bluuebunny/crossref_metadata_2025 huggingface dataset:
Active tuberculosis in inflammatory bowel disease patients: a case–control study
Authors: Freitas Cardoso de Azevedo Matheus , Barros Luísa Leite , Fernandes Justus Filipe , Oba Jane , Soares Garcia Karoline , de Almeida Martins Camilla , de Sousa Carlos Alexandre , Arruda Leite André Zonetti , Miranda Sipahi Aytan , Queiroz Natália Sousa Freitas , Omar Mourão Cintra Damião Adérson
Published: July 2023

Background/Aims:

Anti-tumor necrosis factor (anti-TNF) drugs have been the mainstay therapy for moderate to severe inflammatory bowel disease (IBD) over the past 25 years. Nevertheless, these drugs are associated with serious opportunistic infections like tuberculosis (TB). Brazil is ranked among the 30 countries with the highest incidence of TB in the world. This study aimed at identifying risk factors for the development of active TB and describing clinical characteristics and outcomes in IBD patients followed at a tertiary referral center in Brazil.

Methods:

We conducted a retrospective, case–control study between January 2010 and December 2021. Active TB cases in IBD patients were randomly matched 1:3 to controls (IBD patients with no previous history of active TB) according to gender, age, and type of IBD.

Design:

This was a retrospective, case–control study.

Results:

A total of 38 (2.2%) cases of TB were identified from 1760 patients under regular follow-up at our outpatient clinics. Of the 152 patients included in the analysis (cases and controls), 96 (63.2%) were male, and 124 (81.6%) had Crohn’s disease. Median age at TB diagnosis was 39.5 [interquartile range (IQR) 30.8–56.3]. Half of the active TB cases were disseminated (50%). Overall, 36 patients with TB (94.7%) were being treated with immunosuppressive medications. Of those, 31 (86.1%) were under anti-TNF drugs. Diagnosis of TB occurred at a median of 32 months after the first dose of anti-TNF (IQR 7–84). In multivariate analysis, IBD diagnosis older than 17 years and anti-TNF therapy were significantly associated with the development of TB ( p < 0.05). After the TB treatment, 20 (52.7%) patients received anti-TNF therapy, and only one developed ‘de novo’ TB 10 years after the first infection.

Conclusions:

TB remains a significant health problem in IBD patients from endemic regions, especially those treated with anti-TNFs. In addition, age at IBD diagnosis (>17 years old) was also a risk factor for active TB. Most cases occur after long-term therapy, suggesting a new infection. The reintroduction of anti-TNFs agents after the anti-TB treatment seems safe. These data highlight the importance of TB screening and monitoring in IBD patients living in endemic areas.
Spontaneous improvement of olisthetic scoliosis in children following lumbosacral fusion for high-grade spondylolisthesis: A report of four new cases and systematic review of the literature
Authors: Mehlman Charles T , Crawford Alvin H
Published: July 2023

Background:

The study aim was to present four new well-documented cases of spontaneous improvement of olisthetic scoliosis and to analyze well-documented cases from the literature.

Methods:

Surgical log search and systematic review were conducted. Inclusion criteria were (1) age less than 18 years, (2) symptomatic high-grade (≥50%) spondylolisthesis, (3) scoliosis ≥20o, (4) primary surgical treatment via lumbosacral fusion, (5) complete x-rays, and (6) minimum 1-year radiographic follow-up or until curve resolution.

Results:

A total of 13 patients with average age of 13.9 years were included in the study, 4 from the authors’ surgical logs and 9 from the literature. Slip percentage of L5-S1 ranged from 51% to 95%. Olisthetic curve magnitude averaged 34.6° (range: 20°–45°) with majority (8/13) demonstrating long thoracic curves with lateral trunk shift. All but one of these were apex right with rightward trunk shift. The remainder of the curves were isolated lumbar curves, with an apex left morphology without trunk shift. Eleven of the 13 patients showed curve improvement following isolated lumbosacral fusion. Three patients experienced a decrease in curve magnitude of 12°–28° and eight patients enjoyed complete resolution (≤10°) of their scoliosis.

Conclusion:

The current study summarizes 13 well-documented cases of olisthetic scoliosis (4 new cases and 9 from the literature) that associated with symptomatic high-grade spondylolisthesis. All were treated via a primary posterior lumbosacral fusion strategy. Eleven of the 13 curves showed spontaneous improvement (8 complete resolution of scoliosis) following their lumbosacral surgery.

