bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete mitochondrial genome of Melia azedarach L., reveals two conformations generated by the repeat sequence mediated recombination
Authors: Hao Zhigang , Zhang Zhiping , Jiang Juan , Pan Lei , Zhang Jinan , Cui Xiufen , Li Yingbin , Li Jianqiang , Luo Laixin
Published: July 2024

Melia azedarach is a species of enormous value of pharmaceutical industries. Although the chloroplast genome of M. azedarach has been explored, the information of mitochondrial genome (Mt genome) remains surprisingly limited. In this study, we used a hybrid assembly strategy of BGI short-reads and Nanopore long-reads to assemble the Mt genome of M. azedarach. The Mt genome of M. azedarach is characterized by two circular chromosomes with 350,142 bp and 290,387 bp in length, respectively, which encodes 35 protein-coding genes (PCGs), 23 tRNA genes, and 3 rRNA genes. A pair of direct repeats (R1 and R2) were associated with genome recombination, resulting in two conformations based on the Sanger sequencing and Oxford Nanopore sequencing. Comparative analysis identified 19 homologous fragments between Mt and chloroplast genome, with the longest fragment of 12,142 bp. The phylogenetic analysis based on PCGs were consist with the latest classification of the Angiosperm Phylogeny Group. Notably, a total of 356 potential RNA editing sites were predicted based on 35 PCGs, and the editing events lead to the formation of the stop codon in the rps10 gene and the start codons in the nad4L and atp9 genes, which were verified by PCR amplification and Sanger sequencing. Taken together, the exploration of M. azedarach gap-free Mt genome provides a new insight into the evolution research and complex mitogenome architecture.
A gibberellin-assisted study of the transcriptional and hormonal changes occurring at floral transition in peach buds (Prunus persica L. Batsch)
Authors: Girardi Francesco , Canton Monica , Populin Francesca , Tijero Verónica , Bettio Giorgia , Munné-Bosch Sergi , Rasori Angela , Cardillo Valerio , Costa Guglielmo , Botton Alessandro
Published: July 2024

Background

Flower load in peach is an important determinant of final fruit quality and is subjected to cost-effective agronomical practices, such as the thinning, to finely balance the sink-source relationships within the tree and drive the optimal amount of assimilates to the fruits. Floral transition in peach buds occurs as a result of the integration of specific environmental signals, such as light and temperature, into the endogenous pathways that induce the meristem to pass from vegetative to reproductive growth. The cross talk and integration of the different players, such as the genes and the hormones, are still partially unknown. In the present research, transcriptomics and hormone profiling were applied on bud samples at different developmental stages. A gibberellin treatment was used as a tool to identify the different phases of floral transition and characterize the bud sensitivity to gibberellins in terms of inhibition of floral transition.

Results

Treatments with gibberellins showed different efficacies and pointed out a timeframe of maximum inhibition of floral transition in peach buds. Contextually, APETALA1 gene expression was shown to be a reliable marker of gibberellin efficacy in controlling this process. RNA-Seq transcriptomic analyses allowed to identify specific genes dealing with ROS, cell cycle, T6P, floral induction control and other processes, which are correlated with the bud sensitivity to gibberellins and possibly involved in bud development during its transition to the reproductive stage. Transcriptomic data integrated with the quantification of the main bioactive hormones in the bud allowed to identify the main hormonal regulators of floral transition in peach, with a pivotal role played by endogenous gibberellins and cytokinins.

Conclusions

The peach bud undergoes different levels of receptivity to gibberellin inhibition. The stage with maximum responsiveness corresponded to a transcriptional and hormonal crossroad, involving both flowering inhibitors and inductors. Endogenous gibberellin levels increased only at the latest developmental stage, when floral transition was already partially achieved, and the bud was less sensitive to exogenous treatments. A physiological model summarizes the main findings and suggests new research ideas to improve our knowledge about floral transition in peach.
Association between preoperative persistent hyperglycemia and postoperative delirium in geriatric hip fracture patients
Authors: Wang Wei , Zhang Yingqi , Yao Wei , Tang Wanyun , Li Yuhao , Sun Hongbo , Ding Wenbo
Published: July 2024

Background

The management of preoperative blood glucose levels in reducing the incidence of postoperative delirium (POD) remains controversial. This study aims to investigate the impact of preoperative persistent hyperglycemia on POD in geriatric patients with hip fractures.

Methods

This retrospective cohort study analyzed medical records of patients who underwent hip fracture surgery at a tertiary medical institution between January 2013 and November 2023. Patients were categorized based on preoperative hyperglycemia (hyperglycemia defined as ≥ 6.1mmol/L), clinical classification of hyperglycemia, and percentile thresholds. Multivariate logistic regression and propensity score matching analysis (PSM) were employed to assess the association between different levels of preoperative glucose and POD. Subgroup analysis was conducted to explore potential interactions.

