bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of iterative removal of low-information cluster-period cells from a stepped wedge design
Authors: Rezaei-Darzi Ehsan , Grantham Kelsey L. , Forbes Andrew B. , Kasza Jessica
Published: July 2023

Background

Standard stepped wedge trials, where clusters switch from the control to the intervention condition in a staggered manner, can be costly and burdensome. Recent work has shown that the amount of information contributed by each cluster in each period differs, with some cluster-periods contributing a relatively small amount of information. We investigate the patterns of the information content of cluster-period cells upon iterative removal of low-information cells, assuming a model for continuous outcomes with constant cluster-period size, categorical time period effects, and exchangeable and discrete-time decay intracluster correlation structures.

Methods

We sequentially remove pairs of “centrosymmetric” cluster-period cells from an initially complete stepped wedge design which contribute the least amount of information to the estimation of the treatment effect. At each iteration, we update the information content of the remaining cells, determine the pair of cells with the lowest information content, and repeat this process until the treatment effect cannot be estimated.

Results

We demonstrate that as more cells are removed, more information is concentrated in the cells near the time of the treatment switch, and in “hot-spots” in the corners of the design. For the exchangeable correlation structure, removing the cells from these hot-spots leads to a marked reduction in study precision and power, however the impact of this is lessened for the discrete-time decay structure.

Conclusions

Removing cluster-period cells distant from the time of the treatment switch may not lead to large reductions in precision or power, implying that certain incomplete designs may be almost as powerful as complete designs.
Revascularization of acute stent thrombosis caused by diarrhea after carotid artery stenting in an intermediate clopidogrel metabolizer
Authors: Wang Huaishun , Xu Longdong , Qin Yan , Xiao Guodong
Published: July 2023

Carotid artery stenting (CAS) is an alternative treatment to carotid endarterectomy for carotid artery stenosis. Acute stent thrombosis (ACST) is an extremely rare complication but can have devastating consequences. Although many cases have been reported, the best treatment is still uncertain. In this study, we report the treatment of ACST caused by diarrhea in an intermediate clopidogrel metabolizer. We also review the literature and discuss appropriate treatment strategies for this rare event.
Determinants of postpartum uterine atony in urban South Ethiopia: a community-based unmatched nested case–control study
Authors: Jena Belayneh Hamdela , Biks Gashaw Andargie , Gete Yigzaw Kebede , Gelaye Kassahun Alemu
Published: July 2023

Background

Uterine atony is the most common cause of postpartum hemorrhage, which is the leading preventable cause of maternal morbidity and mortality. Despite several interventions uterine atony-related postpartum hemorrhage remains a global challenge. Identifying risk factors of uterine atony helps to reduce the risk of postpartum hemorrhage and subsequent maternal death. However, evidence about risk factors of uterine atony is limited in the study areas to suggest interventions. This study aimed to assess determinants of postpartum uterine atony in urban South Ethiopia.

Methods

A community-based unmatched nested case–control study was conducted from a cohort of 2548 pregnant women who were followed-up until delivery. All women with postpartum uterine atony (n = 93) were taken as cases. Women who were randomly selected from those without postpartum uterine atony (n = 372) were taken as controls. Using a case to control ratio of 1:4, the total sample size was 465. An unconditional logistic regression analysis was done using R version 4.2.2 software. In the binary unconditional logistic regression model variables that have shown association at p < 0.20 were recruited for multivariable model adjustment. In the multivariable unconditional logistic regression model, statistically significant association was declared using 95% CI and p < 0.05. Adjusted odds ratio (AOR) used to measure the strength of association. Attributable fraction (AF) and population attributable fraction (PAF) were used to interpret the public health impacts of the determinants of uterine atony.

Results

In this study, short inter-pregnancy interval < 24 months (AOR = 2.13, 95% CI: 1.26, 3.61), prolonged labor (AOR = 2.35, 95% CI: 1.15, 4.83), and multiple birth (AOR = 3.46, 95% CI: 1.25, 9.56) were determinants of postpartum uterine atony. The findings suggest that 38%, 14%, and 6% of uterine atony in the study population was attributed to short inter-pregnancy interval, prolonged labor, and multiple birth, respectively, which could be prevented if those factors did not exist in the study population.

Conclusions

Postpartum uterine atony was related to mostly modifiable conditions that could be improved by increasing the utilization of maternal health services such as modern contraceptive methods, antenatal care and skilled birth attendance in the community.
Apigenin inhibits angiogenesis in retinal microvascular endothelial cells through regulating of the miR-140-5p/HDAC3-mediated PTEN/PI3K/AKT pathway
Authors: Fu Chaojun , Peng Jun , Ling Yanjun , Zhao Hongqing , Zhao Yongwang , Zhang Xiuli , Ai Min , Peng Qinghua , Qin Yuhui
Published: July 2023

Background

Diabetic retinopathy (DR) is a common cause of visual impairment. Apigenin has been shown to have antiangiogenic effects in various diseases. Our study aimed to investigate the role of apigenin in DR and elucidate the underlying mechanism.

