bluuebunny/crossref_metadata_2025 huggingface dataset:
Participatory pathways to the Sustainable Development Goals: inviting divergent perspectives through a cross-scale systems approach
Authors: Collste David , Aguiar Ana Paula D , Harmáčková Zuzana V , Galafassi Diego , Pereira Laura M , Selomane Odirilwe , van Der Leeuw Sander
Published: April 2023

The United Nations Sustainable Development Goals (SDGs) include social and ecological goals for humanity. Navigating towards reaching the goals requires the systematic inclusion of perspectives from a diversity of voices. Yet, the development of global sustainability pathways often lacks perspectives from the Global South. To help fill this gap, this paper introduces a participatory approach for visioning and exploring sustainable futures - the Three Horizons for the Sustainable Development Goals (3H4SDG). 3H4SDG facilitates explorations of (a) systemic pathways to reach the SDGs in an integrated way, and (b) highlights convergences and divergences between the pathways. We illustrate the application of 3H4SDG in a facilitated dialogue bringing together participants from four sub-regions of Africa: West Africa, Central Africa, East Africa, and Southern Africa. The dialogue focused on food and agricultural systems transformations. The case study results incorporate a set of convergences and divergences in relation to the future of urbanization, population growth, consumption, and the role of agriculture in the African economy. These were subsequently compared with the perspectives in global sustainability pathways, including the shared socioeconomic pathways (SSPs). The study illustrates that participatory approaches that are systemic and highlight divergent perspectives represent a promising way to link local aspirations with global goals.
The potential of in vitro neuronal networks cultured on micro electrode arrays for biomedical research
Authors: Cerina Marta , Piastra Maria Carla , Frega Monica
Published: April 2023

In vitro neuronal models have become an important tool to study healthy and diseased neuronal circuits. The growing interest of neuroscientists to explore the dynamics of neuronal systems and the increasing need to observe, measure and manipulate not only single neurons but populations of cells pushed for technological advancement. In this sense, micro-electrode arrays (MEAs) emerged as a promising technique, made of cell culture dishes with embedded micro-electrodes allowing non-invasive and relatively simple measurement of the activity of neuronal cultures at the network level. In the past decade, MEAs popularity has rapidly grown. MEA devices have been extensively used to measure the activity of neuronal cultures mainly derived from rodents. Rodent neuronal cultures on MEAs have been employed to investigate physiological mechanisms, study the effect of chemicals in neurotoxicity screenings, and model the electrophysiological phenotype of neuronal networks in different pathological conditions. With the advancements in human induced pluripotent stem cells (hiPSCs) technology, the differentiation of human neurons from the cells of adult donors became possible. hiPSCs-derived neuronal networks on MEAs have been employed to develop patient-specific in vitro platforms to characterize the pathophysiological phenotype and to test drugs, paving the way towards personalized medicine. In this review, we first describe MEA technology and the information that can be obtained from MEA recordings. Then, we give an overview of studies in which MEAs have been used in combination with different neuronal systems (i.e. rodent 2D and three-dimensional (3D) neuronal cultures, organotypic brain slices, hiPSCs-derived 2D and 3D neuronal cultures, and brain organoids) for biomedical research, including physiology studies, neurotoxicity screenings, disease modeling, and drug testing. We end by discussing potential, challenges and future perspectives of MEA technology, and providing some guidance for the choice of the neuronal model and MEA device, experimental design, data analysis and reporting for scientific publications.
ibn Said, Omar
Authors: Lo Mbaye
Published: April 2023

Omar ibn Sayyid (Said is the more prevalent Anglicized version of his name; 1770–1863), a West African Muslim scholar, was enslaved in North Carolina from 1810 until his death in 1863. Omar was captured in Futa Toro, modern-day Senegal in 1807 and transported to Charleston, South Carolina, in 1808, and he spent the first two years of his American life enslaved on a plantation there. He left behind a body of Arabic writings including his 1831 autobiography, which was the subject of two limited translations in the 19th century by Alexander Cotheal in 1848 and Isaac Bird in 1863; a more elaborated translation was produced by John Franklin Jameson in 1925. Since the 1980s, Omar has attracted scholarly interest as a striking example of the presence of enslaved Muslim scholars in the antebellum United States. The Library of Congress has created an Omar ibn Said Collection of documents in English and Arabic to serve as a resource for research on slavery and Islam in America. North Carolina governor Roy Cooper declared May 23, 2019, Omar ibn Said Day.
Results of the Eighth Scientific Workshop of ECCO: Diagnosing Postoperative Recurrence of Crohn’s Disease After an Ileocolonic Resection With Ileocolonic Anastomosis
Authors: Dragoni Gabriele , Allocca Mariangela , Myrelid Pär , Noor Nurulamin M , Hammoudi Nassim ,   Eighth Scientific Workshop of the European Crohn’s and Colitis Organisation, Rivière Pauline , Ferrante Marc , Panis Yves , Pouillon Lieven , Mañosa Míriam , Savarino Edoardo , Allez Matthieu , Kapizioni Christina , Arebi Naila , Carvello Michele , De Vries Annemarie C , Domènech Eugeni , Bislenghi Gabriele , Verstockt Bram , Brown Steven , Cunha Melissa Oliveira , Bemelman Willem , Pellino Gianluca , Kotze Paulo Gustavo , Rivière Pauline , Panis Yves , Ferrante Marc
Published: April 2023

