bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of genetically proxied lipid-lowering drugs on acute myocardial infarction: a drug-target mendelian randomization study
Authors: Xiao Wendi , Li Yueying , Zhuang Zhenhuang , Song Zimin , Wang Wenxiu , Huang Ninghao , Dong Xue , Jia Jinzhu , Liu Zhonghua , Zhao Yimin , Qi Lu , Huang Tao
Published: June 2024

Objective

High low-density-lipoprotein (LDL) cholesterol has been associated with an increased risk of coronary artery diseases (CAD) including acute myocardial infarction (AMI). However, whether lipids lowering drug treatment is causally associated with decreased risk of AMI remains largely unknown. We used Mendelian randomization (MR) to evaluate the influence of genetic variation affecting the function of lipid-lowering drug targets on AMI.

Methods

Single-nucleotide polymorphisms (SNPs) associated with lipids as instruments were extracted from the Global Lipids Genetics Consortium (GLGC). The genome-wide association study (GWAS) data for AMI were obtained from UK Biobank. Two sample MR analysis was used to study the associations between high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) with AMI (n = 3,927). Genetic variants associated with LDL cholesterol at or near drug target gene were used to mimic drug effects on the AMI events in drug target MR.

Results

Genetically predicted higher LDL-C (per one SD increase in LDL-C of 38.67 mg/dL, OR 1.006, 95% CI 1.004–1.007) and TG (per one SD increase in TG of 90.72 mg/dL, 1.004, 1.002–1.006) was associated with increased risk of AMI, but decreased risk for higher HDL-C (per one SD increase in HDL-C of 15.51 mg/dL, 0.997, 0.995–0.999) in univariable MR. Association remained significant for LDL-C, but attenuated toward the null for HDL-C and TG in multivariable MR. Genetically proxied lower LDL-C with genetic variants at or near the PCSK9 region (drug target of evolocumab) and NPC1L1 (drug target of ezetimibe) were associated with decreased risk of AMI (0.997, 0.994–0.999 and 0.986, 0.975–0.998, respectively), whereas genetic variants at HMGCR region (drug target of statin) showed marginal association with AMI (0.995, 0.990-1.000). After excluding drug target-related SNPs, LDL-C related SNPs outside the drug target region remained a causal effect on AMI (0.994, 0.993–0.996).

Conclusions

The findings suggest that genetically predicted LDL-C may play a predominant role in the development of AMI. The drug MR results imply that ezetimibe and evolocumab may decrease the risk of AMI due to their LDL-C lowering effect, and there are other non-drug related lipid lowering pathways that may be causally linked to AMI.
STING agonists as promising vaccine adjuvants to boost immunogenicity against SARS-related coronavirus derived infection: possible role of autophagy
Authors: Rezabakhsh Aysa , Sadaie M. Reza , Ala Alireza , Roosta Yousef , Habtemariam Solomon , Sahebnasagh Adeleh , Khezri Mohammad Rafi
Published: June 2024

As a major component of innate immunity and a positive regulator of interferons, the Stimulator of interferon gene (STING) has an immunotherapy potential to govern a variety of infectious diseases. Despite the recent advances regarding vaccines against COVID-19, nontoxic novel adjuvants with the potential to enhance vaccine efficacy are urgently desired. In this connection, it has been well-documented that STING agonists are applied to combat COVID-19. This approach is of major significance for boosting immune responses most likely through an autophagy-dependent manner in susceptible individuals against infection induced by severe acute respiratory syndrome Coronavirus (SARS‑CoV‑2). Given that STING agonists exert substantial immunomodulatory impacts under a wide array of pathologic conditions, these agents could be considered novel adjuvants for enhancing immunogenicity against the SARS-related coronavirus. Here, we intend to discuss the recent advances in STING agonists’ recruitment to boost innate immune responses upon vaccination against SARS-related coronavirus infections. In light of the primordial role of autophagy modulation, the potential of being an antiviral vaccine adjuvant was also explored.
ER stress inhibition enhances formation of triacylglcerols and protects endothelial cells from lipotoxicity
Authors: Kovacevic Igor , Schmidt Paula Henriette , Kowalski Annkatrin , Helms Bernd J. , Lest Chris H. A. van de , Kluttig Alexander , Posern Guido
Published: June 2024

Elevated concentrations of palmitate in serum of obese individuals can impair endothelial function, contributing to development of cardiovascular disease. Although several molecular mechanisms of palmitate-induced endothelial dysfunction have been proposed, there is no consensus on what signaling event is the initial trigger of detrimental palmitate effects. Here we report that inhibitors of ER stress or ceramid synthesis can rescue palmitate-induced autophagy impairment in macro- and microvascular endothelial cells. Furthermore, palmitate-induced cholesterol synthesis was reverted using these inhibitors. Similar to cell culture data, autophagy markers were increased in serum of obese individuals. Subsequent lipidomic analysis revealed that palmitate changed the composition of membrane phospholipids in endothelial cells and that these effects were not reverted upon application of above-mentioned inhibitors. However, ER stress inhibition in palmitate-treated cells enhanced the synthesis of trilglycerides and restored ceramide levels to control condition. Our results suggest that palmitate induces ER-stress presumably by shift in membrane architecture, leading to impaired synthesis of triglycerides and enhanced production of ceramides and cholesterol, which altogether enhances lipotoxicity of palmitate in endothelial cells.
Migraine self-management at work: a qualitative study
Authors: Knauf Clara , Heinrichs Katherina , Süllwold Rolf , Icks Andrea , Loerbroks Adrian
Published: June 2024

