bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study
Authors: Hu Chunyan , Zhou Yulin , Wu Xueyan , Jia Xiaojing , Zhu Yuanyue , Zheng Ruizhi , Wang Shuangyuan , Lin Lin , Qi Hongyan , Lin Hong , Li Mian , Wang Tiange , Zhao Zhiyun , Xu Min , Xu Yu , Chen Yuhong , Ning Guang , Borges Maria-Carolina , Wang Weiqing , Zheng Jie , Bi Yufang , Lu Jieli
Published: June 2023

Background

Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two.

Methods

Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM.

Results

Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45–0.59), and decreased HOMA-IR (β = − 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06–1.15), and decreased HOMA-B (β = − 0.04, SE = 0.01, P = 4.52 × 10–5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2.

Conclusions

This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.
Re-evaluating the risk factors for radiation pneumonitis in the era of immunotherapy
Authors: Chen Feihu , Niu Jiling , Wang Min , Zhu Hui , Guo Zhijun
Published: June 2023

As one of the common complications of radiotherapy, radiation pneumonia (RP) limits the prognosis of patients. Therefore, better identifying the high-risk factors that lead to RP is essential to effectively prevent its occurrence. However, as lung cancer treatment modalities are being replaced and the era of immunotherapy has arrived, literature that reviews the parameters and mode of radiotherapy, chemotherapy drugs, targeted drugs and current hot immune checkpoint inhibitors related to RP is lacking. This paper summarizes the risk factors for radiation pneumonia by retrieving and analysing previously published literature and the results of large clinical trials. The literature primarily included retrospective analyses, including clinical trials in different periods and a part of the literature review. A systematic literature search of Embase, PubMed, Web of Science, and Clinicaltrials.gov was performed for relevant publications up to 6 Dec. 2022. Search keywords include, but are not limited to, “radiation pneumonia”, “pneumonia”, “risk factors”, “immunotherapy”, etc. The factors related to RP in this paper include physical parameters of radiotherapy, including V5, V20, and MLD; chemoradiotherapy mode and chemotherapy drugs, including paclitaxel and gemcitabine; EGFR-TKI; ALK inhibitors; antiangiogenic drugs; immune drugs and the underlying disease of the patient. We also introduce the possible mechanism of RP. In the future, we hope that this article not only sounds the alarm for clinicians but also helps to identify a method that can effectively intervene and reduce the occurrence of RP, significantly improve the quality of life and prognosis of patients, and more effectively improve the therapeutic effect of radiation therapy.
The interplay between noncoding RNAs and drug resistance in hepatocellular carcinoma: the big impact of little things
Authors: Fang Yuan , Zhang XiaoLi , Huang HanFei , Zeng Zhong
Published: June 2023

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in people, and a common primary liver cancer. Lacking early diagnosis and a high recurrence rate after surgical resection, systemic treatment is still an important treatment method for advanced HCC. Different drugs have distinct curative effects, side effects and drug resistance due to different properties. At present, conventional molecular drugs for HCC have displayed some limitations, such as adverse drug reactions, insensitivity to some medicines, and drug resistance. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), have been well documented to be involved in the occurrence and progression of cancer. Novel biomarkers and therapeutic targets, as well as research into the molecular basis of drug resistance, are urgently needed for the management of HCC. We review current research on ncRNAs and consolidate the known roles regulating drug resistance in HCC and examine the potential clinical applications of ncRNAs in overcoming drug resistance barriers in HCC based on targeted therapy, cell cycle non-specific chemotherapy and cell cycle specific chemotherapy.
Mental health and adherence to antiretroviral therapy among Mexican people living with HIV during the COVID-19 pandemic
Authors: Gutiérrez-Velilla Ester , Barrientos-Casarrubias Vania , Gómez-Palacio Schjetnan María , Perrusquia-Ortiz Lydia E. , Cruz-Maycott Rosa , Alvarado-de la Barrera Claudia , Ávila-Ríos Santiago , Caballero-Suárez Nancy Patricia
Published: June 2023

Background

The mental health and medical follow-up of people living with HIV (PLWH) have been disrupted by the COVID-19 pandemic. The objectives of this study were to assess anxiety, depression and substance use in Mexican PLWH during the pandemic; to explore the association of these symptoms with adherence to antiretroviral therapy (ART), and to compare patients with and without vulnerability factors (low socioeconomic level, previous psychological and/or psychiatric treatment).

Methods

We studied 1259 participants in a cross-sectional study, PLWH receiving care at the HIV clinic in Mexico City were contacted by telephone and invited to participate in the study. We included PLWH were receiving ART; answered a structured interview on sociodemographic data and adherence to ART; and completed the psychological instruments to assess depressive and anxiety symptoms and substance use risk. Data collection was performed from June 2020 to October 2021.

Results

84.7% were men, 8% had inadequate ART adherence, 11% had moderate-severe symptoms of depression, and 13% had moderate-severe symptoms of anxiety. Adherence was related to psychological symptoms (p < 0.001). Vulnerable patients were more likely to be women, with low educational level and unemployed (p < 0.001).

