bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycemic control and clinical outcomes in diabetic patients with heart failure and reduced ejection fraction: insight from ventricular remodeling using cardiac MRI
Authors: Shi Ke , Zhang Ge , Fu Hang , Li Xue-Ming , Gao Yue , Shi Rui , Xu Hua-Yan , Li Yuan , Guo Ying-Kun , Yang Zhi-Gang
Published: April 2024

Background

Glycemic control, as measured by glycosylated hemoglobin (HbA1c), is an important biomarker to evaluate diabetes severity and is believed to be associated with heart failure development. Type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) commonly coexist, and the combination of these two diseases indicates a considerably poorer outcome than either disease alone. Therefore, glycemic control should be carefully managed. The present study aimed to explore the association between glycemic control and clinical outcomes, and to determine the optimal glycemic target in this specific population.

Methods

A total of 262 patients who underwent cardiac MRI were included and were split by HbA1c levels [HbA1c < 6.5% (intensive control), HbA1c 6.5-7.5% (modest control), and HbA1c > 7.5% (poor control)]. The biventricular volume and function, as well as left ventricular (LV) systolic strains in patients in different HbA1c categories, were measured and compared. The primary and secondary outcomes were recorded. The association of different HbA1c levels with adverse outcomes was assessed.

Results

Despite similar biventricular ejection fractions, both patients with intensive and poor glycemic control exhibited prominent deterioration of LV systolic strain in the longitudinal component (P = 0.004). After a median follow-up of 35.0 months, 55 patients (21.0%) experienced at least one confirmed endpoint event. Cox multivariable analysis indicated that both patients in the lowest and highest HbA1c categories exhibited a more than 2-fold increase in the risk for primary outcomes [HbA1c < 6.5%: hazard ratio (HR) = 2.42, 95% confidence interval (CI) = 1.07–5.45; P = 0.033; HbA1c > 7.5%: HR = 2.24, 95% CI = 1.01–4.99; P = 0.038] and secondary outcomes (HbA1c < 6.5%: HR = 2.84, 95% CI = 1.16–6.96; P = 0.022; HbA1c > 7.5%: HR = 2.65, 95% CI = 1.08–6.50; P = 0.038) compared with those in the middle HbA1c category.

Conclusions

We showed a U-shaped association of glycemic control with clinical outcomes in patients with T2DM and HFrEF, with the lowest risk of adverse outcomes among patients with modest glycemic control. HbA1c between 6.5% and 7.5% may be served as the optimal hypoglycemic target in this specific population.
Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance
Authors: Cui Jianfeng , Liu Xiaochen , Shang Qinghong , Sun Shuna , Chen Shouzhen , Dong Jianping , Zhu Yaofeng , Liu Lei , Xia Yangyang , Wang Yong , Xiang Lu , Fan Bowen , Zhan Jiafeng , Zhou Yadi , Chen Pengxiang , Zhao Renchang , Liu Xiaofei , Xing Nianzeng , Wu Dalei , Shi Benkang , Zou Yongxin
Published: April 2024

Background

CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated.

Methods

The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6.

Results

OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer.

Conclusions

We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.
Impact of resection margin on outcome in soft-tissue sarcomas of the extremities treated with limb-sparing surgery and postoperative radiotherapy
Authors: Chen Chun-Chieh , Wu Yao-Yu , Kao Jo-Ting , Chang Chih‑Hsiang , Huang Shih-Chiang , Shih Hsin‑Nung
Published: April 2024

Background

The standard curative treatments for extremity soft tissue sarcoma (ESTS) include surgical resection with negative margins and perioperative radiotherapy. However, the optimal resection margin remains controversial. This study aimed to evaluate the outcomes in ESTS between microscopically positive margin (R1) and microscopically negative margin (R0) according to the Union for International Cancer Control (UICC) (R + 1 mm) classification.

Methods

Medical records of patients with localized ESTS who underwent primary limb-sparing surgery and postoperative radiotherapy between 2004 and 2015 were retrospectively reviewed. Patients were followed for at least 5 years or till local or distant recurrence was diagnosed during follow-up. Outcomes were local and distal recurrences and survival.

Results

A total of 52 patients were included in this study, in which 17 underwent R0 resection and 35 underwent R1 resection. No significant differences were observed in rates of local recurrence (11.4% vs. 35.3%, p = 0.062) or distant recurrence (40.0% vs. 41.18%, p = 0.935) between R0 and R1 groups. Multivariate analysis showed that distant recurrences was associated with a Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade (Grade III vs. I, adjusted hazard ratio (aHR): 12.53, 95% confidence interval (CI): 2.67–58.88, p = 0.001) and tumor location (lower vs. upper extremity, aHR: 0.23, 95% CI: 0.07–0.7, p = 0.01). Kaplan–Meier plots showed no significant differences in local (p = 0.444) or distant recurrent-free survival (p = 0.161) between R0 and R1 groups.