Background

Migraine is common and can be highly disabling. Adequate migraine self-management (SM) can mitigate the potentially adverse health effects of migraine. However, adequate SM can be challenging to implement in everyday life, for instance, at the workplace. We aimed to explore how migraine SM is carried out at work and which occupational factors may determine effective implementation according to employees with migraine. We also explored the potential impact of the COVID-19 pandemic and the associated re-arrangement of working conditions on migraine SM at work.

Methods

We conducted semi-structured qualitative interviews (08/2020–01/2021). Participants were eligible if they have worked for at least six months with a minimum of twenty hours per week and with a migraine diagnosis. The interviews were transcribed and content-analyzed using MAXQDA.

Results

Migraine SM was perceived to be influenced by social interactions at work (e.g., in terms of understanding vs. stigmatization), the level of job decision latitude (JDL, i.e., the extent to which one is able to influence work processes, e.g., when working from home), and workplace design (e.g., in terms of opportunities to withdraw from work). During the COVID-19 pandemic, especially increased JDL appeared to favorably influence migraine SM.

Conclusions

Migraine SM at work is fostered or complicated by various psychosocial working conditions. By considering these facilitators and barriers, more migraine-friendly workplaces can be created.
The IMPACT Survey: the economic impact of osteogenesis imperfecta in adults
Authors: Hart Tracy , Westerheim Ingunn , van Welzenis Taco , Semler Oliver , Raggio Cathleen , Rauch Frank , Dadzie Ruby , Prince Samantha , Wekre Lena Lande
Published: June 2024

Background

The IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of osteogenesis imperfecta (OI) on individuals with OI, their families, caregivers and wider society. Research methodology, demographics and initial insights from the survey have been previously reported. The cost of illness (healthcare resource use, productivity loss, out-of-pocket spending) and drivers of the economic impact of OI are reported here.

Methods

IMPACT was an international mixed-methods online survey in eight languages (fielded July–September 2021) targeting adults (aged ≥ 18 years) or adolescents (aged ≥ 12–17 years) with OI, caregivers with or without OI and other close relatives. Survey domains included demographics, socioeconomic factors, clinical characteristics, treatment patterns, quality of life and health economics. The health economic domain for adults, which included questions on healthcare resource use, productivity loss and out-of-pocket spending, was summarised. Regression and pairwise analyses were conducted to identify independent drivers and associations with respondent characteristics.

Results

Overall, 1,440 adults with OI responded to the survey. Respondents were mostly female (70%) and from Europe (63%) with a median age of 43 years. Within a 12-month period, adults with OI reported visiting a wide range of healthcare professionals. Two-thirds (66%) of adults visited a hospital, and one-third (33%) visited the emergency department. The mean total number of diagnostic tests undergone by adults within these 12 months was 8.0. Adults had undergone a mean total of 11.8 surgeries up to the time point of the survey. The proportions of adults using queried consumables or services over 12 months ranged from 18–82%, depending on the type of consumable or service. Most adults (58%) were in paid employment, of which nearly one-third (29%) reported missing a workday. Of the queried expenses, the mean total out-of-pocket spending in 4 weeks was €191. Respondent characteristics such as female sex, more severe self-reported OI and the experience of fractures were often associated with increased economic burden.

Conclusion

IMPACT provides novel insights into the substantial cost of illness associated with OI on individuals, healthcare systems and society at large. Future analyses will provide insights into country-specific economic impact, humanistic impact and the healthcare journey of individuals with OI.
AI-based prediction of protein–ligand binding affinity and discovery of potential natural product inhibitors against ERK2
Authors: Yang Ruoqi , Zhang Lili , Bu Fanyou , Sun Fuqiang , Cheng Bin
Published: June 2024

Determination of protein–ligand binding affinity (PLA) is a key technological tool in hit discovery and lead optimization, which is critical to the drug development process. PLA can be determined directly by experimental methods, but it is time-consuming and costly. In recent years, deep learning has been widely applied to PLA prediction, the key of which lies in the comprehensive and accurate representation of proteins and ligands. In this study, we proposed a multi-modal deep learning model based on the early fusion strategy, called DeepLIP, to improve PLA prediction by integrating multi-level information, and further used it for virtual screening of extracellular signal-regulated protein kinase 2 (ERK2), an ideal target for cancer treatment. Experimental results from model evaluation showed that DeepLIP achieved superior performance compared to state-of-the-art methods on the widely used benchmark dataset. In addition, by combining previously developed machine learning models and molecular dynamics simulation, we screened three novel hits from a drug-like natural product library. These compounds not only had favorable physicochemical properties, but also bound stably to the target protein. We believe they have the potential to serve as starting molecules for the development of ERK2 inhibitors.
Enhancing anaerobic digestion of lignocellulosic biomass by mechanical cotreatment
Authors: Bharadwaj Anahita , Holwerda Evert K. , Regan John M. , Lynd Lee R. , Richard Tom L.
Published: June 2024

Background

The aim of this study was to increase the accessibility and accelerate the breakdown of lignocellulosic biomass to methane in an anaerobic fermentation system by mechanical cotreatment: milling during fermentation, as an alternative to conventional pretreatment prior to biological deconstruction. Effluent from a mesophilic anaerobic digester running with unpretreated senescent switchgrass as the predominant carbon source was collected and subjected to ball milling for 0.5, 2, 5 and 10 min. Following this, a batch fermentation test was conducted with this material in triplicate for an additional 18 days with unmilled effluent as the ‘status quo’ control.