Methods

Human retinal microvascular endothelial cells (HRMECs) were exposed to high glucose (HG) to establish a DR model. HRMECs were treated with apigenin. Then we knocked down or overexpressed miR-140-5p and HDAC3, and added PI3K/AKT inhibitor LY294002. The expression levels of miR-140-5p, HDAC3, and PTEN were measured using qRT-PCR. Western blot analysis was performed to assess the expression of HDAC3, PTEN, and PI3K/AKT pathway-related proteins. Finally, cell proliferation and migration were evaluated using MTT, wound-healing assay, and transwell assay, while angiogenesis was examined using the tube formation assay.

Results

HG treatment resulted in reduced miR-140-5p expression and overexpression of miR-140-5p suppressed proliferation, migration, and angiogenesis of the HG-induced HRMECs. Apigenin treatment significantly restored the decreased level of miR-140-5p caused by HG treatment and inhibited proliferation, migration, and angiogenesis of the HG-induced HRMECs by upregulating miR-140-5p. Moreover, miR-140-5p targeted HDAC3, and overexpression of miR-140-5p reversed the HG-inducted upregulation of HDAC3 expression. HDAC3 was found to bind to the promoter region of PTEN, inhibiting its expression. Knockdown of HDAC3 suppressed the PI3K/AKT pathway by elevating PTEN expression. Furthermore, apigenin inhibited angiogenesis in DR cell models through the regulating of the miR-140-5p/HDAC3-mediated PTEN/PI3K/AKT pathway.

Conclusions

Apigenin effectively suppressed angiogenesis in HG-induced HRMECs by modulating the miR-140-5p/HDAC3-mediated PTEN/PI3K/AKT pathway. Our study may contribute to the development of novel therapeutic approaches and identification of potential targets for the treatment of DR.
Longitudinal social contact data analysis: insights from 2 years of data collection in Belgium during the COVID-19 pandemic
Authors: Loedy Neilshan , Coletti Pietro , Wambua James , Hermans Lisa , Willem Lander , Jarvis Christopher I. , Wong Kerry L. M. , Edmunds W. John , Robert Alexis , Leclerc Quentin J. , Gimma Amy , Molenberghs Geert , Beutels Philippe , Faes Christel , Hens Niel
Published: July 2023

Background

During the COVID-19 pandemic, the CoMix study, a longitudinal behavioral survey, was designed to monitor social contacts and public awareness in multiple countries, including Belgium. As a longitudinal survey, it is vulnerable to participants’ “survey fatigue”, which may impact inferences.

Methods

A negative binomial generalized additive model for location, scale, and shape (NBI GAMLSS) was adopted to estimate the number of contacts reported between age groups and to deal with under-reporting due to fatigue within the study. The dropout process was analyzed with first-order auto-regressive logistic regression to identify factors that influence dropout. Using the so-called next generation principle, we calculated the effect of under-reporting due to fatigue on estimating the reproduction number.

Results

Fewer contacts were reported as people participated longer in the survey, which suggests under-reporting due to survey fatigue. Participant dropout is significantly affected by household size and age categories, but not significantly affected by the number of contacts reported in any of the two latest waves. This indicates covariate-dependent missing completely at random (MCAR) in the dropout pattern, when missing at random (MAR) is the alternative. However, we cannot rule out more complex mechanisms such as missing not at random (MNAR). Moreover, under-reporting due to fatigue is found to be consistent over time and implies a 15-30% reduction in both the number of contacts and the reproduction number ($$R_0$$R0) ratio between correcting and not correcting for under-reporting. Lastly, we found that correcting for fatigue did not change the pattern of relative incidence between age groups also when considering age-specific heterogeneity in susceptibility and infectivity.

Conclusions

CoMix data highlights the variability of contact patterns across age groups and time, revealing the mechanisms governing the spread/transmission of COVID-19/airborne diseases in the population. Although such longitudinal contact surveys are prone to the under-reporting due to participant fatigue and drop-out, we showed that these factors can be identified and corrected using NBI GAMLSS. This information can be used to improve the design of similar, future surveys.
Multi-morbidity and its association with common cancer diagnoses: a UK Biobank prospective study
Authors: Conroy Megan C. , Reeves Gillian K. , Allen Naomi E.
Published: July 2023

Background

Whilst multi-morbidity is known to be a concern in people with cancer, very little is known about the risk of cancer in multi-morbid patients. This study aims to investigate the risk of being diagnosed with lung, colorectal, breast and prostate cancer associated with multi-morbidity.

Methods

We investigated the association between multi-morbidity and subsequent risk of cancer diagnosis in UK Biobank. Cox models were used to estimate the relative risks of each cancer of interest in multi-morbid participants, using the Cambridge Multimorbidity Score. The extent to which reverse causation, residual confounding and ascertainment bias may have impacted on the findings was robustly investigated.

