viral diversity in the pediatric population as a function of age, vaccine, and health status
Authors: Sobel Leonard Ashley , Mendoza Lydia , McFarland Alexander G , Marques Andrew D , Everett John K , Moncla Louise , Bushman Frederic D , Odom John Audrey R , Hensley Scott E
Published: April 2024

Seasonal influenza virus predominantly evolves through antigenic drift, marked by the accumulation of mutations at antigenic sites. Because of antigenic drift, influenza vaccines are frequently updated, though their efficacy may still be limited due to strain mismatches. Despite the high levels of viral diversity observed across populations, most human studies reveal limited intrahost diversity, leaving the origin of population-level viral diversity unclear. Previous studies show host characteristics, such as immunity, might affect within-host viral evolution. Here we investigate influenza A viral diversity in children aged between 6 months and 18 years. Influenza virus evolution in children is less well characterized than in adults, yet may be associated with higher levels of viral diversity given the lower level of pre-existing immunity and longer durations of infection in children. We obtained influenza isolates from banked influenza A-positive nasopharyngeal swabs collected at the Children’s Hospital of Philadelphia during the 2017–18 influenza season. Using next-generation sequencing, we evaluated the population of influenza viruses present in each sample. We characterized within-host viral diversity using the number and frequency of intrahost single-nucleotide variants (iSNVs) detected in each sample. We related viral diversity to clinical metadata, including subjects’ age, vaccination status, and comorbid conditions, as well as sample metadata such as virus strain and cycle threshold. Consistent with previous studies, most samples contained low levels of diversity with no clear association between the subjects’ age, vaccine status, or health status. Further, there was no enrichment of iSNVs near known antigenic sites. Taken together, these findings are consistent with previous observations that the majority of intrahost influenza virus infection is characterized by low viral diversity without evidence of diversifying selection.
ENO1 promotes trophoblast invasion regulated by E2F8 in recurrent miscarriage
Authors: Liu Zhenzhen , Wang Chengjie , Tang Yao , Zhang Xiaoyue , Pei Jiangnan , Liu Haiyan , Yu Yi , Gu Weirong
Published: April 2024

Recurrent miscarriage (RM) is related to the dysfunction of extravillous trophoblast cells (EVTs), but the comprehensive mechanisms remain largely unexplored. We analyzed single‐cell RNA sequencing (scRNA‐seq), bulk RNA sequencing and microarray datasets obtained from Gene Expression Omnibus (GEO) database to explore the hub genes in the mechanisms of RM. We identified 1724 differentially expressed genes (DEGs) in EVTs from the RM, and they were all expressed along the trajectory of EVTs. These DEGs were associated with hypoxia and glucose metabolism. Single‐cell Regulatory Network Inference and Clustering (SCENIC) analysis revealed that E2F transcription factor (E2F) 8 (E2F8) was a key transcription factor for these DEGs. And the expression of ENO1 can be positively regulated by E2F8 via RNA sequencing analysis. Subsequently, we performed immunofluorescence assay (IF), plasmid transfection, western blotting, chromatin immunoprecipitation (ChIP), real‐time quantitative polymerase chain reaction (qRT‐PCR), and transwell assays for validation experiments. We found that the expression of alpha‐Enolase 1 (ENO1) was lower in the placentas of RM. Importantly, E2F8 can transcriptionally regulate the expression of ENO1 to promote the invasion of trophoblast cells by inhibiting secreted frizzled‐related protein 1/4 (SFRP1/4) to activate Wnt signaling pathway. Our results suggest that ENO1 can promote trophoblast invasion via an E2F8‐dependent manner, highlighting a potential novel target for the physiological mechanisms of RM.
All the Ways Nurses Make the World
Authors: Brown Theresa
Published: April 2024

A testament to the evolutionary power of nursing
Climate change and its impact on asthma
Authors: Arceneaux Leslie S. , Gregory Karen L.
Published: April 2024