Results

The results indicate 0.5 – 10 min of cotreatment increased sugar solubilization by 5– 13% when compared to the unmilled control, with greater solubilization correlated with increased milling duration. Biogas concentrations ranged from 44% to 55.5% methane with the balance carbon dioxide. The total biogas production was statistically higher than the unmilled control for all treatments with 2 or more minutes of milling (α = 0.1). Cotreatment also decreased mean particle size. Energy consumption measurements of a lab-scale mill indicate that longer durations of milling offer diminishing benefits with respect to additional methane production.

Conclusions

Cotreatment in anaerobic digestion systems, as demonstrated in this study, provides an alternative approach to conventional pretreatments to increase biogas production from lignocellulosic grassy material.
Harder, better, faster, stronger: understanding and improving the tractability of large energy system models
Authors: Bröchin Manuel , Pickering Bryn , Tröndle Tim , Pfenninger Stefan
Published: June 2024

Background

Energy system models based on linear programming have been growing in size with the increasing need to model renewables with high spatial and temporal detail. Larger models lead to high computational requirements. Furthermore, seemingly small changes in a model can lead to drastic differences in runtime. Here, we investigate measures to address this issue.

Results

We review the mathematical structure of a typical energy system model, and discuss issues of sparsity, degeneracy and large numerical range. We introduce and test a method to automatically scale models to improve numerical range. We test this method as well as tweaks to model formulation and solver preferences, finding that adjustments can have a substantial impact on runtime. In particular, the barrier method without crossover can be very fast, but affects the structure of the resulting optimal solution.

Conclusions

We conclude with a range of recommendations for energy system modellers: first, on large and difficult models, manually select the barrier method or barrier+crossover method. Second, use appropriate units that minimize the model’s numerical range or apply an automatic scaling procedure like the one we introduce here to derive them automatically. Third, be wary of model formulations with cost-free technologies and dummy costs, as those can dramatically worsen the numerical properties of the model. Finally, as a last resort, know the basic solver tolerance settings for your chosen solver and adjust them if necessary.
In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use
Authors: López-Carbonero Juan I. , García-Toledo Irene , Fernández-Hernández Laura , Bascuñana Pablo , Gil-Moreno María J. , Matías-Guiu Jordi A. , Corrochano Silvia
Published: June 2024

TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer’s disease, Huntington’s disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.
Mendelian randomization evidence based on European ancestry for the causal effects of leukocyte telomere length on prostate cancer
Authors: Wu Xinrui , Hu Cong , Wu Tianyang , Du Xinxing , Peng Zehong , Xue Wei , Chen Yonghui , Dong Liang
Published: June 2024

Background

Several lines of evidence suggest that leukocyte telomere length (LTL) can affect the development of prostate cancer (PC).

Methods

Here, we employed single nucleoside polymorphisms (SNPs) as instrumental variables (IVs) for LTL (n = 472,174) and conducted Mendelian randomization analysis to estimate their causal impact on PCs (79,148 patients/61,106 controls and 6311 patients/88,902 controls).

Results

Every 1-s.d extension of LTL increased the risk of PCs by 34%. Additionally, the analysis of candidate mediators between LTL and PCs via two-step Mendelian randomization revealed that among the 23 candidates, Alzheimer’s disease, liver iron content, sex hormone binding global levels, naive CD4–CD8-T cell% T cell, and circulating leptin levels played substantial mediating roles. There is no robust evidence to support the reverse causal relationship between LTL and the selected mediators of PCs. Adjusting for the former four mediators, rather than adjusting for circulating leptin levels, decreased the impact of LTL on PCs.

Conclusion

This study provides potential intervention measures for preventing LTL-induced PCs.
Does clinical T1N0 GGN really require checking for distant metastasis during initial staging for lung cancer?
Authors: Imai Kazuhiro , Kurihara Nobuyasu , Konno Motoko , Mori Naoko , Takashima Shinogu , Kuriyama Shoji , Demura Ryo , Suzuki Haruka , Harata Yuzu , Fujibayashi Tatsuki , Shibano Sumire , Wakita Akiyuki , Nagaki Yushi , Sato Yusuke , Nomura Kyoko , Minamiya Yoshihiro
Published: June 2024

Background

Accurate clinical staging is crucial for selection of optimal oncological treatment strategies in non-small cell lung cancer (NSCLC). Although brain MRI, bone scintigraphy and whole-body PET/CT play important roles in detecting distant metastases, there is a lack of evidence regarding the indication for metastatic staging in early NSCLCs, especially ground-grass nodules (GGNs). Our aim was to determine whether checking for distant metastasis is required in cases of clinical T1N0 GGN.