Conclusions

It is important to address mental health of PLWH during the COVID-19 pandemic, with special attention to the most vulnerable individuals. Future studies are needed to understand the relationship between mental health and ART adherence.
The POP (Permanent Supportive Housing Overdose Prevention) Study: protocol for a hybrid type 3 stepped-wedge cluster randomized controlled trial
Authors: Doran Kelly M. , Torsiglieri Allison , Blaufarb Stephanie , Hernandez Patricia , Melnick Emily , Velez Lauren , Cleland Charles M. , Neighbors Charles , O’Grady Megan A. , Shelley Donna
Published: June 2023

Background

Permanent supportive housing (PSH)—subsidized housing paired with support services such as case management—is a key part of national strategic plans to end homelessness. PSH tenants face high overdose risk due to a confluence of individual and environmental risk factors, yet little research has examined overdose prevention in PSH.

Methods

We describe the protocol for a hybrid type 3 stepped-wedge cluster randomized controlled trial (RCT) of overdose prevention practice implementation in PSH. We adapted evidence-based overdose prevention practices and implementation strategies for PSH using input from stakeholder focus groups. The trial will include 20 PSH buildings (with building size ranging from 20 to over 150 tenants) across New York City and New York’s Capital Region. Buildings will be randomized to one of four 6-month intervention waves during which they will receive a package of implementation support including training in using a PSH Overdose Prevention (POP) Toolkit, time-limited practice facilitation, and learning collaboratives delivered to staff and tenant implementation champions appointed by each building. The primary outcome is building-level fidelity to a defined list of overdose prevention practices. Secondary and exploratory implementation and effectiveness outcomes will be examined using PSH staff and tenant survey questionnaires, and analysis of tenant Medicaid data. We will explore factors related to implementation success, including barriers and facilitators, using qualitative interviews with key stakeholders. The project is being conducted through an academic-community partnership, and an Advisory Board including PSH tenants and other key stakeholders will be engaged in all stages of the project.

Discussion

We describe the protocol for a hybrid type 3 stepped-wedge cluster RCT of overdose prevention practice implementation in PSH. This study will be the first controlled trial of overdose prevention implementation in PSH settings. The research will make a significant impact by testing and informing future implementation strategies to prevent overdose for a population at particularly high risk for overdose mortality. Findings from this PSH-focused research are expected to be broadly applicable to other housing settings and settings serving people experiencing homelessness.

Trial registration

ClinicalTrials.gov, NCT05786222, registered 27 March 2023.
A systematic review of radiomics in giant cell tumor of bone (GCTB): the potential of analysis on individual radiomics feature for identifying genuine promising imaging biomarkers
Authors: Zhong Jingyu , Xing Yue , Zhang Guangcheng , Hu Yangfan , Ding Defang , Ge Xiang , Pan Zhen , Yin Qian , Zhang Huizhen , Yang Qingcheng , Zhang Huan , Yao Weiwu
Published: June 2023

Purpose

To systematically assess the quality of radiomics research in giant cell tumor of bone (GCTB) and to test the feasibility of analysis at the level of radiomics feature.

Methods

We searched PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and Wanfang Data to identify articles of GCTB radiomics until 31 July 2022. The studies were assessed by radiomics quality score (RQS), transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) statement, checklist for artificial intelligence in medical imaging (CLAIM), and modified quality assessment of diagnostic accuracy studies (QUADAS-2) tool. The radiomic features selected for model development were documented.

Results

Nine articles were included. The average of the ideal percentage of RQS, the TRIPOD adherence rate and the CLAIM adherence rate were 26%, 56%, and 57%, respectively. The risk of bias and applicability concerns were mainly related to the index test. The shortness in external validation and open science were repeatedly emphasized. In GCTB radiomics models, the gray level co-occurrence matrix features (40%), first order features (28%), and gray-level run-length matrix features (18%) were most selected features out of all reported features. However, none of the individual feature has appeared repeatably in multiple studies. It is not possible to meta-analyze radiomics features at present.

Conclusion

The quality of GCTB radiomics studies is suboptimal. The reporting of individual radiomics feature data is encouraged. The analysis at the level of radiomics feature has potential to generate more practicable evidence for translating radiomics into clinical application.
Type 2 diabetes has a protective causal association with thoracic aortic aneurysm: a Mendelian randomization study
Authors: Zhang Yiran , Li Yongxin , Dai Xiaoyi , Lin Haokai , Ma Liang
Published: June 2023

Background

Observational studies have reported an inverse association of type 2 diabetes (T2D) with thoracic aortic aneurysm (TAA). However, the causality of the association has not been established yet. The present study aims to clarify the causal relationship between T2D and TAA via a Mendelian randomization (MR) approach.

Methods

Causality of associations were assessed using a two-sample MR framework. Genome-wide association study (GWAS) summary statistics were obtained for T2D, glycated hemoglobin (HbA1c), fasting glucose (FG) and fasting insulin (FI) as exposures, and TAA, ascending aortic diameter (AAoD) and descending aortic diameter (DAoD) as outcomes. Four different methods (inverse variance weighted [IVW], weight median, MR-Egger and MR-PRESSO) were used to calculate causal estimates. Heterogeneity and horizontal pleiotropy were assessed using Cochran Q test and MR-Egger regression intercept, respectively.

