bluuebunny/crossref_metadata_2025 huggingface dataset:
μ-band desynchronization in the contralateral central and central-parietal areas predicts proprioceptive acuity
Authors: Albanese Giulia Aurora , Marini Francesca , Morasso Pietro , Campus Claudio , Zenzeri Jacopo
Published: March 2023

Introduction

Position sense, which belongs to the sensory stream called proprioception, is pivotal for proper movement execution. Its comprehensive understanding is needed to fill existing knowledge gaps in human physiology, motor control, neurorehabilitation, and prosthetics. Although numerous studies have focused on different aspects of proprioception in humans, what has not been fully investigated so far are the neural correlates of proprioceptive acuity at the joints.

Methods

Here, we implemented a robot-based position sense test to elucidate the correlation between patterns of neural activity and the degree of accuracy and precision exhibited by the subjects. Eighteen healthy participants performed the test, and their electroencephalographic (EEG) activity was analyzed in its μ band (8–12 Hz), as the frequency band related to voluntary movement and somatosensory stimulation.

Results

We observed a significant positive correlation between the matching error, representing proprioceptive acuity, and the strength of the activation in contralateral hand motor and sensorimotor areas (left central and central-parietal areas). In absence of visual feedback, these same regions of interest (ROIs) presented a higher activation level compared to the association and visual areas. Remarkably, central and central-parietal activation was still observed when visual feedback was added, although a consistent activation in association and visual areas came up.

Conclusion

Summing up, this study supports the existence of a specific link between the magnitude of activation of motor and sensorimotor areas related to upper limb proprioceptive processing and the proprioceptive acuity at the joints.
Functional mapping of sensorimotor activation in the human thalamus at 9.4 Tesla
Authors: Charyasz Edyta , Heule Rahel , Molla Francesko , Erb Michael , Kumar Vinod Jangir , Grodd Wolfgang , Scheffler Klaus , Bause Jonas
Published: March 2023

Although the thalamus is perceived as a passive relay station for almost all sensory signals, the function of individual thalamic nuclei remains unresolved. In the present study, we aimed to identify the sensorimotor nuclei of the thalamus in humans using task-based fMRI at a field strength of 9.4T by assessing the individual subject-specific sensorimotor BOLD response during a combined active motor (finger-tapping) and passive sensory (tactile-finger) stimulation. We demonstrate that both tasks increase BOLD signal response in the lateral nuclei group (VPL, VA, VLa, and VLp), and in the pulvinar nuclei group (PuA, PuM, and PuL). Finger-tapping stimuli evokes a stronger BOLD response compared to the tactile stimuli, and additionally engages the intralaminar nuclei group (CM and Pf). In addition, our results demonstrate reproducible thalamic nuclei activation during motor and tactile stimuli. This work provides important insight into understanding the function of individual thalamic nuclei in processing various input signals and corroborates the benefits of using ultra-high-field MR scanners for functional imaging of fine-scale deeply located brain structures.
A hybrid P300-SSVEP brain-computer interface speller with a frequency enhanced row and column paradigm
Authors: Bai Xin , Li Minglun , Qi Shouliang , Ng Anna Ching Mei , Ng Tit , Qian Wei
Published: March 2023

Objective

This study proposes a new hybrid brain-computer interface (BCI) system to improve spelling accuracy and speed by stimulating P300 and steady-state visually evoked potential (SSVEP) in electroencephalography (EEG) signals.

Methods

A frequency enhanced row and column (FERC) paradigm is proposed to incorporate the frequency coding into the row and column (RC) paradigm so that the P300 and SSVEP signals can be evoked simultaneously. A flicker (white-black) with a specific frequency from 6.0 to 11.5 Hz with an interval of 0.5 Hz is assigned to one row or column of a 6 × 6 layout, and the row/column flashes are carried out in a pseudorandom sequence. A wavelet and support vector machine (SVM) combination is adopted for P300 detection, an ensemble task-related component analysis (TRCA) method is used for SSVEP detection, and the two detection possibilities are fused using a weight control approach.

Results

The implemented BCI speller achieved an accuracy of 94.29% and an information transfer rate (ITR) of 28.64 bit/min averaged across 10 subjects during the online tests. An accuracy of 96.86% is obtained during the offline calibration tests, higher than that of only using P300 (75.29%) or SSVEP (89.13%). The SVM in P300 outperformed the previous linear discrimination classifier and its variants (61.90–72.22%), and the ensemble TRCA in SSVEP outperformed the canonical correlation analysis method (73.33%).

Conclusion

The proposed hybrid FERC stimulus paradigm can improve the performance of the speller compared with the classical single stimulus paradigm. The implemented speller can achieve comparable accuracy and ITR to its state-of-the-art counterparts with advanced detection algorithms.
Roxadustat (FG-4592) abated lipopolysaccharides-induced depressive-like symptoms via PI3K signaling
Authors: Li Axiang , Liu Zizhen , Ali Tahir , Gao Ruyan , Luo Yanhua , Gong Qichao , Zheng Chenyou , Li Weifen , Guo Hongling , Liu Xinshe , Li Shupeng , Li Tao
Published: March 2023

Background

Despite its role in inflammation and the redox system under hypoxia, the effects and molecular mechanisms of hypoxia-inducible factor (HIF) in neuroinflammation-associated depression are poorly explored. Furthermore, Prolyl hydroxylase domain-containing proteins (PHDs) regulate HIF-1; however, whether and how PHDs regulate depressive-like behaviors under Lipopolysaccharides (LPS)-induced stress conditions remain covered.