Results

Of the 436,990 participants included in the study who were cancer-free at baseline, 21.6% (99,965) were multi-morbid (≥ 2 diseases). Over a median follow-up time of 10.9 [IQR 10.0–11.7] years, 9,019 prostate, 7,994 breast, 5,241 colorectal, and 3,591 lung cancers were diagnosed. After exclusion of the first year of follow-up, there was no clear association between multi-morbidity and risk of colorectal, prostate or breast cancer diagnosis. Those with ≥ 4 diseases at recruitment had double the risk of a subsequent lung cancer diagnosis compared to those with no diseases (HR 2.00 [95% CI 1.70–2.35] p for trend < 0.001). These findings were robust to sensitivity analyses aimed at reducing the impact of reverse causation, residual confounding from known cancer risk factors and ascertainment bias.

Conclusions

Individuals with multi-morbidity are at an increased risk of lung cancer diagnosis. While this association did not appear to be due to common sources of bias in observational studies, further research is needed to understand what underlies this association.
Non-pharmacological interventions to manage psychological distress in patients living with cancer: a systematic review
Authors: Paley Carole A. , Boland Jason W. , Santarelli Martina , Murtagh Fliss E. M. , Ziegler Lucy , Chapman Emma J.
Published: July 2023

Background

Psychological distress is common in patients with cancer; interfering with physical and psychological wellbeing, and hindering management of physical symptoms. Our aim was to systematically review published evidence on non-pharmacological interventions for cancer-related psychological distress, at all stages of the disease.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review was registered on PROSPERO (CRD42022311729). Searches were made using eight online databases to identify studies meeting our inclusion criteria.

Data were collected on outcome measures, modes of delivery, resources and evidence of efficacy. A meta-analysis was planned if data allowed. Quality was assessed using the Mixed Methods Appraisal Tool (MMAT).

Results

Fifty-nine studies with 17,628 participants were included. One third of studies included mindfulness, talking or group therapies. Half of all studies reported statistically significant improvements in distress. Statistically significant intervention effects on distress were most prevalent for mindfulness techniques. Four of these mindfulness studies had moderate effect sizes (d = -0.71[95% CI: -1.04, -0.37] p < 0.001) (d = -0.60 [95% CI: -3.44, -0.89] p < 0.001) (d = -0.77 [CI: -0.146, -1.954] p < 0.01) (d = -0.69 [CI: -0.18, -1.19] p = 0.008) and one had a large effect size (d = -1.03 [95% CI: -1.51, -0.54] p < 0.001). Heterogeneity of studies precluded meta-analysis. Study quality was variable and some had a high risk of bias.

Conclusions

The majority of studies using a mindfulness intervention in this review are efficacious at alleviating distress. Mindfulness—including brief, self-administered interventions—merits further investigation, using adequately powered, high-quality studies.

Systematic review registration

This systematic review is registered on PROSPERO, number CRD42022311729.
Exploring different stakeholders’ perspectives on ward rounds in paediatric oncology: a qualitative study
Authors: Berndt Lea P. , Sellin Julia , Mücke Urs , Mücke Martin , Conrad Rupert , Grigull Lorenz
Published: July 2023

Rational/Aims and Objectives

Ward rounds are a core routine for interprofessional communication and clinical care planning: Health care professionals and patients meet regularly and it encourages patients to actively participate. In paediatric oncology, the long treatment process, the serious diagnosis, and involvement of both patients and their parents in shared-decision-making require specific ward round skills. Despite its high value for patient-centred care, a universal definition of ward round is lacking. Little is known about attitudes and expectations of different participants towards a ‘good’ ward round. This study aims to capture experiences and expectations of different stakeholders to better understand ward round needs in paediatric oncology and serve as a basis to improve future ward rounds.

Method

Semi-structured interviews were conducted with patients, parents, nurses and medical doctors of a paediatric oncology ward until theoretical saturation (13 interviews). A standardised qualitative analysis using the phenomenological framework defined by Colaizzi was used to identify important aspects in the interviews.

Results

Three major themes were identified in the interviews: [1] Structure and Organisation; [2] Communication; [3] Education. Further analysis revealed 23 categories and elucidated several opportunities and unmet needs recognized by stakeholders: Ward round functions in comforting families in stressful situations, and relationship building. Interviewees expressed their concerns about missing structures. Families pleaded for smaller ward round teams and layperson language. Health care professionals underscored the lack of ward round training. Paediatric patients stated that ward round scared them without proper explanation. All interviewees emphasized the need for professionalization of the ward round in the setting of paediatric oncology.

Conclusion

This study gives important insights into ward round functions and organisational requirements. It addresses special challenges for ward round participants in paediatric oncology, such as consideration of the emotional aspect of cancer treatment or the limits of shared decision making. Furthermore, this study underscores the great significance of ward rounds in paediatric oncology, with an emphasis on communication and relationship-building. Although performed universally, ward rounds are poorly explored or evaluated. This structured analysis synthesizes important expectations of different WR stakeholders, revealing opportunities of improvement and stressing the need for guidelines, training, and preparation.
Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer
Authors: Ye Feng , Dewanjee Saikat , Li Yuehua , Jha Niraj Kumar , Chen Zhe-Sheng , Kumar Ankush , Vishakha  , Behl Tapan , Jha Saurabh Kumar , Tang Hailin
Published: July 2023

Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.
The impact of policy interventions to promote the uptake of biosimilar medicines in Belgium: a nationwide interrupted time series analysis
Authors: Vandenplas Yannick , Simoens Steven , Van Wilder Philippe , Vulto Arnold G. , Huys Isabelle
Published: July 2023

Background

The Belgian government has taken several measures to increase the uptake of biosimilars in past years. However, no formal evaluation of the impact of these measures has been made yet. This study aimed to investigate the impact of the implemented measures on biosimilar uptake.

