bluuebunny/crossref_metadata_2025 huggingface dataset:
PrCRS: a prediction model of severe CRS in CAR-T therapy based on transfer learning
Authors: Wei Zhenyu , Zhao Chengkui , Zhang Min , Xu Jiayu , Xu Nan , Wu Shiwei , Xin Xiaohui , Yu Lei , Feng Weixing
Published: May 2024

Background

CAR-T cell therapy represents a novel approach for the treatment of hematologic malignancies and solid tumors. However, its implementation is accompanied by the emergence of potentially life-threatening adverse events known as cytokine release syndrome (CRS). Given the escalating number of patients undergoing CAR-T therapy, there is an urgent need to develop predictive models for severe CRS occurrence to prevent it in advance. Currently, all existing models are based on decision trees whose accuracy is far from meeting our expectations, and there is a lack of deep learning models to predict the occurrence of severe CRS more accurately.

Results

We propose PrCRS, a deep learning prediction model based on U-net and Transformer. Given the limited data available for CAR-T patients, we employ transfer learning using data from COVID-19 patients. The comprehensive evaluation demonstrates the superiority of the PrCRS model over other state-of-the-art methods for predicting CRS occurrence. We propose six models to forecast the probability of severe CRS for patients with one, two, and three days in advance. Additionally, we present a strategy to convert the model's output into actual probabilities of severe CRS and provide corresponding predictions.

Conclusions

Based on our findings, PrCRS effectively predicts both the likelihood and timing of severe CRS in patients, thereby facilitating expedited and precise patient assessment, thus making a significant contribution to medical research. There is little research on applying deep learning algorithms to predict CRS, and our study fills this gap. This makes our research more novel and significant. Our code is publicly available at https://github.com/wzy38828201/PrCRS. The website of our prediction platform is: http://prediction.unicar-therapy.com/index-en.html.
HMMF: a hybrid multi-modal fusion framework for predicting drug side effect frequencies
Authors: Liu Wuyong , Zhang Jingyu , Qiao Guanyu , Bian Jilong , Dong Benzhi , Li Yang
Published: May 2024

Background

The identification of drug side effects plays a critical role in drug repositioning and drug screening. While clinical experiments yield accurate and reliable information about drug-related side effects, they are costly and time-consuming. Computational models have emerged as a promising alternative to predict the frequency of drug-side effects. However, earlier research has primarily centered on extracting and utilizing representations of drugs, like molecular structure or interaction graphs, often neglecting the inherent biomedical semantics of drugs and side effects.

Results

To address the previously mentioned issue, we introduce a hybrid multi-modal fusion framework (HMMF) for predicting drug side effect frequencies. Considering the wealth of biological and chemical semantic information related to drugs and side effects, incorporating multi-modal information offers additional, complementary semantics. HMMF utilizes various encoders to understand molecular structures, biomedical textual representations, and attribute similarities of both drugs and side effects. It then models drug-side effect interactions using both coarse and fine-grained fusion strategies, effectively integrating these multi-modal features.

Conclusions

HMMF exhibits the ability to successfully detect previously unrecognized potential side effects, demonstrating superior performance over existing state-of-the-art methods across various evaluation metrics, including root mean squared error and area under receiver operating characteristic curve, and shows remarkable performance in cold-start scenarios.
Transcriptomic analysis of polysaccharide utilization loci reveals substrate preferences in ruminal generalists Segatella bryantii TF1-3 and Xylanibacter ruminicola KHP1
Authors: Murovec Urška , Accetto Tomaž
Published: May 2024

Bacteria of the genera Xylanibacter and Segatella are among the most dominant groups in the rumen microbiota. They are characterized by the ability to utilize different hemicelluloses and pectin of plant cell-wall as well as plant energy storage polysaccharides. The degradation is possible with the use of cell envelope bound multiprotein apparatuses coded in polysaccharide utilization loci (PULs), which have been shown to be substrate specific. The knowledge of PUL presence in rumen Xylanibacter and Segatella based on bioinformatic analyses is already established and transcriptomic and genetic approaches confirmed predicted PULs for a limited number of substrates. In this study, we transcriptomically identified additional different PULs in Xylanibacter ruminicola KHP1 and Segatella bryantii TF1-3. We also identified substrate preferences and found that specific growth rate and extent of growth impacted the choice of substrates preferentially used for degradation. These preferred substrates were used by both strains simultaneously as judged by their PUL upregulation. Lastly, β-glucan and xyloglucan were used by these strains in the absence of bioinformatically and transcriptomically identifiable PUL systems.
Exogenous indole-3-acetic acid promotes the plant growth and accumulation of selenium in grapevine under selenium stress
Authors: Wang Jin , Liu Lei , Zhang Haiyan , Zhang Dilian , Dai Zhen , Luo Xian , Zhang Xiaoli , Xia Hui , Liang Dong , Lv Xiulan , Lin Lijin
Published: May 2024