Methods

This was a retrospective study of initial staging using imaging tests in patients who had undergone complete surgical R0 resection for clinical T1N0 Stage IA NSCLC.

Results

A total of 273 patients with cT1N0 GGNs (n = 183) or cT1N0 solid tumors (STs, n = 90) were deemed eligible. No cases of distant metastasis were detected on initial routine imaging evaluations. Among all cT1N0M0 cases, there were 191 incidental findings on various modalities (128 in the GGN). Most frequently detected on brain MRI was cerebral leukoaraiosis, which was found in 98/273 (35.9%) patients, while cerebral infarction was detected in 12/273 (4.4%) patients. Treatable neoplasms, including brain meningioma and thyroid, gastric, renal and colon cancers were also detected on PET/CT (and/or MRI). Among those, 19 patients were diagnosed with a treatable disease, including other-site cancers curable with surgery.

Conclusions

Extensive staging (MRI, scintigraphy, PET/CT etc.) for distant metastasis is not required for patients diagnosed with clinical T1N0 GGNs, though various imaging modalities revealed the presence of adventitious diseases with the potential to increase surgical risks, lead to separate management, and worsen patient outcomes, especially in elderly patients. If clinically feasible, it could be considered to complement staging with whole-body procedures including PET/CT.
Role of cellular senescence in inflammation and regeneration
Authors: Saito Yuki , Yamamoto Sena , Chikenji Takako S.
Published: June 2024

Cellular senescence is the state in which cells undergo irreversible cell cycle arrest and acquire diverse phenotypes. It has been linked to chronic inflammation and fibrosis in various organs as well as to individual aging. Therefore, eliminating senescent cells has emerged as a potential target for extending healthy lifespans. Cellular senescence plays a beneficial role in many biological processes, including embryonic development, wound healing, and tissue regeneration, which is mediated by the activation of stem cells. Therefore, a comprehensive understanding of cellular senescence, including both its beneficial and detrimental effects, is critical for developing safe and effective treatment strategies to target senescent cells. This review provides an overview of the biological and pathological roles of cellular senescence, with a particular focus on its beneficial or detrimental functions among its various roles.
Seventy years of study on ethnic paleography in China
Authors: Shi Jinbo , Huang Runhua
Published: June 2024

This paper systematically presents the development process of studying ancient Chinese ethnic scripts over the past seven decades since the founding of the People’s Republic of China in 1949, including the establishment of related research institutions and academic disciplines. Firstly, it records the establishment of the Chinese Association for Ethnic Paleography, the emergence of ancient scripts of ethnic groups in China as an academic discipline, and the conduction of a comprehensive and in-depth study of ancient Chinese ethnic literature in history. Secondly, this paper outlines the establishment of the National Leading Group for Compilation and Publication Planning of Ancient Ethnic Books, the census of ancient books written in ethnic scripts, the specialized preservation and conservation of ancient ethnic books in Xizang and Xinjiang, the promotion of compiling and publishing ancient ethnic books, and how the promotion further drives the protection of and research on ancient books written in ethnic scripts. Thirdly, the paper lists many innovative outcomes in studying ancient ethnic books. Fourthly, the paper proposes to conduct further censuses and in-depth research in this area, establish a grading system for ancient ethnic books, and utilize the resource of ancient ethnic books written in ethnic scripts in a modern context to further promote the excellent cultural heritages of the Chinese nation and enhancing ethnic unity and national unity.
In-depth Correlation Power Analysis Attacks on a Hardware Implementation of CRYSTALS-Dilithium
Authors: Wang Huaxin , Gao Yiwen , Liu Yuejun , Zhang Qian , Zhou Yongbin
Published: June 2024

During the standardisation process of post-quantum cryptography, NIST encourages research on side-channel analysis for candidate schemes. As the recommended lattice signature scheme, CRYSTALS-Dilithium, when implemented on hardware, has seen limited research on side-channel analysis, and current attacks are incomplete or requires a substantial quantity of traces. Therefore, we conducted a more complete analysis to investigate the leakage of an FPGA implementation of CRYSTALS-Dilithium using the Correlation Power Analysis (CPA) method, where with a minimum of 70,000 traces partial private key coefficients can be recovered. Furthermore, we optimise the attack by extracting Point-of-Interests using known information due to parallelism (named CPA-PoI) and by iteratively utilising parallel leakages (named CPA-ITR). Our experimental results show that CPA-PoI reduces the number of traces by up to 16.67%, CPA-ITR by up to 25%, and both increase the number of recovered key coefficients by up to 55.17% and 93.10% using the same number of traces. They outperfom the CPA method. As a result, it suggests that the FPGA implementation of CRYSTALS-Dilithium is more vulnerable than thought before to side-channel analysis.
Dobutamine stress cardiac magnetic resonance-feature tracking in assessment of myocardial ischemia and viability
Authors: Ibrahim Ghada S. , AbdelDayem Emad H. , Abbas Sherif N. , Mozy Wesam E. El , Ibrahim Ahmed S.
Published: June 2024