Results

Genetically predicted T2D was inversely associated with the risk of TAA (OR: 0.931, 95% CI 0.870 to 0.997, p = 0.040, IVW method) and AAoD (Beta: -0.065, 95%CI −0.099 to  − 0.031, p = 1.7e−04, IVW method), but not with DAoD (p > 0.05). Genetically predicted FG level was inversely associated with AAoD (Beta: −0.273, 95% CI −0.396 to –0.150, p = 1.41e−05, IVW method) and DAoD (Beta: −0.166, 95% CI −0.281 to −0.051, p = 0.005, IVW method), but not with TAA (p > 0.05). The effect of genetically predicted HbA1c and FI on TAA, AAoD and DAoD did not reach statistical significance (p > 0.05).

Conclusions

Genetic predisposition to T2D decreases the risk of TAA. Genetically predicted T2D is inversely associated with AAoD, but not with DAoD. Genetically predicted FG level was inversely associated with AAoD and DAoD.
Tora3D: an autoregressive torsion angle prediction model for molecular 3D conformation generation
Authors: Zhang Zimei , Wang Gang , Li Rui , Ni Lin , Zhang RunZe , Cheng Kaiyang , Ren Qun , Kong Xiangtai , Ni Shengkun , Tong Xiaochu , Luo Li , Wang Dingyan , Lu Xiaojie , Zheng Mingyue , Li Xutong
Published: June 2023

Three-dimensional (3D) conformations of a small molecule profoundly affect its binding to the target of interest, the resulting biological effects, and its disposition in living organisms, but it is challenging to accurately characterize the conformational ensemble experimentally. Here, we proposed an autoregressive torsion angle prediction model Tora3D for molecular 3D conformer generation. Rather than directly predicting the conformations in an end-to-end way, Tora3D predicts a set of torsion angles of rotatable bonds by an interpretable autoregressive method and reconstructs the 3D conformations from them, which keeps structural validity during reconstruction. Another advancement of our method over other conformational generation methods is the ability to use energy to guide the conformation generation. In addition, we propose a new message-passing mechanism that applies the Transformer to the graph to solve the difficulty of remote message passing. Tora3D shows superior performance to prior computational models in the trade-off between accuracy and efficiency, and ensures conformational validity, accuracy, and diversity in an interpretable way. Overall, Tora3D can be used for the quick generation of diverse molecular conformations and 3D-based molecular representation, contributing to a wide range of downstream drug design tasks.

Graphical Abstract
Hydrophobic surface for direct PEGDA micro-pattern fabrication
Authors: Danielak Anna , Ko Juhee , Islam Aminul , Pedersen David Bue , Lee Jungchul
Published: June 2023

Photopolymerization of hydrogels films has gained interest in many biomedical and industrial fields. Hydrogel micro-patterns fabricated directly on a device are used as filtering barriers, however, due to weak mechanical properties, these parts require a stable support but deposition of hydrogel in non-polymerized state brings a risk of sinking inside the structure. These limitations can be overcome by applying a hydrophobic surface. This paper presents a novel two-step method, in which a hydrophobic surface was designed and manufactured using mask-projection vat photopolymerization additive manufacturing (VPP). Afterwards, PEGDA-based hydrogel photopolymers were deposited on the surface and a micro-scale patterns were cured. The parts were subjected to water immersion and heating in order to evaluate the swelling and shrinking behaviour of hydrogel. The parts remained stable on the substrate and maintained the properties and the results revealed the shape retention over 97%. This work shows that VPP can be applied in the manufacturing of hydrophobic surfaces for hydrogel photopolymer deposition and curing without sacrificing critical properties.

Graphical Abstract
Abdominal wall defect repair with component separation technique for giant omphalocele with previous relaxing incisions on the abdominal skin
Authors: Matsukubo Makoto , Muto Mitsuru , Yamada Koji , Nishida Nanako , Kedoin Chihiro , Matsui Mayu , Nagano Ayaka , Murakami Masakazu , Sugita Koshiro , Yano Keisuke , Onishi Shun , Harumatsu Toshio , Yamada Waka , Kawano Takafumi , Kaji Tatsuru , Ieiri Satoshi
Published: June 2023

Background

The repair of large abdominal wall defects that cannot be closed primarily is quite challenging. The component separation technique (CST) is a surgical approach using autologous tissue to close large abdominal wall defects. The CST requires extensive dissection between the abdominal skin and the anterior sheath of the rectus abdominis muscle. Subsequently, incisions are made at both sides of the external oblique aponeurosis, releasing the external oblique muscle from the internal oblique muscle, and then the right and left rectus abdominis muscles are brought together in the midline for defect closure. However, impairment of blood flow in the abdominal wall skin and necrotic changes are recognized as potential complications.

Case presentation

The CST was performed in a 4-year-old boy with a large ventral hernia who had undergone skin closure with abdominal wall relaxing incisions for the primary treatment of giant omphalocele in the neonatal period. Given his history of incisions on the abdominal wall, he was speculated to be at high risk for postoperative skin ischemia. Dissection was therefore kept to a minimum to preserve the blood supply from the superior and inferior epigastric arteries and perforating branches of those arteries through the rectus abdominis muscle. In addition, care was taken to adjust the muscle relaxant dosage while monitoring the intravesical pressure, ensuring that it did not exceed 20 mmHg to avoid impaired circulation in the abdominal wall caused by abdominal compartment syndrome. He was discharged 23 days after the surgery without any complications, and neither recurrence of the ventral hernia nor bowel obstruction was observed in 4 years.