To alleviate the selenium (Se) stress in fruit trees and improve its accumulation, the effects of exogenous indole-3-acetic acid (IAA) on the growth and Se accumulation of grapevine under Se stress were studied. The application of exogenous IAA increased the biomass of grapevine, and the concentration of exogenous IAA had a regression relationship with the biomass. The root and shoot biomass were the maximum at 60 mg L− 1 IAA, increasing by 15.61% and 23.95%, respectively, compared with the control. Exogenous IAA also increased the photosynthetic pigments and the activities of superoxide dismutase and peroxidase in grapevine. Moreover, exogenous IAA increased the contents of total Se, organic Se, and inorganic Se, and the concentration of exogenous IAA had a regression relationship with the total Se content. The highest contents of root total Se and shoot total Se were accumulated at 90 mg L− 1 IAA, increasing by 29.94% and 55.77% respectively,. In addition, the correlation and path analyses revealed that the carotenoid content and root total Se content were closely associated with the shoot total Se content. Therefore, the application of exogenous IAA can alleviate the stress of Se to grape and promote its uptake and the most effective amount for the uptake of Se is 90 mg L− 1 IAA.
Early myocardial injury in children on doxorubicin for cancer chemotherapy: a cross-sectional study in a tertiary referral centre in Kenya
Authors: Kariuki Nyambura , Kimani Esther , Jowi Christine , Wamalwa Dalton , Suen Jacky Y. , Fraser John F. , Obonyo Nchafatso G.
Published: May 2024

Introduction

Use of doxorubicin, an anthracycline chemotherapeutic agent has been associated with late-occurring cardiac toxicities. Detection of early-occurring cardiac effects of cancer chemotherapy is essential to prevent occurrence of adverse events including toxicity, myocardial dysfunction, and death.

Objective

To investigate the prevalence of elevated cardiac troponin T (cTnT) and associated factors of myocardial injury in children on doxorubicin cancer chemotherapy.

Methods

Design: A cross-sectional study.

Setting and subjects: A hospital-based study conducted on children aged 1-month to 12.4-years who had a diagnosis of cancer and were admitted at Kenyatta National Hospital (KNH).

Interventions and outcomes: The patients underwent Echocardiography (ECHO) before their scheduled chemotherapy infusion. Twenty-four (24) hours after the chemotherapy infusion the patients had an evaluation of the serum cardiac troponin T (cTnT) and a repeat ECHO. Myocardial injury was defined as cTnT level > 0.014 ng/ml or a Fractional Shortening (FS) of < 29% on ECHO.

Results

One hundred (100) children were included in the final analysis. Thirty-two percent (32%) of the study population had an elevated cTnT. A cumulative doxorubicin dose of > 175 mg/m2 was significantly associated with and elevated cTnT (OR, 10.76; 95% CI, 1.18–97.92; p = 0.035). Diagnosis of nephroblastoma was also associated with an elevated cTnT (OR, 3.0; 95% CI, 1.23–7.26) but not statistically significant (p = 0.105). Nine percent (9%) of the participants had echocardiographic evidence of myocardial injury.

Conclusion

When compared to echocardiography, elevated levels of cTnT showed a higher association with early-occurring chemotherapy-induced myocardial injury among children on cancer treatment at a tertiary teaching and referral hospital in Kenya.
Nonlinear association of fibrinogen levels with functional prognosis in patients with acute ischemic stroke: a prospective cohort study
Authors: Chen Feng , Han Yong , Hu Haofei , Guo Yuying , Deng Zhe , Liu Dehong
Published: May 2024

Objective

Fibrinogen, essential in primary hemostasis, platelet aggregation, and leukocyte-endothelial interactions, is also associated with a heightened risk of acute ischemic stroke (AIS). However, its influence on AIS patient outcomes is unclear. This study examines the correlation between fibrinogen levels and the risk of unfavorable outcomes three months post-AIS.

Methods

This is a secondary analysis of a prospective cohort study conducted in Korea. The sample consisted of 1851 AIS patients who received treatment at a Korean hospital between January 2010 and December 2016. Statistical models were established to understand the relationship between fibrinogen levels(mg/dL) and unfavorable outcomes(mRs ≥ 3), including logistic regression models, Generalized Additive Models (GAM), and smooth curve fitting (penalized splines). The log-likelihood ratio test has been utilized to evaluate the best fit. To ensure the robustness of the results, sensitivity analyses were conducted by reanalyzing the relationship after excluding participants with TG > 200 mg/dl and BMI > 25 kg/m2. Subgroup analyses were also performed to assess whether influencing factors modify the association between fibrinogen levels and unfavorable outcomes.

Results

After adjusting for multiple covariates including age, BMI, sex, LDL-c, TG, HGB, HDL-c, BUN, FPG, ALB, PLT, AF, hypertension, smoking, DM, mRs score at admission, the binary logistic regression model demonstrated revealed a significant positive association between fibrinogen levels and the risk of unfavorable outcomes in AIS patients (OR = 1.215, 95% CI: 1.032–1.429, p = 0.019). Sensitivity analyses supported these findings, with similar ORs observed in subsets of patients with TG < 200 mg/dL (OR = 1.221, 95% CI: 1.036–1.440) and BMI < 25 kg/m2 (OR = 1.259, 95% CI: 1.051–1.509). Additionally, the relationship between fibrinogen levels and outcomes was nonlinear, with a critical threshold of 2.74 g/L. Below the inflection point, the OR for unfavorable outcomes was 0.666 ((95% CI: 0.360, 1.233, p = 0.196), whereas above it, the OR increased to 1.374 (95% CI: 1.138, 1.659).