Background

Cardiovascular magnetic resonance-feature tracking (CMR-FT) is a novel quantitative objective noninvasive technique in the assessment of myocardial deformation. The purpose of that study was to assess the capability of the CMR-FT in the detection of myocardial ischemia and viability. We investigated 30 patients (n = 480 myocardial segments), with known or suspected coronary artery disease (CAD). Dobutamine stress cardiovascular magnetic resonance (DS-CMR) and late gadolinium enhancement (LGE) were used to identify the viable non-ischemic, ischemic, and non-viable myocardial segments. Cine images at rest were used to calculate the segmental radial (Err), circumferential (Ecc), and longitudinal (Ell) strain parameters by manual contouring of endocardial and epicardial borders using Segment Software.

Results

Of the 480 myocardial segments and based on the DS-CMR and LGE results, 338 segments were defined as viable non-ischemic (remote), 101 segments were viable ischemic, and 41 segments were non-viable. Rest segmental Ecc, Err, and Ell values were significantly impaired in the non-viable (mean ± SD = − 3.94 ± 4.99%, 11.81 ± 12.55%, and − 7.50 ± 6.96%, respectively) compared to both viable groups, p < 0.001. Ecc and Err significantly differentiated between the non-ischemic and ischemic groups (mean ± SD = − 19.14 ± 7.20% vs − 13.18 ± 8.57% and 44.03 ± 19.56% vs 32.79 ± 17.91% respectively), p < 0.001. However, Ell showed no statistical significance between them (mean ± SD = − 16.44 ± 8.78% vs − 16.12 ± 10.00%, p = 0.945).

Conclusions

CMR-FT can differentiate between viable and non-viable as well as ischemic and non-ischemic myocardial segments. So, such a noninvasive technique has a promising additional objective diagnostic role in conjunction with CMR in ischemia and viability assessment or even may replace stress and LGE studies in the future.
Quantitative multistage fracturing efficiency evaluation using cross-well strain measurements
Authors: Mjehovich Joseph , Jin Ge , Wu Kan
Published: June 2024

Cross-well strain measurements acquired through low-frequency distributed acoustic sensing (LF-DAS) is a maturing technique used to monitor and diagnose the efficiency of hydraulic fracturing treatments. Although LF-DAS has demonstrated potential in characterizing far-field fracture communication and geometry, the prevailing analysis in this field has historically relied on qualitative interpretations, focusing on the timing and location of frac hits. In response to the evolving landscape of quantitative studies in this area, we present an advanced quantitative technique using our novel Green-function based inversion algorithm to calculate time-dependent far-field fracture width. The adopted algorithm uses the 3D displacement discontinuity method to relate fracture aperture to strains measured by LF-DAS along a monitor well during stimulation treatments. This approach is demonstrated on a subset of four treatment stages where distributed acoustic sensing (DAS) and distributed temperature sensing (DTS) were acquired within the injection well, alongside LF-DAS from a nearby monitor well. LF-DAS inversion results indicate the loss of zonal isolation in three of the monitored stages, leading to significantly smaller fracture widths at the monitor well for targeted treatment stages, and reactivated fractures in the adjacent previous stages. These interpretations are cross validated through the integration of in-well DAS and DTS analysis, where severe interstage fluid communication is observed. The inverted fracture widths quantify the impact on far-field fracture geometry associated with poor stage isolation and decreased fracturing efficiency. This new approach demonstrates the potential of LF-DAS for quantitative analysis and interpretation, facilitating improved understanding and optimization of hydraulic stimulation, going beyond its conventional qualitative role in fracturing diagnostics.
Perspectives on competency-based feedback for training non-specialists to deliver psychological interventions: multi-site qualitative study of the EQUIP competency-based approach
Authors: Elnasseh Abdelrhman , Mehta Varun S. , Manolova Gergana , Pedersen Gloria A. , Golden Shannon , Eloul Liyam , Gebrekristos Frezgi , Collins Pamela Y. , Mutavi Teresia , Mbwayo Anne W. , Mathai Muthoni , Concepcion Tessa , El Masri Rozane , Steen Frederik , Galea Jerome T. , Contreras Carmen , Akellot Josephine , Kasujja Rosco , Wasereka Samuel , Mutamba Byamah Brian , Tol Wietse A. , Raji Mansurat , Moufarrej Sacha , Schafer Alison , Kohrt Brandon A.
Published: June 2024

Background

The use of feedback to address gaps and reinforce skills is a key component of successful competency-based mental health and psychosocial support intervention training approaches. Competency-based feedback during training and supervision for personnel delivering psychological interventions is vital for safe and effective care.

Aims

For non-specialists trained in low-resource settings, there is a lack of standardised feedback systems. This study explores perspectives on competency-based feedback, using structured role-plays that are featured on the Ensuring Quality in Psychosocial and Mental Health Care (EQUIP) platform developed by the World Health Organization and United Nations Children’s Fund.

Method

Qualitative data were collected from supervisors, trainers and trainees from multiple EQUIP training sites (Ethiopia, Kenya, Lebanon, Peru and Uganda), from 18 key informant interviews and five focus group discussions (N = 41 participants). Qualitative analysis was conducted in Dedoose, using a codebook with deductively and inductively developed themes.