Conclusions

R1 margins, when complemented by radiotherapy, did not significantly alter outcomes of ESTS as R0 margins. Further studies with more histopathological types and larger cohorts are necessary to highlight the path forward.
The value of low-intensity pulsed ultrasound in reducing ovarian injury caused by chemotherapy in mice
Authors: Zhou Yi , Zhu Fengyu , Zhou Yuanyuan , Li Xuqing , Zhao Shuhan , Zhang Yiqing , Zhu Ying , Li Hongyan , Cao Yunxia , Zhang Chaoxue
Published: April 2024

Background

Ovarian damage and follicle loss are major side effects of chemotherapy in young female patients with cancer. However, effective strategies to prevent these injuries are still lacking. The purpose of this study was to verify low-intensity pulsed ultrasound (LIPUS) can reduce ovarian injury caused by chemotherapy and to explore its underlying mechanisms in mice model.

Methods

The mice were randomly divided into the Control group, Cisplatin group, and Cisplatin + LIPUS group. The Cisplatin group and Cisplatin + LIPUS group were intraperitoneally injected with cisplatin every other day for a total of 10 injections, and the Control group was injected with saline. On the second day of each injection, the Cisplatin + LIPUS group received irradiation, whereas the other two groups received sham irradiation. We used a variety of biotechnologies to detect the differences in follicle count, granulosa cell apoptosis, fibrosis, transcriptome level, oxidative damage, and inflammation in differently treated mice.

Result

LIPUS was able to reduce primordial follicle pool depletion induced by cisplatin and inhibit the apoptosis of granulosa cells. Transcriptomic results confirmed that LIPUS can reduce ovarian tissue injury. We demonstrated that LIPUS can relieve ovarian fibrosis by inhibiting TGF-β1/Smads pathway. Meanwhile, it can reduce the oxidative damage and reduced the mRNA levels of proinflammatory cytokines caused by chemotherapy.

Conclusion

LIPUS can reduce the toxic effects of chemotherapy drugs on ovaries, inhibit ovarian fibrosis, reduce the inflammatory response, and redcue the oxidative damage, reduce follicle depletion and to maintain the number of follicle pools.
PTEN: an emerging target in rheumatoid arthritis?
Authors: Zhou Pan , Meng Xingwen , Nie Zhimin , Wang Hua , Wang Kaijun , Du Aihua , Lei Yu
Published: April 2024

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical tumor suppressor protein that regulates various biological processes such as cell proliferation, apoptosis, and inflammatory responses by controlling the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PI3K/AKT) signaling pathway. PTEN plays a crucial role in the pathogenesis of rheumatoid arthritis (RA). Loss of PTEN may contribute to survival, proliferation, and pro-inflammatory cytokine release of fibroblast-like synoviocytes (FLS). Also, persistent PI3K signaling increases myeloid cells’ osteoclastic potential, enhancing localized bone destruction. Recent studies have shown that the expression of PTEN protein in the synovial lining of RA patients with aggressive FLS is minimal. Experimental upregulation of PTEN protein expression could reduce the damage caused by RA. Nonetheless, a complete comprehension of aberrant PTEN drives RA progression and its interactions with other crucial molecules remains elusive. This review is dedicated to promoting a thorough understanding of the signaling mechanisms of aberrant PTEN in RA and aims to furnish pertinent theoretical support for forthcoming endeavors in both basic and clinical research within this domain.
PAX1 represses canonical Wnt signaling pathway and plays dual roles during endoderm differentiation
Authors: Miao Danxiu , Ren Jie , Jia Yanhan , Jia Yihui , Li Yanshu , Huang Huizhe , Gao Rui
Published: April 2024

Background

Paired box 1 (PAX1) is a transcription factor and essential for the development of pharyngeal pouches-derived tissues, including thymus. PAX1 mutations are identified in Severe Combined Immunodeficiency (SCID) patients with Otofaciocervical Syndrome Type 2 (OTFCS2). However, despite the critical roles of PAX1 in embryonic development and diseases, detailed insights into its molecular mode of action are critically missing.

Methods

The repressing roles of PAX1 and SCID associated mutants on Wnt signaling pathway were investigated by luciferase reporter assays, qRT-PCR and in situ hybridization in HEK293FT, HCT116 cells and zebrafish embryos, respectively. Co-immunoprecipitation (co-IP) and western blotting assays were carried out to identify the molecular mechanisms underlying PAX1’s role on Wnt signaling pathway. hESC based endoderm differentiation, flow cytometry, high-throughput sequencing data analysis, and qRT-PCR assays were utilized to determine the roles of PAX1 during endoderm differentiation.

Results

Here, we show that PAX1 represses canonical Wnt signaling pathway in vertebrate cells. Mechanically, PAX1 competes with SUMO E3 ligase PIASy to bind to TCF7L2, thus perturbing TCF7L2 SUMOylation level, further reducing its transcriptional activity and protein stability. Moreover, we reveal that PAX1 plays dual roles in hESC-derived definitive and foregut/pharyngeal endoderm cells, which give rise to the thymus epithelium, by inhibiting Wnt signaling. Importantly, our data show PAX1 mutations found in SCID patients significantly compromise the suppressing ability of PAX1 on Wnt signaling.