Results

A total of 1440 patients were included in this study, with an incidence rate of POD at 19.1% (275/1440). Utilizing multiple logistic analysis, we found that patients with hyperglycemia had a 1.65-fold increased risk of experiencing POD compared to those with normal preoperative glucose levels (95% CI: 1.17–2.32). Moreover, a significant upward trend was discerned in both the strength of association and the predicted probability of POD with higher preoperative glucose levels. PSM did not alter this trend, even after meticulous adjustments for potential confounding factors. Additionally, when treating preoperative glucose levels as a continuous variable, we observed a 6% increase in the risk of POD (95% CI: 1-12%) with each 1mmol/L elevation in preoperative glucose levels.

Conclusions

There exists a clear linear dose-response relationship between preoperative blood glucose levels and the risk of POD. Higher preoperative hyperglycemia was associated with a greater risk of POD.

Clinical trial number

NCT06473324.
Case presentation: a severe case of cobalamin c deficiency presenting with nephrotic syndrome, malignant hypertension and hemolytic anemia
Authors: Akar Halil Tuna , Yıldız Harun , Öztürk Zeynelabidin , Karakaya Deniz , Sezer Abdullah , Olgaç Asburçe
Published: July 2024

Background

The etiology of nephrotic syndrome can vary, with underlying metabolic diseases being a potential factor. Cobalamin C (cblC) defect is an autosomal recessive inborn error of metabolism caused by mutations in the MMACHC gene, resulting in impaired vitamin B12 processing. While cblC defect typically manifests with hematological and neurological symptoms, renal involvement is increasingly recognized but remains rare.

Case Presentation

We describe a 7-month-old male patient presenting with fatigue and edema. His initial laboratory findings showed anemia, thrombocytopenia, hypoalbuminemia and proteinuria. Further examinations reveals hemolysis in peripheral blood smear. During his follow up respiratory distress due to pleural effusion in the right hemithorax was noticed. And fluid leakage to the third spaces supported a diagnosis of nephrotic syndrome. The patient’s condition deteriorated, leading to intensive care admission due to, hypertensive crisis, and respiratory distress. High total plasma homocysteine and low methionine levels raised suspicion of cobalamin metabolism disorders. Genetic testing confirmed biallelic MMACHC gene mutations, establishing the diagnosis of cblC defect. Treatment with hydroxycobalamin, folic acid, and betaine led to remarkable clinical improvement.

Discussion/Conclusion

This case underscores the significance of recognizing metabolic disorders like cblC defect in atypical presentations of nephrotic syndrome. Early diagnosis and comprehensive management are vital to prevent irreversible renal damage. While cblC defects are more commonly associated with atypical hemolytic uremic syndrome, this case highlights the importance of considering cobalamin defects in the differential diagnosis of nephrotic syndrome, especially when associated with accompanying findings such as hemolysis. Our case, which has one of the highest homocysteine levels reported in the literature, emphasizes this situation again.
A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC)
Authors: Wigg Alan , Tibballs Jonathan , Woodman Richard , Stuart Katherine , Le Hien , Roberts Stuart K. , Olynyk John K. , Strasser Simone I. , Wallace Michael , Martin Jarad , Haworth Annette , Hardcastle Nicholas , Loo Kee Fong , Tang Colin , Lee Yoo Young , Chu Julie , De Abreu Lourenco Richard , Koukourou Adam , De Boo Diederick , McLean Kate , Buck Jackie , Sawhney Rohit , Nicoll Amanda , Dev Anouk , Wood Marnie , Braund Alicia , Weltman Martin , Khor Richard , Levy Miriam , Wang Tim , Potter Michael , Haridy James , Raj Ashok , Duncan Oliver , Zekry Amany , Collier Natalie , O’Beirne James , Holliday Catherine , Trada Yuvnik , Tronidjaja Jaw , George Jacob , Pryor David
Published: July 2024

Background

Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking.

Methods

Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses.

Discussion

The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research.

Trial registration

anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.
Investigating depression, anxiety, perceived stress and resilience in fathers faced with their spouse’s abortion in Iran: a longitudinal study
Authors: Jafari Seyede Zahra , Hajifoghaha Mahboubeh , Azima Sara , Maghami Parvin Ghaem , Panahi Zahra Yazdan
Published: July 2024

Background

Abortion is a stressful event that can often affect the mental health of both parents. It seems that resilient people can adapt to stressful situations. The mental health of fathers plays an important role in improving the mental health of the family, but few studies have been conducted in this regard. Therefore, this study aimed to investigate depression, anxiety, perceived stress and resilience of fathers faced with their spouse’s abortion.

Methods

This longitudinal study was conducted on 125 spouses of women hospitalized in the post-partum department of Shiraz hospitals in 2023. Data collection tools included questionnaires of demographic and fertility characteristics, hospital depression and anxiety (HADS), Cohen’s perceived stress, and Connor’s resilience. The data were analyzed through Spss24 software using Friedman’s tests and post hoc tests, Adjusted Bonferroni, Kruskal-Wallis and Mann-Whitney tests.

Results

The mean age of the fathers was 35.02 ± 6.22. The scores of the father’s anxiety, depression, and perceived stress from 24 h to 12 weeks after abortion were decreased significantly. However, their resilience score increased significantly. Also, there was a significant relationship between the fathers’ age, education, job, duration of marriage, type of abortion, number and history of abortion, unwanted pregnancy, number of children and economic status with the mean score of anxiety, depression, perceived stress, and resilience in fathers over time.