Methods

An interrupted time series analysis was performed using an autoregressive integrated moving average (ARIMA) model with the Box-Jenkins method. All data were expressed as defined daily doses (DDD) per month/quarter and obtained from the Belgian National Institute for Health and Disability Insurance (NIHDI). Three molecules were included in the analysis: etanercept (ambulatory), filgrastim (hospital), and epoetin (hospital). A significance level of 5% was used for all analyses.

Results

In the ambulatory care, the effect of a financial prescriber incentive of 2019 was investigated. After this intervention, 44.504 (95% CI −61.61 to −14.812; P < 0.001) fewer etanercept biosimilar DDDs were dispensed monthly than expected in the absence of the intervention. Two interventions were modelled for biosimilars in the hospital setting. The first intervention of 2016 includes prescription targets for biosimilars and monitoring of hospitals on adequate tendering. The second intervention involves an information campaign on biosimilars. After the first intervention, a small decrease in quarterly epoetin biosimilar uptake of 449.820 DDD (95% CI −880.113 to −19.527; P = 0.05) was observed. The second intervention led to a larger increase in quarterly epoetin biosimilar uptake of 2733.692 DDD (95% CI 1648.648–3818.736; P < 0.001). For filgrastim, 1809.833 DDD (95% CI 1354.797–2264.869; P < 0.001) more biosimilars were dispensed immediately after the first intervention and 151.639 DDD (95% CI −203.128 to −100.150; P < 0.001) fewer biosimilars each quarter after the first intervention. An immediate and sustained increase of 700.932 DDD (95% CI 180.536–1221.328; P = 0.016) in quarterly biosimilar volume was observed after the second intervention. All other parameter estimates were not statistically significant.

Conclusions

The results of this study suggest that the impact of past policy interventions to increase the uptake of biosimilars has been variable and limited. A holistic policy framework is required to develop a competitive and sustainable off-patent biologicals market in Belgium.
The use of participatory systems mapping as a research method in the context of non-communicable diseases and risk factors: a scoping review
Authors: van den Akker Amber , Fabbri Alice , Alardah Dima I. , Gilmore Anna B. , Rutter Harry
Published: July 2023

Context

Participatory systems mapping is increasingly used to gain insight into the complex systems surrounding non-communicable diseases (NCDs) and their risk factors.

Objectives

To identify and synthesize studies that used participatory systems mapping in the context of non-communicable diseases.

Design

Scoping review.

Eligibility criteria

Peer-reviewed studies published between 2000 and 2022.

Study selection

Studies that focused on NCDs and/or related risk factors, and included participants at any stage of their system’s mapping process, were included.

Categories for analysis

The main categories for analysis were: (1) problem definition and goal-setting, (2) participant involvement, (3) structure of the mapping process, (4) validation of the systems map, and (5) evaluation of the mapping process.

Results

We identified 57 studies that used participatory systems mapping for a variety of purposes, including to inform or evaluate policies or interventions and to identify potential leverage points within a system. The number of participants ranged from 6 to 590. While policymakers and professionals were the stakeholder groups most often included, some studies described significant added value from including marginalized communities. There was a general lack of formal evaluation in most studies. However, reported benefits related mostly to individual and group learning, whereas limitations described included a lack of concrete actions following from systems mapping exercises.

Conclusions

Based on the findings of this review, we argue that research using participatory systems mapping would benefit from considering three different but intertwined actions: explicitly considering how different participants and the power imbalances between them may influence the participatory process, considering how the results from a systems mapping exercise may effectively inform policy or translate into action, and including and reporting on evaluation and outcomes of the process, wherever possible.
Targeting GBM with an Oncolytic Picornavirus SVV-001 alone and in combination with fractionated Radiation in a Novel Panel of Orthotopic PDX models
Authors: Zhang Huiyuan , Du Yuchen , Qi Lin , Xiao Sophie , Braun Frank K. , Kogiso Mari , Huang Yulun , Huang Frank , Abdallah Aalaa , Suarez Milagros , Karthick Sekar , Ahmed Nabil M. , Salsman Vita S. , Baxter Patricia A. , Su Jack M. , Brat Daniel J. , Hellenbeck Paul L. , Teo Wan-Yee , Patel Akash J. , Li Xiao-Nan
Published: July 2023

Background

Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It’s capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM.

Materials and methods

23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 105 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 1011 viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage.

Results

PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times.

Conclusion

A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo.
PARP1 negatively regulates transcription of BLM through its interaction with HSP90AB1 in prostate cancer
Authors: Huang Mengqiu , Chen Lin , Guo Yingchu , Ruan Yong , Xu Houqiang
Published: July 2023

Background

Prostate cancer (PCa) is a prevalent malignant disease affecting a significant number of males globally. Elevated expression of the Bloom’s syndrome protein (BLM) helicase has emerged as a promising cancer biomarker, being associated with the onset and progression of PCa. Nevertheless, the precise molecular mechanisms governing BLM regulation in PCa remain elusive.