Conclusions

Our study presents a novel molecular mode of action of PAX1 in regulation of canonical Wnt signaling and endoderm differentiation, thus providing insights for the molecular basis of PAX1 associated SCID, offering better understanding of the behavior of PAX1 in embryogenesis.
Cellular response of keratinocytes to the entry and accumulation of nanoplastic particles
Authors: Martin Leisha , Simpson Kayla , Brzezinski Molly , Watt John , Xu Wei
Published: April 2024

Plastic accumulation in the environment is rapidly increasing, and nanoplastics (NP), byproducts of environmental weathering of bulk plastic waste, pose a significant public health risk. Particles may enter the human body through many possible routes such as ingestion, inhalation, and skin absorption. However, studies on NP penetration and accumulation in human skin are limited. Loss or reduction of the keratinized skin barrier may enhance the skin penetration of NPs. The present study investigated the entry of NPs into a human skin system modeling skin with compromised barrier functions and cellular responses to the intracellular accumulations of NPs. Two in vitro models were employed to simulate human skin lacking keratinized barriers. The first model was an ex vivo human skin culture with the keratinized dermal layer (stratum corneum) removed. The second model was a 3D keratinocyte/dermal fibroblast cell co-culture model with stratified keratinocytes on the top and a monolayer of skin fibroblast cells co-cultured at the bottom. The penetration and accumulation of the NPs in different cell types were observed using fluorescent microscopy, confocal microscopy, and cryogenic electron microscopy (cryo-EM). The cellular responses of keratinocytes and dermal fibroblast cells to stress induced by NPs stress were measured. The genetic regulatory pathway of keratinocytes to the intracellular NPs was identified using transcript analyses and KEGG pathway analysis. The cellular uptake of NPs by skin cells was confirmed by imaging analyses. Transepidermal transport and penetration of NPs through the skin epidermis were observed. According to the gene expression and pathway analyses, an IL-17 signaling pathway was identified as the trigger for cellular responses to internal NP accumulation in the keratinocytes. The transepidermal NPs were also found in co-cultured dermal fibroblast cells and resulted in a large-scale transition from fibroblast cells to myofibroblast cells with enhanced production of α-smooth muscle actin and pro-Collagen Ia. The upregulation of inflammatory factors and cell activation may result in skin inflammation and ultimately trigger immune responses.
Revisiting the complexity of and algorithms for the graph traversal edit distance and its variants
Authors: Qiu Yutong , Shen Yihang , Kingsford Carl
Published: April 2024

The graph traversal edit distance (GTED), introduced by Ebrahimpour Boroojeny et al. (2018), is an elegant distance measure defined as the minimum edit distance between strings reconstructed from Eulerian trails in two edge-labeled graphs. GTED can be used to infer evolutionary relationships between species by comparing de Bruijn graphs directly without the computationally costly and error-prone process of genome assembly. Ebrahimpour Boroojeny et al. (2018) propose two ILP formulations for GTED and claim that GTED is polynomially solvable because the linear programming relaxation of one of the ILPs always yields optimal integer solutions. The claim that GTED is polynomially solvable is contradictory to the complexity results of existing string-to-graph matching problems. We resolve this conflict in complexity results by proving that GTED is NP-complete and showing that the ILPs proposed by Ebrahimpour Boroojeny et al. do not solve GTED but instead solve for a lower bound of GTED and are not solvable in polynomial time. In addition, we provide the first two, correct ILP formulations of GTED and evaluate their empirical efficiency. These results provide solid algorithmic foundations for comparing genome graphs and point to the direction of heuristics. The source code to reproduce experimental results is available at https://github.com/Kingsford-Group/gtednewilp/.
Peripheral-central network analysis of cancer cachexia status accompanied by the polarization of hypothalamic microglia with low expression of inhibitory immune checkpoint receptors
Authors: Suda Yukari , Nakamura Keiko , Matsuyama Fukiko , Hamada Yusuke , Makabe Hitoshi , Narita Michiko , Nagumo Yasuyuki , Mori Tomohisa , Kuzumaki Naoko , Narita Minoru
Published: April 2024

While the excessive inflammation in cancer cachexia is well-known to be induced by the overproduction of inflammatory mediators in the periphery, microflora disruption and brain dysfunction are also considered to contribute to the induction of cancer cachexia. Hypothalamic microglia play a crucial role in brain inflammation and central-peripheral immune circuits via the production of inflammatory mediators. In the present study, we evaluated possible changes in excessive secretion of gut microbiota-derived endotoxin and the expression timeline of several inflammation-regulatory mediators and their inhibiting modulators in hypothalamic microglia of a mouse model of cancer cachexia following transplantation of pancreatic cancer cells. We demonstrated that the plasma level of lipopolysaccharide (LPS) was significantly increased with an increase in anaerobic bacteria, especially Firmicutes, in the gut at the late stage of tumor-bearing mice that exhibited dramatic appetite loss, sarcopenia and severe peripheral immune suppression. At the early stage, in which tumor-bearing mice had not yet displayed “cachexia symptoms”, the mRNA expression of pro-inflammatory cytokines, but not of the neurodegenerative and severe inflammatory modulator lipocalin-2 (LCN2), was significantly increased, whereas at the late “cachexia stage”, the level of LCN2 mRNA was significantly increased along with significant decreases in levels of inhibitory immune checkpoint receptors programmed death receptor-1 (PD-1) and CD112R in hypothalamic microglia. In addition, a high density of activated neurons in the paraventricular nucleus (PVN) of the hypothalamus region and a significant increase in corticosterone secretion were found in cachexia model mice. Related to the cachexia state, released corticosterone was clearly increased in normal mice with specific activation of PVN neurons. A marked decrease in the natural killer cell population was also observed in the spleen of mice with robust activation of PVN neurons as well as mice with cancer cachexia. On the other hand, in vivo administration of LPS in normal mice induced hypothalamic microglia with low expression of inhibitory immune checkpoint receptors. These findings suggest that the induction of cancer cachexia may parallel exacerbation of the hypothalamic inflammatory status with polarization to microglia expressed with low levels of inhibitory immune checkpoint receptors following LPS release from the gut microflora.
A higher CD34 + cell dose correlates with better event-free survival after KIR-ligand mismatched cord blood transplantation for childhood acute myeloid leukemia
Authors: Ishida Hisashi , Kawahara Yuta , Tomizawa Daisuke , Okamoto Yasuhiro , Hama Asahito , Cho Yuko , Koh Katsuyoshi , Koga Yuhki , Yoshida Nao , Sato Maho , Terui Kiminori , Miyagawa Naoyuki , Watanabe Akihiro , Takita Junko , Kobayashi Ryoji , Yamamoto Masaki , Watanabe Kenichiro , Okada Keiko , Kato Koji , Matsumoto Kimikazu , Hino Moeko , Tabuchi Ken , Sakaguchi Hirotoshi
Published: April 2024