Conclusions

This study has provided evidence of a positive and nonlinear correlation between fibrinogen levels and 3-month poor functional outcomes in patients with AIS. When fibrinogen levels exceeded 2.74 g/L, a significant and positive association was observed with the risk of poor outcomes. This study provides a further reference for optimizing rehabilitation exercises and facilitating clinical counseling in patients with acute ischemic stroke.
Spatial distribution and determinants of intermittent preventive treatment for malaria during pregnancy: a secondary data analysis of the 2019 Ghana malaria indicators survey
Authors: Ndayishimiye Jean Claude , Teg-Nefaah Tabong Philip
Published: May 2024

Background

Malaria during pregnancy is associated with poor maternal, foetal, and neonatal outcomes. To prevent malaria infection during pregnancy, the World Health Organization recommended the use of intermittent preventive therapy with sulfadoxine-pyrimethamine (IPTp-SP) in addition to vector control strategies. Although Ghana’s target is to ensure that all pregnant women receive at least three (optimal) doses of SP, the uptake of SP has remained low; between 2020 and 2022, only 60% of pregnant women received optimal SP during their most recent pregnancy. This study sought to map the geospatial distribution and identify factors associated with SP uptake during pregnancy in Ghana.

Methods

Secondary data analysis was conducted using the 2019 Ghana Malaria Indicator Survey dataset. The data analysed were restricted to women aged 15–49 years who reported having a live birth within the two years preceding the survey. A modified Poisson regression model was used to determine factors associated with SP uptake during pregnancy. Geospatial analysis was employed to map the spatial distribution of optimal SP uptake across the ten regions of Ghana using R software.

Results

The likelihood that pregnant women received optimal SP correlated with early initiation of first antenatal care (ANC), number of ANC contacts, woman’s age, region of residence, and family size. Overall, the greater the number of ANC contacts, the more likely for pregnant women to receive optimal SP. Women with four or more ANC contacts were 2 times (aPR: 2.16; 95% CI: [1.34–3.25]) more likely to receive optimal SP than pregnant women with fewer than four ANC contacts. In addition, early initiation and a high number of ANC contacts were associated with a high number of times a pregnant woman received SP. Regarding spatial distribution, a high uptake of optimal SP was significantly observed in the Upper East and Upper West Regions, whereas the lowest was observed in the Eastern Region of Ghana.

Conclusions

In Ghana, there were regional disparities in the uptake of SP during pregnancy, with the uptake mainly correlated with the provision of ANC services. To achieve the country’s target for malaria control during pregnancy, there is a need to strengthen intermittent preventive treatment for malaria during pregnancy by prioritizing comprehensive ANC services.
Community medical service construction: identifying factors that influence medical choice for patients with non-communicable chronic diseases in the Southwest China
Authors: Zhang Xue , Dai Jing , Li Wei , Chen Yu , He Yunyu , Yang Yunjuan , Yang Liuyang
Published: May 2024

Background

Community medical institutions play a vital role in China’s healthcare system. While the number of these institutions has increased in recent years, their construction contents remain insufficient. The potential of community medical institutions in preventing, screening, diagnosing, and treating non-communicable chronic diseases (NCDs) has not been fully utilized. This study aims to assess the status of construction contents in community medical institutions in Southwest China and examine how these contents influence the medical choices of NCD patients.

Methods

Descriptive statistics were used to evaluate the construction content of community medical institutions. Multiple-sets of multinomial logistic regression were employed to analyze the associations and marginal impacts between construction content and medical choices. Shapley value analysis was applied to determine the contribution and ranking of these impacts.

Results

Descriptive statistics revealed satisfactory construction contents in community medical institutions. Notably, factors such as service attitude, nursing services, expert consultations, charging standards, medical equipment, medical examinations, privacy protection, and referrals significantly influenced medical choices. Among these, service attitude, charging standards, and privacy protection had the most significant marginal improvement effects on NCD patients’ choices, with improvements of 12.7%, 10.2%, and 5.9%, respectively. The combined contribution of privacy protection, medical examinations, service attitude, charging standards, and nursing services to medical choices exceeded 80%.

Conclusion

Optimizing the service contents of community institutions can encourage NCD patients to seek medical care at grassroots hospitals. This study addresses crucial gaps in existing literature and offers practical insights for implementing new medical reform policies, particularly in underdeveloped regions of Southwest China focusing on hierarchical diagnosis and treatment.
Physical activity and functional social support in community-dwelling older adults: a scoping review
Authors: Steinhoff Paula , Reiner Amelie
Published: May 2024

Background

Globally, the population of older people is increasing and is estimated to reach nearly 2.1 billion by 2050. Physical activity (PA) is one of the key components for successful ageing. However, PA decreases with age and many older adults do not meet PA guidelines. Previous research has shown that social support (SOSU) is related to PA in older people. The aim of this scoping review is to identify and map all of the available evidence and to explore the association between functional SOSU and PA in older adults. Functional SOSU consists of emotional, informational, instrumental and companionship SOSU and social comparison.