Conclusion

This research pointed out the effect of abortion on depression, anxiety, and perceived stress in fathers; also, resilience as a coping factor could affect these disorders and improve the fathers’ mental health. Therefore, screening and managing mental disorders in them are important to improve family health.
Exploring the course of functional somatic symptoms (FSS) from pre- to late adolescence and associated internalizing psychopathology – an observational cohort-study
Authors: Münker Lina , Rimvall Martin Køster , Frostholm Lisbeth , Ørnbøl Eva , Wellnitz Kaare Bro , Jeppesen Pia , Maria Rosmalen Judith Gerarda , Rask Charlotte Ulrikka
Published: July 2024

Background

Functional somatic symptoms (FSS), which commonly cannot be attributed to well-defined organic pathology, often co-occur with internalizing psychopathology and fluctuate throughout different life stages. We examined FSS courses throughout adolescence, and the association between preadolescent FSS, FSS severity and internalizing psychopathology at late adolescence.

Methods

Data from the Copenhagen Child Cohort (CCC2000) were utilized from assessments at ages 11–12 years (preadolescence; T0) and 16–17 years (late adolescence; T1). Self-report questionnaire and interview data on FSS, internalizing psychopathology, chronic medical conditions, and sociodemographic data from Danish national registers were available for 1285 youths. FSS courses were categorized into persistent (high FSS at T0 & T1), remission (high FSS only at T0), incident (high FSS only at T1) or no FSS (no FSS at T0 & T1). Multiple linear and multinomial logistic regressions were conducted to investigate the FSS/psychopathology association.

Results

1.8% of adolescents fell into the persistent FSS course group throughout adolescence. Higher preadolescent FSS predicted FSS (b = 0.07, p < .001), anxiety (b = 0.05, p < .001) and depression (b = 0.06, p < .001) at age 16/17, even after controlling for sex, parental education, a chronic medical condition and internalizing psychopathology in preadolescence. Persistent, incident, and remittent FSS courses were associated with significantly higher mean levels of anxiety and depression compared to the reference group (no FSS).

Conclusions

FSS during pre- and late adolescence might increase and co-occur with anxiety and depression throughout adolescence, potentially due to shared underlying risk factors and processes.
The interplay between diabetes Mellitus and soft tissue infections in general surgical patients
Authors: Cheng Stephanie , Poh Benjamin Rui-Min , Tay Vivyan Wei Yen , Lee Piea Peng , Mathur Sachin
Published: July 2024

Background

Diabetes mellitus (DM) is a worldwide pandemic affecting 500 million people. It is known to be associated with increased susceptibility to soft tissue infections (STI). Despite being a major public health burden, the literature relating the effects of DM and the presentation, severity and healing of STIs in general surgical patients remain limited.

Method

We conducted a retrospective review of all patients admitted with STI in a tertiary teaching hospital over a 12-month period. Patient demographics and surgical outcomes were collected and analysed.

Results

During the study period, 1059 patients were admitted for STIs (88% required surgery). DM was an independent risk factor for LOS. Diabetic patients presented with higher body-mass index (28 vs. 26), larger abscess size (24 vs. 14 cm2) and had a longer length of stay (4.4 days vs. 2.9 days). They also underwent a higher proportion of wide debridement and application of negative pressure wound therapy (42% vs. 35%). More diabetic patients underwent subsequent re-operation within the same sitting (8 vs. 4). Diabetic patients were two times more likely to present with carbuncles (p = 0.02).

Conclusion

The incidence of STIs among DM patients represent a significant disease burden, surgeons should consider intensive patient counselling and partnering with primary care providers in order to help reduce the incidence of future STI admissions based upon lifestyle modification and glucose control.
Optimization of vision transformer-based detection of lung diseases from chest X-ray images
Authors: Ko Jinsol , Park Soyeon , Woo Hyun Goo
Published: July 2024

Background

Recent advances in Vision Transformer (ViT)-based deep learning have significantly improved the accuracy of lung disease prediction from chest X-ray images. However, limited research exists on comparing the effectiveness of different optimizers for lung disease prediction within ViT models. This study aims to systematically evaluate and compare the performance of various optimization methods for ViT-based models in predicting lung diseases from chest X-ray images.

Methods

This study utilized a chest X-ray image dataset comprising 19,003 images containing both normal cases and six lung diseases: COVID-19, Viral Pneumonia, Bacterial Pneumonia, Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and Tuberculosis. Each ViT model (ViT, FastViT, and CrossViT) was individually trained with each optimization method (Adam, AdamW, NAdam, RAdam, SGDW, and Momentum) to assess their performance in lung disease prediction.

Results

When tested with ViT on the dataset with balanced-sample sized classes, RAdam demonstrated superior accuracy compared to other optimizers, achieving 95.87%. In the dataset with imbalanced sample size, FastViT with NAdam achieved the best performance with an accuracy of 97.63%.