Although killer Ig-like receptor ligands (KIR-L) mismatch has been associated with alloreactive natural killer cell activity and potent graft-versus-leukemia (GVL) effect among adults with acute myeloid leukemia (AML), its role among children with AML receiving cord blood transplantation (CBT) has not been determined. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients who were diagnosed with de novo non-M3 AML and who underwent their first CBT in remission between 2000 and 2021 at under 16 years old were included. A total of 299 patients were included; 238 patients were in the KIR-L match group, and 61 patients were in the KIR-L mismatch group. The cumulative incidence rates of neutrophil recovery, platelet engraftment, and acute/chronic graft-versus-host disease did not differ significantly between the groups. The 5-year event-free survival (EFS) rate was 69.8% in the KIR-L match group and 74.0% in the KIR-L mismatch group (p = 0.490). Stratification by CD34 + cell dose into four groups revealed a significant correlation between CD34 + cell dose and EFS in the KIR-L mismatch group (p = 0.006) but not in the KIR-L match group (p = 0.325). According to our multivariate analysis, KIR-L mismatch with a high CD34 + cell dose (≥ median dose) was identified as an independent favorable prognostic factor for EFS (hazard ratio = 0.19, p = 0.029) and for the cumulative incidence of relapse (hazard ratio = 0.09, p = 0.021). Our results suggested that higher CD34 + cell doses are crucial for achieving a potent GVL effect in the context of KIR-L-mismatched CBT.
Disruption of metazoan gene regulatory networks in cancer alters the balance of co-expression between genes of unicellular and multicellular origins
Authors: Trigos Anna S. , Bongiovanni Felicia , Zhang Yangyi , Zethoven Maia , Tothill Richard , Pearson Richard , Papenfuss Anthony T. , Goode David L.
Published: April 2024

Background

Metazoans inherited genes from unicellular ancestors that perform essential biological processes such as cell division, metabolism, and protein translation. Multicellularity requires careful control and coordination of these unicellular genes to maintain tissue integrity and homeostasis. Gene regulatory networks (GRNs) that arose during metazoan evolution are frequently altered in cancer, resulting in over-expression of unicellular genes. We propose that an imbalance in co-expression of unicellular (UC) and multicellular (MC) genes is a driving force in cancer.

Results

We combine gene co-expression analysis to infer changes to GRNs in cancer with protein sequence conservation data to distinguish genes with UC and MC origins. Co-expression networks created using RNA sequencing data from 31 tumor types and normal tissue samples are divided into modules enriched for UC genes, MC genes, or mixed UC-MC modules. The greatest differences between tumor and normal tissue co-expression networks occur within mixed UC-MC modules. MC and UC genes not commonly co-expressed in normal tissues form distinct co-expression modules seen only in tumors. The degree of rewiring of genes within mixed UC-MC modules increases with tumor grade and stage. Mixed UC-MC modules are enriched for somatic mutations in cancer genes, particularly amplifications, suggesting an important driver of the rewiring observed in tumors is copy number changes.

Conclusions

Our study shows the greatest changes to gene co-expression patterns during tumor progression occur between genes of MC and UC origins, implicating the breakdown and rewiring of metazoan gene regulatory networks in cancer development and progression.
Effects of different treatment frequencies of electromagnetic stimulation for urinary incontinence in women: study protocol for a randomized controlled trial
Authors: Chen Chunmei , Zhang Jing , Zhang Hong , Li Haiyan , Yu Jucheng , Pei Yao , Fang Yuan
Published: April 2024

Background

Urinary incontinence is highly prevalent in women while pelvic floor muscle training is recommended as the first-line therapy. However, the exact treatment regimen is poorly understood. Also, patients with pelvic floor muscle damage may have decreased muscle proprioception and cannot contract their muscles properly. Other conservative treatments including electromagnetic stimulation are suggested by several guidelines. Thus, the present study aims to compare the effectiveness of electromagnetic stimulation combined with pelvic floor muscle training as a conjunct treatment for urinary incontinence and different treatment frequencies will be investigated.