Level of evidence:

Therapeutic level IV.
The Teddy Bear Clinic: Engaging School-Aged Children in Health Education
Authors: Alexander-Ruff Julie H. , Ruff Sarah A. , Roper Chelsey , Wilz Alexandra
Published: July 2023

This article describes the use of play therapy in a school-based health clinic on an American Indian Reservation. The project used the play therapy model, a nursing intervention focused on using play materials in a therapeutic manner as a form of communication and self-expression for children, enhancing the development of social, emotional, and behavioral skills through the nursing process. The purpose of the Teddy Bear Clinic was to establish relationships among non-Native student nurses and Native American children and their community on a Northern Plains Indian Reservation. A discussion of the potential benefits addresses opportunities for school nurses and student nurses to enhance their understanding of children’s perceptions of the health care clinic and the effects of historical trauma on the health and wellbeing of Native American children while offering an opportunity for young children to engage in the health care setting in a fun way, without fear or discomfort is provided.
Invited Commentary: Achieving Post-Bypass Hemostasis in Young Children: At What Cost?
Authors: Nicholson Susan
Published: July 2023

Young children requiring bypass often develop coagulopathy resulting in major postoperative blood loss. Increased post-bypass bleeding and donor exposures are independently associated with adverse outcomes. When transfusion of hemostatic blood products fails to reduce bleeding to an acceptable level, rescue therapies including prothrombin complex concentrates (PCCs), and/or recombinant activated factor VII are being given “off-label” with increasing frequency. A number of studies attempting to determine the safety and efficacy of PCCs in neonates and young children are being published. These studies are most commonly retrospective, observational, performed in a single center with varying doses, indications for, and timing of administration in a small number of patients with varying results. The results of these individual studies are questionable and are not to be generalized to other center's patients. Because factor VIII inhibitor bypassing activity (FEIBA) contains the activated form of factor VII and factor X there are concerns regarding the potential for thrombotic events in a population with a known risk of postoperative thromboembolism. Currently, there is no validated assay with which to measure the efficacy of FEIBA in vivo to determine dose titration. Well-designed multicenter randomized control trials are needed to determine the optimal dose and risk–benefit of PCCs after pediatric cardiac surgery. Until such data are available the decision to give a procoagulant to neonates and young children after bypass needs to be made when the consequences of blood loss and replacement pose more risk than the risk of thrombotic complications from the drug.
The Relationship Between Cultural Intelligence and Cultural Competence of Students of Nursing and Midwifery During COVID-19: A Cross-Sectional Study
Authors: Bakhtiari Zeynab , Hanifi Nasrin , Varjoshani Nasrin Jafari
Published: July 2023

Objectives

This study aimed to determine the relationship between cultural intelligence and cultural competence (CC) of the school of nursing and midwifery students from the Zanjan University of Medical Sciences in 2020-2021.

Methods

This cross-sectional study was conducted on 245 from 600 nursing and midwifery students of the Zanjan University of Medical Sciences from November 24, 2020, to March 18, 2021. Data were collected using three questionnaires of demographic information, Cultural Intelligence Scale, and The Nurse Cultural Competence Scale. Data analysis was done through Pearson's test and the logistic regression model using SPSS Version 22.

Results

The response rate was 40.83%. The results showed that the total score of cultural intelligence had a strong positive relationship with CC ( r = 0.88). Also, the logistic regression model showed that the cultural intelligence variable could predict nursing and midwifery students’ CC (B = 0.1, P = .013).

Conclusion

It is recommended to pay more attention to increasing the cultural intelligence and CC of nursing and midwifery students.
Person Perception of Students on Reservation in Higher Education in India
Authors: Mohanan Syama M. , Netto Sibu G.
Published: July 2023

The present study aimed to determine the person perception of students on reservation in higher education. The respondents of the study were from three districts of Kerala. The data were collected using a Person Perception Scale. The brief profile of the total respondents ( N = 490) shows 195 boys and 295 girls; 305 rural and 185 urban; 320 government and 170 private; 338 Above Poverty Line (APL) and 152 Below Poverty Line (BPL)), respectively. The study adopted a random sampling technique. The data collected were analysed for mean, standard deviation and t-test techniques. The result of the study revealed that boys have a higher person perception than girls; rural students have a higher person perception than urban students; government school students have a higher person perception than private school students; students who belong to the APL category have a higher person perception than BPL category; regarding reservation in higher education. And in total, students possess an average level (60%) of person perception on reservation in higher education.
An Analysis of Craniofacial Surgery Fellowship Websites and Social Media Presence
Authors: Ho Isabel , Wang Howard D.
Published: July 2023

Background:

Applying to craniofacial surgery fellowship is a competitive process, and applicants may find it challenging to determine which programs are the best fit. We sought to evaluate the quality of information available on craniofacial surgery fellowship websites (CFWs), identify areas for improvement, and evaluate social media presence.

Methods:

Individual CFWs were identified from the ASCFS directory and Google search. Demographic information was collected from the ASCFS directory, and CFWs were evaluated for qualitative information. Social media presence was assessed by querying Facebook, Instagram, and Twitter for official and active accounts.

Results:

Thirty-one programs were identified. While most ASCFS listings included addresses (93.6%) and program coordinator contact (87.1%), only half included program director contact. The majority of CFWs included a procedure list (71.0%), research opportunities (58.1%), current fellows (56.7%), and didactic schedules (71.0%). Few CFWs included case logs (16.1%), call schedule (22.6%), salary/benefits (25.8%), and alumni information (38.7%). Regarding social media presence, only 3 craniofacial fellowship programs were on Facebook (9.7%), 2 on Instagram (6.5%), and none on Twitter. In comparison, affiliated plastic surgery residencies were more active on Instagram (64.5%), Facebook (38.7%), and Twitter (25.8%).