Conclusions

A giant omphalocele with primary skin closure was treated by applying the CST. The procedure can be performed safely while preserving the blood flow to the abdominal wall, even in patients with a history of relaxing incisions on the abdominal skin. The CST is expected to be effective for repairing the large abdominal wall defects seen in giant omphalocele when primary closure is not possible.
Regional biogeography versus intra-annual dynamics of the root and soil microbiome
Authors: Bell-Dereske Lukas P. , Benucci Gian Maria Niccolò , da Costa Pedro Beschoren , Bonito Gregory , Friesen Maren L. , Tiemann Lisa K. , Evans Sarah E.
Published: June 2023

Background

Root and soil microbial communities constitute the below-ground plant microbiome, are drivers of nutrient cycling, and affect plant productivity. However, our understanding of their spatiotemporal patterns is confounded by exogenous factors that covary spatially, such as changes in host plant species, climate, and edaphic factors. These spatiotemporal patterns likely differ across microbiome domains (bacteria and fungi) and niches (root vs. soil).

Results

To capture spatial patterns at a regional scale, we sampled the below-ground microbiome of switchgrass monocultures of five sites spanning > 3 degrees of latitude within the Great Lakes region. To capture temporal patterns, we sampled the below-ground microbiome across the growing season within a single site. We compared the strength of spatiotemporal factors to nitrogen addition determining the major drivers in our perennial cropping system. All microbial communities were most strongly structured by sampling site, though collection date also had strong effects; in contrast, nitrogen addition had little to no effect on communities. Though all microbial communities were found to have significant spatiotemporal patterns, sampling site and collection date better explained bacterial than fungal community structure, which appeared more defined by stochastic processes. Root communities, especially bacterial, were more temporally structured than soil communities which were more spatially structured, both across and within sampling sites. Finally, we characterized a core set of taxa in the switchgrass microbiome that persists across space and time. These core taxa represented < 6% of total species richness but > 27% of relative abundance, with potential nitrogen fixing bacteria and fungal mutualists dominating the root community and saprotrophs dominating the soil community.

Conclusions

Our results highlight the dynamic variability of plant microbiome composition and assembly across space and time, even within a single variety of a plant species. Root and soil fungal community compositions appeared spatiotemporally paired, while root and soil bacterial communities showed a temporal lag in compositional similarity suggesting active recruitment of soil bacteria into the root niche throughout the growing season. A better understanding of the drivers of these differential responses to space and time may improve our ability to predict microbial community structure and function under novel conditions.
What is the Prevalence of General Anxiety Disorder and Depression Symptoms in Semi-elite Australian Football Players: A Cross-Sectional Study
Authors: Henderson Anthony , Harris Sarah Ann , Kirkham Troy , Charlesworth Jonathon , Murphy Myles Calder
Published: June 2023

Background

The prevalence of anxiety and depression symptoms in semi-elite Australian footballers is unknown. The primary objective of this study was to determine the prevalence of generalised anxiety disorder (GAD) and depressive symptoms in semi-elite Australian Football players. Our secondary objective was to explore the association between demographic and football-specific factors with GAD and depressive symptoms. A cross-sectional epidemiological study including 369 semi-elite Western Australian Football League (WAFL) players from the Men and Women’s 2022 season (n = 337 men, 91%) was conducted. Symptoms of depression were measured using the Patient Health Questionnaire-9 scale (PHQ-9) and symptoms of GAD with the GAD-7 scale.

Results

Our response rate was 82.9%. Thirteen players had missing data. The prevalence of GAD symptoms was 8.5% in men and 28.6% in women (10% overall). The prevalence of depressive symptoms was 20% in men and 57% in women (23% overall). Being a woman (gender) was associated with a sevenfold increased risk of GAD and/or depression symptoms [odds ratio (OR): 7.33, 95% confidence interval (CI): 3.18–16.92; p < 0.001]. Players of ‘Aboriginal or Torres Strait Islander’ ethnicity were two times more likely to report GAD and/or depression symptoms in comparison to players of ‘Australian’ ethnicity (OR: 2.13; 95% CI: 1.01–4.49; p = 0.048). Concussion history was not a significant risk factor for GAD or depression symptoms.

Conclusion

This study demonstrated that approximately 1 in 10 WAFL players met the diagnostic cut-off criteria for probable GAD, and 1 in 5 for probable depression. The prevalence for depression symptoms in this study were far higher than the national average in the comparative age bracket. WAFL women’s players also reported a substantially higher prevalence of GAD and depressive symptoms than men, and should be further investigated as a priority by the WAFL.
Progress of tissue adhesives based on proteins and synthetic polymers
Authors: Han Gi-Yeon , Hwang Soo-Kyung , Cho Ki-Hyun , Kim Hyun-Joong , Cho Chong-Su
Published: June 2023

In recent years, polymer-based tissue adhesives (TAs) have been developed as an alternative to sutures to close and seal incisions or wounds owing to their ease of use, rapid application time, low cost, and minimal tissue damage. Although significant research is being conducted to develop new TAs with improved performances using different strategies, the applications of TAs are limited by several factors, such as weak adhesion strength and poor mechanical properties. Therefore, the next-generation advanced TAs with biomimetic and multifunctional properties should be developed. Herein, we review the requirements, adhesive performances, characteristics, adhesive mechanisms, applications, commercial products, and advantages and disadvantages of proteins- and synthetic polymer-based TAs. Furthermore, future perspectives in the field of TA-based research have been discussed.
Radiographic involvement of cervical facet joints in ankylosing spondylitis: a longitudinal analysis in correlation with vertebral body lesions
Authors: Lee Tae-Han , Lee Seunghun , Koo Bon San , Joo Kyung Bin , Kim Tae-Hwan
Published: June 2023

Background

The inability to assess structural changes in facet joints is a limitation of established radiographic scoring systems for ankylosing spondylitis (AS). We compared radiographic evidence of ankylosis in cervical facet joints and cervical vertebral bodies in patients with AS.