Methods/design

This is a randomized, controlled clinical trial. We will include 165 patients with urinary incontinence from the outpatient center. Participants who meet the inclusion criteria will be randomly allocated to three groups: the pelvic floor muscle training group (active control group), the low-frequency electromagnetic stimulation group (group 1), and the high-frequency electromagnetic stimulation group (group 2). Both group 1 and group 2 will receive ten sessions of electromagnetic stimulation. Group 1 will be treated twice per week for 5 weeks while group 2 will receive 10 days of continuous treatment. The primary outcome is the change in International Consultation on Incontinence Questionnaire–Short Form cores after the ten sessions of the treatment, while the secondary outcomes include a 3-day bladder diary, pelvic floor muscle function, pelvic organ prolapse quantification, and quality of life assessed by SF-12. All the measurements will be assessed at baseline, after the intervention, and after 3 months of follow-up.

Discussion

The present trial is designed to investigate the effects of a conjunct physiotherapy program for urinary incontinence in women. We hypothesize that this strategy is more effective than pelvic floor muscle training alone, and high-frequency electromagnetic stimulation will be superior to the low-frequency magnetic stimulation group.
Shining a spotlight on the inclusion of disabled participants in clinical trials: a mixed methods study
Authors: Sakuma Yoshiko , Miller Marie L. E. , Babalis Daphne S. , Baker Alex , Reddi Meena , Anjum Aisha , Bruton Jane , Jones Kathryn N , Mulla Umm Zeinab , Taddese Henock
Published: April 2024

Background

It is crucial to include a wide range of the population in clinical trials for the outcome to be applicable in real-world settings. Existing literature indicates that under-served groups, including disabled people, have been excluded from participating in clinical trials without justification. Exclusion from clinical trials exacerbates disparities in healthcare and diminishes the benefits for excluded populations. Therefore, this study was conducted to investigate potential obstacles that prevent disabled people from participating in clinical trials in the United Kingdom (UK).

Methods

The study was carried out through an explanatory sequential mixed methods design. The Imperial Clinical Trials Unit devised and implemented an online questionnaire-based survey (with open/closed-ended questions) and an online focus group discussion. The target population were disabled people, family members/carers of disabled people and staff involved in clinical trials, whereupon the sample was recruited by convenience sampling methods via posters and emails through various networks. The Qualtrics XM survey system was used as the host platform for the online survey, and Microsoft Teams was used for an online focus group discussion. The focus group discussion was conducted to gain a deeper understanding of the themes identified from the survey responses. We analysed responses to the survey via descriptive analysis and used thematic analysis to synthesise the free-text answers from the survey and focus group discussion.

Results

We received 45 responses to the survey questionnaire and 5 disabled people took part in a focus group discussion. Our findings highlighted the differences between the perspectives of researchers and those “being researched” and different types of barriers experienced by disabled people: opportunity barriers (inadequate recruitment strategy and ambiguous eligibility criteria), awareness barriers (perception of disability) and acceptance/refusal barriers (available support and adjustment, and sharing of trial results).

Conclusion

Our findings support perspectives drawn from the Ford Framework regarding the need to consider all barriers, not just up to the point of enrolment into trials but also beyond the point of inclusion in clinical trials. We support calls for the introduction of legislation on including disabled people in clinical trials, implementation of industry/community-wide participatory approaches and the development of guidelines, a combined public–private approach.
Community Health workers United to Reduce Colorectal cancer and cardiovascular disease among people at Higher risk (CHURCH): study protocol for a randomized controlled trial
Authors: Williams Olajide , Ting Tina , Matthews Lisa , Block Gladys , Block Torin , Teresi Jeanne , Eimicke Joseph , Kong Jian , Silver Stephanie , Ravenell Joseph , Mallaiah Janhavi , Jammalamadaka Soujanya , Nelson Laura Maudene , Karmally Wahida , Hankerson Sidney
Published: April 2024

Background

Colorectal cancer (CRC) is the second most lethal cancer in the United States (U.S.) with the highest incidence and mortality rates among African Americans (AAs) compared to other racial groups. Despite these disparities, AAs are the least likely to undergo CRC screening, have precancerous colorectal polyps removed, and have CRC detected at stages early enough for curative excision. In addition, compelling evidence links inflammatory dietary patterns to increased CRC and cardiovascular disease risk. Studies show that AA churches can successfully engage in health promotion activities including those related to cancer control. The current study seeks to leverage church-placed Community Health Workers (CHWs) to increase CRC screening and reduce CRC risk.

Design and methods

We aim to (1) increase guideline concordant CRC screening uptake using church-placed CHWs trained in screening with a validated instrument, Brief Intervention using Motivational Interviewing, and Referral to Treatment (SBIRT); and (2) reduce dietary risk factors (inflammatory dietary patterns) linked to CRC. The latter will be addressed by culturally adapting an existing, web-based lifestyle program called Alive!. Using a Hybrid Type 1 Implementation-Effectiveness cluster randomized design, we will randomize 22 AA churches into either the dual intervention arm (CHW-led SBIRT intervention plus Alive!) or a usual care arm comprised of CRC prevention educational pamphlets and a list of CRC screening sites. We will recruit 440 subjects and evaluate the effects of both arms on screening uptake (colonoscopy, fecal DNA) (primary outcome) and dietary inflammation score (secondary outcome) at 6-month follow-up, and Life Simple7 (LS7)—a cardiovascular disease (CVD) risk score—at 6 months and 1 year (secondary outcome). Finally, guided by a racism-conscious adaptation of the Consolidated Framework for Implementation Research (CFIR), we will conduct a mixed-methods process evaluation with key stakeholders to understand multi-level influences on CRC screening and CVD risk behaviors.