Despite the introduction of potent biologic therapies, many patients with Crohn’s disease [CD] still require an ileocolonic resection [ICR] during the course of their disease. Furthermore, the need of redo ICR has not decreased over the past few decades, highlighting the need for better strategies to prevent and treat postoperative recurrence [POR]. The first step to develop such a strategy would be to define and standardise the description of POR with adequate diagnostic instruments. In this article, we will describe the different methodologies used to report POR [endoscopic, histological, radiological, biochemical, clinical, and surgical], and review their potential benefits and limitations, as well as the optimal timing of evaluation.
Total neoadjuvant treatment for MRI-stratified high-risk rectal cancer: a single-center, single-arm, prospective Phase II trial (PKUCH-R02)
Authors: Chen Peng-Ju , Wang Lin , Sun Ting-Ting , Yao Yun-Feng , Peng Yi-Fan , Zhao Jun , Zhan Tian-Cheng , Leng Jia–Hua , Cai Yong , Li Yong-Heng , Zhang Xiao-Yan , Sun Ying-Shi , Li Zhong-Wu , Wang Wei-Hu , Wu Ai-Wen
Published: April 2023

Background

Induction chemotherapy combined with neoadjuvant chemoradiotherapy has been recommended for patients with high-risk, locally advanced rectal cancer. However, the benefit of more intensive total neoadjuvant treatment (TNT) is unknown. This study aimed to assess the safety and efficacy of induction chemotherapy combined with chemoradiotherapy and consolidation chemotherapy for magnetic resonance imaging-stratified high-risk rectal cancer.

Methods

This was a single-center, single-arm, prospective Phase II trial in Peking University Cancer Hospital (Beijing, China). Patients received three cycles of induction oxaliplatin and capecitabine (CapeOX) followed by chemoradiotherapy and two cycles of consolidation CapeOX. The primary end point was adverse event rate and the second primary end points were 3-year disease-free survival rate, completion of TNT, and pathological downstaging rate.

Results

Between August 2017 and August 2018, 68 rectal cancer patients with at least one high risk factor (cT3c/3d/T4a/T4b, cN2, mesorectal fascia involvement, or extramural venous invasion involvement) were enrolled. The overall compliance of receiving the entire treatment was 88.2% (60/68). All 68 patients received induction chemotherapy, 65 received chemoradiotherapy, and 61 received consolidation chemotherapy. The Grade 3–4 adverse event rate was 30.8% (21/68). Nine patients achieved clinical complete response and then watch and wait. Five patients (7.4%) developed distant metastasis during TNT and received palliative chemotherapy. Fifty patients underwent surgical resection. The complete response rate was 27.9%. After a median follow-up of 49.2 months, the overall 3-year disease-free survival rate was 69.7%.

Conclusions

For patients with high-risk rectal cancer, this TNT regimen can achieve favorable survival and complete response rates but with high toxicity. However, it is necessary to pay attention to the possibility of distant metastasis during the long treatment period.
Reassessing the productivity of enslavement on large-scale plantations and small farms in Brazilian cotton production (c.1750–c.1810)
Authors: Melo Felipe Souza , Martins Diego de Cambraia
Published: April 2023

This article compares the two largest raw cotton regions in Brazil between the 1750s and the 1810s. Through the analysis of new data on cotton export records and parish records, we argue that the high pattern of ownership of enslaved people, together with the organization of labour, the specialization in cotton and the cultivation of short fibres, made enforced labour more productive in Maranhão. In turn, the low pattern of ownership of enslaved people and food production, together with the cultivation of long and fine fibres of cotton made it less productive in the North-East. Yet the enormous manpower working on small farms in the North-East grew cotton at quantities close to the productive large-scale plantations in Maranhão.
GA signaling protein LsRGL1 interacts with the abscisic acid signaling-related gene LsWRKY70 to affect the bolting of leaf lettuce
Authors: Chen Li , Liu Chaojie , Hao Jinghong , Fan Shuangxi , Han Yingyan
Published: April 2023