Methods

We analysed longitudinal data collected from 1106 AS patients and assessed 4984 spinal radiographs obtained up to 16 years of follow-up. Comparisons between cervical facet joints and cervical vertebral bodies focused on the presence of ankylosis, which was defined by at least one facet joint exhibiting complete ankylosis (according to the method of de Vlam) or at least one vertebral body with a bridging syndesmophyte (according to the modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS]). Ankylosis was assessed over time using spinal radiographs collected during follow-up periods stratified in 4-year increments.

Results

Patients with cervical facet joint ankylosis had higher cervical mSASSS, sacroiliitis grades, and inflammatory markers, with more prevalent hip involvement and uveitis. Overall, the numbers of spinal radiographs indicating ankylosis were comparable between cervical facet joints (17.8%) and cervical vertebral bodies (16.8%), and they usually presented together (13.5%). We observed similar proportions of radiographs with ankylosis only in cervical facet joints (4.3%) and cervical vertebral bodies (3.3%). As damage progressed, configurations with both cervical facet joint ankylosis and bridging syndesmophytes became more predominant with longer follow-up times, while configurations with cervical facet joint ankylosis only or bridging syndesmophytes only were less frequently observed.

Conclusions

Evidence of cervical facet joint ankylosis appears as often as bridging syndesmophytes on routine AS spinal radiographs. Presence of cervical facet joint ankylosis should be considered because it may have a higher disease burden.
Four-years retention rate of golimumab administered after discontinuation of non-TNF inhibitors in patients with inflammatory rheumatic diseases
Authors: Pombo-Suárez Manuel , Seoane-Mato Daniel , Díaz-González Federico , Sánchez-Alonso Fernando , Sánchez-Jareño Marta , Cea-Calvo Luis , Castrejón Isabel
Published: June 2023

Background

In patients with rheumatic diseases, the use of biological (b) or targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) after discontinuation of tumor necrosis factor inhibitors (TNFi) is known to be effective. However, data on the use of TNFi after discontinuation of non-TNFi bDMARDs or tsDMARDs (non-TNFi) are scarce. This study assessed the 4-years golimumab retention in patients with rheumatic diseases when used after discontinuation of non-TNFi.

Methods

Adults with rheumatoid arthritis (RA; n = 72), psoriatic arthritis (PsA; n = 30) or axial spondyloarthritis (axSpA; n = 23) who initiated golimumab after discontinuation of non-TNFi from the Spanish registry of biological drugs (BIOBADASER) were analyzed retrospectively. The retention rate (drug survival or persistence) of golimumab up to 4 years was evaluated.

Results

The golimumab retention rate was 60.7% (51.4–68.8) at year 1, 45.9% (36.0–55.2) at year 2, 39.9% (29.8–49.7) at year 3 and 33.4% (23.0–44.2) at year 4. Retention rates did not differ significantly whether golimumab was used as second, third, or fourth/subsequent line of therapy (p log-rank = 0.462). Golimumab retention rates were higher in axSpA or PsA patients than in RA patients (p log-rank = 0.002). When golimumab was administered as third or fourth/subsequent line, the 4-years retention rate after discontinuation of non-TNFi was similar to that after discontinuation of TNFi.

Conclusion

In patients who discontinued non-TNFi, most of whom received golimumab as third/subsequent line of therapy, one-third of patients remained on golimumab at year 4. Retention rates were higher in patients with axSpA and PsA than in those with RA.
Incidence of soft tissue releases in robotic assisted cementless TKA with mechanical alignment and flexion gap balancing
Authors: Selvanathan Nanchappan , Ayeni Femi E. , Sorial Rami
Published: June 2023

Background

To ensure the success of total knee arthroplasty (TKA), precise bone cuts and a well-balanced soft tissue envelope are crucial. Soft tissue release may be necessary, subject to various factors. Therefore, documenting the type, frequency, and necessity of soft tissue releases can establish a benchmark for comparing different alignment techniques and philosophies and evaluating their outcomes. The purpose of this study was to demonstrate that robotic-assisted knee surgery requires minimal soft tissue release.

Methods

We prospectively documented and retrospectively reviewed the soft tissue releases employed in securing ligament balance in the first 175 patients who received robotic-assisted TKAs at Nepean Hospital. ROSA was utilized in all surgeries with the aim of restoring mechanical coronal alignment, with a flexion gap balancing technique. Surgeries were performed between December 2019 to August 2021 by a single surgeon who used a standard medial parapatellar approach without a tourniquet, and the cementless persona prosthesis. All patients were followed up for a minimum of 6 months post-surgery. Soft tissue releases included any form of medial release for varus knee, posterolateral release for valgus knee and PCL fenestration or sacrifice.