Discussion

Church-placed CHWs are trusted influential connectors between communities and health systems. Studies have shown that these CHWs can successfully implement health prevention protocols in churches, including those related to cancer control, making them potentially important community mediators of CRC screening uptake and CRC/CVD risk reduction.

Trial registration

NCT05174286; clinicaltrials.gov; August 31st, 2023
Seroprevalence and molecular detection of Toxoplasma gondii and Neospora caninum in beef cattle and goats in Hunan province, China
Authors: Yi Xi-Long , Yang Wen-He , Zheng He-Liang , Cao Mei-Ling , Xiong Jun , Chen Wen-Cheng , Zhou Yu-Jing , Li Fen , Zhu Xing-Quan , Liu Guo-Hua
Published: April 2024

Background

Toxoplasma gondii and Neospora caninum are closely related protozoan parasites that are considered important causes of abortion in livestock, causing huge economic losses. Hunan Province ranks 12th in the production of beef and mutton in China. However, limited data are available on the seroprevalence, risk factors and molecular characterization of T. gondii and N. caninum in beef cattle and goats in Hunan province, China.

Methods

Sera of 985 beef cattle and 1147 goats were examined for the presence of specific antibodies against T. gondii using indirect hemagglutination test (IHAT) and anti-N. caninum IgG using competitive-inhibition enzyme-linked immunoassay assay (cELISA). Statistical analysis of possible risk factors was performed using PASW Statistics. Muscle samples of 160 beef cattle and 160 goats were examined for the presence of T. gondii DNA (B1 gene) and N. caninum DNA (Nc-5 gene) by nested PCR. The B1 gene-positive samples were genotyped at 10 genetic markers using the multilocus nested PCR-RFLP (Mn-PCR-RFLP).

Results

Specific IgG against T. gondii were detected in 8.3% (82/985) and 13.3% (153/1147) and against N. caninum in 2.1% (21/985) and 2.0% (23/1147) of the beef cattle and goats, respectively. Based on statistical analysis, the presence of cats, semi-intensive management mode and gender were identified as significant risk factors for T. gondii infection in beef cattle. Age was a significant risk factor for T. gondii infection in goats (P < 0.05), and age > 3 years was a significant risk factor for N. caninum infection in beef cattle (P < 0.05). PCR positivity for T. gondii was observed in three beef samples (1.9%; 3/160) and seven chevon samples (4.4%; 7/160). Genotyping of PCR positive samples identified one to be ToxoDB#10. The N. caninum DNA was observed in one beef sample (0.6%; 1/160) but was negative in all chevon samples.

Conclusions

To our knowledge, this is the first large-scale serological and molecular investigation of T. gondii and N. caninum and assessment of related risk factors in beef cattle and goats in Hunan Province, China. The findings provide baseline data for executing prevention and control of these two important parasites in beef cattle and goats in China.

Graphical Abstract
Reinforcement of repressive marks in the chicken primordial germ cell epigenetic signature: divergence from basal state resetting in mammals
Authors: Kress Clémence , Jouneau Luc , Pain Bertrand
Published: April 2024

Background

In mammals, primordial germ cells (PGCs), the embryonic precursors of the germline, arise from embryonic or extra-embryonic cells upon induction by the surrounding tissues during gastrulation, according to mechanisms which are elucidated in mice but remain controversial in primates. They undergo genome-wide epigenetic reprogramming, consisting of extensive DNA demethylation and histone post-translational modification (PTM) changes, toward a basal, euchromatinized state. In contrast, chicken PGCs are specified by preformation before gastrulation based on maternally-inherited factors. They can be isolated from the bloodstream during their migration to the genital ridges. Our prior research highlighted differences in the global epigenetic profile of cultured chicken PGCs compared with chicken somatic cells and mammalian PGCs. This study investigates the acquisition and evolution of this profile during development.

Results

Quantitative analysis of global DNA methylation and histone PTMs, including their distribution, during key stages of chicken early development revealed divergent PGC epigenetic changes compared with mammals. Unlike mammalian PGCs, chicken PGCs do not undergo genome-wide DNA demethylation or exhibit a decrease in histone H3 lysine 9 dimethylation. However, chicken PGCs show 5‑hydroxymethylcytosine loss, macroH2A redistribution, and chromatin decompaction, mirroring mammalian processes. Chicken PGCs initiate their epigenetic signature during migration, progressively accumulating high global levels of H3K9me3, with preferential enrichment in inactive genome regions. Despite apparent global chromatin decompaction, abundant heterochromatin marks, including repressive histone PTMs, HP1 variants, and DNA methylation, persists in chicken PGCs, contrasting with mammalian PGCs.