Earth's climate is changing at an unprecedented pace, primarily due to anthropogenic causes including greenhouse gas emissions. Evidence shows a strong link between climate change and its effects on asthma. Healthcare professionals must be educated to advocate for and lead effective strategies to reduce the health risks of climate change.
Predictors of Persistent Limp Following Proximal Femoral Varus Osteotomy for Perthes Disease
Authors: Orellana Kevin J. , Bram Joshua T. , Batley Morgan , Novotny Susan , Shah Hitesh , Laine Jennifer C. , Kelly Derek M. , Martin Benjamin , Schrader Tim , Kim Harry , Sankar Wudbhav N. ,   the International Perthes Study Group
Published: April 2024

Introduction:

One of the most popular containment procedures for Legg-Calvé-Perthes disease (LCPD) is proximal femur varus osteotomy (PFO). While generally successful in achieving containment, PFO can cause limb length discrepancy, abductor weakness, and (of most concern for families) a persistent limp. While many studies have focused on radiographic outcomes following containment surgery, none have analyzed predictors of this persistent limp. The aim of this study was to determine clinical, radiographic, and surgical risk factors for persistent limp 2 years after PFO in children with LCPD.

Methods:

A retrospective review of a prospectively collected multicenter database was conducted for patients aged 6 to 11 years at disease onset with unilateral early-stage LCPD (Waldenström I) who underwent PFO. Limp status (no, mild, and severe), age, BMI, and pain scores were obtained at initial presentation, 3-month, and 2-year postoperative visits. Preoperative and follow-up radiographs were used to measure traditional morphologic hip metrics including acetabular index (AI), lateral center-edge angle (LCEA), and femoral neck-shaft angle (NSA). Univariate analysis as well as multivariate logistic regression models were used to analyze factors associated with mild and severe limp at the 2-year visit.

Results:

A total of 95 patients met the inclusion criteria, and of these 50 patients underwent concomitant greater trochanter apophysiodesis (GTA) at the time of PFO. At the 2-year visit, there were 38 patients (40%) with a mild or severe limp. Multivariate logistic regression revealed no significant radiographic factors associated with a persistent limp. However, lower 2-year BMI and undergoing GTA were associated with decreased rates of persistent limp regardless of age (P<0.05). When stratifying by age of disease onset, apophysiodesis appeared to be protective against any severity of limp in patients aged 6 to 8 years old (P= 0.03), but not in patients 8 years or older (P= 0.49).

Conclusions:

Persistent limp following PFO is a frustrating problem that was seen in 40% of patients at 2 years. However, lower follow-up BMI and performing a greater trochanter apophysiodesis, particularly in patients younger than 8 years of age, correlated with a lower risk of postoperative limp.
Comments and illustrations of the European Federation of Societies for Ultrasound in Medicine guidelines: Rare pancreatic tumors, ultrasound and contrast-enhanced ultrasound features—Malignant mesenchymal tumors
Authors: Möller Kathleen , Ntovas Sotirios , Hocke Michael , On Wei , Everett Simon M. , Braden Barbara , Jenssen Christian , Misselwitz Benjamin , Ge Nan , Sun Siyu , Gerber Michael , Faiss Siegbert , Dietrich Christoph F.
Published: April 2024

Rare malignant mesenchymal pancreatic tumors are systematized and reported in this review. The focus is on the appearance on imaging. The present overview summarizes the data and shows that not every pancreatic tumor corresponds to the most common entities of ductal adenocarcinoma or neuroendocrine tumor.
Myocarditis in children 2024, new themes and continued questions
Authors: Goldberg Jason F. , Spinner Joseph A. , Soslow Jonathan H.
Published: April 2024

Purpose

While pediatric myocarditis incidence has increased since the coronavirus disease 2019 (COVID-19) pandemic, there remain questions regarding diagnosis, risk stratification, and optimal therapy. This review highlights recent publications and continued unanswered questions related to myocarditis in children.