Results

There were 131 female and 44 male patients, aged between 48 to 89 years (average 60 years). The preoperative HKA ranged from 22 degrees varus to 28 degrees valgus, with 71% of patients presenting with a varus deformity. For the whole group, the no need for soft tissue release was documented in 123 patients (70.3%), small fenestrated releases of PCL in 27 (15.4%), sacrifice of PCL in 8 (4.5%), medial releases in 4 (2.3%) and posterolateral releases in 13 (7.4%). In 29.7% of patients in whom a soft tissue release was necessary for balance, over half were/received minor fenestrations of the PCL. Outcomes to date included no revisions or impending revisions, 2 MUAs (1%), and Oxford knee scores averaged 40 at 6 months.

Conclusion

We concluded that Robot technology enhanced the precision of bone cuts and allowed for titration of required soft tissue releases to achieve optimal balance.
Sailing between Scylla and Charybdis: invited response to ‘Blame or discovery?’
Authors: Hilton Claire
Published: June 2023

This brief commentary reflects on navigating two dangers of historical research into psychiatry: hagiographic representations of psychiatrists; and accusations of their self-interest and oppression of vulnerable people.
A phase 1/2, first-in-human trial of ZB131, a novel antibody targeting cancer-specific plectin (CSP) in advanced solid tumors.
Authors: Sommerhalder David , Piha-Paul Sarina A. , Pelster Meredith , Borad Mitesh J. , Vandross Andrae Lavon , Spira Alexander I. , Perez Samantha , Brinton Lindsey , Kelly Kimberly , Ramanathan Ramesh K. , Reilley Matthew
Published: June 2023

3083

Background: Cancer-Specific Plectin (CSP) is a novel pro-tumorigenic target that is selectively expressed on the surface of tumors, while absent from benign tissue. CSP is highly expressed in many solid cancers, particularly pancreatic (PC), cholangiocarcinoma (CCA), and ovarian (OC). ZB131 (Zielbio), is a humanized anti-CSP IgG1 monoclonal antibody that binds specifically to CSP on the surface of tumor cells, rapidly internalizes and modulates key proliferative and cytoskeletal remodeling signaling pathways to decrease cancer cell growth and increase the recruitment of anti-tumor immune infiltrates. Methods: The dose escalation (3+3 design) and expansion are enrolling adult patients (pts) with advanced treatment-refractory solid tumors. ZB131 was administered IV over 60 minutes (without premedication) weekly. The starting dose of ZB131 is 0.3 mg/kg followed by 1,3, 9, 15 and 30 mg/kg. Primary objectives are safety, tolerability, and maximum tolerated dose/determination of Phase 2 dose. Secondary objectives are preliminary efficacy (RECIST v1.1), Pharmacokinetic (PK) and pharmacodynamic parameters in blood and paired tumor biopsies. Results: As of 31 Jan 2023, 24 pts had enrolled (9 PC, 6 CCA, 4 OC, 5 other). The median age was 59.5 yr (range, 35 – 84) with a median of 4 prior lines of therapy. The median ZB131 treatment duration is 5.3 weeks (range, 1 – 33). No dose-limiting toxicities were observed up to the dose of 30 mg/kg which is currently enrolling. Treatment-related adverse events (TRAEs) were grade 1/ 2: nausea (n=6), fatigue (n=5), anemia (n=3), diarrhea (n=2), flulike symptoms (n=2), and vomiting (n=2). Mild flu-like symptoms and nausea/vomiting were observed during or following infusion at doses of 9 mg/kg and above. Except for one episode of Gr 3 neutropenia at the 30 mg/kg dose, no other drug-related grade 3/4 TRAE’s were reported. Five pts had stable disease range, 12 – 33 weeks (2 PC, 1 CCA, 2 OC), with a 43% decrease in CA-125 observed in one OC pt. The PKs are linear and dose-proportional for all dose levels evaluated (estimated T½ of 6-9 days). No antidrug antibodies have been detected. Conclusions: Interim data from dose-escalation of this first-in-class, anti CSP antibody, demonstrates good tolerability with encouraging signs of activity and target engagement in heavily pretreated pts. Results support further clinical evaluation of ZB131 in dose-expansion cohorts including OC and including combination therapy with gemcitabine. Clinical trial information: NCT 05074472 .
First-in-human study of ZG19018, targeting KRAS G12C, as monotherapy in patients with advanced solid tumors.
Authors: Liu Rongrui , Qu Xiujuan , Yang Nong , Chai Xiaoli , Xu Jianming
Published: June 2023