Conclusions

Chicken PGCs’ epigenetic signature does not align with the basal chromatin state observed in mammals, suggesting a departure from extensive epigenetic reprogramming. Despite disparities in early PGC development, the persistence of several epigenetic features shared with mammals implies their involvement in chromatin-regulated germ cell properties, with the distinctive elevation of chicken-specific H3K9me3 potentially participating in these processes.
Effect of acute high-intensity interval exercise on a mouse model of doxorubicin-induced cardiotoxicity: a pilot study
Authors: Legault Elise P. , Ribeiro Paula A. B. , Petrenyov Daniil R. , Drumeva Gergana O. , Leduc Charles , Khullar Sharmila , DaSilva Jean N. , Comtois Alain Steve , Tournoux François B.
Published: April 2024

Background

It is unknown whether high-intensity interval exercise (HIIE) may potentiate or attenuate the cardiotoxic effect of chemotherapy agents such as doxorubicin (DOX) when performed shortly after treatment. The study aimed to investigate the effect of acute HIIE on cardiac function and structure performed either 1, 2 or 3 days after DOX injection in an animal model.

Methods

Female C57bl/6 mice (n = 28), 70 days old, received a bolus 20 mg/kg intravenous tail vein DOX injection. Three exercise groups performed 1 HIIE session (16 sets of 1 min at 85–90% of peak running speed) at 1 (n = 7), 2 (n = 7), and 3 days (n = 8) following the DOX injection. A sedentary (SED) group of mice (n = 6) did not exercise. Animals underwent echocardiography under light anesthesia (isoflurane 0.5-1%) before and 7 days after the DOX injection. Animals were sacrificed on day 9 and hearts were collected for morphometric and histological analysis.

Results

Animals exercising on day 3 had the smallest pre-post reduction in left ventricular fractional shortening (LVFS) (MΔ= -1.7 ± 3.3;p = 0.406) and the SED group had the largest reduction (MΔ=-6.8 ± 7.5;p = 0.009). After reclassification of animals according to their exercise compliance (performing > 8/16 of high-intensity bouts), LVFS in compliant mice was unchanged over time (LVFS MΔ= -1.3 ± 5.6;p = 0.396) while non-compliant animals had a LVFS reduction similar to sedentary animals. There were no significant differences in myocardial histology between groups.

Conclusions

In this pilot murine study, one single HIIE session did not exacerbate acute doxorubicin-induced cardiotoxicity. The timing of the HIIE session following DOX injection and the level of compliance to exercise could influence the negative impact of DOX on cardiac function.
Cognitive performance of post-covid patients in mild, moderate, and severe clinical situations
Authors: de Pádua Serafim Antonio , Saffi Fabiana , Soares Amanda Rafaella A. , Morita Alessandra Mara , Assed Mariana Medeiros , de Toledo Sandro , Rocca Cristiana C. A. , Durães Ricardo S. S.
Published: April 2024

Background

Studying individuals with varying symptoms, from mild to severe, can provide valuable insights into the spectrum of cognitive outcomes after COVID-19. We investigated the cognitive performance of adults who recovered from the novel coronavirus disease (COVID-19) without prior cognitive complaints, considering mild (not hospitalized), moderate (ward), and severe (intensive care unit) symptoms.

Methods

This cross-sectional study included 302 patients who recovered from COVID-19 (mild, n = 102; moderate, n = 102; severe, n = 98). We assessed intellectual quotient (IQ), attention, memory, processing speed, visual-constructive ability, as well as symptoms of depression, anxiety, and stress, at least eighteen months after infection. The mean length of hospitalization was Mdays=8.2 (SD = 3.9) and Mdays=14.4 (SD = 8.2) in the moderate and severe groups, respectively.

Results

Cognitive difficulties were present in all three groups: mild (n = 12, 11.7%), moderate (n = 40, 39.2%), and severe (n = 48, 48.9%). Using Multinomial Logistic Regression and considering the odds ratio, our results indicated that a one-point increase in sustained attention, visual memory, and working memory might decrease the odds of being categorized in the severe group by 20%, 24%, and 77%, respectively, compared to the mild group.

Conclusions

Our findings provide empirical evidence regarding the long-term cognitive effects of COVID-19, particularly in individuals experiencing severe manifestations of the disease. We also highlighted the need for a comprehensive, multidimensional approach in rehabilitation programs to address the enduring cognitive impacts of COVID-19.
Medication reconciliation by pharmacists for pre-admission patients improves patient safety
Authors: Yamada Yunami , Kobayashi Ryo , Yamamoto Taishi , Fujii Hironori , Iihara Hirotoshi , Hiroko Kato-Hayashi , Nishida Shohei , Hoshino Ryo , Niwa Takashi , Kumada Keisuke , Shimizu Masahito , Suzuki Akio
Published: April 2024

Background

Medication errors related to the pre-admission medication history obtained on admission are a major cause of medication error during hospitalization. Medication reconciliation (MR) improves patient safety through the detection of inadvertent medication discrepancies at transitions of care. The aim of this study was to evaluate the effect of MR by pharmacists for patients prior to hospital admission on the incidence of medication errors in the early post-admission period.

Patients and methods

Patients admitted to the orthopedic ward for surgery between April 2012 and March 2020 were included. Pharmacist-led MR for pre-admission patients was started on April 1, 2017. The incidence of medication errors related to pre-admission medications that occurred during hospitalization were compared between the pre- and post-initiation of pharmacist-led MR (pre-initiation: April 1, 2012 to March 31, 2015, post-initiation: April 1, 2017 to March 31, 2020).