Recent findings

Emergence from the COVID-19 era has allowed more accurate description of the incidence and prognosis of myocarditis adjacent to COVID-19 infection and vaccine administration as well that of multi-system inflammatory disease in children (MIS-C). As cardiac magnetic resonance technology has shown increased availability and evidence in pediatric myocarditis, it is important to understand conclusions from adult imaging studies and define the use of this imaging biomarker in children. Precision medicine has begun to allow real-time molecular evaluations to help diagnose and risk-stratify cardiovascular diseases, with emerging evidence of these modalities in myocarditis.

Recent information regarding COVID-19 associated myocarditis, cardiac magnetic resonance, and molecular biomarkers may help clinicians caring for children with myocarditis and identify needs for future investigations.
Corneal Complications Related to Dupilumab Use
Authors: Tauber Jenna , Ritterband David C. , Kang Joann J.
Published: April 2024

Objectives:

The aim of this report is to describe atypical corneal complications associated with dupilumab use.

Methods:

This is a series of four cases of adult patients with infiltrative or ulcerative keratitis secondary to dupilumab use.

Results:

All four patients in this series were prescribed dupilumab for the treatment of atopic dermatitis and developed infiltrative or ulcerative corneal lesions. In all cases, corneal disease was successfully managed with immediate discontinuation of dupilumab and topical steroid treatment. In two cases, the patient also received antibiotic eye drops for infection precautions.

Conclusions:

Although dupilumab is most commonly associated with conjunctivitis, physicians should be aware of potential severe corneal complications for early identification and intervention.
Long-term astigmatism after intraocular pressure sensor implantation and nonpenetrating glaucoma surgery: EYEMATE-SC trial
Authors: Englisch Colya N. , Boden Karl T. , Szurman Peter , Mansouri Kaweh , Dick H. Burkhard , Hoffmann Esther M. , Mackert Marc J. , Schütte Paul , Langenbucher Achim , Messias André , Wakili Philip
Published: April 2024

Purpose:

To investigate long-term astigmatism after combined nonpenetrating glaucoma surgery (NPGS) and implantation of the first miniaturized suprachoroidal intraocular pressure (IOP) sensor EYEMATE-SC.

Setting:

The study was conducted in 5 medical centers in 2 different countries.

Design:

Retrospective multicenter clinical study.

Methods:

Astigmatism of patients instrumented with the EYEMATE-SC IOP sensor was assessed over a follow-up period of 3 years. Refraction and corrected distance visual acuity (CDVA) were obtained preoperatively, after 6 months, 1, 2, and 3 years. A canaloplasty-operated patient cohort served as control. Astigmatism was evaluated using 3-dimensional power vector analysis involving the spherical equivalent M, and the Jackson crossed cylinder projections J0and J45. Exclusion criteria included neovascular and angle-closure glaucoma, myopia, axial length outside 22 to 26 mm, other ocular diseases, prior glaucoma surgery, other ocular surgery within 6 months (cataract surgery within 3 months) before NPGS, serious generalized conditions, and other active medical head/neck implants.

Results:

Multivariate analysis indicated no changes in astigmatism along the observation period in both the EYEMATE-SC (n = 24) and the canaloplasty (n = 24) group (P> .05 or nonsignificant after Bonferroni correction). Astigmatism was unchanged between the EYEMATE-SC and the canaloplasty group at all timepoints (P> .05). CDVA did not change along the observation period of 3 years in each of both groups (P> .05).