A variety of endogenous hormone signals, developmental cues, and environmental stressors can trigger and promote leaf lettuce bolting. One such factor is gibberellin (GA), which has been linked to bolting. However, the signaling pathways and the mechanisms that regulate the process have not been discussed in full detail. To clarify the potential role of GAs in leaf lettuce, significant enrichment of GA pathway genes was found by RNA-seq, among which the LsRGL1 gene was considered significant. Upon overexpression of LsRGL1, a noticeable inhibition of leaf lettuce bolting was observed, whereas its knockdown by RNA interference led to an increase in bolting. In situ hybridization analysis indicated a significant accumulation of LsRGL1 in the stem tip cells of overexpressing plants. Leaf lettuce plants stably expressing LsRGL1 were examined concerning differentially expressed genes through RNA-seq analysis, and the data indicated enhanced enrichment of these genes in the ‘plant hormone signal transduction’ and ‘phenylpropanoid biosynthesis’ pathways. Additionally, significant changes in LsWRKY70 gene expression were identified in COG (Clusters of Orthologous Groups) functional classification. The results of yeast one-hybrid, β-glucuronidase (GUS), and biolayer interferometry (BLI) experiments showed that LsRGL1 proteins directly bind to the LsWRKY70 promoter. Silencing LsWRKY70 by virus-induced gene silencing (VIGS) can delay bolting, regulate the expression of endogenous hormones, abscisic acid (ABA)-linked genes, and flowering genes, and improve the nutritional quality of leaf lettuce. These results strongly associate the positive regulation of bolting with LsWRKY70 by identifying its vital functions in the GA-mediated signaling pathway. The data obtained in this research are invaluable for further experiments concerning the development and growth of leaf lettuce.
Two-step model of paleohexaploidy, ancestral genome reshuffling and plasticity of heat shock response in Asteraceae
Authors: Kong Xiangming , Zhang Yan , Wang Ziying , Bao Shoutong , Feng Yishan , Wang Jiaqi , Yu Zijian , Long Feng , Xiao Zejia , Hao Yanan , Gao Xintong , Li Yinfeng , Ding Yue , Wang Jianyu , Lei Tianyu , Xu Chuanyuan , Wang Jinpeng
Published: April 2023

An ancient hexaploidization event in the most but not all Asteraceae plants, may have been responsible for shaping the genomes of many horticultural, ornamental, and medicinal plants that promoting the prosperity of the largest angiosperm family on the earth. However, the duplication process of this hexaploidy, as well as the genomic and phenotypic diversity of extant Asteraceae plants caused by paleogenome reorganization, are still poorly understood. We analyzed 11 genomes from 10 genera in Asteraceae, and redated the Asteraceae common hexaploidization (ACH) event ~70.7–78.6 million years ago (Mya) and the Asteroideae specific tetraploidization (AST) event ~41.6–46.2 Mya. Moreover, we identified the genomic homologies generated from the ACH, AST and speciation events, and constructed a multiple genome alignment framework for Asteraceae. Subsequently, we revealed biased fractionations between the paleopolyploidization produced subgenomes, suggesting the ACH and AST both are allopolyplodization events. Interestingly, the paleochromosome reshuffling traces provided clear evidence for the two-step duplications of ACH event in Asteraceae. Furthermore, we reconstructed ancestral Asteraceae karyotype (AAK) that has 9 paleochromosomes, and revealed a highly flexible reshuffling of Asteraceae paleogenome. Of specific significance, we explored the genetic diversity of Heat Shock Transcription Factors (Hsfs) associated with recursive whole-genome polyploidizations, gene duplications, and paleogenome reshuffling, and revealed that the expansion of Hsfs gene families enable heat shock plasticity during the genome evolution of Asteraceae. Our study provides insights on polyploidy and paleogenome remodeling for the successful establishment of Asteraceae, and is helpful for further communication and exploration of the diversification of plant families and phenotypes.
Back to the Future: Attempts to Buy, Swap, and Annex Territories in Contemporary Sovereignty Practices
Authors: Berg Eiki , Kursani Shpend
Published: April 2023

This article examines recent Great Powers’ revisionist attempts at challenging the post–World War II norm of territorial integrity. These attempts may invigorate sovereignty claims in the old-time fashion of buying, swapping, or annexing territories. We show that recent dynamics in international politics speak a language that challenges the status quo consensus in territorial matters. While the article focuses mainly on the evidence during the period of Trump presidency, it concludes that this is not only about “Trump just being Trump.” The article shows that despite changes in domestic power in the United States, no changes in, or challenges to, Trump's decisions and proposals regarding territorial revisionisms have taken place. With several brief illustrative examples on board, the article tries to assess how the contemporary international order based on fixed territorial entities and inviolability of borders is contrasted by representations manifested in contemporary sovereignty practices.
Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy
Authors: Beach Thomas G , Sue Lucia I , Scott Sarah , Intorcia Anthony J , Walker Jessica E , Arce Richard A , Glass Michael J , Borja Claryssa I , Cline Madison P , Hemmingsen Spencer J , Qiji Sanaria , Stewart Analisa , Martinez Kayleigh N , Krupp Addison , McHattie Rylee , Mariner Monica , Lorenzini Ileana , Kuramoto Angela , Long Kathy E , Tremblay Cécilia , Caselli Richard J , Woodruff Bryan K , Rapscak Steven Z , Belden Christine M , Goldfarb Danielle , Choudhury Parichita , Driver-Dunckley Erika D , Mehta Shyamal H , Sabbagh Marwan N , Shill Holly A , Atri Alireza , Adler Charles H , Serrano Geidy E
Published: April 2023

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as “small vessel disease” or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.
Language games meet multi-agent reinforcement learning: A case study for the naming game
Authors: Van Eecke Paul , Beuls Katrien , Botoko Ekila Jérôme , Rădulescu Roxana
Published: April 2023