Result

In the post-initiation group, 94.2% (1245/1321) of patients who were taking medications on admission had a pharmacist-led MR before admission. The proportion of patients whose physicians ordered the prescription of their pre-admission medications at the time before hospitalization to continue from admission was significantly higher in the post-initiation group than in the pre-initiation group (47.4% vs. 1.0%, p < 0.001). The incidence of medication errors related to pre-admission medications during hospitalization was significantly lower in the post-initiation group than in the pre-initiation group (1.83% vs. 0.85%, p = 0.025). Pharmacist-led MR prior to admission was a significant protective factor against incidents related to pre-admission medication (odds ratio (OR), 0.3810; 95% confidence interval (CI); 0.156–0.9320, p = 0.035).

Conclusion

Pharmacist-led MR for patients prior to hospital admission led to a reduction in medication errors related to pre-admission medications during hospitalization. Patient safety during hospitalization can be improved by accurate medication histories provided early by pharmacists.
Factors affecting E-HRM practices in Greek shipping management companies: the role of organizational culture, cultural intelligence, and innovation
Authors: Theotokas Ioannis N. , Lagoudis Ioannis N. , Syntychaki Athina , Prosilias John
Published: April 2024

HRM is forced to adapt and reinvent its practices towards more innovative and creative frameworks and models, due to the impetus technological developments in the modern business environment. The same applies to the elements of the organizational culture and corporate structure, which are decisive for the success of such initiatives. To undergo the shift to digital transformation, there is a need for human resource development professionals to invest in advanced competencies and capabilities. The scope of this paper is to examine the concept of digital innovation and HRM digitalization in the shipping industry and their relationship with corporate culture, intelligence, and leadership. Data were collected via a survey conducted in Greek shipping companies, and personal interviews with maritime professionals. Findings show that organizational culture and cultural intelligence are significant factors for digital innovation. Digital culture and digital leadership are proving to be important components in achieving this, whereas organizational cultural intelligence has a major impact on e-HRM. The present research contributes at both academic and policy level. In the former case is assists in bridging the gap in the maritime literature by examining digital innovation and e-HRM practices in the shipping industry along with the required skills for their development or enhancement. In the latter case the paper assists in the documentation of challenges maritime companies face in relation to digitalization practices and how policy makers can assist in their adoption.
To be or not to B27 positive: implications for the phenotypes of axial spondyloarthritis outcomes. Data from a large multiracial cohort from the Brazilian Registry of Spondyloarthritis
Authors: Resende Gustavo Gomes , Saad Carla Goncalves Schahin , Marques Claudia Diniz Lopes , Ribeiro Sandra Lúcia Euzébio , de Oliveira Gavi Maria Bernadete Renoldi , Yazbek Michel Alexandre , de Oliveira Marinho Adriana , de Cássia Menin Rita , Ochtrop Manuella Lima Gomes , Soares Andressa Miozzo , Cavalcanti Nara Gualberto , Carneiro Jamille Nascimento , Werner de Castro Glaucio Ricardo , Fernandes José Mauro Carneiro , da Cruz Ribeiro E Souza Elziane , de Menezes Alvarenga Corina Quental , de Abreu Vieira Rejane Maria Rodrigues , Machado Natalia Pereira , Ximenes Antônio Carlos , Gazzeta Morgana Ohira , de Albuquerque Cleandro Pires , Skare Thelma Larocca , Waldemar Keiserman Mauro , Kohem Charles Lubianca , Benacon Gabriel Sarkis , Rocha Vítor Florêncio Santos , da Cruz Lage Ricardo , Malheiro Olivio Brito , Golebiovski Rywka Tenenbaum Medeiros , Oliveira Thauana Luiza , Duque Ruben Horst , Londe Ana Carolina , de Medeiros Pinheiro Marcelo , Sampaio-Barros Percival Degrava
Published: April 2024

Background

There is a remarkable variability in the frequency of HLA-B27 positivity in patients with spondyloarthritis (SpA), which may be associated with different clinical presentations worldwide. However, there is a lack of data considering ethnicity and sex on the evaluation of the main clinical and prognostic outcomes in mixed-race populations. The aim of this study was to evaluate the frequency of HLA-B27 and its correlation with disease parameters in a large population of patients from the Brazilian Registry of Spondyloarthritis (RBE).

Methods

The RBE is a multicenter, observational, prospective cohort that enrolled patients with SpA from 46 centers representing all five geographic regions of Brazil. The inclusion criteria were as follow: (1) diagnosis of axSpA by an expert rheumatologist; (2) age ≥18 years; (3) classification according to ASAS axial. The following data were collected via a standardized protocol: demographic data, disease parameters and treatment historical.

Results

A total of 1096 patients were included, with 73.4% HLA-B27 positivity and a mean age of 44.4 (±13.2) years. Positive HLA-B27 was significantly associated with male sex, earlier age at disease onset and diagnosis, uveitis, and family history of SpA. Conversely, negative HLA-B27 was associated with psoriasis, higher peripheral involvement and disease activity, worse quality of life and mobility.

Conclusions

Our data showed that HLA-B27 positivity was associated with a classic axSpA pattern quite similar to that of Caucasian axSpA patients around the world. Furthermore, its absence was associated with peripheral manifestations and worse outcomes, suggesting a relevant phenotypic difference in a highly miscegenated population.