Conclusion:

There are several potential areas for improvement of CFWs, including maintaining an updated ASCFS directory of CFWs. Programs may consider adding information about case logs, call schedule, and alumni career path. Creating comprehensive websites and increasing social media presence would provide a valuable source of information to potential applicants and serve as an effective tool for recruitment.
Exploring the bidirectional relationship between pain and mental disorders: a comprehensive Mendelian randomization study
Authors: Yao Chongjie , Zhang Yuchen , Lu Ping , Xiao Bin , Sun Pingping , Tao Jiming , Cheng Yanbin , Kong Lingjun , Xu Dongsheng , Fang Min
Published: July 2023

Background

The close relationship between pain and mental health problems is well-known, and psychological intervention can provide an effective alternative to medication-based pain relief. However, previous studies on the connection between pain and psychological problems, the findings thus far have been inconclusive, limiting the potential for translating psychological interventions into clinical practice. To complement the gap, this study utilized genetic data and Mendelian randomization (MR) to examine the potential relationship between pain in different parts and common mental disorders.

Methods

Based on the instrumental variables selected from the Genome-wide association study summary statistics of localized pain and mental disorders, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between pain and mental disorders. The inverse-variance weighted MR method and MR-Egger were used as the primary statistical method according to the horizontal pleiotropy and heterogeneity level. We reported the odds ratio to infer the causal effect between pain and mental disorders. F statistic was calculated to measure the statistical efficacy of the analyses.

Results

Insomnia is causally related to the genetic susceptibility of multisite pain including head (OR = 1.09, 95% CI: 1.06–1.12), neck/shoulder (OR = 1.12, 95% CI: 1.07–1.16), back (OR = 1.12, 95% CI: 1.07–1.18) and hip (OR = 1.08, 95% CI: 1.05–1.10). Reversely, headache (OR = 1.14, 95% CI: 1.05–1.24), neck/shoulder pain (OR = 1.95, 95% CI: 1.03–3.68), back pain (OR = 1.40, 95% CI: 1.22–1.60), and hip pain (OR = 2.29, 95% CI: 1.18–4.45) promote the genetic liability of insomnia. Depression is strongly associated with the predisposition of multisite pain including headache (OR = 1.28, 95% CI: 1.08–1.52), neck/shoulder pain (OR = 1.32, 95% CI: 1.16–1.50), back pain (OR = 1.35, 95% CI: 1.10–1.66) and stomach/abdominal pain (OR = 1.14, 95% CI: 1.05–1.25), while headache (OR = 1.06, 95% CI: 1.03–1.08), neck/shoulder (OR = 1.09, 95% CI: 1.01–1.17), back (OR = 1.08, 95% CI: 1.03–1.14), and stomach/abdominal pain (OR = 1.19, 95% CI: 1.11–1.26) are predisposing factors for depression. Additionally, insomnia is associated with the predisposition of facial, stomach/abdominal, and knee pain, anxiety was associated with the predisposition of neck/shoulder and back pain, while the susceptibilities of hip and facial pain are influenced by depression, but these associations were unidirectional.

Conclusions

Our results enhance the understanding of the complex interplay between pain and mental health and highlight the importance of a holistic approach to pain management that addresses both physical and psychological factors.
E-GWAS: an ensemble-like GWAS strategy that provides effective control over false positive rates without decreasing true positives
Authors: Zhou Guang-Liang , Xu Fang-Jun , Qiao Jia-Kun , Che Zhao-Xuan , Xiang Tao , Liu Xiao-Lei , Li Xin-Yun , Zhao Shu-Hong , Zhu Meng-Jin
Published: July 2023

Background

Genome-wide association studies (GWAS) are an effective way to explore genotype–phenotype associations in humans, animals, and plants. Various GWAS methods have been developed based on different genetic or statistical assumptions. However, no single method is optimal for all traits and, for many traits, the putative single nucleotide polymorphisms (SNPs) that are detected by the different methods do not entirely overlap due to the diversity of the genetic architecture of complex traits. Therefore, multi-tool-based GWAS strategies that combine different methods have been increasingly employed. To take this one step further, we propose an ensemble-like GWAS strategy (E-GWAS) that statistically integrates GWAS results from different single GWAS methods.

Results

E-GWAS was compared with various single GWAS methods using simulated phenotype traits with different genetic architectures. E-GWAS performed stably across traits with different genetic architectures and effectively controlled the number of false positive genetic variants detected without decreasing the number of true positive variants. In addition, its performance could be further improved by using a bin-merged strategy and the addition of more distinct single GWAS methods. Our results show that the numbers of true and false positive SNPs detected by the E-GWAS strategy slightly increased and decreased, respectively, with increasing bin size and when the number and the diversity of individual GWAS methods that were integrated in E-GWAS increased, the latter being more effective than the bin-merged strategy. The E-GWAS strategy was also applied to a real dataset to study backfat thickness in a pig population, and 10 candidate genes related to this trait and expressed in adipose-associated tissues were identified.