Today, computational models of emergent communication in populations of autonomous agents are studied through two main methodological paradigms: multi-agent reinforcement learning (MARL) and the language game paradigm. While both paradigms share their main objectives and employ strikingly similar methods, the interaction between both communities has so far been surprisingly limited. This can to a large extent be ascribed to the use of different terminologies and experimental designs, which sometimes hinder the detection and interpretation of one another’s results and progress. Through this paper, we aim to remedy this situation by (1) formulating the challenge of re-conceptualising the language game experimental paradigm in the framework of MARL, and by (2) providing both an alignment between their terminologies and an MARL−based reformulation of the canonical naming game experiment. Tackling this challenge will enable future language game experiments to benefit from the rapid and promising methodological advances in the MARL community, while it will enable future MARL experiments on learning emergent communication to benefit from the insights and results gained through language game experiments. We strongly believe that this cross-pollination has the potential to lead to major breakthroughs in the modelling of how human-like languages can emerge and evolve in multi-agent systems.
Posterolateral thoracotomy: unique approach to tricuspid valve replacement after right pneumonectomy
Authors: Hingtgen Austin , Siems Chesney , Huddleston Stephen J , John Ranjit
Published: April 2023

A 72-year-old patient presented with severe tricuspid regurgitation and patent foramen ovale (PFO) in the setting of severe mediastinal shifting after remote right pneumonectomy. Surgical approach was challenging given the significant herniation of the heart and left lung into the right hemithorax. This report describes tricuspid valve replacement with PFO closure via a right posterolateral thoracotomy and alternative cardiopulmonary bypass cannulation strategy.
Atp7b deficiency induces zebrafish eye developmental defects
Authors: Wu You , Liu Wenye , Li Lingya , Tai Zhipeng , Gao BaoXiang , Liu Jing-Xia
Published: April 2023

As a copper (Cu) transport ATPase, ATP7B plays an important role in maintaining Cu homeostasis in the body and its dysfunction is associated with retinal disease. How ATP7B dysfunction and the subsequent Cu overload induce retinal damage, however, are unknown. Here, we show that atp7b−/− homozygous zebrafish larvae are insensitive to light stimulation, with a reduction in retinal cells but normal like morphological phenotypes. Additionally, a series of differentially expressed genes are unveiled in atp7b−/− mutated larvae, which enrich in photo-transduction, structural constituent of eye lens, sensory perception of light stimulus, oxidative phosphorylation, and ATPase activity. Moreover, we show the Cu accumulation in retinal cells in atp7b−/− mutated larvae, which results in endoplasmic reticulum (ER) stress and retinal cell apoptosis and subsequent retinal defects. The integral data in this study demonstrate that atp7b mutation leads to Cu accumulation in zebrafish retinal cells and the consequence ER stress and retinal cell death. These data may give some possible hints to explain retinal disease occurred in the Cu dysregulation syndromes Wilson’s disease with ATP7B mutation.
A dual gene-specific mutator system installs all transition mutations at similar frequencies in vivo
Authors: Seo Daeje , Koh Bonghyun , Eom Ga-eul , Kim Hye Won , Kim Seokhee
Published: April 2023

Targeted in vivo hypermutation accelerates directed evolution of proteins through concurrent DNA diversification and selection. Although systems employing a fusion protein of a nucleobase deaminase and T7 RNA polymerase present gene-specific targeting, their mutational spectra have been limited to exclusive or dominant C:G→T:A mutations. Here we describe eMutaT7transition, a new gene-specific hypermutation system, that installs all transition mutations (C:G→T:A and A:T→G:C) at comparable frequencies. By using two mutator proteins in which two efficient deaminases, PmCDA1 and TadA-8e, are separately fused to T7 RNA polymerase, we obtained similar numbers of C:G→T:A and A:T→G:C substitutions at a sufficiently high frequency (∼6.7 substitutions in 1.3 kb gene during 80-h in vivo mutagenesis). Through eMutaT7transition-mediated TEM-1 evolution for antibiotic resistance, we generated many mutations found in clinical isolates. Overall, with a high mutation frequency and wider mutational spectrum, eMutaT7transition is a potential first-line method for gene-specific in vivo hypermutation.
DeepNeo: a webserver for predicting immunogenic neoantigens
Authors: Kim Jeong Yeon , Bang Hyoeun , Noh Seung-Jae , Choi Jung Kyoon
Published: April 2023

Non-self epitopes, whether originated from foreign substances or somatic mutations, trigger immune responses when presented by major histocompatibility complex (MHC) molecules and recognized by T cells. Identification of immunogenically active neoepitopes has significant implications in cancer and virus medicine. However, current methods are mostly limited to predicting physical binding of mutant peptides and MHCs. We previously developed a deep-learning based model, DeepNeo, to identify immunogenic neoepitopes by capturing the structural properties of peptide-MHC pairs with T cell reactivity. Here, we upgraded our DeepNeo model with up-to-date training data. The upgraded model (DeepNeo-v2) was improved in evaluation metrics and showed prediction score distribution that better fits known neoantigen behavior. The immunogenic neoantigen prediction can be conducted at https://deepneo.net.
Differential effects of hypergravity on immune dysfunctions induced by simulated microgravity
Authors: Moser Dominique , Biere Katharina , Liemersdorf Christian , Tuschen Marina , Hemmersbach Ruth , Choukér Alexander
Published: April 2023