Results

Four main themes demonstrated how a competency-based structure enhanced the feedback process: (a) competency-based feedback was personalised and goal-specific, (b) competency-based feedback supported a feedback loop, (c) competency-based feedback supported a comfortable and objective feedback environment, and (d) competency-based feedback created greater opportunities for flexibility in training and supervision.

Conclusions

A better understanding of the role of feedback supports the implementation of competency-based training that is systematic and effective for trainers and supervisors, which ultimately benefits the learning process for trainees.
CINSARC score use in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) in the Children’s Oncology Group (COG) studies ARST0332 and ARST1321.
Authors: Hurley Rachel M , Guo Lei , Barkauskas Donald A. , Yu Lei , Chen Yen-Lin , Gutstein Lauren , Hawkins Douglas S. , Scharschmidt Thomas , Skapek Stephen X , Spunt Sheri L. , Wang Dian , Weiss Aaron R. , Xu Lin , Laetsch Theodore Willis
Published: June 2024

10013

Background: Despite genomic and histologic heterogeneity, limited risk stratification is used in the treatment of NRSTS (grade, size, presence of metastases, and extent of surgical resection). Genomic signatures including CINSARC score and Genomic Index (GI), both measures of genomic instability, have been shown to be prognostic in retrospective studies, but are not routinely used clinically. Here we evaluated the association of these scores with EFS and OS on two consecutive, prospective COG NRSTS studies, ARST0332 and ARST1321. Methods: All patients enrolled to ARST0332 or ARST1321 with sufficient banked tumor in the COG biospecimen repository were included in this analysis. Whole exome and transcriptome sequencing was performed on DNA and RNA from banked FFPE and flash frozen specimens. Raw WES reads were mapped to hg38 using BWA. The base qualities of the aligned reads were recalibrated and realigned by GATK. RNAseq data was aligned to hg38 by STAR. Differential expression analysis was performed by DESeq2. Stratified log rank and proportional hazards models were used to evaluate the association of CINSARC score and GI above or below the median with EFS and OS. Results: Tumors from 197 patients yielded sufficient DNA and 166 sufficient RNA, of which 177 and 142, respectively, passed sequencing quality metrics and were included. Demographics of these patients were generally representative of overall trial enrollment with most patients between ages 10-17 years (53%) with localized disease (77-80%). The most common histologic diagnoses were synovial sarcoma (35-37%) and MPNST (9-12%). Median follow-up was 6 years. CINSARC high vs low was associated with worse EFS (5-year 52.1% vs 74.6%, p < 0.01) and OS (5-year 66.2% vs 83.6%, p < 0.01). Accounting for sex and presence of metastatic disease, the hazard ratio for CINSARC high was 2.4 for EFS and 2.7 for OS (p < 0.01). CINSARC maintained the association with EFS among patients with non-metastatic disease (p = 0.017), and with OS among patients with metastatic disease (p = 0.031). GI analysis is ongoing and will be reported. Conclusions: In this analysis from the largest prospective North American pediatric NRSTS studies to date, CINSARC score was prognostic for EFS and OS. Further analysis including additional clinical prognostic factors (tumor size, grade, and extent of resection) is ongoing and will be reported. Use of CINSARC score for risk stratification should be considered on future NRSTS clinical trials. Clinical trial information: NCT00346164 , NCT02180867 .
Interpretable artificial intelligence-based analysis for morphologic classification of neuroblastic tumors.
Authors: Ramesh Siddhi , Pomaville Monica , Doytcheva Kristina , Dolezal James M , Kochanny Sara , TerHaar Rachel , Brewer Jacob , Kusswurm Benjamin , Shimada Hiroyuki , Naranjo Arlene , Pytel Peter , Cohn Susan Lerner , George Rani , Pearson Alexander T. , Applebaum Mark A.
Published: June 2024