Methods

To highlight the roles and underlying mechanisms of PHDs-HIF-1 in depression, we employed behavioral, pharmacological, and biochemical analyses using the LPS-induced depression model.

Results

Lipopolysaccharides treatment induced depressive-like behaviors, as we found, increased immobility and decreased sucrose preference in the mice. Concurrently, we examined increased cytokine levels, HIF-1 expression, mRNA levels of PHD1/PHD2, and neuroinflammation upon LPS administration, which Roxadustat reduced. Furthermore, the PI3K inhibitor wortmannin reversed Roxadustat-induced changes. Additionally, Roxadustat treatment attenuated LPS-induced synaptic impairment and improved spine numbers, ameliorated by wortmannin.

Conclusion

Lipopolysaccharides-dysregulates HIF-PHDs signaling may contribute to neuroinflammation-coincides depression via PI3K signaling.
Disexcitation in the ASH/RIM/ADL negative feedback circuit fine-tunes hyperosmotic sensation and avoidance in Caenorhabditis elegans
Authors: Liu Hui , Wu Jing-Jing , Li Rong , Wang Ping-Zhou , Huang Jia-Hao , Xu Yu , Zhao Jia-Lu , Wu Piao-Ping , Li Si-Jia , Wu Zheng-Xing
Published: March 2023

Sensations, especially nociception, are tightly controlled and regulated by the central and peripheral nervous systems. Osmotic sensation and related physiological and behavioral reactions are essential for animal well-being and survival. In this study, we find that interaction between secondary nociceptive ADL and primary nociceptive ASH neurons upregulates Caenorhabditis elegans avoidance of the mild and medium hyperosmolality of 0.41 and 0.88 Osm but does not affect avoidance of high osmolality of 1.37 and 2.29 Osm. The interaction between ASH and ADL is actualized through a negative feedback circuit consisting of ASH, ADL, and RIM interneurons. In this circuit, hyperosmolality-sensitive ADL augments the ASH hyperosmotic response and animal hyperosmotic avoidance; RIM inhibits ADL and is excited by ASH; thus, ASH exciting RIM reduces ADL augmenting ASH. The neuronal signal integration modality in the circuit is disexcitation. In addition, ASH promotes hyperosmotic avoidance through ASH/RIC/AIY feedforward circuit. Finally, we find that in addition to ASH and ADL, multiple sensory neurons are involved in hyperosmotic sensation and avoidance behavior.
Consumption of sugar sweetened beverages, artificially sweetened beverages and fruit juices and risk of type 2 diabetes, hypertension, cardiovascular disease, and mortality: A meta-analysis
Authors: Li Baoyu , Yan Ni , Jiang Hong , Cui Meng , Wu Min , Wang Lina , Mi Baibing , Li Zhaofang , Shi Jia , Fan Yahui , Azalati Mougni Mohamed , Li Chao , Chen Fangyao , Ma Mao , Wang Duolao , Ma Le
Published: March 2023

Introduction

Sugar-sweetened beverage (SSB) intake is associated with an increased risk of cardiometabolic diseases. However, evidence regarding associations of artificially sweetened beverages (ASBs) and fruit juices with cardiometabolic diseases is mixed. In this study, we aimed to investigate the association between the SSB, ASB and fruit juice consumption with the incidence of cardiometabolic conditions and mortality.

Methods

Relevant prospective studies were identified by searching PubMed, Web of Science, Embase, and Cochrane Library until December 2022 without language restrictions. The pooled relative risk (RR) and 95% confidence intervals (CIs) were estimated for the association of SSBs, ASBs, and fruit juices with the risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and mortality by using random-effect models.

Results

A total of 72 articles were included in this meta-analysis study. Significantly positive associations were observed between the consumption of individual beverages and T2D risk (RR: 1.27; 95% CI: 1.17, 1.38 for SSBs; RR: 1.32; 95% CI: 1.11, 1.56 for ASBs; and RR:0.98; 95% CI: 0.93, 1.03 for fruit juices). Moreover, our findings showed that intakes of SSBs and ASBs were significantly associated with risk of hypertension, stroke, and all-cause mortality (RR ranging from 1.08 to 1.54; all p < 0.05). A dose-response meta-analysis showed monotonic associations between SSB intake and hypertension, T2D, coronary heart disease (CHD), stroke and mortality, and the linear association was only significant between ASB consumption and hypertension risk. Higher SSB and ASB consumptions were associated with a greater risk of developing cardiometabolic diseases and mortality. Fruit juice intake was associated with a higher risk of T2D.

Conclusion

Therefore, our findings suggest that neither ASBs nor fruit juices could be considered as healthier beverages alternative to SSBs for achieving improved health.