Conclusions

Using both simulated and real datasets, we show that E-GWAS is a reliable and robust strategy that effectively integrates the GWAS results of different methods and reduces the number of false positive SNPs without decreasing that of true positive SNPs.
Intermediate complex morphophysiological dormancy in seeds of Aconitum barbatum (Ranunculaceae)
Authors: Zhang Lei , Xu Chaohan , Liu Huina , Wu Qingqing , Tao Jun , Zhang Keliang
Published: July 2023

Background

Seed dormancy and germination are key components of plant regeneration strategies. Aconitum barbatum is a plant commonly found in northeast China. Although it has potential for use in gardening and landscaping, its seed dormancy and regeneration strategy, which adapt to its natural habitat, are not well understood. Our aim was to identify conditions for breaking A. barbatum seed dormancy and determine its dormancy type. Embryo growth and germination were determined by collecting seeds over time in the field. Laboratory experiments that control light, temperature, and stratification period were conducted to assess dormancy breaking and germination, and GA3 was used to identify dormancy type.

Results

Seeds of A. barbatum have undeveloped embryos with physiological dormancy at maturity in autumn. The embryo-to-seed length ratio increases from 0.33 to 0.78 before the emergence of the radical. Under natural environmental conditions, embryo development begins in early winter. Laboratory experiments have shown that long-term incubation under 4 °C (cold stratification) promotes embryo development and seed dormancy break. With an extension of cold stratification, an increase in germination percentages was observed when seeds were transferred from 4 °C to warmer temperatures. Seeds exposed to light during incubation show a higher germination percentage than those kept in the dark. Seed germination can also be enhanced by a 100 mg/L GA3 concentration.

Conclusions

Seeds of A. barbatum display intermediate complex morphophysiological dormancy at maturity. In addition to the underdeveloped embryo, there are also physiological barriers that prevent the embryo from germinating. Dormancy breaking of A. barbatum seeds can be achieved by natural winter cold stratification, allowing seeds to germinate and sprout seedlings at the beginning of the following growing season. Our findings provide valuable insights into the seed dormancy and regeneration strategy of A. barbatum, which could facilitate its effective utilization in gardening and landscaping.
The association of intrauterine and postnatal growth patterns and nutritional status with toddler body composition
Authors: Masiakwala Elizabeth , Nyati Lukhanyo H. , Norris Shane A.
Published: July 2023

Background

Growth patterns may be indicative of underlying changes in body composition. However, few studies have assessed the association of growth and body composition in poorly resourced regions experiencing the double-burden of malnutrition exists. Thus, the aims of this study were to investigate the association of intrauterine and postnatal growth patterns with infant body composition at 2 years in a middle-income country.

Methods

Participants were from the International Atomic Energy Agency Multicentre Body Composition Reference study. Fat mass (FM), fat free mass (FFM), Fat mass index (FMI), fat free mass index (FFMI), and percentage fat mass (%FM) were measured in 113 infants (56 boys and 57 girls), from Soweto, South Africa, using deuterium dilution from 3 to 24 months. Birthweight categories were classified using the INTERGROWTH-21 standards as small (SGA), appropriate (AGA), and large-for gestational age (LGA). Stunting (> -2 SDS) was defined using the WHO child growth standards. Birthweight z-score, conditional relative weight and conditional length at 12 and 24 mo were regressed on body composition at 24 mo.

Results

There were no sex differences in FM, FFM, FMI and FFMI between 3 and 24 mo. SGA and AGA both had significantly higher %FM than LGA at 12 mo. LGA had higher FM at 24 mo. Children with stunting had lower FM (Mean = 1.94, 95% CI; 1.63–2.31) and FFM (Mean = 5.91, 95% CI; 5.58–6.26) at 12 mo than non-stunting, while the reverse was true for FFMI (Mean = 13.3, 95% CI; 12.5–14.2) at 6 mo. Birthweight and conditionals explained over 70% of the variance in FM. CRW at both 12 and 24 mo was positively associated with FM and FMI. CRW at 12 mo was also positively associated with FMI, while CH at 24 mo was negatively associated with both FFMI and FMI in boys.