Conclusions:

Despite its suprachoroidal localization, this study indicated that the miniaturized EYEMATE-SC IOP sensor did not negatively affect long-term astigmatism after combined implantation with NPGS.
Risk of adverse outcomes during gabapentinoid therapy and factors associated with increased risk in UK primary care using the clinical practice research datalink: a cohort study
Authors: Muller Sara , Bailey James , Bajpai Ram , Helliwell Toby , Harrisson Sarah A. , Whittle Rebecca , Mallen Christian D. , Ashworth Julie
Published: April 2024

Growing evidence from pharmacovigilance data and postmortem toxicology reports highlights the misuse potential of gabapentinoids. This study aimed to investigate the risk of serious adverse outcomes (drug misuse, overdose, major trauma), and their risk factors, in primary care patients who are prescribed gabapentinoids. Using the UK Clinical Practice Research Datalink, a matched cohort study calculated adverse event rates separately for gabapentinoid-exposed and unexposed cohorts. In the exposed cohort, event rates for exposure to a range of potential risk factors were calculated. Event rates were compared using Cox proportional hazards models, adjusted for age, sex, deprivation, previous mental health diagnosis, and coprescribing with potentially interacting medicines. Substance misuse (gabapentin adjusted hazard ratio [95% CI]: 2.40 [2.25-2.55]), overdose (2.99 [2.56-3.49]), and major trauma (0-2.5 years: 1.35 [1.28-1.42]; 2.5 to 10 years: 1.73 [1.56-1.95]) were more common among patients prescribed gabapentinoids than matched individuals who were not. The association with overdose was stronger for pregabalin than gabapentin. All adverse outcomes were significantly associated with smoking, history of substance misuse, overdose, or a mental health condition and prescription of opioids, benzodiazepines, antidepressants, and Z-drug hypnotics (eg, gabapentin hazard ratios for association of concurrent opioid use: misuse 1.49 [1.47-1.51]; overdose 1.87 [1.78-1.96]; major trauma 1.28 [1.26-1.30]). Our findings highlight the importance of careful patient selection when prescribing gabapentinoids and the need to educate prescribers about the risks of these drugs, particularly in combination with other central nervous system depressants.
The Lived Experience of Patients with Vascular Malformations: A Qualitative Meta-synthesis
Authors: Hill Lauren R. S. , Coats Heather
Published: April 2024

Objective:

The purpose of this study was to synthesize the existing qualitative literature on the lived experience of patients with vascular malformations to identify emergent themes and new areas for clinical care and research.

Methods:

A formal meta-synthesis was conducted, which followed 4 steps: (1) form the clinical question and refine search criteria; (2) complete a literature review following Preferred Reporting Items for Reviews and Meta-Analysis; (3) quality appraisal of included literature with Lett’s Critical Review Form; and (4) completion of team-based reciprocal translation and thematic analysis to synthesize the literature. PubMed, CINAHL, Johanna Briggs, and Embase were used to retrieve English language, peer-reviewed qualitative, and mixed-method articles from 1996 to May 2023.

Results:

Six articles met the criteria for inclusion. A wide range of vascular malformations were represented, ranging from slow-flow malformation to high-flow or complex with associated overgrowth. Studies were conducted in the United States, France, and Germany, focusing mainly on the adult experience, with 1 article focusing solely on pediatrics. Three main themes emerged: social isolation, uncertainty and hope, and healthcare experiences.

Conclusion:

The overarching themes of social isolation, uncertainty and hope, and healthcare experiences each offer avenues to inform clinical practice, provide education for healthcare providers managing patients with vascular malformations, and future research to better understand how each of these themes affect patients. This qualitative meta-synthesis is a novel method for this field and provides new insights into the lived experience of those with vascular malformations.
Ethical Dilemmas of Using Artificial Intelligence in Medicine
Authors: Astărăstoae Vasile , Rogozea Liliana M. , Leaşu Florin , Ioan Beatrice Gabriela
Published: April 2024

Background:

Artificial intelligence (AI) is considered the fourth industrial revolution that will change the evolution of humanity technically and relationally. Although the term has been around since 1956, it has only recently become apparent that AI can revolutionize technologies and has many applications in the medical field.

Areas of Uncertainty:

The ethical dilemmas posed by the use of AI in medicine revolve around issues related to informed consent, respect for confidentiality, protection of personal data, and last but not least the accuracy of the information it uses.