Systematic Review Registration: [PROSPERO], identifier [No. CRD42022307003].
An inverse causal association between genetically predicted vitamin D and chronic obstructive pulmonary disease risk
Authors: Lu Kening , Tan Jiang-Shan , Li Tian-Qi , Yuan Jiaqin , Wang Han , Wang Wenting
Published: March 2023

Aim

Observational studies have reported that levels of vitamin D were associated with the incidence of chronic obstructive pulmonary disease (COPD), but the relationship between them may have been confounded in previous studies. In this study, we aimed to determine the relationship between the levels of 25-hydroxyvitamin D (25OHD) and the risk of COPD by two-sample Mendelian randomization (MR) analysis.

Methods

Summary statistics for 25OHD and COPD in this study were obtained from the EBI (n = 496,946) consortium and Finn (n = 187,754) consortium. MR was adopted to explore the effect of the genetically predicted levels of 25OHD on the risk of COPD. Based on three assumptions of MR analysis, inverse variance weighting was used as the main analysis. To make our results more robust and reliable, MR Egger’s intercept test, Cochran’s Q test, funnel plot, and “leave-one-out” sensitivity analysis were used to assess the potential pleiotropy and heterogeneity in this study. Then, colocalization analysis and MR Steiger approaches were used to estimate the possible directions of estimates between them. Finally, we analyzed the causal associations between the four core genes (DHCR7, GC, CYP2R1, and CYP24A1) of vitamin D and the levels of 25OHD or the risk of COPD.

Results

Our results showed that each 1 standard deviation (SD) increase in the genetically predicted 25OHD level was associated with a 57.2% lower relative risk of COPD [odds ratio (OR): 0.428, 95% Cl: 0.279–0.657, p = 1.041 × 10−4], and the above association was also verified by maximum likelihood (OR: 0.427, 95% Cl: 0.277–0.657, p = 1.084 × 10−4), MR–Egger (OR: 0.271, 95% CI: 0.176–0.416, p = 2.466 × 10−4), MR-PRESSO (OR: 0.428, 95% Cl: 0.281–0.652, p = 1.421 × 10−4) and MR-RAPS (OR: 0.457, 95% Cl: 0.293–0.712, p = 5.450 × 10−4). Furthermore, colocalization analyses (rs3829251, PP.H4 = 0.99) and MR Steiger (“TRUE”) also showed a reverse association between them. Besides, the core genes of vitamin D also showed similar results except for CYP24A1.

Conclusion

Our findings provide evidence for a reverse association between genetically predicted 25OHD levels and COPD risk. Taking measures to supplement 25OHD may help reduce the incidence of COPD.
Factors affecting the role of canonical Wnt inhibitor Dickkopf-1 in cancer progression
Authors: Doucet Dakota , Brubaker Connor , Turner Donald , Gregory Carl A.
Published: March 2023

Background

The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) has the capacity to modulate homeostasis between canonical and non-canonical Wnt pathways and also signal independently of Wnt. The specific effects of Dkk-1 activity on tumor physiology are therefore unpredictable with examples of Dkk-1 serving as either a driver or suppressor of malignancy. Given that Dkk-1 blockade may serve as a potential treatment for some types of cancer, we questioned whether it is possible to predict the role of Dkk-1 on tumor progression based on the tissue origin of the tumor.

Methods

Original research articles that described Dkk-1 in terms a tumor suppressor or driver of cancer growth were identified. To determine the association between tumor developmental origin and the role of Dkk-1, a logistic regression was performed. The Cancer Genome Atlas database was interrogated for survival statistics based on tumor Dkk-1 expression.

Results

We report that Dkk-1 is statistically more likely to serve as a suppressor in tumors arising from the ectoderm (p = 0.0198) or endoderm (p = 0.0334) but more likely to serve as a disease driver in tumors of mesodermal origin (p = 0.0155). Survival analyses indicated that in cases where Dkk-1 expression could be stratified, high Dkk-1 expression is usually associated with poor prognosis. This in part may be due to pro-tumorigenic role Dkk-1 plays on tumor cells but also through its influence on immunomodulatory and angiogenic processes in the tumor stroma.

Conclusion

Dkk-1 has a context-specific dual role as a tumor suppressor or driver. Dkk-1 is significantly more likely to serve as a tumor suppressor in tumors arising from ectoderm and endoderm while the converse is true for mesodermal tumors. Patient survival data indicated high Dkk-1 expression is generally a poor prognostic indicator. These findings provide further support for the importance of Dkk-1 as a therapeutic cancer target in some cases.
A key driver to promote HCC: Cellular crosstalk in tumor microenvironment
Authors: Liu Pengyue , Kong Lingyu , Liu Ying , Li Gang , Xie Jianjia , Lu Xin
Published: March 2023