Microgravity (μg) is among the major stressors in space causing immune cell dysregulations. These are frequently expressed as increased pro‐inflammatory states of monocytes and reduced activation capacities in T cells. Hypergravity (as artificial gravity) has shown to have beneficial effects on the musculoskeletal and cardiovascular system both as a countermeasure option for μg‐related deconditioning and as “gravitational therapy” on Earth. Since the impact of hypergravity on immune cells is sparsely explored, we investigated if an application of “mild” mechanical loading of 2.8 g is able to avoid or treat μg‐mediated immune dysregulations. For this, T cell and monocyte activation states and cytokine pattern were first analyzed after whole blood antigen incubation in simulated μg (s‐μg) by using the principle of fast clinorotation or in hypergravity. Subsequent hypergravity countermeasure approaches were run at three different sequences: one preconditioning setting, where 2.8 g was applied before s‐μg exposure and two therapeutic approaches in which 2.8 g was set either intermediately or at the end of s‐μg. In single g‐grade exposure experiments, monocyte pro‐inflammatory state was enhanced in s‐μg and reduced in hypergravity, whereas T cells displayed reduced activation when antigen incubation was performed in s‐μg. Hypergravity application in all three sequences did not alleviate the increased pro‐inflammatory potential of monocytes. However, in T cells the preconditioning approach restored antigen‐induced CD69 expression and IFNγ secretion to 1 g control values and beyond. This in vitro study demonstrates a proof of concept that mild hypergravity is a gravitational preconditioning option to avoid adaptive immune cell dysfunctions induced by (s‐)μg and that it may act as a booster of immune cell functions.
Three‐dimensional‐printed MPBI@β‐TCP scaffold promotes bone regeneration and impedes osteosarcoma under near‐infrared laser irradiation
Authors: Lu Liangjie , Wang Huihan , Yang Minjie , Wang Lijun , Gan Kaifeng
Published: April 2023

Beta‐tricalcium phosphate (β‐TCP) is considered as one of the most promising biomaterials for bone reconstruction. This study generated a functional molybdenum disulfide (MoS2)/polydopamine (PDA)/−bone morphogenetic protein 2 (BMP2)‐insulin‐like growth factor‐1 (IGF‐1) coating on the β‐TCP scaffold and analyzed the outcomes. The MoS2/PDA‐BMP2‐IGF‐1@β‐TCP (MPBI@β‐TCP) scaffold was prepared by 3D printing and physical adsorption, followed by characterization to validate its successful construction. The in vitro osteogenic effect of the MPBI@β‐TCP scaffold was evaluated. It was found that MPBI@β‐TCP augmented the adhesion, diffusion and proliferation of mesenchymal stem cells (MSCs). The alkaline phosphatase (ALP) activity, collagen secretion and extracellular matrix (ECM) mineralization along with the expression of Runx2, ALP and OCN were also enhanced in the presence of MPBI@β‐TCP. Additionally, MPBI@β‐TCP stimulated endothelial cells to secrete VEGF and promoted capillary‐like tubule formation. We then confirmed the biocompatibility of MPBI@β‐TCP to macrophages and its anti‐inflammatory effects. Furthermore, under near‐infrared (NIR) laser irradiation, MPBI@β‐TCP produced photothermal effect to not only kill MG‐63 osteosarcoma cells, but also enhance bone regeneration in vivo with biosafety. Overall, this work demonstrates that 3D‐printed MPBI@β‐TCP with enhanced osteogenic activity under NIR laser irradiation has a vast potential in the field of tissue defects.
Student and Teacher Perspectives on Equity in Clinical Feedback: A Qualitative Study Using a Critical Race Theory Lens
Authors: Mason Hyacinth R.C. , Pérez Maria , Colson Eve R. , Jeffe Donna B. , Aagaard Eva M. , Teherani Arianne , Hanson Janice L.
Published: April 2023

Purpose

The authors aimed to gain a better understanding of students’ and teachers’ perspectives about whether clinical clerkship feedback is provided equitably irrespective of a student’s race/ethnicity.

Method

A secondary analysis of existing interview data was conducted, focusing on racial/ethnic disparities in clinical grading. Data had been acquired from 29 students and 30 teachers at 3 U.S. medical schools. The authors performed secondary coding on all 59 transcripts, writing memos focused on statements related to aspects of feedback equity and developing a template for coding students’ and teachers’ observations and descriptions specific to clinical feedback. Using the template, memos were coded, and thematic categories emerged describing perspectives on clinical feedback.

Results

Forty-eight (22 teachers and 26 students) participants’ transcripts provided narratives about feedback. Both student and teacher narratives described how students who are racially/ethnically underrepresented in medicine may receive less helpful formative clinical feedback needed for professional development. Thematic analysis of narratives yielded 3 themes related to feedback inequities: 1) teachers’ racial/ethnic biases influence the feedback they provide students, 2) teachers have limited skill sets to provide equitable feedback, and 3) racial/ethnic inequities in the clinical learning environment shape clinical and feedback experiences.

Conclusions

Narratives indicated that both students and teachers perceived racial/ethnic inequities in clinical feedback. Teacher- and learning environment-related factors influenced these racial/ethnic inequities. These results can inform medical education’s efforts to mitigate biases in the learning environment and provide equitable feedback to ensure every student has what they need to develop into the competent physician they aspire to be.
Correlation of Computed Tomography, Pathological Findings, and Clinical Outcomes for Appendicoliths in Appendicitis
Authors: Weitzner Zachary N. , Chung Alex , Naini Bita V. , Graham Danielle , Livingston Edward H.
Published: April 2023

Objectives:

To correlate preoperative imaging of fecaliths with what is seen in surgical specimens.