Conclusion

Both LGA and SGA were associated with higher body fat suggesting that both are disadvantaged nutritional states, likely to increase the risk of obesity. Growth patterns through infancy and toddler period (1–2 years) are indicative of body fat, while growth patterns beyond infancy are less indicative of fat-free mass.
A computational approach to optimising laccase-mediated polyethylene oxidation through carbohydrate-binding module fusion
Authors: Gollan Michael , Black Gary , Munoz-Munoz Jose
Published: July 2023

Plastic pollution is a major global concern to the health and wellbeing of all terrestrial and marine life. However, no sustainable method for waste management is currently viable. This study addresses the optimisation of microbial enzymatic polyethylene oxidation through rational engineering of laccases with carbohydrate-binding module (CBM) domains. An explorative bioinformatic approach was taken for high-throughput screening of candidate laccases and CBM domains, representing an exemplar workflow for future engineering research. Molecular docking simulated polyethylene binding whilst a deep-learning algorithm predicted catalytic activity. Protein properties were examined to interpret the mechanisms behind laccase-polyethylene binding. The incorporation of flexible GGGGS(x3) hinges were found to improve putative polyethylene binding of laccases. Whilst CBM1 family domains were predicted to bind polyethylene, they were suggested to detriment laccase-polyethylene associations. In contrast, CBM2 domains reported improved polyethylene binding and may thus optimise laccase oxidation. Interactions between CBM domains, linkers, and polyethylene hydrocarbons were heavily reliant on hydrophobicity. Preliminary polyethylene oxidation is considered a necessity for consequent microbial uptake and assimilation. However, slow oxidation and depolymerisation rates inhibit the large-scale industrial implementation of bioremediation within waste management systems. The optimised polyethylene oxidation of CBM2-engineered laccases represents a significant advancement towards a sustainable method of complete plastic breakdown. Results of this study offer a rapid, accessible workflow for further research into exoenzyme optimisation whilst elucidating mechanisms behind the laccase-polyethylene interaction.
Perturbing BEAMs: EEG adversarial attack to deep learning models for epilepsy diagnosing
Authors: Yu Jianfeng , Qiu Kai , Wang Pengju , Su Caixia , Fan Yufeng , Cao Yongfeng
Published: July 2023

Deep learning models have been widely used in electroencephalogram (EEG) analysis and obtained excellent performance. But the adversarial attack and defense for them should be thoroughly studied before putting them into safety-sensitive use. This work exposes an important safety issue in deep-learning-based brain disease diagnostic systems by examining the vulnerability of deep learning models for diagnosing epilepsy with brain electrical activity mappings (BEAMs) to white-box attacks. It proposes two methods, Gradient Perturbations of BEAMs (GPBEAM), and Gradient Perturbations of BEAMs with Differential Evolution (GPBEAM-DE), which generate EEG adversarial samples, for the first time by perturbing BEAMs densely and sparsely respectively, and find that these BEAMs-based adversarial samples can easily mislead deep learning models. The experiments use the EEG data from CHB-MIT dataset and two types of victim models each of which has four different deep neural network (DNN) architectures. It is shown that: (1) these BEAM-based adversarial samples produced by the proposed methods in this paper are aggressive to BEAM-related victim models which use BEAMs as the input to internal DNN architectures, but unaggressive to EEG-related victim models which have raw EEG as the input to internal DNN architectures, with the top success rate of attacking BEAM-related models up to 0.8 while the top success rate of attacking EEG-related models only 0.01; (2) GPBEAM-DE outperforms GPBEAM when they are attacking the same victim model under a same distortion constraint, with the top attack success rate 0.8 for the former and 0.59 for the latter; (3) a simple modification to the GPBEAM/GPBEAM-DE will make it have aggressiveness to both BEAMs-related and EEG-related models (with top attack success rate 0.8 and 0.64), and this capacity enhancement is done without any cost of distortion increment. The goal of this study is not to attack any of EEG medical diagnostic systems, but to raise concerns about the safety of deep learning models and hope to lead to a safer design.
Dysregulated Rbfox2 produces aberrant splicing of CaV1.2 calcium channel in diabetes-induced cardiac hypertrophy
Authors: Li Pengpeng , Qin Dongxia , Chen Tiange , Hou Wei , Song Xinyu , Yin Shumin , Song Miaomiao , Fernando W.C. Hewith A. , Chen Xiaojie , Sun Yu , Wang Juejin
Published: July 2023

Background

L-type Ca2+ channel CaV1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac CaV1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of CaV1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how CaV1.2 channels are alternatively spliced in diabetic heart remains unknown.

Methods

Diabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac CaV1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca2+ concentration was monitored by using Fluo-4 AM.

Results

We find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased CaV1.2 channel with alternative exon 9* (CaV1.2E9*), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of CaV1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates CaV1.2E9* channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac CaV1.2 channels. Moreover, GS treatment raises K+-triggered intracellular Ca2+ concentration ([Ca2+]i), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates CaV1.2E9* channel, shifts CaV1.2 window currents to hyperpolarization, increases [Ca2+]i and induces cardiomyocyte hypertrophy.

Conclusions

AGEs, not glucose, dysregulates Rbfox2 which thereby increases CaV1.2E9* channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca2+]i in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for CaV1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced CaV1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.
Impact of the SGLT2-inhibitor empagliflozin on inflammatory biomarkers after acute myocardial infarction – a post-hoc analysis of the EMMY trial
Authors: Benedikt Martin , Mangge Harald , Aziz Faisal , Curcic Pero , Pailer Sabine , Herrmann Markus , Kolesnik Ewald , Tripolt Norbert J. , Pferschy Peter N. , Wallner Markus , Zirlik Andreas , Sourij Harald , von Lewinski Dirk
Published: July 2023

Background

SGTL2-inhibitors are a cornerstone in the treatment of heart failure, but data on patients with acute myocardial infarction (AMI) is limited. The EMMY trial was the first to show a significant reduction in NTproBNP levels as well as improved cardiac structure and function in post-AMI patients treated with Empagliflozin compared to placebo. However, data on the potential impact of SGLT2-inhibitors on inflammatory biomarkers after AMI are scarce.