Liver cancer is the third greatest cause of cancer-related mortality, which of the major pathological type is hepatocellular carcinoma (HCC) accounting for more than 90%. HCC is characterized by high mortality and is predisposed to metastasis and relapse, leading to a low five-year survival rate and poor clinical prognosis. Numerous crosstalk among tumor parenchymal cells, anti-tumor cells, stroma cells, and immunosuppressive cells contributes to the immunosuppressive tumor microenvironment (TME), in which the function and frequency of anti-tumor cells are reduced with that of associated pro-tumor cells increasing, accordingly resulting in tumor malignant progression. Indeed, sorting out and understanding the signaling pathways and molecular mechanisms of cellular crosstalk in TME is crucial to discover more key targets and specific biomarkers, so that develop more efficient methods for early diagnosis and individualized treatment of liver cancer. This piece of writing offers insight into the recent advances in HCC-TME and reviews various mechanisms that promote HCC malignant progression from the perspective of mutual crosstalk among different types of cells in TME, aiming to assist in identifying the possible research directions and methods in the future for discovering new targets that could prevent HCC malignant progression.
Head-to-head comparison of Sonazoid and SonoVue in the diagnosis of hepatocellular carcinoma for patients at high risk
Authors: Huang Jiayan , Gao Ling , Li Jiawu , Yang Rui , Jiang Zhenpeng , Liao Min , Luo Yan , Lu Qiang
Published: March 2023

Objectives

To compare the diagnostic efficacy of SonoVue-enhanced and Sonazoid-enhanced ultrasound (US) for hepatocellular carcinoma (HCC) in patients at high risk.

Methods

Between August 2021 and February 2022, participants at high risk for HCC with focal liver lesions were enrolled and underwent both SonoVue- and Sonazoid-enhanced US. Vascular-phase and Kupffer phase (KP) imaging features of contrast-enhanced US (CEUS) were analyzed. The diagnostic performance of both contrast agent-enhanced US according to the CEUS liver imaging reporting and data system (LI-RADS) and the modified criteria (using KP defect instead of late and mild washout) were compared. Histopathology and contrast-enhanced MRI/CT were used as reference standards.

Results

In total, 62 nodules, namely, 55 HCCs, 3 non-HCC malignancies and 4 hemangiomas, from 59 participants were included. SonoVue-enhanced US had comparable sensitivity to Sonazoid-enhanced US for diagnosing HCC [80% (95% confidential interval (CI): 67%, 89.6%) versus 74.6% (95% CI: 61%, 85.3%), p = 0.25]. Both SonoVue and Sonazoid-enhanced US achieved a specificity of 100%. Compared with CEUS LI-RADS, the modified criteria with Sonazoid did not improve sensitivity for HCC diagnosis [74.6% (95% CI: 61%, 85.3%) versus 76.4% (95% CI: 63%, 86.8%), p = 0.99].

Conclusions

Sonazoid-enhanced US had comparable diagnostic performance to SonoVue-enhanced US for patients with HCC risk. KP did not considerably improve the diagnostic efficacy, whereas KP defects in atypical hemangioma may be pitfalls in diagnosing HCC. Further studies with larger sample sizes are needed to further validate the conclusions in the present study.
New insights into hepatitis B virus lymphotropism: Implications for HBV-related lymphomagenesis
Authors: Svicher Valentina , Salpini Romina , D’Anna Stefano , Piermatteo Lorenzo , Iannetta Marco , Malagnino Vincenzo , Sarmati Loredana
Published: March 2023

HBV is one of the most widespread hepatitis viruses worldwide, and a correlation between chronic infection and liver cancer has been clearly reported. The carcinogenic capacity of HBV has been reported for other solid tumors, but the largest number of studies focus on its possible lymphomagenic role. To update the correlation between HBV infection and the occurrence of lymphatic or hematologic malignancies, the most recent evidence from epidemiological and in vitro studies has been reported. In the context of hematological malignancies, the strongest epidemiological correlations are with the emergence of lymphomas, in particular non-Hodgkin’s lymphoma (NHL) (HR 2.10 [95% CI 1.34-3.31], p=0.001) and, more specifically, all NHL B subtypes (HR 2.14 [95% CI 1.61-2.07], p<0.001). Questionable and unconfirmed associations are reported between HBV and NHL T subtypes (HR 1.11 [95% CI 0.88-1.40], p=0.40) and leukemia. The presence of HBV DNA in peripheral blood mononuclear cells has been reported by numerous studies, and its integration in the exonic regions of some genes is considered a possible source of carcinogenesis. Some in vitro studies have shown the ability of HBV to infect, albeit not productively, both lymphomonocytes and bone marrow stem cells, whose differentiation is halted by the virus. As demonstrated in animal models, HBV infection of blood cells and the persistence of HBV DNA in peripheral lymphomonocytes and bone marrow stem cells suggests that these cellular compartments may act as HBV reservoirs, allowing replication to resume later in the immunocompromised patients (such as liver transplant recipients) or in subjects discontinuing effective antiviral therapy. The pathogenetic mechanisms at the basis of HBV carcinogenic potential are not known, and more in-depth studies are needed, considering that a clear correlation between chronic HBV infection and hematological malignancies could benefit both antiviral drugs and vaccines.
Moderation of parental socioeconomic status on the relationship between birth health and developmental coordination disorder at early years
Authors: Tran Huynh-Truc , Tseng Yu-Ting , Chen Shuya , Wu Sheng K. , Li Yao-Chuen
Published: March 2023

Objective

This study investigated whether parental SES moderates the effect of birth health on Developmental Coordination Disorder (DCD) in preschool children.