Methods

The expression of BLM in human specimens was analyzed using immnohistochemistry (IHC). A 5′-biotin-labeled DNA probe containing the promoter region of BLM was synthesized to pull down BLM promoter-binding proteins. Functional studies were conducted using a range of assays, including CCK-8, EdU incorporation, clone formation, wound scratch, transwell migration, alkaline comet assay, xenograft mouse model, and H&E staining. Mechanistic studies were carried out using various techniques, including streptavidin-agarose-mediated DNA pull-down, mass spectrometry (MS), immunofluorescence (IF), dual luciferase reporter assay system, RT-qPCR, ChIP-qPCR, co-immunoprecipitation (co-IP), and western blot.

Results

The results revealed significant upregulation of BLM in human PCa tissues, and its overexpression was associated with an unfavorable prognosis in PCa patients. Increased BLM expression showed significant correlations with advanced clinical stage (P = 0.022) and Gleason grade (P = 0.006). In vitro experiments demonstrated that BLM knockdown exerted inhibitory effects on cell proliferation, clone formation, invasion, and migration. Furthermore, PARP1 (poly (ADP-ribose) polymerase 1) was identified as a BLM promoter-binding protein. Further investigations revealed that the downregulation of PARP1 led to increased BLM promoter activity and expression, while the overexpression of PARP1 exerted opposite effects. Through mechanistic studies, we elucidated that the interaction between PARP1 and HSP90AB1 (heat shock protein alpha family class B) enhanced the transcriptional regulation of BLM by counteracting the inhibitory influence of PARP1 on BLM. Furthermore, the combination treatment of olaparib with ML216 demonstrated enhanced inhibitory effects on cell proliferation, clone formation, invasion, and migration. It also induced more severe DNA damage in vitro and exhibited superior inhibitory effects on the proliferation of PC3 xenograft tumors in vivo.

Conclusions

The results of this study underscore the significance of BLM overexpression as a prognostic biomarker for PCa, while also demonstrating the negative regulatory impact of PARP1 on BLM transcription. The concurrent targeting of BLM and PARP1 emerges as a promising therapeutic approach for PCa treatment, holding potential clinical significance.
Identifying a distinct fibrosis subset of NAFLD via molecular profiling and the involvement of profibrotic macrophages
Authors: He Weiwei , Huang Yinxiang , Shi Xiulin , Wang Qingxuan , Wu Menghua , Li Han , Liu Qiuhong , Zhang Xiaofang , Huang Caoxin , Li Xuejun
Published: July 2023

Background

There are emerging studies suggesting that non-alcoholic fatty liver disease (NAFLD) is a heterogeneous disease with multiple etiologies and molecular phenotypes. Fibrosis is the key process in NAFLD progression. In this study, we aimed to explore molecular phenotypes of NAFLD with a particular focus on the fibrosis phenotype and also aimed to explore the changes of macrophage subsets in the fibrosis subset of NAFLD.

Methods

To assess the transcriptomic alterations of key factors in NAFLD and fibrosis progression, we included 14 different transcriptomic datasets of liver tissues. In addition, two single-cell RNA sequencing (scRNA-seq) datasets were included to construct transcriptomic signatures that could represent specific cells. To explore the molecular subsets of fibrosis in NAFLD based on the transcriptomic features, we used a high-quality RNA-sequencing (RNA-seq) dataset of liver tissues from patients with NAFLD. Non-negative matrix factorization (NMF) was used to analyze the molecular subsets of NAFLD based on the gene set variation analysis (GSVA) enrichment scores of key molecule features in liver tissues.

Results

The key transcriptomic signatures on NAFLD including non-alcoholic steatohepatitis (NASH) signature, fibrosis signature, non-alcoholic fatty liver (NAFL) signature, liver aging signature and TGF-β signature were constructed by liver transcriptome datasets. We analyzed two liver scRNA-seq datasets and constructed cell type-specific transcriptomic signatures based on the genes that were highly expressed in each cell subset. We analyzed the molecular subsets of NAFLD by NMF and categorized four main subsets of NAFLD. Cluster 4 subset is mainly characterized by liver fibrosis. Patients with Cluster 4 subset have more advanced liver fibrosis than patients with other subsets, or may have a high risk of liver fibrosis progression. Furthermore, we identified two key monocyte-macrophage subsets which were both significantly correlated with the progression of liver fibrosis in NAFLD patients.