Methods

A scoping review was conducted using the Joanna-Briggs manual. Quantitative and qualitative studies investigating associations between functional SOSU and PA levels in older adults (mean age ≥ 60 years) were identified through a systematic search in seven electronic databases up to August 2023. After removing duplicates, 20,907 articles were screened for titles and abstracts. The results were analysed separately for different types of SOSU.

Results

116 articles met the inclusion criteria; 72% were quantitative studies and 28% were qualitative studies. Most studies used self-reported PA measures, only 23% of the studies used objective-reported PA measures. Most studies of SOSU for PA reported positive associations but the evidence is inconclusive when the source of support is considered. PA is positively associated with general, emotional, informational, and companionship SOSU, while instrumental support may occasionally be negatively associated. Companionship support is particularly influential on PA, especially in group settings, as it promotes social connectedness. Qualitative studies show that social comparison also supports PA. Different forms of SOSU generally show positive associations with PA.

Conclusions

While the evidence on the association between functional SOSU and PA is mixed, most studies show that there is a positive association. PA may also be a strategy for improving social contact and social integration. This study offers a comprehensive overview of measures for SOSU and PA and thereby informs future research and policy-making.
Development and internal validation of a clinical prediction model for osteopenia in Chinese middle-aged and elderly men: a prospective cohort study
Authors: Li Ting , Zeng Jing , Pan Zimo , Hu Fan , Cai Xiaoyan , Wang Xinjiang , Liu Guanzhong , Hu Xinghe , Deng Xinli , Gong Meiliang , Yang Xue , Gong Yanping , Li Nan , Li Chunlin
Published: May 2024

Background

Early identification of patients at risk of osteopenia is an essential step in reducing the population at risk for fractures. We aimed to develop and validate a prediction model for osteopenia in Chinese middle-aged and elderly men that provides individualized risk estimates.

Methods

In this prospective cohort study, 1109 patients who attend regular physical examinations in the Second Medical Centre of Chinese PLA General Hospital were enrolled from 2015.03 to 2015.09. The baseline risk factors included dietary habits, exercise habits, medical histories and medication records. Osteopenia during follow-up were collected from Electronic Health Records (EHRs) and telephone interviews. Internal validation was conducted using bootstrapping to correct the optimism. The independent sample T-test analysis, Mann_Whitney U test, Chi-Square Test and multivariable Cox regression analysis were utilized to identify predictive factors for osteopenia in Chinese middle-aged and elderly men. A nomogram based on the seven variables was built for clinical use. Concordance index (C-index), receiver operating characteristic curve (ROC), decision curve analysis (DCA) and calibration curve were used to evaluate the efficiency of the nomogram.

Results

The risk factors included in the prediction model were bone mineral density at left femoral neck (LNBMD), hemoglobin (Hb), serum albumin (ALB), postprandial blood glucose (PBG), fatty liver disease (FLD), smoking and tea consumption. The C-index for the risk nomogram was 0.773 in the prediction model, which presented good refinement. The AUC of the risk nomogram at different time points ranged from 0.785 to 0.817, exhibiting good predictive ability and performance. In addition, the DCA showed that the nomogram had a good clinical application value. The nomogram calibration curve indicated that the prediction model was consistent.

Conclusions

Our study provides a novel nomogram and a web calculator that can effectively predict the 7-year incidence risk of osteopenia in Chinese middle-aged and elderly men. It is convenient for clinicians to prevent fragility fractures in the male population.
The fracture resistance of pulpotomized primary molars restored with zirconia crowns, lithium disilicate or resin based ceramic endocrowns
Authors: Ali Amany Abd Elhady Muhammad , Abo-ELsoud Asmaa Ali Emam , Helmy Yousra Samir
Published: May 2024

Background

Endocrown in pediatric dentistry was rooted in the fundamental principles of preserving healthy dental tissues, leveraging contemporary adhesive methodologies.

Aim

This research aimed on assessing and comparing the fracture resistance of pulpotomized primary molars when rehabilitated with zirconia crowns and two distinct types of endocrowns, namely E-Max and Brilliant Crios.

Methods

The study involved thirty, anonymized, freshly extracted second primary molars that underwent pulpotomy. These teeth were then evenly divided into three groups, each consisting of ten specimens: the zirconia crown, the E-Max endocrown, and the Brilliant Crios endocrown groups. Post-pulpotomy, the teeth were prepared for their respective restorations. Subsequent to this preparation, the zirconia crowns, E-Max endocrowns, and Brilliant Crios endocrowns were secured. To evaluate the fracture resistance using a computer-controlled testing machine (Instron), a progressively increasing load was applied to each group until fracture occurred. The gathered data were then analyzed for outliers and subjected to normality testing using the Shapiro-Wilk and/or Kolmogorov-Smirnov tests, with a significance threshold set at 0.05.