e15127

Background: ZG19018 tablet is a selective KRAS G12C inhibitor that inhibits the activation of KRAS G12C and multiple downstream signaling pathways. It showed very promising anti-tumor effects in preclinical studies. Here we report the preliminary results from a phase 1 dose escalation study that assessed the tolerability, safety, pharmacokinetics and efficacy of ZG19018 in patients (pts) with advanced solid tumors. Methods: This is an open-label, multi-center study in pts with KRAS G12C mutated solid tumors and progressed following prior standard therapies. The study consisted of a rapid dose-escalation phase for the low-dose groups (50 mg qd and 150 mg qd, orally) and a standard 3+3 design phase for the high-dose groups (300 mg qd, 300 mg bid and 450 mg bid, orally). The first treatment cycle (21 days) was defined as the dose-limiting toxicity (DLT) assessment period. Patients could continue to receive ZG19018 until one of the treatment discontinuation criteria was met. Tumor response was assessed by the investigator per RECIST1.1 criteria. Pharmacokinetics profiles were also assessed in all pts. Results: As of January 31st, 2023, 14 pts (8 males and 6 females) completed the DLT assessments, with a median age of 65 years. Of them, 11 (78.6%) were non-small cell lung cancer (NSCLC) pts, 2 (14.3%) with colorectal cancer (CRC), and 1 (7.1%) with cervical cancer (CESC); 12 pts (85.7%) had received ≥ 1 line of stand therapies and 2 pts (14.3%) had received ≥ 3 lines. The dose group of 450 mg bid was determined as the maximally administered dose, where 2 pts experienced a DLT (grade 3 γ-GGT elevation and grade 3 ALT elevation, respectively), therefore an additional dose group of 400 mg bid has been added and is currently undergoing. Treatment-related adverse events (TRAEs) occurred in 13 pts (92.9%), most frequent in nausea (42.9%), diarrhea (42.9%), vomiting (35.7%), AST elevation (35.7%), γ-GGT elevation (35.7%), ALT elevation (28.6%), hypertriglyceridemia (28.6%), blood creatine phosphokinase MB elevation (21.4%) and ALP elevation (21.4%). No SAE was reported. In 12 pts evaluated for the best overall responses, 2 (16.7%) had PR (1 NSCLC, 1 CRC), 6 (50%) had SD (4 NSCLC, 1 CRC，1 CESC) and 4 (33.3%) had PD (4 NSCLC). The maximum drug exposure of ZG19018 is 8 months in 1 patient with colorectal cancer who is SD and remaining in the study. The Cmax and AUC0-t increased from 50 mg qd to 450 mg bid approximately in dose proportion. Conclusions: ZG19018 is tolerable and demonstrates a good safety under the dose level of 450 mg bid. It also demonstrates preliminary antitumor effects in pts with solid tumors, with reasonable PK profiles. Clinical trial information: ChiCTR20220296 .
Preliminary results of a phase I, first-in-human, dose escalation study of IMM2902 in patients with HER2-expressing advanced solid tumors.
Authors: Meng Yanchun , Zhang Jian , Zhao Chuanhua , Cheng Ying , Zhu Liming , Song Zhengbo , Xu Nong , Wang Zhen , Wang Yanping , Du Yiqun , Jing Deqiang , Chen Dinglu , Qu Qiaofeng , Zhao Xiwen , Li Wei , Lu Qiying , Tian Wenzhi , Xu Jianming
Published: June 2023

e15185

Background: IMM2902 is a novel recombinant bispecific fusion protein containing SIRPα binding domain trapped to the light chain of a humanized anti-HER2 antibody. With its high affinity to HER2 and CD47 on tumor cell membrane, IMM2902 can drive several anti-tumoral killing mechanisms such as directly targeting HER2 expressing tumor cells; restoring the phagocytic function of macrophages against tumor cells via CD47-SIRPα blockade; activating NK cells and macrophages mediated antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC); and most importantly, inducing accelerated HER2 internalization and degradation. Phase I dose escalation studies of IMM2902 in advanced solid tumors are conducted in both China and the United States, here we present the preliminary results from China trial. Methods: The dose escalation study of IMM2902 was conducted following a modified 3+3 design to evaluate the safety and tolerability of the study drug and to determine the MTD/RP2D. IMM2902 was administered intravenously every week (QW) in 4-week cycles, and the first cycle was the DLT observation period. The tumor responses were evaluated based on RECIST v1.1. IMM2902 pharmacokinetics (PK) and pharmacodynamics (PD) were also evaluated. Results: As of 26 December 2022, a total of 16 subjects had received at least one dose of IMM2902 in 5 dose cohorts (0.03, 0.1, 0.3, 0.9 and 2.0 mg/kg). Of the 16 subjects, no DLTs were observed. Treatment related adverse events (TRAEs) occurred in all 16 subjects (100%), with 4 subjects (25%) reported to have grade 3 TRAEs. No subject discontinued IMM2902 treatment due to TRAEs. The most common TRAEs were platelet count decreased (62.5%), infusion related reaction (50%), and anemia (43.8%). The most common grade 3 or above TRAE was platelet count decreased (18.8%). One SAE (grade 3 gastrointestinal hemorrhage) was reported, which was unrelated to IMM2902. Among 13 evaluable subjects, 4 patients achieved SD (2 pts with gastric cancer at 0.1 mg/kg, 1 pt with skin cancer at 0.9 mg/kg, and 1 pt with breast cancer at 2.0 mg/kg). Preliminary PK analysis showed IMM2902 had a non-linear PK. Serum concentration of IMM2902 reached steady state after the third administration. Preliminary PD data showed that, beginning at 0.3 mg/kg, the number of peripheral CD3+ and CD8+ T-cells increased after 4 weeks of treatment. Conclusions: IMM2902 showed an encouraging preliminary safety, tolerability and anti-tumor activity up to 2.0 mg/kg. The phase I/II study is ongoing. Clinical trial information: ChiCTR20212375 .
Observational constraints on the modification of standard ΛCDM cosmology with dark radiation
Authors: Zhao Yifei , Qiang Ling-Xuan
Published: June 2023