Methods

One hundred and twenty-two children aged 4 to 6 years were enrolled in the study. The Movement Assessment Battery for Children --2nd Edition (MABC-2) test was used to assess the motor coordination of children. They were preliminarily categorized into either the DCD (<=16th percentile, n = 23) or typically developing (TD) group (>16th percentile, n = 99) based on the testing results. All children in the DCD group were further confirmed to meet other diagnostic criteria of the DSM-V using the intellectual test and parental questionnaires. Moderation analysis was conducted using the PROCESS macro for SPSS, and 95% confidence intervals with a bootstrap procedure were calculated to identify the significant moderating effect.

Results

Maternal education (unstandardized coefficient = 0.6805, SE = 0.3371, p < 0.05) and maternal employment status (unstandardized coefficient = 0.6100, SE = 0.3059, p < 0.05) were found to moderate the relationship between birth length and the probability of having DCD. Moreover, the relationship between birth weight and the probability of having DCD was moderated by the annual household income (unstandardized coefficient = −0.0043, SE = 0.0022, p < 0.05).

Conclusion

The lower maternal education level and maternal unemployment strengthened the negative relationship between birth length and the probability of having DCD. Additionally, the negative relationship between birth weight and the probability of having DCD was statistically significant in high annual household salaries.
Two novel heterozygote mutations of ATM in a Chinese family with dystonia-dominant ataxia telangiectasia and literature review
Authors: Liu Zhi-Jun , Wang Ya-Ling , Xu Yan
Published: March 2023

Background

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity. A-T may present in complicated variable forms, including classic A-T and milder form of AT. Contrary to the classic A-T, the milder form does not present the cardinal features of A-T such as ataxia and telangiectasia. A few ATM mutations have been reported in variant A-T cases manifesting isolated generalized or segmental dystonia without any signs of classical A-T.

Methods

An A-T pedigree with predominant dystonia was collected. Genetic testing was performed by targeted panel of genes involved in movement disorders. The candidate variants were further confirmed by Sanger sequencing. We then reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia and summarized the clinical characteristics of dystonia-dominant A-T.

Results

Two novel ATM mutations, p.I2683T and p.S2860P, were identified in the family. The proband presented isolated segmental dystonia without any signs of ataxia and telangiectasias. We reviewed the literatures and found that the patients with dystonia-dominant A-T tend to have a later-onset and slower progression of the disease.

Conclusion

To our knowledge, this is the first report of A-T patient with predominant dystonia in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. Early ATM genetic testing should be considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.
Antibiotic consumption and antimicrobial resistance in the SARS-CoV-2 pandemic: A single-center experience
Authors: Sokolović Dragana , Drakul Dragana , Vujić‐Aleksić Vesna , Joksimović Bojan , Marić Siniša , Nežić Lana
Published: March 2023

Introduction: Antimicrobial resistance and the rapid spread of multiresistant bacteria represent one of the main public health problem in limited resources countries. This issue is significantly worsening since the COVID-19 pandemic due to the unreasonably increased antibiotics prescription to patients with confirmed SARS-CoV-2 infection. The aim of this study was to examine whether COVID-19 pandemic (2020, 2021) was associated with increased antibiotic consumption in inpatient and outpatient settings in the middle size urban region (Republic of Srpska/Bosnia and Herzegovina) in comparison to period before the pandemic (2019). Additionally, we aimed to determine antimicrobial resistance and the presence of multiresistant bacteria in the regional hospital (“Saint Apostol Luka” Hospital Doboj) in 2021.

Methodology: The consumption of antibiotics in inpatient was calculated as Defined Daily Dose per one hundred of patient-days. The consumption of antibiotics in outpatient was calculated as Defined Daily Dose per thousand inhabitants per day. Resistance of bacteria to antibiotics is expressed as a rates and density for each observed antibiotic. The rate of resistance was calculated as a percentage in relation to the total number of isolates of individual bacteria. The density of resistance of isolated bacteria against a specific antibiotic was expressed as the number of resistant pathogens/1000 patient days.

Results: Antibiotic consumption in hospital setting registered during 2019, 2020 and 2021 was as follows: carbapenems (meropenem: 0.28; 1.91; 2.33 DDD/100 patient-days, respectively), glycopeptides (vancomycin: 0.14; 1.09, 1.54 DDD/100 patient-days, respectively), cephalosporins (ceftriaxone: 6.69; 14.7; 14.0 DDD/100 patient-days, respectively) and polymyxins (colistin: 0.04; 0.25; 0.35 DDD/100 bed-days, respectively). Consumption of azithromycin increased drastically in 2020, and dropped significantly in 2021 (0.48; 5.61; 0.93 DDD/100 patient-days). In outpatient setting, an increase in the consumption of oral forms of azithromycin, levofloxacin and cefixime, as well as parenteral forms of amoxicillin-clavulanic acid, ciprofloxacin and ceftriaxone, was recorded. In 2021, antimicrobial resistance to reserve antibiotics in hospital setting was as follows: Acinetobacter baumanii to meropenem 66.0%, Klebsiella spp to cefotaxime 67.14%, Pseudomonas to meropenem 25.7%.