Conclusion

Our study revealed the molecular subtypes of NAFLD by integrating key information from transcriptomic expression profiling and liver microenvironment, and identified a novel and distinct fibrosis subset of NAFLD. The fibrosis subset is significantly correlated with the profibrotic macrophages and M2 macrophage subset. These two liver macrophage subsets may be important players in the progression of liver fibrosis of NAFLD patients.
Dissemination and genome characterization of a human adenovirus F41 in a patient with B-Cell lymphoma
Authors: Fall Amary , Campodónico Victoria L. , Howard Craig , Gallagher Nicholas , Bailey Gabrielle , Kajon Adriana E. , Mostafa Heba H.
Published: July 2023

Adenovirus (HAdV) F41 is a common cause of gastroenteritis and has rarely been reported associated with disseminated disease. In this report, an adult patient with a history of ulcerative colitis, cryptogenic cirrhosis, stage III adenocarcinoma, high-grade diffuse large B-cell lymphoma on chemotherapy was diagnosed with disseminated adenovirus infection. HAdV DNA was quantified in stool, plasma, and urine with viral loads of 7, 4, and 3 log10 copies/mL, respectively. The patient’s course was rapidly progressive and he passed away 2 days after initiation of antiviral therapy. The patient’s infecting virus was characterized as HAdV-F41 by whole genome sequencing.
A rapid and robust leaf ablation method to visualize bundle sheath cells and chloroplasts in C3 and C4 grasses
Authors: Billakurthi Kumari , Hibberd Julian M.
Published: July 2023

Background

It has been proposed that engineering the C4 photosynthetic pathway into C3 crops could significantly increase yield. This goal requires an increase in the chloroplast compartment of bundle sheath cells in C3 species. To facilitate large-scale testing of candidate regulators of chloroplast development in the rice bundle sheath, a simple and robust method to phenotype this tissue in C3 species is required.

Results

We established a leaf ablation method to accelerate phenotyping of rice bundle sheath cells. The bundle sheath cells and chloroplasts were visualized using light and confocal laser microscopy. Bundle sheath cell dimensions, chloroplast area and chloroplast number per cell were measured from the images obtained by confocal laser microscopy. Bundle sheath cell dimensions of maize were also measured and compared with rice. Our data show that bundle sheath width but not length significantly differed between C3 rice and C4 maize. Comparison of paradermal versus transverse bundle sheath cell width indicated that bundle sheath cells were intact after leaf ablation. Moreover, comparisons of planar chloroplast areas and chloroplast numbers per bundle sheath cell between wild-type and transgenic rice lines expressing the maize GOLDEN-2 (ZmG2) showed that the leaf ablation method allowed differences in chloroplast parameters to be detected.

Conclusions

Leaf ablation is a simple approach to accessing bundle sheath cell files in C3 species. We show that this method is suitable for obtaining parameters associated with bundle sheath cell size, chloroplast area and chloroplast number per cell.
Risk factors for postoperative myocardial injury-related cardiogenic shock in patients undergoing cardiac surgery
Authors: Cheng Xiao-Feng , Wang Kuo , Zhang Hai-Tao , Zhang He , Jiang Xin-Yi , Lu Li-Chong , Chen Cheng , Cheng Yong-Qing , Wang Dong-Jin , Li Kai
Published: July 2023

Background

Myocardial injury-related cardiogenic shock (MICS) is significantly associated with poor outcomes in patients after cardiac surgery. Herein, we aimed to investigate the risk factor for postoperative MICS.

Methods

We performed a case-control study on 792 patients undergoing cardiac surgery from 2016 to 2019, including 172 patients with postoperative MICS and 620 age- and sex-matched controls. MICS was defined as composite criteria: a cardiac index of < 2.2 L/m2/min, arterial lactate levels of > 5 mmol/L at the end of the surgery, a vasoactive-inotropic score of > 40 at the end of the surgery, and a cardiac troponin T (cTnT) level of > 0.8 µg/L on postoperative day 1 (POD1) with an increase of > 10% on POD 2.

Results

A total of 4671 patients who underwent cardiac surgery in our hospital between 2016 and 2019 were included; of these, 172 (3.68%) had MICS and the remaining 4499 did not. For investigating the risk factors, we selected 620 age- and sex-matched controls. In the univariate analysis, MICS was significantly associated with death (P < 0.05), extracorporeal membrane oxygenation (P < 0.05), continuous renal replacement therapy (P < 0.01), and ventricular arrhythmias (P < 0.05). Multivariable logistic regression analysis revealed that diabetes mellitus (OR:8.11, 95% CI: 3.52–18.66, P < 0.05) and a cardiopulmonary bypass (CPB) time of > 2 h (OR: 3.16, 95% CI: 1.94–5.15, P < 0.05) were associated with postoperative MICS. Moreover, long-time administration of preoperative calcium channel blocker (CCB) was associated with a less incidence of MICS (OR: 0.11, 95% CI: 0.05–0.27, P < 0.05).

Conclusions

Postoperative MICS is significantly associated with poor outcomes. Diabetes mellitus and long CPB time are associated with MICS. Preoperative CCB administration is associated with less incidence of MICS.
Association of dietary intake and cervical cancer: a prevention strategy
Authors: Nazari Elham , Hasanzadeh Malihe , Rezvani Reza , Rejali Marzieh , Badpeyma Mohaddeseh , Delaram Zeinab , Mousavi-Seresht Leila , Akbari Mahdieh , Khazaei Majid , Ferns Gordon A. , Avan Amir
Published: July 2023

Introduction

Cervical cancer is one of lethal cancers in women. As a global concern, identifying important factors of cancer is a useful strategy for prevention. Due to the role of diet/nutrition factors for cancer, the purpose of our study was to determine the impact of 150 nutrition/vitamin factors and 50 non-nutritional factor in cervical cancer and phase.