Conclusions

We provide comprehensive optimization strategies for developing ViT-based model architectures, which can enhance the performance of these models for lung disease prediction from chest X-ray images.
The cost of delivering COVID-19 vaccines in Vietnam
Authors: Nguyen Van Minh , Moi Flavia , Boonstoppel Laura , Duong Hong Thi , Vien Chien Chinh , Van Hoang Minh
Published: July 2024

Background

The COVID-19 pandemic affected hundreds of millions of people and lives, and vaccination was the safest and most effective strategy to prevent and mitigate the burden of this disease. The implementation of COVID-19 vaccination in Vietnam in 2021 was unprecedentedly challenging in scale and complexity, yet economic evidence on the cost of delivery vaccines thought the program was lacking.

Methods

This retrospective costing study utilized a bottom-up, ingredient-based approach to estimate the cost of delivering COVID-19 vaccines in Vietnam in 2021, from a payer perspective. The study included 38 study sites across all administrative and implementation level, including three geographic areas and two delivery strategies, in two provinces, Hanoi and Dak Lak. The study findings were complemented with qualitative interviews with health staff and stakeholders.

Results

The economic cost to deliver one COVID-19 vaccine dose was $1.73, mostly comprised of opportunity costs ($1.14 per dose) which were driven by labor costs ($1.12 per dose). The delivery cost in urban areas was the highest ($2.02), followed by peri-urban areas ($1.45) and remote areas ($1.37). Delivery costs were higher at temporary sites ($1.78) when compared to facility-based delivery ($1.63). Comparing low-volume and high-volume periods showed that the delivery cost decreased significantly as volume increased, from $5.24 per dose to $1.65 per dose.

Conclusions

The study estimates the cost of delivering COVID-19 vaccines in Vietnam in 2021. Enabling factors and challenges during the implementation of the program were explored. Study limitations may lead to underestimation of results and reduce generalizability.
Mining the interpretable prognostic features from pathological image of intrahepatic cholangiocarcinoma using multi-modal deep learning
Authors: Ding Guang-Yu , Tan Wei-Min , Lin You-Pei , Ling Yu , Huang Wen , Zhang Shu , Shi Jie-Yi , Luo Rong-Kui , Ji Yuan , Wang Xiao-Ying , Zhou Jian , Fan Jia , Cai Mu-Yan , Yan Bo , Gao Qiang
Published: July 2024

Background

The advances in deep learning-based pathological image analysis have invoked tremendous insights into cancer prognostication. Still, lack of interpretability remains a significant barrier to clinical application.

Methods

We established an integrative prognostic neural network for intrahepatic cholangiocarcinoma (iCCA), towards a comprehensive evaluation of both architectural and fine-grained information from whole-slide images. Then, leveraging on multi-modal data, we conducted extensive interrogative approaches to the models, to extract and visualize the morphological features that most correlated with clinical outcome and underlying molecular alterations.

Results

The models were developed and optimized on 373 iCCA patients from our center and demonstrated consistent accuracy and robustness on both internal (n = 213) and external (n = 168) cohorts. The occlusion sensitivity map revealed that the distribution of tertiary lymphoid structures, the geometric traits of the invasive margin, the relative composition of tumor parenchyma and stroma, the extent of necrosis, the presence of the disseminated foci, and the tumor-adjacent micro-vessels were the determining architectural features that impacted on prognosis. Quantifiable morphological vector extracted by CellProfiler demonstrated that tumor nuclei from high-risk patients exhibited significant larger size, more distorted shape, with less prominent nuclear envelope and textural contrast. The multi-omics data (n = 187) further revealed key molecular alterations left morphological imprints that could be attended by the network, including glycolysis, hypoxia, apical junction, mTORC1 signaling, and immune infiltration.

Conclusions

We proposed an interpretable deep-learning framework to gain insights into the biological behavior of iCCA. Most of the significant morphological prognosticators perceived by the network are comprehensible to human minds.

Graphical Abstract
Investigation of Babesia spp. and Theileria spp. in ticks from Western China and identification of a novel genotype of Babesia caballi
Authors: Zhang Bing , Zhang Niuniu , Gao Chunyan , Liu Mengyun , Jie Runda , Lu Miao , Ma Yanran , Meng Fanming , Huang Jingjing , Wang Xiao , Li Kun
Published: July 2024