Results

There was no statistically significant difference in fracture resistance of pulpotomized primary molars among lithium disilicate (E-Max) group (mean=1367.59N), Brilliant Crios group (mean=1349.73N) and zirconia group (mean=1240.82N).

Conclusion

Endocrowns can be considered a promising restoration for pulpotomized primary molars.
“You get out of the house, you talk to each other, you laugh…And that’s fantastic” – a qualitative study about older people’s perceptions of social prescribing in mainland Portugal
Authors: Costa Andreia , Henriques Joana , Alarcão Violeta , Madeira Teresa , Virgolino Ana , Polley Marie J. , Henriques Adriana , Feteira-Santos Rodrigo , Arriaga Miguel , Nogueira Paulo
Published: May 2024

Background

Social prescribing (SP) is a non-clinical approach, most commonly based in healthcare units, that aims to address non-medical health-related social needs by connecting individuals with community-based services. This qualitative study explores the perception of Portuguese older adults regarding the benefits of SP and their willingness to participate in SP initiatives.

Methods

Three face-to-face focus group sessions were conducted with 23 participants in different cities in Portugal. Open and semi-open questions were used to guide the discussions and thematic analysis was used to analyze the data.

Results

The participants recognized the potential benefits of SP for older adults, including diversifying leisure activities, improving mental health, and complementing existing support systems. They highlighted the need for external support, usually in the form of link workers, to facilitate personalized referrals and consider individual characteristics and preferences. While some participants expressed reluctance to engage in SP due to their existing busy schedules and a perceived sense of imposition, others showed openness to having new experiences and recognized the potential value of SP in promoting activity. Barriers to participation, including resistance to change, mobility issues, and family responsibilities, were identified.

Conclusions

The study emphasizes the importance of a person-centered and co-designed approach to SP, involving older adults in the planning and implementation of interventions. The findings provide valuable insights for the development of SP programs tailored to the unique needs and aspirations of older adults in Portugal, ultimately promoting active and healthy aging. Future research should consider the perspectives of family doctors and include a broader representation of older adults from diverse geographic areas.
Exonuclease editor promotes precision of gene editing in mammalian cells
Authors: Shi Hui , Li Lei , Mu Shuangshuang , Gou Shixue , Liu Xiaoyi , Chen Fangbing , Chen Menglong , Jin Qin , Lai Liangxue , Wang Kepin
Published: May 2024

Background

Many efforts have been made to improve the precision of Cas9-mediated gene editing through increasing knock-in efficiency and decreasing byproducts, which proved to be challenging.

Results

Here, we have developed a human exonuclease 1-based genome-editing tool, referred to as exonuclease editor. When compared to Cas9, the exonuclease editor gave rise to increased HDR efficiency, reduced NHEJ repair frequency, and significantly elevated HDR/indel ratio. Robust gene editing precision of exonuclease editor was even superior to the fusion of Cas9 with E1B or DN1S, two previously reported precision-enhancing domains. Notably, exonuclease editor inhibited NHEJ at double strand breaks locally rather than globally, reducing indel frequency without compromising genome integrity. The replacement of Cas9 with single-strand DNA break-creating Cas9 nickase further increased the HDR/indel ratio by 453-fold than the original Cas9. In addition, exonuclease editor resulted in high microhomology-mediated end joining efficiency, allowing accurate and flexible deletion of targeted sequences with extended lengths with the aid of paired sgRNAs. Exonuclease editor was further used for correction of DMD patient-derived induced pluripotent stem cells, where 30.0% of colonies were repaired by HDR versus 11.1% in the control.

Conclusions

Therefore, the exonuclease editor system provides a versatile and safe genome editing tool with high precision and holds promise for therapeutic gene correction.
Association between being large for gestational age and cardiovascular metabolic health in children conceived from assisted reproductive technology: a prospective cohort study
Authors: Zhang Yiyuan , Dai Kexin , Chen Xiaojing , Cui Linlin , Chen Zi-Jiang
Published: May 2024

Background

To the best of our knowledge, no study has investigated the potential joint effect of large for gestational age (LGA) and assisted reproductive technology (ART) on the long-term health of children.

Methods

This was a prospective cohort study that recruited children whose parents had received ART treatment in the Center for Reproductive Medicine, Shandong Provincial Hospital, affiliated to Shandong University, between January 2006 and December 2017. Linear mixed model was used to compare the main outcomes. The mediation model was used to evaluate the intermediary effect of body mass index (BMI).

Results

4138 (29.5%) children born LGA and 9910 (70.5%) children born appropriate for gestational age (AGA) were included in the present study. The offspring ranged from 0.4 to 9.9 years. LGAs conceived through ART were shown to have higher BMI, blood pressure, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance values, even after controlling for all covariates. The odds of overweight and insulin resistance are also higher in LGA subjects. After adjusting for all covariates, LGAs conceived through ART had BMI and BMI z-scores that were 0.48 kg/m2 and 0.34 units greater than those of AGAs, respectively. The effect of LGA on BMI was identified as early as infancy and remained consistently significant throughout pre-puberty.