Background:

Early studies considered radiological findings of appendicoliths as a contraindication for nonoperative treatment of appendicitis. There is no standard definition for what is labeled as an appendicolith radiologically and little is known about the pathological correlates of these lesions.

Methods:

A single center, retrospective study of a consecutive series of adult patients who underwent appendectomy for acute appendicitis from March 2021 to February 2022 was performed. The primary outcome was concordance between preoperative cross-sectional imaging description of appendicolith with postoperative gross pathology description. Images were retrospectively reviewed by an independent radiologist, and the presence and characteristics of appendicoliths and appendices were examined.

Results:

Of 88 cases of appendicitis, 86 were diagnosed preoperatively by computed tomography (CT) imaging. Appendicoliths were seen either on CT or pathology in 45 (51%) patients. Of these 45 patients, a total of 38 (84%) were identified radiographically, and 28 (62%) were identified on pathology. Of the 38 appendicoliths diagnosed on preoperative imaging, only 21 (55%) were confirmed pathologically. Additionally, of the 28 appendicoliths observed on pathology, only 21 (75%) were identified preoperatively on imaging. There was no appendiceal obstruction in 10 of the 40 cases (25%) in which retrospective radiological review identified appendicoliths.

Conclusions:

Discrepancies were observed between CT and pathology findings of appendicoliths. Not all appendicoliths seem to cause appendicitis. Because the presence of appendicolith influences the treatment decisions, there is a need to standardize their radiological diagnosis and better understand their pathophysiology.
Go or no-go for treat-to-target in axial spondyloarthritis?
Authors: Webers Casper , Been Marin , van Tubergen Astrid
Published: April 2023

Purpose of review

For almost a decade, treat-to-target (T2T) has been advocated as a management strategy for axial spondyloarthritis (axSpA), despite a lack of trial evidence. Recently, the first and only published T2T trial in axSpA did not meet its primary endpoint. The purpose of this review is to discuss whether we should continue with a T2T approach in axSpA and to describe some experiences with T2T in clinical practice.

Recent findings

The trial showed no superiority of T2T compared with usual care; however, several secondary trial outcomes and the health economic analysis actually favoured T2T, and there are conceivable reasons for the negative trial results. Furthermore, several knowledge gaps related to an optimal T2T approach in axSpA were identified. In clinical practice, a T2T approach was applied to only a limited extent, possibly because of several challenges.

Despite one negative trial, it is too early to abandon T2T in axSpA. Not only more evidence from clinical trials but also research on the optimal target and management of all facets of axSpA, are highly needed. For successful implementation of T2T in clinical practice, it is important that barriers and facilitators to application are identified and subsequently addressed.
Evinacumab-dgnb (Evkeeza-REGN1500), A Novel Lipid-Lowering Therapy for Homozygous Familial Hypercholesterolemia
Authors: White Raechel T. , Sankey Kjersten H. , Nawarskas James J.
Published: April 2023

Chronically elevated low-density lipoprotein (LDL) has harmful effects on the vasculature including increased vasoconstriction and the formation of plaques which may rupture, causing coronary heart disease and stroke. In patients with familial hypercholesterolemia, adequate reduction of LDL is especially challenging. Although HMG-CoA reductase inhibitors (statins) are the mainstays for LDL lowering, other treatments such as proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, incliseran, lomitapide, and apheresis have been employed in an effort to achieve adequate LDL reduction in these patients. Despite these available therapies, many patients with familial hypercholesterolemia do not meet the LDL targets suggested in current guidelines. Evinacumab is a novel lipid-lowering therapy that exerts its LDL-lowering effect through inhibition of angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 inhibits the breakdown of triglyceride-rich lipoproteins, such as very low-density lipoprotein and chylomicrons. By inhibiting ANGPTL3, evinacumab allows these lipoproteins to be degraded, ultimately leading to reductions in LDL, high-density lipoprotein, and triglycerides. Clinical trials have demonstrated evinacumab to be safe and effective in reducing LDL. However, data are lacking regarding its potential to reduce risk of atherosclerotic cardiovascular disease. Evinacumab is generally well tolerated with the primary adverse effects comprising infusion reactions, nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. While evinacumab is an interesting therapy, until it is proven to reduce cardiovascular events, its high cost leaves its anticipated role in therapy somewhat ambiguous. In the meantime, it may be a useful therapy for those with homozygous familial hypercholesterolemia.
Potential Novel RNA-Targeting Agents for Effective Lipoprotein(a) Lowering: A Systematic Assessment of the Evidence From Completed and Ongoing Developmental Clinical Trials
Authors: Milosavljevic Milos N. , Stefanovic Srdjan M. , Pejcic Ana V.
Published: April 2023