We revisit a cosmological model modified by an extra “radiation-like” energy component in the Universe, which can be interpreted as many physical phenomena. Here, we derive the constraint on the energy density

from this modification with current cosmological observations, including Cosmic Microwave Background, Baryon Acoustic Oscillation, Observational Hubble Parameter data and Type Ia supernovae. Performing a Bayesian analysis gives

at 95% confidence level. Our work shows the dark radiation energy is small. Alleviating H
0 tension by introducing this term can also be interpreted as the systematic error caused by the numerical method.
Unexpected paths to cooperation on tied hyperbolic networks
Authors: Duh Maja , Gosak Marko , Perc Matjaž
Published: June 2023

Hyperbolic networks have high clustering, short average path lengths, and community structure, which are all properties that are commonly associated with social networks. As such, these networks constitute the perfect playing ground for probing factors that may affect public cooperation in realistic scenarios. And although much is already known about the evolution of cooperation on networks, we here consider the public goods game on tied hyperbolic networks, such that payoffs in one network layer influence the payoffs in the other and vice versa. We also consider random, assortative, and disassortative mixing in the networks to account for varying connections between players over time. While our research confirms the overall positive impact of interdependent payoffs, we also find that mixing on the network where cooperation thrives may strongly promote the cooperation in the other network, while destroying it completely in the former. We show that this is related to the mapping of lower payoffs from one network to the other, where cooperators in one network benefit from the failure of cooperators in the other network. Namely, as soon as the multiplication factor for the public goods is high enough to nullify the negative effects of mixing and cooperators thus recover, the positive effect on cooperation in the other network vanishes. We determine optimal conditions for this phenomenon in terms of the frequency of mixing and the strength of ties between the payoffs on both networks, and we discuss the implications of our research for enhanced cooperation in coupled populations, in particular in the light of mutual success not always being desirable for cooperation to thrive.
Association Between Educational Attainment and Thyroid Function: Results From Mendelian Randomization and the NHANES Study
Authors: Yuan Jie , Liu Xue , Wang Xinhui , Zhou Huizhi , Wang Yuyao , Tian Guoyu , Liu Xueying , Tang Mulin , Meng Xue , Kou Chunjia , Yang Qingqing , Li Juyi , Zhang Li , Yuan Zhongshang , Zhang Haiqing
Published: June 2023

Context

Many observational studies have reported on the association between educational attainment (EA) and thyroid function, but the causal relationship remains unclear.

Objective

We aimed to obtain causal effects of EA on thyroid function and to quantify the mediating effects of modifiable risk factors.

Methods

Two-sample mendelian randomization (MR) was performed by using summary statistics from large genome-wide association studies (GWAS) to assess the effect of EA on thyroid function, including hypothyroidism, hyperthyroidism, thyrotropin (TSH), and free thyroxine (FT4). A multivariable analysis was conducted to assess the mediating role of smoking and help to explain the association between EA and thyroid function. Similar analysis was further performed using data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2002.

Results

In MR analysis, EA was causally associated with TSH (β = .046; 95% CI, 0.015-0.077; P = 4.00 × 10−3), rather than hypothyroidism, hyperthyroidism, and FT4. Importantly, smoking could serve as a mediator in the association between EA and TSH, in which the mediating proportion was estimated to be 10.38%. After adjusting for smoking in the multivariable MR analysis, the β value of EA on TSH was attenuated to 0.030 (95% CI, 0.016-0.045; P = 9.32 × 10−3). Multivariable logistic regression model in NHANES suggested a dose-response relationship between TSH (quartile [Q]4 vs Q1: odds ratio = 1.33; 95% CI, 1.05-1.68; P for trend = .023) and EA. Smoking, systolic blood pressure, and body mass index partially mediated the association between EA and TSH, with the proportion of the mediation effects being 43.82%, 12.28%, and 6.81%, respectively.

Conclusion

There is a potentially causal association between EA and TSH, which could be mediated by several risk factors, such as smoking.
Horizontal Advantage: Choice of Postsecondary Field of Study Among Children of Immigrants
Authors: Borgen Solveig Topstad , Hermansen Are Skeie
Published: June 2023

Educational expansion has raised the influence of sorting across postsecondary educational fields on children's future life chances. Yet, little is known about horizontal ethnic stratification in the choice of field of study among children of immigrant parents, whose parents often have moderate absolute levels of education relative to native-born parents but tend to be positively selected on education relative to nonmigrants in the origin country. Using rich administrative data from Norway, we study the educational careers of immigrant descendants relative to the careers of children of native-born parents. Our results show that children of immigrants from non-European countries have a higher likelihood of entering higher education and enrolling in high-paying fields of study compared with children of natives, despite having poorer school grades and disadvantaged family backgrounds. However, immigrant parents' positive selectivity provides limited insight into why children of immigrants exhibit high ambitions later in their postsecondary educational careers. These findings document a persistent pattern of horizontal ethnic advantage in postsecondary education in which ambitious children of immigrants are more likely to enter into more prestigious and economically rewarding fields of study than their fellow students with native-born parents.