Conclusions

Compared to AGA, LGA children conceived from ART were associated with increased cardiovascular-metabolic events, which appeared as early as infancy and with no recovery by pre-puberty.
Preparation and evaluation of fenbendazole methyl-β-cyclodextrin inclusion complexes
Authors: Ding Yili , Zhang Zhiyuan , Ding Charles , Xu Shufeng , Xu Zhe
Published: May 2024

As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but also shows anti-cancer effects against several types of cancer, exhibits anti-cancer effects in paclitaxel and doxorubicin-resistant cancer cells. However, fenbendazole’s poor in water solubility (0.3 µg/mL), limits its clinical applications. Even great efforts were made toward increasing its water solubility, the results were not significant to reach anti-cancer drug delivery requirement (5–10 mg/mL). Through single factor and orthogonal strategy, many complex conditions were designed and used to prepare the complexes, the inclusion complex with methyl-β-cyclodextrin with 29.2 % of inclusion rate and 89.5% of inclusion yield can increase drug’s water solubility to 20.21 mg/mL, which is the best result so far. Its structure was confirmed by differential scanning calorimetry, scanning electron microscopic image, 1D and 2D NMR spectra in D2O. In its in vitro pharmacokinetic study, fenbendazole was 75% released in 15 min., in its in vivo pharmacokinetic study, the bio-availabilities of fenbendazole, its major metabolic anthelmintic agent oxfendazole and its minor metabolic anthelmintic agent oxfendazole were increased to 138%, 149% and 169% respectively, which would allow for fewer drug doses to achieve the same therapeutic effect and suggest that the complex can be used as a potential anticancer agent.
Association of prediabetes with clinical outcomes in patients with chronic coronary syndrome: a post hoc analysis of the ISCHEMIA and ISCHEMIA-CKD trials
Authors: Jorda Anselm , Hengstenberg Christian , Lang Irene M. , Kautzky-Willer Alexandra , Harreiter Jürgen , Zeitlinger Markus , Jilma Bernd , Gelbenegger Georg
Published: May 2024

Background

There is conflicting evidence whether prediabetes is associated with adverse clinical outcomes in patients with chronic coronary syndrome. We aimed to assess the effect of prediabetes in patients with chronic coronary syndrome on clinical outcomes.

Methods

This is a secondary analysis of data from the ISCHEMIA and ISCHEMIA-CKD trials, including patients with chronic coronary syndrome determined by coronary computed tomography angiography or exercise-stress testing. Participants were assigned to the normoglycemia group (HbA1c < 5.7% [< 39 mmol/mol]), prediabetes group (HbA1c 5.7–6.4% [40–47 mmol/mol]), or diabetes group (HbA1c ≥ 6.5% [≥ 48 mmol/mol]). The primary end point of this study was all-cause mortality. Secondary endpoints included major adverse cardiovascular events and composites thereof.

Results

Overall, the primary endpoint all-cause mortality occurred in 330 (8.4%) of 3910 patients over a median follow-up time of 3.1 years (IQR 2.1–4.1). The primary endpoint all-cause mortality occurred in 37 (5.2%) of 716 patients in the normoglycemia group, in 63 (6.9%) of 911 in the prediabetes group, and in 230 (10.1%) of 2283 in the diabetes group. In the covariate-adjusted Cox model analysis, the estimated adjusted HR (aHR) in the prediabetes group as compared with the normoglycemia group was 1.45 (95%CI, 0.95–2.20). The aHR in the diabetes group as compared with the normoglycemia group was 1.84 (95%CI, 1.29–2.65). Prediabetes, compared with normoglycemia, was associated with an increased risk of stroke (aHR, 3.44, 95%CI, 1.15–10.25). Subgroup analyses suggested an increased risk of all-cause death associated with prediabetes in males and patients under 65 years.

Conclusions

In patients with chronic coronary syndrome, diabetes but not prediabetes was associated with significantly increased risk of all-cause death within a median follow-up period of 3.1 years.

Trial Registration NCT01471522, BioLINCC ID 13936.
Exploring existing malaria services and the feasibility of implementing community engagement approaches amongst conflict-affected communities in Cameroon: a qualitative study
Authors: Ebob Besem E.O Margaret , Chestnutt Elisabeth G. , Donovan Laura , Stratil Ann-Sophie , Counihan Helen , Nkfusai Claude Ngwayu , Hawkings Helen , Homolova Blanka , Maxwell Kolawole , Baker Kevin , Zoungrana Yakouba , Tanue Elvis Asangbeng , Ayuk Glennise , Modjenpa Noukeme Bibiche , Metuge Alain , Nganmou Isabelle , Achu Dorothy , Wanji Samuel , Berryman Elizabeth , Omam Lundi-Anne
Published: May 2024

Background

Cameroon is one of the countries with the highest burden of malaria. Since 2018, there has been an ongoing conflict in the country, which has reduced access to healthcare for populations in affected regions, and little is known about the impact on access to malaria services. The objective of this study was to understand the current situation regarding access to malaria services in Cameroon to inform the design of interventions to remove barriers and encourage the use of available services.