10023

Background: Rapid and accurate identification of morphologic features of neuroblastic tumors (NTs) is critical for risk stratification and therapeutic decision making. The prognostic value of features like neuroblast differentiation, mitosis-karyorrhexis index (MKI), and Schwannian stromal presence is well established. Deep learning permits objective histopathological analysis, streamlining workflows for pathologists, notably in rare cancers. In rare cancers, our method minimizes bias and optimizes limited data using transfer and self-supervised learning (SSL) for feature extraction, with improved explainability. Here, we used an artificial intelligence-based model to morphologically classify NT tumors and MYCN-amplification. Methods: Annotated H&E-stained slides of diagnostic NT tumor biopsies from the University of Chicago and the Children’s Oncology Group were digitalized. Pathologists defined three binarized measures including diagnostic category (ganglioneuroblastoma/neuroblastoma), grade (differentiating/poorly differentiating), and MKI (low and intermediate/high). MYCN status was abstracted from patient records (amplified/non-amplified). Using Slideflow, our open-source pipeline, we developed an attention-based multiple instance learning model with features extracted by CTransPath, a SSL model pretrained on pan-cancer images from The Cancer Genome Atlas. For each measure, model performance was evaluated using 5-fold cross validation by aggregating k-fold model predictions across multiple metrics. Patients were excluded from a model if the measure of interest was unknown. Feature significance was assessed visually using Class Activation Mapping (Grad-CAM). Results: The mean age of the study cohort (n = 172) was 3.66 years. Of patients with clinical information, 84 of 138 (60.2%) had metastatic disease and 94 of 133 (70.7%) were high-risk. Of the 148 tumors with a diagnostic category of neuroblastoma, 93.2% were poorly differentiated and 25% had high MKI. Of the 135 tumors with known MYCN status, 40 were amplified (29.6%). The final models excelled across all outcomes, performing best for diagnostic category, grade, and MYCN status (Table 1). Physician review of the attention-based heatmaps for all measures highlighted biologically relevant regions such as neuropil. Conclusions: We created a deep learning pipeline for auto-characterization of digitized H&E-stained NT pathology slides. Our approach may also aid in identifying molecular features including MYCN-amplification. Review of heatmaps showed pertinent biological tissue, boosting model reliability.[Table: see text]
Phase I trial of chidamide, an oral HDAC inhibitor, in combination with oral etoposide in patients with refractory/recurrent neuroblastoma.
Authors: Sun Feifei , Zhen Zijun , Lu Suying , Zhu Jia , Wang Juan , Huang Junting , Que Yi , Zhang Yizhuo
Published: June 2024

10034

Background: Chidamide, an oral subtype-selective histone deacetylase (HDAC) inhibitor, has been shown to be effective in adult patients with hematological tumors. However, there is no data on its safety and efficacy in pediatric cancer patients. Combination of HDAC inhibitors and etoposide have shown synergistic anti-tumor effects in preclinical studies of neuroblastoma. We conducted a phase I trial in pediatric patients with recurrent or refractory neuroblastoma to determine the maximum tolerable dose (MTD) of chidamide combined with oral etoposide treatment. Methods: Daily oral etoposide 35 mg/m2/dose was administered on days 1–21 in combination with escalating doses of chidamide (14 and 17 mg/m2/d) twice weekly in each 28-day cycle using the standard 3 + 3 design. Patients with response or stable disease after two cycles would maintain treatment until disease progression or unacceptable toxicity occurred. Chidamide pharmacokinetic testing was performed. Results: 31 patients were enrolled in this study. The median age was 7 years (range 3 – 18). 14 patients were included in the dose escalation phase (Ia), 17 patients in the expansion cohort (Ib). The MTD of chidamide was 14 mg/m2/d, with dose limiting neutropenia and thrombocytopenia observed at 17 mg/m2/d. Median number of cycles completed was 2.5 (range 1–11). A total of 19 patients (61.3%) experienced treatment-related grade 3/4 hematologic toxicity, and no grade 3/4 non-hematological toxicity was observed. No objective responses were seen. Conclusions: In children with refractory/recurrent neuroblastoma, chidamide is well-tolerated at 14 mg/m2/d twice weekly when combining with oral etoposide 35 mg/m2/d daily. Prolonged disease stability achieved in patients with minimal residual diseases deserves further investigation. Clinical trial information: NCT05338541 .
Targeted treatment in inflammatory myofibroblastic tumors in children.
Authors: Kebudi Rejin , Yildirim Ulku Miray Miray , Zulfikar Osman Bulent
Published: June 2024

10046

Background: Inflammatory myofibroblastic tumors (IMTs) and epithelioid inflammatory myofibroblastic sarcoma (EIMS)-a variant of IMT, are rare mesenchymal neoplasms in children. Surgical resection has been the mainstay of treatment, however it may cause morbidities due to the size, location, invasiveness of the tumor. With the identification of targetable molecular alterations, targeted treatment has begun to be used in inoperable/relapsed/refractory cases. Methods: Files of children with IMT diagnosed and treated between 1990-2023 were retrospectively evaluated for demographic, clinical, molecular characteristics, treatment and outcome. Results: The mean age of 8 patients (5 male, 3 female) at diagnosis was 9 years (8 months-17 years). Six had IMT and two EMS. Tumor localization was intestine, retroperitoneum, lower extremity in two patients each; liver and back in one each. None had metastatic at diagnosis. Three of the six patients (one EMS) who underwent only surgical resection had negative surgical margins (one after re-resection) and are under follow-up with no evidence of disease (NED). Molecular analysis was performed in six patients. ALK was positive in the tumor tissue of five patients. One patient with an inoperable local recurrence received chemotherapy, had a life-threatening infection and resistant hypercalcemia. The molecular analysis by next-generation sequencing revealed a YWHAE-ROS fusion and she was treated by ceritinib, after which a significant (>90%) tumor shrinkage occurred and hypercalcemia resolved. She is currently in remission and continuing treatment. The patient with a positive surgical margin experienced local and metastatic (lung, liver) recurrences during follow-up and was treated with chemotherapy containing vincristine, actinomycin-D, and cyclophosphamide, the patient died due to progressive disease. In a patient with an unresectable tumor and ALK positivity, crizotinib treatment was initiated. After a treatment duration of seven months with crizotinib, the tumor completely regressed and treatment was stopped. On follow-up, local recurrence was detected after two months of cessation of crizotinib, crizotinib was restarted, considering the infiltrative appearance of the tumor and possible morbidities if operated. Two months after readministering crizotinib, complete response was achieved once again. The patient is continuing treatment with crizotinib. Thus, 7/8 patients are alive with NED for a median of 99 (9-174) months. Conclusions: Inflammatory myofibroblastic tumor and epithelioid inflammatory myofibroblastic sarcoma are rare in children. Surgery is the mainstay of treatment. The effectiveness of chemotherapy is yet unclear despite its use in inoperable cases. Molecular analysis of tumor tissue is highly recommended as targets such as ALK rearrangements or ROS fusions may enable the use of targeted treatments with fewer side effects.
Overall survival prediction and risk stratification in patients with neuroblastoma through machine learning in the large multi-institutional PRIMAGE cohort.
Authors: Lozano-Montoya Jose , Jiménez Pastor Ana , Weiss Glen J. , Cerdá-Alberich Leonor , Veiga-Canuto Diana , Martínez de Las Heras Blanca , Hero Barbara , Ladenstein Ruth Lydia , Martí-Bonmatí Luis , Alberich-Bayarri Angel
Published: June 2024