Methods

Population samples of 2088 healthy subjects and patients with cervical cancer were investigated. 200 factors such as vitamin E, B1, B6, fruits, HPV, and age were gathered. Deep learning, Decision tree, and correlation matrix were used for modeling and identifying important factors. SPSS 26, R4.0.3, and Rapid miner were utilized for implementation.

Results

Our findings indicated that zinc, Iron, Niacin, Potassium, Phosphorous, and Cooper have a beneficial impact in reducing the risk of cervical cancer and progression of phase in Iranian women, as well as Salt, snacks and milk Were identified as high-risk food factors (P value < 0.05 and coefficient correlation > 0.6). Also, alcohol, and sex patient with two groups, HPV positive have an impact on cervical cancer incidence. Phosphorus and selenium in the Micronutrients category (R2 = 0.85, AUC = 0.993) and polyunsaturated fatty acid and salt in the Macronutrients category and other categories of nutrients were identified as the most effective factors in cervical cancer using deep learning (R2 = 0.93, AUC = 0.999).

Conclusions

A diet and rich nutrition can be helpful for the prevention of cervix cancer and may reduce the risk of disease. Additional research is necessary for different countries.
Clinical outcomes of surgical treatment for Copenhagen syndrome: a case series
Authors: Safaei Saeid , Azimi Parisa , Yazdanian Taravat
Published: July 2023

Background

Copenhagen syndrome (CS) is a rare disorder mostly observed in adolescent. The onset of the disease, with a progressive anterior vertebral ankylosis in the thoracic and/or lumbar areas often clinically revealed by thoracolumbar kyphosis. We report a series of three patients of CS with good outcome.

Case presentation

The mean age of patients were 14.0 (SD = 3.6) years at admission time. Patients underwent clinical and radiological examination (MRI, CT scan, and bone scan) before surgery and revealed Copenhagen syndrome. Case 2 received conservative treatment braces and regular follow-up. Finally, all patients were treated according to their clinical conditions through a combined surgical approach such as pedicle subtraction osteotomy (PSO), ponte osteotomy, hook, pedicular screw insertion, and fusion. In postoperative follow-up, the deformity correction was achieved with proper alignment in all the cases.

Conclusion

The treatment of CS with PSO plus ponte osteotomy seems to result in an excellent surgical procedure and outcome for our patients based on deformity severity. Bone scan imaging could be considered as an aid to differential diagnosis, which is an effective method.
File processing security detection in multi-cloud environments: a process mining approach
Authors: Zhang Xiaolu , Cui Lei , Shen Wuqiang , Zeng Jijun , Du Li , He Haoyang , Cheng Long
Published: July 2023

Cloud computing has gained popularity in recent years, but with its rise comes concerns about data security. Unauthorized access and attacks on cloud-based data, applications, and infrastructure are major challenges that must be addressed. While machine learning algorithms have improved intrusion detection systems in cloud data security, they often fail to consider the entire life cycle of file processing, making it difficult to detect certain issues, especially insider attacks. To address these limitations, this paper proposes a novel approach to analyzing data file processing in multi-cloud environments using process mining. By generating a complete file processing event log from a multi-cloud environment, the proposed approach enables detection from both control flow and performance perspectives, providing a deeper understanding of the underlying file processing in its full life cycle. Through our case study, we demonstrate the power and capabilities of process mining for file security detection and showcase its ability to provide further insights into file security in multi-cloud environments.
Semi-automated quantification of tricuspid valve dynamics and structure in tetralogy of Fallot and hypoplastic left heart syndrome using three-dimensional echocardiography
Authors: Jani Vivek , Li Ling , Craft Mary , Veronesi Federico , Khoo Nee , Danford David , Muraru Denisa , Kutty Shelby
Published: July 2023

Anomalies of the tricuspid valve (TV) are associated with worsened prognosis in congenital heart disease (CHD). Here, we present a descriptive study examining changes in TV morphology in two CHD conditions—repaired tetralogy of Fallot (rTOF) and hypoplastic left heart syndrome (HLSH), using three-dimensional echocardiography. Full volume acquisitions of the TV and right ventricle (RV) were performed from an RV-focused apical view using ECG gating over 2–5 consecutive cardiac cycles using 3D echocardiography, from which TV annulus and leaflet parameters were quantified. A total of 40 rTOF patients (age 14 ± 9.8 years), 40 HLHS patients (age1.0 ± 1.5 years) and 80 age and gender matched controls were included. Among leaflet parameters, antero-posterior and posterior-septal TV coaptation heights were smaller in rTOF (p < 0.001) vs. control. Conversely, only the short-axis TV height was different in HLHS vs. controls (HLHS 1.6 ± 0.4 cm vs. control 1.4 ± 0.3 cm). TV leaflet parameters tended to be larger in HLHS, while leaflet coaptation distances were similar between groups. We demonstrate that 3D echocardiography for assessment of the TV is feasible in rTOF and HLHS patients and identifies unique differences in TV morphology. Future studies should clarify the clinical significance of TV morphology in these patient populations.
Pediatric Precision Medicine at the National Cancer Center Japan: Prospective Genomic Study of Pediatric Patients with Cancer as Part of the TOP-GEAR Project
Authors: Tao Kayoko , Yamazaki Fumito , Kubo Takashi , Sunami Kuniko , Kumamoto Tadashi , Arakawa Ayumu , Sugiyama Masanaka , Watanabe Yuko , Nakajima Miho , Shirakawa Nami , Tanimura Kazuki , Koyama Takafumi , Hirata Makoto , Sudo Kazuki , Tanabe Noriko , Watanabe Tomoko , Yoshida Teruhiko , Kitami Mayuko , Yoshida Akihiko , Yatabe Yasushi , Nakano Yoshiko , Ohira Miki , Kamijo Takehiko , Nakazawa Atsuko , Kato Motohiro , Ichimura Koichi , Kohno Takashi , Yamamoto Noboru , Hishiki Tomoro , Ichikawa Hitoshi , Ogawa Chitose
Published: July 2023