Conclusion: Recent COVID-19 pandemic was associated with increased antibiotic consumption in inpatient and outpatient settings, with characteristic change of pattern of azithromycin consumption. Also, high levels of antimicrobial resistance to reserve antibiotics were registered in hospital setting with low prevalence of identified pathogen-directed antimicrobial prescription. Strategies toward combat antimicrobial resistance in the Doboj region are urgently needed.
Protective effects of extracts from Acer truncatum leaves on SLS-induced HaCaT cells
Authors: Fan Yanxiao , Gu Ronghui , Zhang Ruifei , Wang Miaomiao , Xu Heran , Wang Min , Long Chunlin
Published: March 2023

Introduction:A. truncatum Bunge (Sapindaceae or formerly Aceraceae) is a tall deciduous tree native to China. Traditionally, the leaves of A. truncatum are decocted and used by Chinese Mongolians, Koreans, and Tibetans to treat skin itching, dry cracks, and other skin ailments, which indicates A. truncatum leaves may have a potential inhibitory effect on various skin inflammations.

Methods: To examine the protective effect against skin inflammations of A. truncatum leaf extract (ATLE), an in vitro dermatitis model was established using sodium dodecyl sulfate (SLS)-induced HaCaT cells. The anti-inflammatory effect of ATLE was evaluated by analyzing cell viability, apoptosis, reactive oxygen species (ROS), interleukin 6 (IL-6), and prostaglandin E2 (PGE2) levels.

Results: Orthogonal experiments showed that the pretreatment with ATLE can reduce the IL-6 levels, PGE2 levels, and apoptosis increased in SLS-stimulated HaCaT cells, which indicates that ATLE has positive efficacy for dermatitis. Furthermore, three flavonoid compounds kaempferol-3-O-α-L-rhamnoside, quercetin-3-O-α-L-rhamnopyranoside, kaempferol-3,7-di-O-α-L-rhamnoside, and 1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose (PGG) were isolated and identified. Among them, kaempferol-3,7-di-O-α-L-rhamnoside was isolated from this plant for the first time. These compounds have been proven to have an anti-inflammatory effect. They may contribute to the efficacy of A. truncatumin treating skin inflammation.

Discussion: The results revealed that ATLE has the potential to be used as an additive in various skin care products to prevent skin inflammations and may be incorporated in formulations for topical application as a therapeutic approach against dermatitis.
Pneumocystis jirovecii pneumonia associated with immune checkpoint inhibitors: A systematic literature review of published case reports and disproportionality analysis based on the FAERS database
Authors: Xia Shuang , Gong Hui , Wang Yi-kun , Liu Ling , Zhao Yi-chang , Guo Lin , Zhang Bi-kui , Sarangdhar Mayur , Noguchi Yoshihiro , Yan Miao
Published: March 2023

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features.

Methods: Reports of PJP recorded in FAERS (January 2004–December 2022) were identified through the preferred term “Pneumocystis jirovecii pneumonia”. Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence.

Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed.

Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.
Investigating the effect of dehydromiltirone on septic AKI using a network pharmacology method, molecular docking, and experimental validation
Authors: Chen Sijia , Wang Yanzhe , Liu Yuyuan , Bai Linnan , Li Fengqin , Wu Yue , Xie Xinmiao , Zhang Nan , Zeng Chuchu , Zhang Ling , Wang Xiaoxia
Published: March 2023

Acute kidney injury (AKI) is a severe and frequent complication of sepsis that occurs in intensive care units with inflammation and rapid decline in renal function as the main pathological features. Systemic inflammation, microvascular dysfunction, and tubule injury are the main causes of sepsis-induced AKI (SI-AKI). The high prevalence and death rate from SI-AKI is a great challenge for clinical treatment worldwide. However, in addition to hemodialysis, there is no effective drug to improve renal tissue damage and alleviate the decline in kidney function. We conducted a network pharmacological analysis of Salvia miltiorrhiza (SM), a traditional Chinese medicine, which is widely used for the treatment of kidney disease. Then, we combined molecular docking and a dynamics simulation to screen for the active monomer dehydromiltirone (DHT) that has therapeutic effects on SI-AKI and investigated its potential mechanism of action through experimental validation. The components and targets of SM were obtained by searching the database, and 32 overlapping genes were screened by intersection analysis with AKI targets. GO and KEGG data showed that the functions of a common gene were closely related to oxidative stress, mitochondrial function, and apoptosis. The molecular docking results combined with molecular dynamics simulations provide evidence for a binding model between DHT and cyclooxygenase-2 (COX2), both of which are mainly driven by van der Waals interactions and a hydrophobic effect. In vivo, we found that mice pretreated with an intraperitoneal injection of DHT (20 mg/kg/d) for 3 days ameliorated CLP surgery-induced renal function loss and renal tissue damage and inhibited inflammatory mediators IL-6, IL-1β, TNF-α, and MCP-1 production. In vitro, the DHT pretreatment decreased LPS-induced expression of COX2, inhibited cell death and oxidative stress, alleviated mitochondrial dysfunction, and restrained apoptosis in HK-2 cells. Our research indicates that the renal preventive effect of DHT is related to maintaining mitochondrial dynamic balance, restoring mitochondrial oxidative phosphorylation, and inhibiting cell apoptosis. The findings in this study provide a theoretical basis and a novel method for the clinical therapy of SI-AKI.
Establishment of an assistive diagnostic model for schizophrenia with oxidative stress biomarkers
Authors: Wang Shuying , Yuan Xiuxia , Pang Lijuan , Song Peilun , Jia Rufei , Song Xueqin
Published: March 2023

Objective: In this study, alterations in oxidative stress-related indicators were evaluated in drug-naïve, first-episode schizophrenia (SCZ) patients, and the effectiveness of blood serum glucose, superoxide dismutase (SOD), bilirubin in the objective assistive diagnosis of schizophrenia was explored.