Materials and methods

The EMMY trial is an investigator-initiated, multicentre, double-blind, placebo-controlled trial, which enrolled patients after AMI, receiving either 10 mg Empagliflozin once daily or placebo over a period of 26 weeks on top of standard guideline-recommended therapy starting within 72 h after percutaneous coronary intervention. In this post-hoc subgroup analysis of the EMMY trial, we investigated inflammatory biomarkers of 374 patients. The endpoints investigated were the mean change in inflammatory biomarkers such as high-sensitive c-reactive protein (hsCRP), interleukin-6 (IL-6), neutrophils, leukocytes, neutrophile/lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) from baseline to 26 weeks.

Results

Baseline median (interquartile ranges) IL-6 was 17.9 pg/mL (9.0-38.7), hsCRP 18.9 mg/L (11.2–37.1), neutrophil count 7.9 x G/L (6.2–10.1), leukocyte count 10.8 x G/L (9.1–12.8) and neutrophile/lymphocyte ratio (NLR) of 0.74 (0.67–0.80). At week 26, a significant mean reduction in inflammatory biomarkers was observed, being 35.1 ± 3.2% (p < 0.001) for IL-6, 57.4 ± 0.7% (p < 0.001) for hsCRP, 26.1 ± 0.7% (p < 0.001) for neutrophils, 20.5 ± 0.6% (p < 0.001) for leukocytes, 10.22 ± 0.50% (p < 0.001) for NLR, and − 2.53 ± 0.92% for PLR (p = 0.006) with no significant difference between Empagliflozin and placebo treatment.

Conclusion

Trajectories of inflammatory biomarkers showed a pronounced decline after AMI, but Empagliflozin treatment did not impact this decline indicating no central role in blunted systemic inflammation mediating beneficial effects.
Matcha green tea beverage moderates fatigue and supports resistance training-induced adaptation
Authors: Shigeta Mizuho , Aoi Wataru , Morita Chiharu , Soga Kurumi , Inoue Ryo , Fukushima Yoichi , Kobayashi Yukiko , Kuwahata Masashi
Published: July 2023

Background

Resistance training adaptively increases muscle strength and mass, contributing to athletic performance and health promotion. Dietary intervention with natural foods provides nutrients that help accelerate muscle adaptation to training. Matcha green tea contains several bioactive factors such as antioxidants, amino acids, and dietary fibers; however, its effect on muscle adaptation is unclear. In this study, we aimed to investigate the effects of matcha beverage intake on muscle adaptation to resistance training.

Methods

Healthy, untrained men were randomized into placebo and matcha groups. Participants consumed either a matcha beverage containing 1.5 g of matcha green tea powder or a placebo beverage twice a day and engaged in resistance training programs for 8 (trial 1) or 12 weeks (trial 2).

Results

In trial 1, maximum leg strength after training tended to increase more in the matcha group than that in the placebo group. In the matcha group, subjective fatigue after exercise at 1 week of training was lower than that in the placebo group. Gut microbe analysis showed that the abundance of five genera changed after matcha intake. The change in Ruminococcus, Butyricimonas, and Oscillospira compositions positively correlated with the change in maximum strength. In trial 2, the change in skeletal muscle mass in response to training was larger in the matcha group. In addition, the salivary cortisol level was lower in the matcha group than that in the placebo group.

Conclusion

Daily intake of matcha green tea beverages may help in muscle adaptation to training, with modulations in stress and fatigue responses and microbiota composition.
Nanomedicine-based adjuvant therapy: a promising solution for lung cancer
Authors: Xu Yiming , Hsu Jessica C. , Xu Liyun , Chen Weiyu , Cai Weibo , Wang Kai
Published: July 2023

Lung cancer has been the leading cause of cancer-related deaths worldwide for decades. Despite the increasing understanding of the underlying disease mechanisms, the prognosis still remains poor for many patients. Novel adjuvant therapies have emerged as a promising treatment method to augment conventional methods and boost the therapeutic effects of primary therapies. Adjuvant therapy based on nanomedicine has gained considerable interest for supporting and enhancing traditional therapies, such as chemotherapy, immunotherapy, and radiotherapy, due to the tunable physicochemical features and ease of synthetic design of nanomaterials. In addition, nanomedicine can provide protective effects against other therapies by reducing adverse side effects through precise disease targeting. Therefore, nanomedicine-based adjuvant therapies have been extensively employed in a wide range of preclinical and clinical cancer treatments to overcome the drawbacks of conventional therapies. In this review, we mainly discuss the recent advances in adjuvant nanomedicine for lung cancer treatment and highlight their functions in improving the therapeutic outcome of other therapies, which may inspire new ideas for advanced lung cancer therapies and stimulate research efforts around this topic.