An increase in blood lipoprotein (a) [Lp(a)] levels, mostly genetically determined, has been identified as an independent risk factor of atherosclerotic cardiovascular disease. No drug has yet been approved that markedly lowers Lp(a) and thereby reduces residual cardiovascular risk. The aim of this article was to critically review the evidence from clinical development studies to date on the efficacy and safety of new RNA-based therapeutics for targeted lowering of Lp(a). PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched without any language or date restriction up to November 5, 2022, and a total of 12 publications and 22 trial records were included. Several drugs were found that are currently in various stages of clinical development, such as the antisense oligonucleotide pelacarsen and the small interfering RNA molecule olpasiran and drugs coded as SLN360 and LY3819469. Among them, pelacarsen has progressed the most, currently reaching phase 3. All these drugs have so far shown satisfactory pharmacokinetic properties, consistently high and stable, dose-dependent efficacy in lowering Lp(a) even by more than 90%, with an acceptable safety profile in subjects with highly elevated Lp(a). In addition, reports of early clinical trials with pelacarsen imply a promising suppressive effect on key mechanisms of atherogenesis. Future research should focus on confirming these beneficial clinical effects in patients with lower average Lp(a) levels and clearly demonstrating the association between lowering Lp(a) and reducing adverse cardiovascular outcomes.
Conjugated bile acids are nutritionally re-programmable antihypertensive metabolites
Authors: Chakraborty Saroj , Lulla Anju , Cheng Xi , Yeo Ji-Youn , Mandal Juthika , Yang Tao , Mei Xue , Saha Piu , Golonka Rachel M. , Yeoh Beng San , Mell Blair , Jia Wei , Putluri Vasanta , Piyarathna Danthasinghe Waduge Badrajee , Putluri Nagireddy , Sreekumar Arun , Meyer Katie , Vijay-Kumar Matam , Joe Bina
Published: April 2023

Background:

Hypertension is the largest risk factor affecting global mortality. Despite available medications, uncontrolled hypertension is on the rise, whereby there is an urgent need to develop novel and sustainable therapeutics. Because gut microbiota is now recognized as an important entity in blood pressure regulation, one such new avenue is to target the gut-liver axis wherein metabolites are transacted via host-microbiota interactions. Knowledge on which metabolites within the gut-liver axis regulate blood pressure is largely unknown.

Method:

To address this, we analyzed bile acid profiles of both human and hypertensive rat models and report that conjugated bile acids are inversely correlated with blood pressure in humans and rats.

Results:

Notably intervening with taurine rescued bile acid conjugation and reduced blood pressure in hypertensive rats. Subsequently, untargeted metabolomics uncovered lower energy metabolism following conjugation of bile acids as a mechanism alleviating high blood pressure.

Conclusion:

Together this work reveals conjugated bile acids as nutritionally re-programmable anti-hypertensive metabolites.

Graphical abstract:

http://links.lww.com/HJH/C165
Relationship between measures of adiposity, blood pressure and arterial stiffness in adolescents. The MACISTE study
Authors: Pucci Giacomo , Martina Maria R. , Bianchini Elisabetta , D’abbondanza Marco , Curcio Rosa , Battista Francesca , Anastasio Fabio , Crapa Mariano E. , Sanesi Leandro , Gemignani Vincenzo , Vaudo Gaetano
Published: April 2023

Objective:

Children and adolescents with adiposity excess are at increased risk of future cardiovascular (CV) disease. Fat accumulation promotes the development of elevated blood pressure (BP) and arterial stiffness, two main determinants of CV risk which are strongly inter-related. We aimed at investigating whether the association between overweight and arterial stiffness, taken at different arterial segments, is mediated by increased BP or is BP-independent.

Methods:

Three hundred and twenty-two Italian healthy adolescents (mean age 16.9±1.4 years, 12% with overweight) attending the “G. Donatelli” High School in Terni, Italy, underwent measurement of arterial stiffness by arterial tonometry (aortic stiffness) and semiautomatical detection of pressure–volume ratio of the common carotid (carotid stiffness). The mediator effect of BP was tested for each anthropometric or biochemical measure of fat excess related to arterial stiffness.

Results:

Both carotid and aortic stiffness showed positive correlations with body mass index, waist, hip, and neck circumferences (NC). Only carotid stiffness, but not aortic stiffness, was associated with serum markers of fat accumulation and metabolic impairment such as insulin, homeostatic model of insulin resistance (HOMA-IR), serum gamma-glutamyl transferase (sGGT) and uric acid. The association with NC was stronger for carotid than for aortic stiffness (Fisher z-to-R 2.07, P = 0.04), and independent from BP.

Conclusions:

In healthy adolescents, fat accumulation is associated with arterial stiffness. The degree of this association differs by arterial segments, since carotid stiffness is more strongly associated to adipose tissue excess than aortic stiffness and shows a BP-independent association with NC whereas aortic stiffness does not.
The renal resistive index is associated with microvascular remodeling in patients with severe obesity
Authors: Moriconi Diego , Mengozzi Alessandro , Duranti Emiliano , Cappelli Federica , Taddei Stefano , Nannipieri Monica , Bruno Rosa Maria , Virdis Agostino
Published: April 2023

Background:

Renal hemodynamics is impaired since the early stage of cardiometabolic disease. However, in obesity, its noninvasive ultrasound assessment still fails to provide pathophysiologic and clinical meaningfulness. We aimed to explore the relationship between peripheral microcirculation and renal hemodynamics in severe obesity.