Materials and methods: We recruited 148 drug-naïve, first-episode SCZ patients and 97 healthy controls (HCs). Blood biochemical indexes including blood glucose, SOD, bilirubin and homocysteine (HCY) in participants were measured, the indexes were compared between patients with SCZ and HCs. The assistive diagnostic model for SCZ was established on the basis of the differential indexes.

Results: In SCZ patients, the blood serum levels of glucose, total (TBIL), indirect bilirubin (IBIL) and homocysteine (HCY) were significantly higher than those in HCs (p < 0.05), and the serum levels of SOD were significantly lower than those in HCs (p < 0.05). There was a negative correlation between SOD with the general symptom scores and total scores of PANSS. After risperidone treatment, the levels of uric acid (UA) and SOD tended to increase in patients with SCZ (p = 0.02, 0.19), and the serum levels of TBIL and HCY tended to decrease in patients with SCZ (p = 0.78, 0.16). The diagnostic model based on blood glucose, IBIL and SOD was internally cross-validated, and the accuracy was 77%, with an area under the curve (AUC) of 0.83.

Conclusion: Our study demonstrated an oxidative state imbalance in drug-naïve, first-episode SCZ patients, which might be associated with the pathogenesis of the disease. Our study proved that glucose, IBIL and SOD may be potential biological markers of schizophrenia, and the model based on these markers can assist the early objective and accurate diagnosis of schizophrenia.
Human umbilical cord blood cells suffer major modification by fixatives and anticoagulants
Authors: Danusso Roberta , Rosati Riccardo , Possenti Luca , Lombardini Elena , Gigli Francesca , Costantino Maria Laura , Ferrazzi Enrico , Casagrande Giustina , Lattuada Debora
Published: March 2023

Introduction: Developing techniques for the tagless isolation of homogeneous cell populations in physiological-like conditions is of great interest in medical research. A particular case is Gravitational Field-Flow Fractionation (GrFFF), which can be run avoiding cell fixation, and that was already used to separate viable cells. Cell dimensions have a key role in this process. However, their dimensions under physiological-like conditions are not easily known since the most diffused measurement techniques are performed on fixed cells, and the fixation used to preserve tissues can alter the cell size. This work aims to obtain and compare cell size data under physiological-like conditions and in the presence of a fixative.

Methods: We developed a new protocol that allows the analysis of blood cells in different conditions. Then, we applied it to obtain a dataset of human cord blood cell dimensions from 32 subjects, comparing two tubes with anticoagulants (EDTA and Citrate) and two tubes with different preservatives (CellRescue and CellSave). We analyzed a total of 2071 cells by using confocal microscopy via bio-imaging to assess dimensions (cellular and nuclear) and morphology.

Results: Cell diameter measured does not differ when using the different anticoagulants, except for the increase reported for monocyte in the presence of citrate. Instead, cell dimensions differ when comparing anticoagulants and cell preservative tubes, with a few exceptions. Cells characterized by high cytoplasm content show a reduction in their size, while morphology appears always preserved. In a subgroup of cells, 3D reconstruction was performed. Cell and nucleus volumes were estimated using different methods (specific 3D tool or reconstruction from 2D projection).

Discussion: We found that some cell types benefit from a complete 3D analysis because they contain non-spherical structures (mainly for cells characterized by poly-lobated nucleus). Overall, we showed the effect of the preservatives mixture on cell dimensions. Such an effect must be considered when dealing with problems highly dependent on cell size, such as GrFFF. Additionally, such information is crucial in computational models increasingly being employed to simulate biological events.
Sex modifies the renal consequences of high fructose consumption introduced after weaning
Authors: Monteiro Letícia Maria , Barbosa Celine Farias , Lichtenecker Débora Conte Kimura , Argeri Rogério , Gomes Guiomar Nascimento
Published: March 2023

After lactation, many children consume fructose-rich processed foods. However, overconsumption of these foods can predispose individuals to non-communicable chronic diseases, which can have different repercussions depending on the sex. Thus, we evaluated the effects of fructose overload introduced after weaning on the renal function of young rats of both sexes.

Methods: After weaning, male and female offspring of Wistar rats were assigned to drink water (the male/water and female/water groups) or 20% D-fructose solution (male/fructose and female/fructose groups). Food and water or fructose solution was offered ad libitum. Rats were evaluated at 4 months. Parameters analyzed: blood pressure, body weight, triglyceride levels, glomerular filtration rate, sodium, potassium, calcium, and magnesium excretion, macrophage infiltration, and eNOS and 8OHdG expression in renal tissue. CEUA-UNIFESP: 2757270117.