Graphical Abstract
Biomimetic hypoxia-triggered RNAi nanomedicine for synergistically mediating chemo/radiotherapy of glioblastoma
Authors: Wang Zhen , Tang Xiang-long , Zhao Meng-jie , Zhang Yi-ding , Xiao Yong , Liu Yu-yang , Qian Chun-fa , Xie Yan-dong , Liu Yong , Zou Yuan-jie , Yang Kun , Liu Hong-yi
Published: July 2023

Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.

Graphical Abstract
Isorhamnetin and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles improve tumor immune microenvironment and inhibit YY1-mediated tumor progression
Authors: Liu Huijuan , Han Jingxia , Lv Ying , Zhao Zihan , Zheng Shaoting , Sun Yu , Sun Tao
Published: July 2023

Background

The immune checkpoint inhibitor (ICI) anti-PD-L1 monoclonal antibody can inhibit the progress of hepatocellular carcinoma (HCC). Epithelial–mesenchymal transformation (EMT) can promote tumor migration and the formation of immune-suppression microenvironment, which affects the therapeutic effect of ICI. Yin-yang-1 (YY1) is an important transcription factor regulating proliferation, migration and EMT of tumor cells. This work proposed a drug-development strategy that combined the regulation of YY1-mediated tumor progression with ICIs for the treatment of HCC.

Methods

We first studied the proteins that regulated YY1 expression by using pull-down, co-immunoprecipitation, and duo-link assay. The active compound regulating YY1 content was screened by virtual screening and cell-function assay. Isorhamnetin (ISO) and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles (HMSN-ISO@ProA-PD-L1 Ab) were prepared as an antitumor drug to play a synergistic anti-tumor role.

Results

YY1 can specifically bind with the deubiquitination enzyme USP7. USP7 can prevent YY1 from ubiquitin-dependent degradation and stabilize YY1 expression, which can promote the proliferation, migration and EMT of HCC cells. Isorhamnetin (ISO) were screened out, which can target USP7 and promote YY1 ubiquitin-dependent degradation. The cell experiments revealed that the HMSN-ISO@ProA-PD-L1 Ab nanoparticles can specifically target tumor cells and play a role in the controlled release of ISO. HMSN-ISO@ProA-PD-L1 Ab nanoparticles inhibited the growth of Hepa1-6 transplanted tumors and the effect was better than that of PD-L1 Ab treatment group and ISO treatment group. HMSN-ISO@ProA-PD-L1 Ab nanoparticles also exerted a promising effect on reducing MDSC content in the tumor microenvironment and promoting T-cell infiltration in tumors.

Conclusions

The isorhamnetin and anti-PD-L1 antibody dual-functional nanoparticles can improve tumor immune microenvironment and inhibit YY1-mediated tumor progression. This study demonstrated the possibility of HCC treatment strategies based on inhibiting USP7-mediated YY1 deubiquitination combined with anti-PD-L1 monoclonal Ab.
3-Bromopyruvate-loaded bismuth sulfide nanospheres improve cancer treatment by synergizing radiotherapy with modulation of tumor metabolism
Authors: He Yiman , Chen Huawan , Li Wenbo , Xu Lu , Yao Huan , Cao Yang , Wang Zhigang , Zhang Liang , Wang Dong , Zhou Di
Published: July 2023

Background

Radiotherapy (RT) is one of the most mainstream cancer therapeutic modalities. However, due to the lack of specificity of the radiation adopted, both normal and cancerous cells are destroyed indiscriminately. This highlights the crucial need to improve radiosensitization. This study aims to address this issue by constructing a multifunctional nanospheres that can sensitize multiple aspects of radiotherapy.

Results

Nanospheres containing high atomic element Bi can effectively absorb ionizing radiation and can be used as radiosensitizers. Cell viability after Bi2S3 + X-ray treatment was half that of X-ray treatment alone. On the other hand, exposed 3-bromopyruvate (3BP) could reduce the overactive oxygen (O2) metabolism of tumor cells and alleviate tumor hypoxia, thereby promoting radiation-induced DNA damage. The combination index (CI) of 3BP and Bi2S3-based RT in Bi2S3-3BP + X-ray was determined to be 0.46 with the fraction affected (fa) was 0.5 via Chou-Talalay’s isobolographic method, which indicated synergistic effect of 3BP and Bi2S3-based RT after integration into Bi2S3-3BP + X-ray. Under the combined effect of 3BP and RT, autophagy was over-activated through starvation-induced and redox homeostasis dysregulation pathways, which in turn exhibited pro-death effects. In addition, the prepared nanospheres possess strong X-ray attenuation and high near-infrared (NIR) optical absorption, thus eliminating the need for additional functional components and could serve as bimodal contrast agents for computed tomography/photoacoustic (CT/PA) imaging.