PURPOSE

This single-center, prospective molecular profiling study characterizes genomic alterations and identifies therapeutic targets in advanced pediatric solid tumors.

METHODS

As part of the TOP-GEAR (Trial of Onco-Panel for Gene profiling to Estimate both Adverse events and Response by cancer treatment) project at the National Cancer Center (NCC), Japan, we enrolled pediatric patients with a refractory or recurrent disease during August 2016-December 2021 and performed genomic analysis of matched tumors and blood using originally developed cancer gene panels, NCC Oncopanel (ver. 4.0) and NCC Oncopanel Ped (ver. 1.0).

RESULTS

Of 142 patients (age, 1-28 years) enrolled, 128 (90%) were evaluable for genomic analysis; 76 (59%) patients harbored at least one reportable somatic or germline alteration. The tumor samples were collected during the initial diagnosis in 65 (51%) patients, after treatment initiation in 11 (9%) patients, and upon either disease progression or relapse in 52 (41%) patients. The leading altered gene was TP53, followed by MYCN, MYC, CDKN2A, and CDK4. The commonly affected molecular processes were transcription, cell-cycle regulation, epigenetic modifiers, and RAS/mitogen-activated protein kinase signaling. Twelve (9%) patients carried pathogenic germline variants in cancer-predisposing genes. Potentially actionable findings were identified in 40 (31%) patients; to date, 13 (10%) patients have received the recommended therapy on the basis of their genomic profiles. Although four patients had access to targeted therapy through clinical trials, the agents were used in nine patients in an off-label setting.

CONCLUSION

The implementation of genomic medicine has furthered our understanding of tumor biology and provided new therapeutic strategies. However, the paucity of proposed agents limits the full potential of actionability, emphasizing the significance of facilitating access to targeted cancer therapies.
Hydra morphogenesis as phase transition dynamics
Authors: Agam Oded , Braun Erez
Published: July 2023

We utilize whole-body Hydra regeneration from a small tissue segment to develop a physics framework for animal morphogenesis. Introducing experimental controls over this process, an external electric field and a drug that blocks gap junctions, allows us to characterize the essential step in the morphological transition —from a spherical shape to an elongated spheroid. We find that spatial fluctuations of the Ca2+ distribution in the Hydra's tissue drive this transition and construct a field-theoretic model that explains the morphological transition as a first-order–like phase transition resulting from the coupling of the Ca2+ field and the tissue's local curvature. Various predictions of this model are verified experimentally.
Epigenetic Dysregulation in Endometriosis: Implications for Pathophysiology and Therapeutics
Authors: Marquardt Ryan M , Tran Dinh Nam , Lessey Bruce A , Rahman Md Saidur , Jeong Jae-Wook
Published: July 2023

Endometriosis is a prevalent gynecological condition associated with pelvic pain and infertility. Despite more than a century of research, the etiology of endometriosis still eludes scientific consensus. This lack of clarity has resulted in suboptimal prevention, diagnosis, and treatment options. Evidence of genetic contributors to endometriosis is interesting but limited; however, significant progress has been made in recent years in identifying an epigenetic role in the pathogenesis of endometriosis through clinical studies, in vitro cell culture experiments, and in vivo animal models. The predominant findings include endometriosis-related differential expression of DNA methyltransferases and demethylases, histone deacetylases, methyltransferases, and demethylases, and regulators of chromatin architecture. There is also an emerging role for miRNAs in controlling epigenetic regulators in the endometrium and endometriosis. Changes in these epigenetic regulators result in differential chromatin organization and DNA methylation, with consequences for gene expression independent of a genetic sequence. Epigenetically altered expression of genes related to steroid hormone production and signaling, immune regulation, and endometrial cell identity and function have all been identified and appear to play into the pathophysiological mechanisms of endometriosis and resulting infertility. This review summarizes and critically discusses early seminal findings, the ever-growing recent evidence of epigenetic contributions to the pathophysiology of endometriosis, and implications for proposed epigenetically targeted therapeutics.