10054

Background: Neuroblastoma (NB) is the most prevalent solid cancer in childhood in which imaging plays a pivotal role at every step of the patient's journey. This investigation aimed to develop a machine learning model using clinical, molecular (MycN amplification), and magnetic resonance (MR) radiomics features at diagnosis to predict patient’s overall survival (OS) and improve their risk stratification. Methods: A database comprising clinical, molecular, and International Neuroblastoma Risk Group (INRG) staging on 513 patients with accessible MR imaging (discovery cohort) was employed for model training, validation, and testing. An additional 22 patients from non-discovery cohort hospitals served as an external validation group. Tumor segmentations of NB were manually and semi-automatically performed on corresponding T2-weighted MR images by an experienced radiologist. In total, 107 radiomics features were extracted and harmonized across MR scan manufacturers and magnetic field strengths using the nested ComBat methodology to correct both batch effects. These radiomics features, combined with clinical and molecular data, were utilized as input for the models. A nested cross-validation approach was employed for model development to determine the optimal preprocessing, machine learning algorithm, and model configuration. Results: The discovery cohort yielded a C-index of 0.788 ± 0.049 in the test partitions, with a random survival forest (RSF) exhibiting the best performance. In the validation cohort, a C-index of 0.934 was achieved. Interpretability analysis identified lesion heterogeneity, size, and molecular variables as crucial factors in OS prediction. The model demonstrated superior predictive performance and patient stratification compared to conventional staging systems in both cohorts. Conclusions: The RSF predictive model exhibited high performance, emphasizing the significant contribution of radiomics features and alignment with established clinical and molecular variables. The model stratified NB patients into low-, intermediate-, and high-risk categories and suggests that radiomics features potentially could improve current risk stratification systems. Additional external validation is warranted as this may present new evidence for enhancing patient care and clinical decision-making for NB patients.
PP2A activation as a new therapeutic strategy in neuroblastoma: Making sense out of senescence.
Authors: Nazam Nazia , Shaikh Maryam G. , Butey Swatika , Erwin Michael H , Stewart Jerry E. , Ohlmeyer Michael , Beierle Elizabeth A
Published: June 2024

10055

Background: Neuroblastoma (NBL) is the most common extracranial solid tumor in children, accounting for 15% of all pediatric cancer deaths. The five-year survival rate for children with high-risk disease is less than 50%, with the primary reasons for mortality being refractory and relapsed disease. One hypothesis for the poor response to therapy and propensity for recurrent disease in high-risk patients is treatment-induced senescence (TIS). Protein phosphatase 2A (PP2A) is a known tumor suppressor that is downregulated in NBL. PP2A activation has been shown to reverse cellular senescence in non-cancerous pathologies, therefore we hypothesized that reactivation of PP2A using novel small molecule activators would function as a novel senotherapeutic in NBL. Methods: We employed MYCNamplified, SK-N-BE(2), and non-amplified, SK-N-AS, established human NBL cell lines. Topotecan, a common NBL chemotherapeutic, known to induce senescence, and ATUX-1215, a small molecule PP2A activator, were utilized. NBL cells were treated with topotecan and ATUX-1215 alone, as well as in combination. Colorimetric assays detected cell viability and proliferation. Immunoblotting identified proteins of interest including γ-H2AX and CCL2. TIS was detected by S-β galactosidase (Sβgal) assay. Results: We found increased expression of the senescence marker, histone γ-H2AX, and increased Sβgal-positive tumor cells supporting the ability of topotecan to generate TIS in NBL. Following treatment with PP2A activator in combination with topotecan, markers of TIS are decreased in both MYCN amplified and non-amplified NBL cells. Further, and importantly, PP2A activation reversed the effects of topotecan TIS and acted in a synergistic fashion to decrease NBL cell viability. Conclusions: Activation of PP2A with a novel small molecule ameliorates topotecan-induced TIS in NBL cells irrespective of MYCN status. These results are promising, providing a potential novel therapeutic adjunct to children who are most in need of innovative interventions.