Methods

A qualitative research study was carried out to understand the barriers preventing communities accessing care, the uptake of community health worker (CHW) services, and to gather perceptions on community engagement approaches, to assess whether these could be an appropriate mechanism to encourage uptake of community health worker (CHW) services. Twenty-nine focus group discussions and 11 in-depth interviews were carried out between May and July 2021 in two regions of Cameroon, Southwest and Littoral. Focus group discussions were held with CHWs and community members and semi-structured, in-depth interviews were conducted with key stakeholders including regional government staff, council staff, community leaders and community-based organisations. The data were analysed thematically; open, descriptive coding was combined with exploration of pre-determined investigative areas.

Results

The study confirmed that access to healthcare has become increasingly challenging in conflict-affected areas. Although the Ministry of Health are providing CHWs to improve access, several barriers remain that limit uptake of these services including awareness, availability, cost, trust in competency, and supply of testing and treatment. This study found that communities were supportive of community engagement approaches, particularly the community dialogue approach.

Conclusion

Communities in conflict-affected regions of Cameroon continue to have limited access to healthcare services, in part due to poor use of CHW services provided. Community engagement approaches can be an effective way to improve the awareness and use of CHWs. However, these approaches alone will not be sufficient to resolve all the challenges faced by conflict-affected communities when accessing health and malaria services. Additional interventions are needed to increase the availability of CHWs, improve the supply of diagnostic tests and treatments and to reduce the cost of treatment for all.
Multi-element analysis of metals in human pathological and unchanged thyroid glands – pilot study
Authors: Kuzan Aleksandra , Rewak-Soroczyńska Justyna , Kardach Marta , Królewicz Emilia , Kaliszewski Krzysztof , Wiglusz Rafał
Published: May 2024

Disturbances in the homeostasis of the elemental composition of thyroid tissue may have serious metabolic and health consequences. It is believed that the accumulation of some metals or the deficiency of others may even cause lethal tumours. Due to the fact that metallomics most often uses human serum to analyse macro and microelements as well as trace elements, it was decided to use material that is more difficult to obtain, but also adds credibility to the research – thyroid tissue samples biopsy. The experiments were conducted on 17 patients diagnosed with: nodular (10) and colloidal goitre (2), chronic thyroiditis (2), follicular adenoma (2) and papillary carcinoma (1). They were recruited by collecting a tumour fragment, control fragment and serum from each of them. The content of Ca, Cd, Co, Cr, Cu, Fe, Mg, Mn, Ni, Pb, Zn was examined using ICP-OES (Inductively Coupled Plasma - Optical Emission Spectrometers). Simultaneously, biochemical methods were used to determine the markers of inflammation, glycation and peroxidation: malondialdehyde, pentosidine, reactive free amine content, compounds with thiol groups and galectin 3 in the sera of the examined patients. Three statistically significant correlations were identified: Ca-Mg and Cu-Zn in control tissues (p < 0.05) and Cr-Mn in pathological tissues (p < 0.05). A comparison of individual groups of patients shows that there are some potentail tendencies to increase or decrease in the concentration of certain elements or markers of inflammation and glycation, therefore we discuss potential relationships between a given parameter and a thyroid disorder. The pilot study is an introduction to a deeper analysis aimed at tracing the pathomechanism of the development of thyroid diseases, so that the risk of developing these diseases can be effectively minimized.
Galectin-receptor interaction: a key player in liver fibrosis induced by Schistosoma japonicum infection
Authors: Huang Ziyun , Liu Xingzhuo , Huang Shiguang , Lu Fangli
Published: May 2024

Background

Schistosoma japonicum eggs lodge in the liver and induce a fibrotic granulomatous immune response in the liver of host. Galectin 3 (Gal-3) is a protein implicated in fibrosis in multiple organs. However, the pathology and molecular mechanisms promoting hepatic granuloma formation remain poorly understood.

Methods

To investigate the effect of blocking galectin-receptor interactions by α-lactose on liver immunopathology in mice with S. japonicum infection, C57BL/6 mice were infected with S. japonicum and alpha (α)-lactose was intraperitoneally injected to block the interactions of galectins and their receptors.

Results

Compared with S. japonicum-infected mice, there were significantly decreased Gal-3 mRNA and protein expression levels, decreased intensity of Gal-3 fluorescence in the liver, decreased serum ALT and AST levels, decreased egg numbers of S. japonicum in the liver section, attenuated hepatic and spleen pathology, and alleviated liver fibrosis accompanied with decreased protein expression levels of fibrosis markers [α-smooth muscle actin (α-SMA), collagen I, and collagen IV] in the liver of S. japonicum-infected mice blocked galectin-receptor interactions with hematoxylin-eosin staining, Masson’s trichrome staining, immunohistochemistry, or Western blot analysis. Compared with S. japonicum-infected mice, blocking galectin-receptor interactions led to increased eosinophil infiltration and higher eosinophil cationic protein (ECP) expression in the liver, accompanied by increased mRNA levels of eosinophil granule proteins [ECP and eosinophil peroxidase (EPO)], IL-5, CCL11, and CCR3 in the liver and decreased mRNA levels of Gal-3 and M2 macrophage cytokines (TGF-β, IL-10, and IL-4) in the liver and spleen by using quantitative real-time reverse transcription-polymerase chain reaction. In addition, there were increased Beclin1 protein expression and protein expression ratio of LC3B-II/LC3B-I and decreased p62 protein expression and protein expression ratios of phospho-mTOR/mTOR and phospho-AKT/AKT by Western blot; increased double-labeled F4/80+/LC3B+ cells by immunofluorescence staining; increased M1 macrophage polarization in the liver of S. japonicum-infected mice blocked galectin-receptor interactions by flow cytometric analysis and immunofluorescence staining.