Data Sources:

A literature search was conducted through PubMed, MEDLINE, Plus, Scopus, and Web of Science (2015–2022) using combinations of keywords, including: AI, future in medicine, and machine learning plus ethical dilemma.

Ethics and Therapeutic Advances:

The ethical analysis of the issues raised by AI used in medicine must mainly address nonmaleficence and beneficence, both in correlation with patient safety risks, ability versus inability to detect correct information from inadequate or even incorrect information. The development of AI tools that can support medical practice can increase people's access to medical information, to obtain a second opinion, for example, but it is also a source of concern among health care professionals and especially bioethicists about how confidentiality is maintained and how to maintain cybersecurity. Another major risk may be related to the dehumanization of the medical act, given that, at least for now, empathy and compassion are accessible only to human beings.

Conclusions:

AI has not yet managed to overcome certain limits, lacking moral subjectivity, empathy, the level of critical thinking is still insufficient, but no matter who will practice preventive or curative medicine in the next period, they will not be able to ignore AI, which under human control can be an important tool in medical practice.
Interventional inflammatory bowel disease: current and future practice
Authors: Clement Benjamin , Reyes Genere Juan
Published: April 2024

Purpose of review

Inflammatory bowel diseases (IBD) are associated with several well described neoplastic and structural complications. Increasing disease prevalence, healthcare barriers, and medication refractory phenotypes contribute to ongoing complications despite significant strides in medical management. Enhancements in endoscopic technology and techniques have allowed a minimally invasive approach for what has historically required surgery. In this article, we review the current and future landscape of endoscopic IBD intervention.

Recent findings

Endoscopic resection is the first line for managing conventional and complex colitis-associated dysplasia. Evidence supporting endoscopic submucosal dissection is mounting, yet there is a paucity of studies evaluating modified endoscopic mucosal resection techniques or hybrid endoscopic submucosal dissection. We also have more clarity in how best to approach fibrostenotic disease, as we learn how to position endoscopic stricturotomy and stenting, relative to balloon dilation. Finally, applications in managing penetrating and postsurgical complications have been described, but still require further study.

While important knowledge gaps still exist, the application of endoscopic therapies in IBD is more refined, especially within the management of colitis-associated dysplasia and strictures. The indications for endoscopy in perianal disease and other penetrating manifestations of Crohn's disease presents exciting opportunities for growth.
Esophageal remodeling in eosinophilic esophagitis
Authors: Shaker Anisa
Published: April 2024

Purpose of review

Eosinophilic esophagitis (EoE) is a Th2 immune/antigen-mediated disorder characterized by esophageal dysfunction and eosinophilic inflammation. Worsening dysphagia and food impactions are significant complications associated with esophageal remodeling and fibrostenotic disease. This review highlights the most recent research findings pertaining to mechanisms of sub-epithelial fibrosis in EoE, current diagnostic tools, and therapeutic approaches.

Recent findings

Recent studies leveraging publicly available single cell sequencing databases and comparative proteomics have furthered our understanding of the mechanisms mediating fibrosis. Fibroblast crosstalk with the extracellular matrix and with epithelial, endothelial, and T cells have been implicated, with the likely existence of multiple fibroblast sub-types. Accurate diagnosis of remodeling with biopsies remains a challenge due to inadequate depth of sampling. Web-based tools incorporating epithelial findings show promise in predicting subepithelial fibrosis. Impedance planimetry with esophageal distensibility measurements are increasingly utilized tools to assess fibrostenotic severity. Immunostaining and luminal captured proteins associated with remodeling show promise as potential molecular markers of fibrosis. Anti-inflammatory therapy may improve esophageal fibrosis and distensibility, although specific fibrosis-targeted therapy is lacking.

Recent studies highlight novel mechanisms of fibrosis in EoE. Improved understanding of these mechanisms may lead to novel diagnostic strategies and therapies, and thereby inform treatment decisions.