Babesia spp. and Theileria spp. are tick-borne protozoan parasites with veterinary importance. In China, epidemiological and genetic investigations on many Babesia and Theileria species were still absent in many areas and many tick species. From Aug 2021 to May 2023, 645 ticks were collected from the body surface of domestic animals (camels, goats, sheep, and cattle) using tweezers in seven counties in three provinces including Xinjiang (Qitai, Mulei, Hutubi, and Shihezi counties), Chongqing (Youyang and Yunyang counties), and Qinghai (Huangzhong county). Three tick species were morphologically and molecularly identified (334 Hyalomma asiaticum from Xinjiang, 245 Rhipicephalus microplus from Chongqing, and 66 Haemaphysalis qinghaiensis from Qinghai). A total of three Babesia species and two Theileria species were detected targeting the 18S gene. The COI and cytb sequences were also recovered from Babesia strains for further identification. In R. microplus from Chongqing, Babesia bigemina, the agent of bovine babesiosis, was detected. Notably, in H. asiaticum ticks from Xinjiang, a putative novel genotype of Babesia caballi was identified (0.90%, 3/334), whose COI and cytb genes have as low as 85.82% and 90.64–90.91% nucleotide identities to currently available sequences. It is noteworthy whether the sequence differences of its cytb contribute to the drug resistance of this variant due to the involvement of cytb in the drug resistance of Babesia. In addition, Theileria orientalis and Theileria annulata were detected in R. microplus from Chongqing (12.20%, 31/245) and H. asiaticum from Xinjiang (1.50%, 5/334), respectively. These results suggest that these protozoan parasites may be circulating in domestic animals in these areas. The pathogenicity of the novel genotype of B. caballi also warrants further investigation.
Age and sex differences in the effects of short- and long-term exposure to air pollution on endothelial dysfunction
Authors: Zhang Haoyu , Yang Jing , Zhang Yinghua , Xiao Keling , Wang Yang , Si Jin , Li Yan , Sun Lijie , Sun Jinghao , Yi Ming , Chu Xi , Li Jing
Published: July 2024

Background

The effects of air pollution on endothelial function remain unclear across populations. We aimed to use brachial artery flow-mediated dilatation (FMD) to identify demographic differences in the effects of air pollution exposure on endothelial dysfunction.

Methods

We measured FMD in 850 participants from October 2016 to January 2020. Location-specific concentrations of fine particulate matter < 2.5 μm aerodynamic diameter (PM2.5), inhalable particulate matter < 10 μm aerodynamic diameter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) measured by fixed ambient air monitoring stations were collected for short- and long-term exposure assessment. Multiple linear regression models and restricted cubic splines were used to assess the associations before and after stratification by age and sex.

Results

This study eventually included 828 participants [551 (66.5%) younger than 65 years and 553 (66.8%) men]. Each 10 µg/m3 increase in 7-day exposure to PM2.5 and PM10 was significantly linearly associated with a 0.07% (β = -0.07, 95% CI: -0.13 to -0.004) and 0.05% (β = -0.05, 95% CI: -0.10 to -0.004) decrease in FMD in the fully adjusted model. After full adjustment, long-term exposure to all air pollutants was significantly associated with impaired FMD. Each 10 µg/m3 increase in long-term exposure to PM2.5 and PM10 was significantly associated with a -0.18% (95% CI: -0.34 to -0.03) and − 0.23% (95% CI: -0.40 to -0.06) change in FMD, respectively. After stratification, the associations of lower FMD with long-term exposure to PM2.5, PM10, SO2, NO2, and CO significantly persisted in men and participants younger than 65 years instead of women or older participants. For short-term exposure, we observed differences consistent with long-term exposure and a stronger effect of 7-day exposure to SO2 in men due to a significant interaction effect.

Conclusion

Short- and long-term exposure to different air pollutants are strongly associated with decreased endothelial function, and susceptibility to air pollution varies significantly with age and sex.
DNA methylation landscape in pregnancy-induced hypertension: progress and challenges
Authors: Deng Fengying , Lei Jiahui , Qiu Junlan , Zhao Chenxuan , Wang Xietong , Li Min , Sun Miao , Zhang Meihua , Gao Qinqin
Published: July 2024

Gestational hypertension (PIH), especially pre-eclampsia (PE), is a common complication of pregnancy. This condition poses significant risks to the health of both the mother and the fetus. Emerging evidence suggests that epigenetic modifications, particularly DNA methylation, may play a role in initiating the earliest pathophysiology of PIH. This article describes the relationship between DNA methylation and placental trophoblast function, genes associated with the placental microenvironment, the placental vascular system, and maternal blood and vascular function, abnormalities of umbilical cord blood and vascular function in the onset and progression of PIH, as well as changes in DNA methylation in the progeny of PIH, in terms of maternal, fetal, and offspring. We also explore the latest research on DNA methylation-based early detection, diagnosis and potential therapeutic strategies for PIH. This will enable the field of DNA methylation research to continue to enhance our understanding of the epigenetic regulation of PIH genes and identify potential therapeutic targets.
Effectiveness of public health spending: Investigating the moderating role of governance using partial least squares structural equation modelling (PLS-SEM)
Authors: Kabongo Wa Ntita Serge , Mbonigaba Josue
Published: July 2024

Background

The link between public health spending (PHS) and population health outcomes (PHO) has been extensively studied. However, in sub-Saharan Africa (SSA), the moderating effects of governance in this relationship are little known. Furthermore, studies have focused on mortality as the main health outcome. This study contributes to this literature by investigating the moderating role of governance in the relationship by simultaneously assessing three dimensions of governance (corruption control, government effectiveness and voice accountability) using disability-adjusted life years (DALYs) as a measure of outcomes.