Results: Fructose intake affected the blood pressure, body weight, and plasma triglyceride in all rats. Glomerular filtration rate was significantly reduced in males that received fructose when compared to that of the control group. Sodium and potassium excretion decreased in all fructose-treated rats; however, the excreted load of these ions was significantly higher in females than in males. In the female control group, calcium excretion was higher than that of the male control group. Fructose overload increased magnesium excretion in females, and also increased macrophage infiltration and reduced eNOS expression in both males and females.

Conclusion: Fructose overload introduced after weaning caused metabolic and renal changes in rats. Renal function was more affected in males; however, several significant alterations were also observed in the female-fructose group.
Imaging peripheral lymphatic dysfunction in chronic conditions
Authors: Sevick-Muraca Eva M. , Fife Caroline E. , Rasmussen John C.
Published: March 2023

The lymphatics play important roles in chronic diseases/conditions that comprise the bulk of healthcare worldwide. Yet the ability to routinely image and diagnose lymphatic dysfunction, using commonly available clinical imaging modalities, has been lacking and as a result, the development of effective treatment strategies suffers. Nearly two decades ago, investigational near-infrared fluorescence lymphatic imaging and ICG lymphography were developed as routine diagnostic for clinically evaluating, quantifying, and treating lymphatic dysfunction in cancer-related and primary lymphedema, chronic venous disease, and more recently, autoimmune and neurodegenerative disorders. In this review, we provide an overview of what these non-invasive technologies have taught us about lymphatic (dys) function and anatomy in human studies and in corollary animal studies of human disease. We summarize by commenting on new impactful clinical frontiers in lymphatic science that remain to be facilitated by imaging.
Beneficial and adverse effects of vitamin E on the kidney
Authors: Baltusnikiene Aldona , Staneviciene Inga , Jansen Eugène
Published: March 2023

This article reviews the beneficial and adverse effects of high-dose vitamin E supplementation on the vitamin E status and renal function in human and rodent studies. The high doses of vitamin E, which can cause renal effects, were compared to upper limits of toxicity (UL) as established by various authorities worldwide. In recent mice studies with higher doses of vitamin E, several biomarkers of tissue toxicity and inflammation were found to be significantly elevated. In these biomarker studies, the severity of inflammation and the increased levels of the biomarkers are discussed together with the need to re-evaluate ULs, given the toxic effects of vitamin E on the kidney and emphasizing oxidative stress and inflammation. The controversy in the literature about vitamin E effects on the kidney is mainly caused by the dose-effects relations that do not give a clear view, neither in human nor animals studies. In addition, more recent studies on rodents with new biomarkers of oxidative stress and inflammation give new insights into possible mechanisms. In this review, the controversy is shown and an advice given on the vitamin E supplementation for renal health.
The effect of 8-weeks of combined resistance training and chocolate milk consumption on maximal strength, muscle thickness, peak power and lean mass, untrained, university-aged males
Authors: Yapici Hakan , Gülü Mehmet , Yagin Fatma Hilal , Ugurlu Dondu , Comertpay Ertan , Eroglu Oguz , Kocoğlu Melike , Aldhahi Monira I. , Karayigit Raci , Badri AL-Mhanna Sameer
Published: March 2023

The overarching aim of this study was to investigate the combined effects of chocolate milk consumption (500 mL) with 8-week of resistance training on muscle hypertrophy, body composition, and maximal strength in untrained healthy men. A total of 22 Participants were randomly divided into two experimental groups: combined resistance training (3 sessions per week for 8 weeks) and chocolate milk consumptions (include 30 g protein) Resistance Training Chocolate Milk (RTCM) (Age: 20.9 ± 0.9 years old) and resistance training (RT) only (Age: 19.8 ± 0.7 years old). Muscle thickness (MT), using a portable ultrasound, body composition, body mass, maximal strength (one repetition maximum (1 RM), counter movement jump (CMJ) and peak power (PP) were determined at baseline and 8 weeks later. In the RTCM, finding showed a significant improvement in the outcomes compared to the RT group, besides the main effect of time (pre and post). The 1 RM total increased by 36.7% in RTCM group compared to 17.6% increased in the RT group (p < 0.001). Muscle thickness increased by 20.8% in the RTCM group and 9.1% in the RT group (p < 0.001). In the RTCM group, the PP increased by 37.8% compared to only 13.8% increase in the RT group (p = 0.001). The group*time interaction effect was significant for MT, 1RM, CMJ, and PP (p < 0.05), and it was observed that the RTCM and the 8-week resistance training protocol maximized performance. Body fat percentage (%) decreased more in the RTCM (18.9%) group than in the RT (6.7%) group (p = 0.002). In conclusion, chocolate milk (500 mL) with high protein content consumed in addition to resistance training provided superior gains in terms of MT, 1 RM, body composition, CMJ, and PP. The finding of the study demonstrated the positive effect of casein-based protein (chocolate milk) and resistance training on the muscle performance. Chocolate milk consumption has a more positive effect on muscle strength when combined with RT and should be considered as a suitable post-exercise nutritional supplement. Future research could be conducted with a larger number of participants of different ages and longer study durations.