Conclusions

Our data found that blockage of galectin-receptor interactions downregulated Gal-3, which in turn led to reduced liver functional damage, elevated liver eosinophil recruitment, promoted macrophage autophagy through the Akt/mTOR signaling pathway, and alleviated liver pathology and fibrosis. Therefore, Gal-3 plays a pivotal role during S. japonicum infection and could be a target of pharmacologic potential for liver fibrosis induced by S. japonicum infection.

Graphical Abstract
Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes
Authors: Cao Xueqi , Huber Sandra , Ahari Ata Jadid , Traube Franziska R. , Seifert Marc , Oakes Christopher C. , Secheyko Polina , Vilov Sergey , Scheller Ines F. , Wagner Nils , Yépez Vicente A. , Blombery Piers , Haferlach Torsten , Heinig Matthias , Wachutka Leonhard , Hutter Stephan , Gagneur Julien
Published: May 2024

Background

Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging.

Methods

To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes.

Results

We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities.

Conclusions

Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.
Type 2 diabetes in latin America: recommendations on the flash glucose monitoring system
Authors: Krakauer Marcio , Gómez Ana M. , Almeda-Valdes Paloma , Manrique Helard , Ruiz Morosini María Lidia , Godoy Jorquera Gonzalo , Nunes Salles João Eduardo , Sanhueza Costa David , de Azeredo Siqueira Rodrigo , Faradji Raquel N. , Rincón Ramírez Alex , Ré Matías , Fériz Bonelo Karen , Proietti Adrián , Lavalle-González Fernando J.
Published: May 2024

Objective

To establish recommendations through the consensus of a Latin American experts panel on the use of the flash glucose monitoring system (fCGM) in people living with type 2 diabetes mellitus (T2DM) regarding the benefits and challenges of using the fCGM.

Methods

An executive committee of experts was created, comprised by a panel of fifteen physicians, including endocrinologists and internal medicine physicians, with expertise in management of adult patients with T2DM. The experts were from various countries: Colombia, Chile, Peru, Mexico, Argentina, and Brazil. The modified Delphi method was used, considering a consensus level of at least 80% of the participants. A seventeen-item instrument was developed to establish recommendations on the use of fCGM in patients with T2DM in Latin American.

Results

The number of glucose scans recommended per day with the fCGM for patients managed with oral antidiabetic drugs or basal insulin was a median of 6 scans per day, and for those managed with multiple insulin doses, a median of 10 scans per day was recommended. Additionally, a holistic and individualized management approach was recommended, taking into account new treatment directions and identifying patients who would benefit from the use of the fCGM.

Conclusion

Continuous use of the fCGM is recommended for people living with T2DM, regardless of their type of treatment. These metrics must be evaluated individually for each patient profile.
Endovascular treatments of acute pulmonary embolism in the post-fibrinolytic era: an up-to-date review
Authors: Ubaldi Nicolò , Krokidis Miltiadis , Rossi Michele , Orgera Gianluigi
Published: May 2024

Pulmonary embolism (PE) is a significant contributor to global cardiovascular-related mortality that mainly depends on the severity of the event. The treatment approach for intermediate and high-risk PE remains a topic of debate due to the fine balance between hemodynamic deterioration and bleeding risk. The initial treatment choice for intermediate-risk PE with hemodynamic deterioration and high-risk PE is historically systemic thrombolysis, but this approach is not always effective and carries a notable risk of severe bleeding. For such patients, various interventional treatments have been introduced to clinical practice, including catheter-directed lysis (CDL), ultrasound-assisted CDL, pharmacomechanical CDL, and aspiration thrombectomy. However, the optimal treatment approach remains uncertain. Encouraging outcomes have been presented assessing the novel endovascular treatments, in terms of reducing right ventricular dysfunction and improving hemodynamic stability, opening the possibility of using these devices to prevent hemodynamic instability in less severe cases. However, ongoing randomized trials that assess the efficacy and the association with mortality, especially for aspiration devices, have not yet published their final results. This article aims to offer a comprehensive update of the available catheter-directed therapies for PE, with a focus on novel mechanical thrombectomy techniques, assessing their safety and efficacy, after comparison to the conventional treatment.

Critical relevance statement

This is a comprehensive review of the indications of use, techniques, and clinical outcomes of the most novel endovascular devices for the treatment of pulmonary embolism.

Key Points

Mechanical thrombectomy is an effective tool for patients with PE.

Aspiration devices prevent hemodynamic deterioration.

Catheter directed therapy reduces bleeding complications.

Graphical Abstract