Methods

The study applies the two-stage moderation approach using partial least squares structural equation modelling (PLS-SEM) to panel data from 43 SSA nations from 2013 to 2019. The study also uses domestic general government health expenditure (DGGHE) as an independent variable and disability-adjusted life years (DALY) as the dependent variable in this relationship.

Results

The analysis reveals that DGGHE affects DALY negatively and that governance improves the effect of DGGHE on DALY, with bigger improvements among countries with worse governance.

Conclusion

These findings provide evidence that good governance is crucial to the effectiveness of PHS in SSA nations. Sub-Saharan Africa (SSA) countries should improve governance to improve population health.
How to strengthen societal impact of research and innovation? Lessons learned from an explanatory research-on-research study on participatory knowledge infrastructures funded by the Netherlands Organization for Health Research and Development
Authors: Oortwijn Wija , Reijmerink Wendy , Bussemaker Jet
Published: July 2024

Background

Scientific research and innovation can generate societal impact via different pathways. Productive interactions, such as collaboration between researchers and relevant stakeholders, play an important role and have increasingly gained interest of health funders around the globe. What works, how and why in research partnerships to generate societal impact in terms of knowledge utilisation is still not well-known. To explore these issues, the Netherlands Organization for Health Research and Development (ZonMw) initiated an exploratory research-on-research study with a focus on participatory knowledge infrastructures (PKIs) that they fund in the field of public health and healthcare. PKIs are sustainable infrastructures in which knowledge production, dissemination and utilisation takes place via committed collaboration between researchers and stakeholders from policy, practice and/or education. Examples are learning networks, academic collaborative centres, care networks and living labs. The aim of the study was twofold: to gain insights in what constitutes effective collaboration in PKIs; and to learn and improve the research governance, particularly of ZonMw as part of their dissemination and implementation activities.

Methods

During 2020–2022, we conducted a literature review on long-term research partnerships, analysed available documentation of twenty ZonMw-funded PKIs, surveyed participants of the 2021 European Implementation Event, interviewed steering committee members, organized a Group Decision Room with lecturers, and validated the findings with key experts.

Results

We identified eight mechanisms (‘how and why’) that are conditional for effective collaboration in PKIs: transdisciplinary collaboration; defining a shared ambition; doing justice to everyone’s interests; investing in personal relationships; a professional organisation or structure; a meaningful collaborative process; mutual trust, sufficient time for and continuity of collaboration. Several factors (‘what’) may hinder (e.g., lack of ownership or structural funding) or facilitate (e.g., stakeholder commitment, embeddedness in an organisation or policy) effective collaboration in research partnerships.

Conclusion

To use the study results in policy, practice, education, and/or (further) research, cultural and behavioural change of all stakeholders is needed. To facilitate this, we provide recommendations for funding organisations, particularly ZonMw and its partners within the relevant knowledge ecosystem. It is meant as a roadmap towards the realisation and demonstration of societal impact of (health) research and innovation in the upcoming years.
Ningetinib, a novel FLT3 inhibitor, overcomes secondary drug resistance in acute myeloid leukemia
Authors: Hu Chuhong , Zhang Yvyin , Yang Jie , Xu Yanli , Deng Tingfen , Li Yumiao , Xu Shilin , Wang Shunqing , Wang Peihong
Published: July 2024

Background

FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a common mutation type in acute myeloid leukemia (AML) and is usually associated with poor patient prognosis. With advancements in molecular diagnostics and the development of tyrosine kinase inhibitors (TKI), the overall survival (OS) of AML patients with FLT3-ITD mutations has been prolonged to some extent, but relapse and drug resistance are still substantial challenges. Ningetinib is a novel TKI against various kinases in relation to tumour pathogenesis and is undergoing clinical trials of lung cancer. In this study, we explored the antitumor activity of ningetinib against AML with FLT3 mutations both in vivo and in vitro.

Methods

Cell proliferation assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutations to validate the antileukemic activity of ningetinib in vitro. Immunoblot assays were used to verify the effect of ningetinib on the FLT3 protein and downstream pathways. Molecular docking and CETSA were used to validate the interaction of ningetinib with target proteins. The survival benefit of ningetinib in vivo was assessed in Ba/F3-FLT3-ITD-, MOLM13, Ba/F3-FLT3-ITD-F691L-, MOLM13-FLT3-ITD-F691L-induced leukemia mouse models. We also used patient-derived primary cells to determine the efficacy of ningetinib.

Results

Ningetinib inhibited cell proliferation, blocked the cell cycle, induced apoptosis and bound FLT3 to inhibit its downstream signaling pathways, including the STAT5, AKT and ERK pathways, in FLT3-ITD AML cell lines. In the mouse models with FLT3-ITD and FLT3-ITD-F691L mutation, ningetinib showed superior anti-leukemia activity to existing clinical drugs gilteritinib and quizartinib, significantly prolongating the survival of mice. In addition, ningetinib exhibited activity against patient-derived primary cells harboring FLT3-ITD mutations.