Conclusions

The rational design of multifunctional nanospheres with the unique properties provided a novel strategy to achieving high therapeutic efficacy in RT. This was accomplished through simultaneous activation of multiple sensitization pathways by increasing ionizing radiation, reducing tumor oxygen consumption, inducing pro-death autophagy, and providing multiple-imaging guidance/monitoring.
Genetic risk assessment of lethal prostate cancer using polygenic risk score and hereditary cancer susceptibility genes
Authors: Ruan Xiaohao , Huang Da , Huang Jingyi , Tsu James Hok-Leung , Na Rong
Published: July 2023

Background

The genetic risk of aggressive prostate cancer (PCa) is hard to be assessed due to the lack of aggressiveness-related single-nucleotide polymorphisms (SNPs). Prostate volume (PV) is a potential well-established risk factor for aggressive PCa, we hypothesize that polygenic risk score (PRS) based on benign prostate hyperplasia (BPH) or PV-related SNPs may also predict the risk of aggressive PCa or PCa death.

Methods

We evaluated a PRS using 21 BPH/PV-associated SNPs, two established PCa risk-related PRS and 10 guideline-recommended hereditary cancer risk genes in the population-based UK Biobank cohort (N = 209,502).

Results

The BPH/PV PRS was significantly inversely associated with the incidence of lethal PCa as well as the natural progress in PCa patients (hazard ratio, HR = 0.92, 95% confidence interval [CI]: 0.87–0.98, P = 0.02; HR = 0.92, 95% CI 0.86–0.98, P = 0.01). Compared with men at the top 25th PRS, PCa patients with bottom 25th PRS would have a 1.41-fold (HR, 95% CI 1.16–1.69, P = 0.001) increased PCa fatal risk and shorter survival time at 0.37 yr (95% CI 0.14–0.61, P = 0.002). In addition, patients with BRCA2 or PALB2 pathogenic mutations would also have a high risk of PCa death (HR = 3.90, 95% CI 2.34–6.51, P = 1.79 × 10–7; HR = 4.29, 95% CI 1.36–13.50, P = 0.01, respectively). However, no interactive but independent effects were detected between this PRS and pathogenic mutations.

Conclusions

Our findings provide a new measurement of PCa patients’ natural disease outcomes via genetic risk ways.
The aging ovary impairs acute stroke outcomes
Authors: Branyan Taylor E. , Aleksa Jocelyn , Lepe Esteban , Kosel Kelby , Sohrabji Farida
Published: July 2023

In experimental stroke, ovariectomized (OVX) adult rats have larger infarct volumes and greater sensory-motor impairment as compared to ovary-intact females and is usually interpreted to indicate that ovarian hormones are neuroprotective for stroke. Previous work from our lab shows that middle-aged, acyclic reproductively senescent (RS) females have worse stroke outcomes as compared to adult (normally cycling) females. We hypothesized that if loss of ovarian estrogen is the critical determinant of stroke outcomes, then ovary-intact middle-aged acyclic females, who have reduced levels of estradiol, should have similar stroke outcomes as age-matched OVX. Instead, the data demonstrated that OVX RS animals showed better sensory-motor function after stroke and reduced infarct volume as compared to ovary-intact females. Inflammatory cytokines were decreased in the aging ovary after stroke as compared to non-stroke shams, which led to the hypothesis that immune cells may be extravasated from the ovaries post-stroke. Flow cytometry indicated reduced overall T cell populations in the aging ovary after middle cerebral artery occlusion (MCAo), with a paradoxical increase in regulatory T cells (Tregs) and M2-like macrophages. Moreover, in the brain, OVX RS animals showed increased Tregs, increased M2-like macrophages, and increased MHC II + cells as compared to intact RS animals, which have all been shown to be correlated with better prognosis after stroke. Depletion of ovary-resident immune cells after stroke suggests that there may be an exaggerated response to ischemia and possible increased burden of the inflammatory response via extravasation of these cells into circulation. Increased anti-inflammatory cells in the brain of OVX RS animals further supports this hypothesis. These data suggest that stroke severity in aging females may be exacerbated by the aging ovary and underscore the need to assess immunological changes in this organ after stroke.
Pharmacotherapies of NAFLD: updated opportunities based on metabolic intervention
Authors: Shao Yaodi , Chen Suzhen , Han Liu , Liu Junli
Published: July 2023

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that is becoming increasingly prevalent, and it ranges from simple steatosis to cirrhosis. However, there is still a lack of pharmacotherapeutic strategies approved by the Food and Drug Administration, which results in a higher risk of death related to carcinoma and cardiovascular complications. Of note, it is well established that the pathogenesis of NAFLD is tightly associated with whole metabolic dysfunction. Thus, targeting interconnected metabolic conditions could present promising benefits to NAFLD, according to a number of clinical studies. Here, we summarize the metabolic characteristics of the development of NAFLD, including glucose metabolism, lipid metabolism and intestinal metabolism, and provide insight into pharmacological targets. In addition, we present updates on the progresses in the development of pharmacotherapeutic strategies based on metabolic intervention globally, which could lead to new opportunities for NAFLD drug development.