Methods:

We enrolled fifty severely obese patients with an indication for bariatric referring to our outpatient clinic. Patients underwent an extensive reno-metabolic examination, paired with Doppler ultrasound and measurement of the renal resistive index (RRI). On the day of the surgery, visceral fat biopsies were collected to perform an ex-vivo complete microcirculatory assessment. Media-to-lumen ratio (M/L) and vascular response to acetylcholine (ACh), alone or co-incubated with NG-nitro arginine methyl ester (L-NAME), were measured.

Results:

Patients were stratified according to their normotensive (NT) or hypertensive (HT) status. HT had lower estimated glomerular filtration rate and higher RRI compared to NT, while the presence and extent of albuminuria were similar between the two groups. Concerning microcirculatory assessment, there were no differences between groups as regards the microvascular structure, while the vasorelaxation to ACh was lower in HT (P = 0.042). Multivariable analysis showed a relationship between M/L and RRI (P = 0.016, St. β 0.37) and between albuminuria and the inhibitory response of L-NAME to Ach vasodilation (P 
= 0.036, St. β = −0.34). Notably, all these correlations were consistent also after adjustment for confounding factors.

Conclusions:

The RRI and albuminuria relationship with microvascular remodeling in patients affected by severe obesity supports the clinical implementation of RRI to improve risk stratification in obesity and suggests a tight pathophysiologic connection between renal haemodynamics and microcirculatory disruption.
Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats
Authors: Chang Chia Lin , Cai Zheqing , Hsu Sheau Yu Teddy
Published: April 2023

Objective(s):

Preeclampsia is a heterogeneous hypertensive disorder of pregnancy. It affects multiorgans and may lead to fetal growth restriction, organ failure, seizure, and maternal death. Unfortunately, current treatments are ineffective at delaying the progression of preeclampsia even for a few days. Clinicians are often forced to deliver preterm fetus if severe preeclampsia occurred early during pregnancy, leading to premature birth-associated complications. Preeclampsia has been associated with defects at the maternal–fetal interface and maternal vascular dysfunction. Of interest, the adrenomedullin peptide and its cognate receptors, calcitonin receptor-like receptor (CLR)/ receptor activity-modifying protein (RAMP) receptor complexes, have been shown to be important regulators of cardiovascular adaptation and feto-placental development during pregnancy. Although the exact role of adrenomedullin-CLR/RAMP signaling in different feto-maternal compartments during pregnancy and how adrenomedullin expression affects preeclampsia development remains to be clarified, we hypothesized that the sustained activation of CLR/RAMP receptors could be a promising strategy to mitigate placental ischemia-associated vascular dysfunction and fetal growth restriction under preeclampsia-like conditions

Methods:

To explore this possibility, we have developed a stable adrenomedullin analog, ADE101, and investigated its effects on human lymphatic microvascular endothelial (HLME) cell proliferation, hemodynamics, and pregnancy outcomes in pregnant rats with reduced uteroplacental perfusion pressure (RUPP) induced by clipping of uterine arteries on gestation day 14

Results:

The ADE101 analog has a potent effect on CLR/RAMP2 receptor activation, and an enhanced stimulatory effect on HLME cell proliferation compared to wild-type peptides. ADE101 also exhibits a lasting effect on hemodynamics in normal and hypertensive rats. In addition, studies using the RUPP model showed that ADE101 significantly reduces placental ischemia-induced hypertension and fetal growth restriction in a dose-dependent manner. Infusion of ADE101 increased the weight of fetuses and placentas in RUPP animals to 252% and 202% of that of RUPP controls, respectively.

Conclusions:

These data suggested that long-acting adrenomedullin analog could be useful for quenching hypertension as well as the vascular ischemia-associated organ damages in preeclamptic patients.
InTraocular EMulsion of Silicone oil (ITEMS) grading system: an evidence-based expert-led consensus.
Authors: Romano Mario R , Ferrara Mariantonia , Coco-Martin Rosa M , Rickmann Annekatrin , Spitzer Martin S , Steel David HW , Pastor J Carlos
Published: April 2023

Purpose:

To propose the InTraocular EMulsion of Silicone oil (ITEMS) grading system for the assessment of silicone oil (SiO) emulsion, applicable in a routine clinical setting and validated through an expert-led consensus procedure.

Methods:

Seven experts on intraocular liquid tamponades, led by a facilitator, performed a literature review on the detection of SiO emulsion. Based on the proposed ideas, a questionnaire was developed and submitted to the experts on the methods to detect SiO emulsion and the items to grade. After two rounds of individual ranking using a nine-point scale and related discussion, the final grading system was developed including items that reached consensus (score ≥7 from ≥75% of members).

Results:

The agreed ITEMS grading system includes the identification of SiO microbubbles and large SiO bubbles through slit lamp biomicroscopy, gonioscopy, fundus examination under mydriasis or ultra-widefield fundus photography. Moreover, macular and disc OCT are used to detect SiO-associated hyperreflective dots.

Conclusion:

An evidence-based expert-led consensus was conducted to develop grading system of SiO emulsion, allowing, for the first time, homogenous collection of data on SiO emulsion. This has the potential to improve our understanding of the role and clinical relevance of SiO emulsion allowing comparisons between different studies.