Conclusion

Overall, our study confirmed the therapeutic role of ningetinib in AML with FLT3-ITD mutations, providing a potential new option for clinically resistant patients.
Improving student diet and food security in higher education using participatory and co-creation approaches: a systematic review
Authors: Assilian Tamar , Dehove Henri , Charreire Hélène , Baudry Julia , Kesse-Guyot Emmanuelle , Péneau Sandrine , Julia Chantal , Gross Olivia , Oppert Jean-Michel , Bellicha Alice
Published: July 2024

Background

Higher education students are an important target group for public health nutrition interventions. When designing tailored and contextually relevant interventions, participatory and co-creation approaches are increasingly recognized as promising but their use and effectiveness has not been assessed in this type of population. We systematically reviewed interventions aiming to improve dietary quality and/or food security in higher education settings with the aims 1) to identify and describe their participatory and co-creation approaches and 2) to compare the effectiveness of interventions using or not using participatory and co-creation approaches.

Methods

Our search in PubMed, Google Scholar, Web of Science, EMBASE was performed in January 2023 and yielded 3658 unique records, out of which 42 articles (66 interventions) were included. Effectiveness of interventions was assessed at the individual level (longitudinal evaluations) or at the group level (repeated cross-sectional evaluations). A five-level classification was used to describe a continuum of engagement from students and other partners in the intervention design and implementation: no participation (level one), consultation, co-production, co-design and co-creation (levels two to five). To synthetize effectiveness, comparisons were made between studies without participation (level one) or with participation (levels two-five).

Results

Ten (24%) out of 42 studies used a participatory and co-creation approach (levels two-five). Studies using a participatory and co-creation approach reported a positive finding on individual-level outcome (i.e. overall diet quality or food group intake or food security) in 5/13 (38%) intervention arms (vs 13/31 or 42% for those without participation). Studies using a participatory and co-creation approach reported a positive finding on group-level outcomes (i.e. food choices in campus food outlets) in 4/7 (57%) (vs 8/23 or 35% in those without participation).

Conclusions

Participatory and co-creation approaches may improve the effectiveness of nutrition interventions in higher education settings but the level of evidence remains very limited. More research is warranted to identify best co-creation practices when designing, implementing and evaluating nutritional interventions in the higher education setting.

Trial registration

PROSPERO registration number CRD42023393004.
CDCA5 accelerates progression of breast cancer by promoting the binding of E2F1 and FOXM1
Authors: Xiong Yiquan , Shi Lan , Li Lei , Yang Wen , Zhang Huiqiong , Zhao Xiangwang , Shen Na
Published: July 2024

Background

Breast cancer is one of the most common malignant tumors in women. Cell division cycle associated 5 (CDCA5), a master regulator of sister chromatid cohesion, was reported to be upregulated in several types of cancer. Here, the function and regulation mechanism of CDCA5 in breast cancer were explored.

Methods

CDCA5 expression was identified through immunohistochemistry staining in breast cancer specimens. The correlation between CDCA5 expression with clinicopathological features and prognosis of breast cancer patients was analyzed using a tissue microarray. CDCA5 function in breast cancer was explored in CDCA5-overexpressed/knockdown cells and mice models. Co-IP, ChIP and dual-luciferase reporter assay assays were performed to clarify underlying molecular mechanisms.

Results

We found that CDCA5 was expressed at a higher level in breast cancer tissues and cell lines, and overexpression of CDCA5 was significantly associated with poor prognosis of patients with breast cancer. Moreover, CDCA5 knockdown significantly suppressed the proliferation and migration, while promoted apoptosis in vitro. Mechanistically, we revealed that CDCA5 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the forkhead box M1 (FOXM1) promoter. Furthermore, the data of in vitro and in vivo revealed that depletion of FOXM1 alleviated the effect of CDCA5 overexpression on breast cancer. Additionally, we revealed that the Wnt/β-catenin signaling pathway was required for CDCA5 induced progression of breast cancer.

Conclusions

We suggested that CDCA5 promoted progression of breast cancer via CDCA5/FOXM1/Wnt axis, CDCA5 might serve as a novel therapeutic target for breast cancer treatment.
Epidemiology, economic, and humanistic burden of hereditary angioedema: a systematic review
Authors: Guan Xin , Sheng Yanan , Liu Shuang , He Miao , Chen Tianxiang , Zhi Yuxiang
Published: July 2024

Background

This systematic study aims to assess the global epidemiologic, economic, and humanistic burden of illness associated with all types of hereditary angioedema.

Methods

A systematic search for articles reporting the epidemiologic, economic, and humanistic burden associated with patients with HAE was conducted using English and Chinese literature databases from the inception to May 23, 2022. The selected studies were assessed for their quality and risk of bias. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022352377).

Results

In total, 65 articles that met the search inclusion criteria reported 10,310 patients with HAE, of whom 5861 were female patients. Altogether, 4312 patients (81%) and 479 patients (9%) had type 1 and type 2 HAE, respectively, whereas 422 patients (8%) had HAE-normal C1-INH. The overall prevalence of all types of HAE was between 0.13 and 1.6 cases per 100,000. The mean or median delay from the first onset of a symptom of HAE to confirmed diagnosis ranged from 3.9 to 26 years. The estimated risk of death from asphyxiation was 8.6% for patients with HAE. Hospitalization, medication, unnecessary surgeries, doctor visits, specialist services, and nursing costs are direct expenses that contribute to the growing economic burden. The indirect cost accounted mostly due to missing work ($3402/year) and loss of productivity ($5750/year). Furthermore, impairment of QoL as reported by patient-reported outcomes was observed. QoL measures identified depression, anxiety, and stress to be the most common symptoms for adult patients and children.

Conclusion

This study highlights the importance of early diagnosis and the need for improving awareness among health care professionals to reduce the burden of HAE on patients and society.
Healthcare resource utilization and costs associated with psychiatric comorbidities in pediatric patients with attention-deficit/hyperactivity disorder: a claims-based case-cohort study
Authors: Schein Jeff , Cloutier Martin , Gauthier-Loiselle Marjolaine , Bungay Rebecca , Chen Kathleen , Chan Deborah , Guerin Annie , Childress Ann
Published: July 2024

Background

Attention-deficit/hyperactivity disorder (ADHD) has been shown to pose considerable clinical and economic burden; however, research quantifying the excess burden attributable to common psychiatric comorbidities of ADHD among pediatric patients is scarce. This study assessed the impact of anxiety and depression on healthcare resource utilization (HRU) and healthcare costs in pediatric patients with ADHD in the United States.

Methods

Patients with ADHD aged 6–17 years were identified in the IQVIA PharMetrics Plus database (10/01/2015-09/30/2021). The index date was the date of initiation of a randomly selected ADHD treatment. Patients with ≥ 1 diagnosis for anxiety and/or depression during both the baseline (6 months pre-index) and study period (12 months post-index) were classified in the ADHD+anxiety/depression cohort; those without diagnoses for anxiety nor depression during both periods were classified in the ADHD-only cohort. Entropy balancing was used to create reweighted cohorts. All-cause HRU and healthcare costs during the study period were compared using regression analyses. Cost analyses were also performed in subgroups by comorbid conditions.

Results

The reweighted ADHD-only cohort (N = 204,723) and ADHD+anxiety/depression cohort (N = 66,231) had similar characteristics (mean age: 11.9 years; 72.8% male; 56.2% had combined inattentive and hyperactive ADHD type). The ADHD+anxiety/depression cohort had higher HRU than the ADHD-only cohort (incidence rate ratios for inpatient admissions: 10.3; emergency room visits: 1.6; outpatient visits: 2.3; specialist visits: 5.3; and psychotherapy visits: 6.1; all p < 0.001). The higher HRU translated to greater all-cause healthcare costs; the mean per-patient-per-year (PPPY) costs in the ADHD-only cohort vs. ADHD+anxiety/depression cohort was $3,988 vs. $8,682 (p < 0.001). All-cause healthcare costs were highest when both comorbidities were present; among patients with ADHD who had only anxiety, only depression, and both anxiety and depression, the mean all-cause healthcare costs were $7,309, $9,901, and $13,785 PPPY, respectively (all p < 0.001).

Conclusions

Comorbid anxiety and depression was associated with significantly increased risk of HRU and higher healthcare costs among pediatric patients with ADHD; the presence of both comorbid conditions resulted in 3.5 times higher costs relative to ADHD alone. These findings underscore the need to co-manage ADHD and psychiatric comorbidities to help mitigate the substantial burden borne by patients and the healthcare system.
Massively integrated coexpression analysis reveals transcriptional regulation, evolution and cellular implications of the yeast noncanonical translatome
Authors: Rich April , Acar Omer , Carvunis Anne-Ruxandra
Published: July 2024

Background

Recent studies uncovered pervasive transcription and translation of thousands of noncanonical open reading frames (nORFs) outside of annotated genes. The contribution of nORFs to cellular phenotypes is difficult to infer using conventional approaches because nORFs tend to be short, of recent de novo origins, and lowly expressed. Here we develop a dedicated coexpression analysis framework that accounts for low expression to investigate the transcriptional regulation, evolution, and potential cellular roles of nORFs inSaccharomyces cerevisiae.

Results

Our results reveal that nORFs tend to be preferentially coexpressed with genes involved in cellular transport or homeostasis but rarely with genes involved in RNA processing. Mechanistically, we discover that young de novo nORFs located downstream of conserved genes tend to leverage their neighbors’ promoters through transcription readthrough, resulting in high coexpression and high expression levels. Transcriptional piggybacking also influences the coexpression profiles of young de novo nORFs located upstream of genes, but to a lesser extent and without detectable impact on expression levels. Transcriptional piggybacking influences, but does not determine, the transcription profiles of de novo nORFs emerging nearby genes. About 40% of nORFs are not strongly coexpressed with any gene but are transcriptionally regulated nonetheless and tend to form entirely new transcription modules. We offer a web browser interface (https://carvunislab.csb.pitt.edu/shiny/coexpression/) to efficiently query, visualize, and download our coexpression inferences.

Conclusions

Our results suggest that nORF transcription is highly regulated. Our coexpression dataset serves as an unprecedented resource for unraveling how nORFs integrate into cellular networks, contribute to cellular phenotypes, and evolve.