bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal order judgment of multisensory stimuli in rat and human
Authors: Mafi Fatemeh , Tang Matthew F. , Afarinesh Mohammad Reza , Ghasemian Sadegh , Sheibani Vahid , Arabzadeh Ehsan
Published: January 2023

We do not fully understand the resolution at which temporal information is processed by different species. Here we employed a temporal order judgment (TOJ) task in rats and humans to test the temporal precision with which these species can detect the order of presentation of simple stimuli across two modalities of vision and audition. Both species reported the order of audiovisual stimuli when they were presented from a central location at a range of stimulus onset asynchronies (SOA)s. While both species could reliably distinguish the temporal order of stimuli based on their sensory content (i.e., the modality label), rats outperformed humans at short SOAs (less than 100 ms) whereas humans outperformed rats at long SOAs (greater than 100 ms). Moreover, rats produced faster responses compared to humans. The reaction time data further revealed key differences in decision process across the two species: at longer SOAs, reaction times increased in rats but decreased in humans. Finally, drift-diffusion modeling allowed us to isolate the contribution of various parameters including evidence accumulation rates, lapse and bias to the sensory decision. Consistent with the psychophysical findings, the model revealed higher temporal sensitivity and a higher lapse rate in rats compared to humans. These findings suggest that these species applied different strategies for making perceptual decisions in the context of a multimodal TOJ task.
Facial image inpainting for big data using an effective attention mechanism and a convolutional neural network
Authors: Lu Xiaoman , Lu Ran , Zhao Wenhao , Ma Erbin
Published: January 2023

Big data facial image is an important identity information for people. However, facial image inpainting using existing deep learning methods has some problems such as insufficient feature mining and incomplete semantic expression, leading to output image artifacts or fuzzy textures. Therefore, it is of practical significance to study how to effectively restore an incomplete facial image. In this study, we proposed a facial image inpainting method using a multistage generative adversarial network (GAN) and the global attention mechanism (GAM). For the overall network structure, we used the GAN as the main body, then we established skip connections to optimize the network structure, and used the encoder–decoder structure to better capture the semantic information of the missing part of a facial image. A local refinement network has been proposed to enhance the local restoration effect and to weaken the influence of unsatisfactory results. Moreover, GAM is added to the network to magnify the interactive features of the global dimension while reducing information dispersion, which is more suitable for restoring human facial information. Comparative experiments on CelebA and CelebA-HQ big datasets show that the proposed method generates realistic inpainting results in both regular and irregular masks and achieves peak signal-to-noise ratio (PSNR) and structural similarity (SSIM), as well as other evaluation indicators that illustrate the performance and efficiency of the proposed model.
Oxidative stress in multiple sclerosis—Emerging imaging techniques
Authors: Hollen Christopher , Neilson Lee E. , Barajas Ramon F. , Greenhouse Ian , Spain Rebecca I.
Published: January 2023

While conventional magnetic resonance imaging (MRI) is central to the evaluation of patients with multiple sclerosis, its role in detecting the pathophysiology underlying neurodegeneration is more limited. One of the common outcome measures for progressive multiple sclerosis trials, atrophy on brain MRI, is non-specific and reflects end-stage changes after considerable neurodegeneration has occurred. Identifying biomarkers that identify processes underlying neurodegeneration before it is irreversible and that reflect relevant neurodegenerative pathophysiology is an area of significant need. Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of multiple neurodegenerative diseases, including multiple sclerosis. Imaging markers related to inflammation, myelination, and neuronal integrity have been areas of advancement in recent years but oxidative stress has remained an area of unrealized potential. In this article we will begin by reviewing the role of oxidative stress in the pathogenesis of multiple sclerosis. Chronic inflammation appears to be directly related to the increased production of reactive oxygen species and the effects of subsequent oxidative stress appear to be amplified by aging and accumulating disease. We will then discuss techniques in development used in the assessment of MS as well as other models of neurodegenerative disease in which oxidative stress is implicated. Multiple blood and CSF markers of oxidative stress have been evaluated in subjects with MS, but non-invasive imaging offers major upside in that it provides real-time assessment within the brain.
Case report: Anti-N-methyl-D-aspartate receptor antibody-associated autoimmunity triggered by primary central nervous system B-cell lymphoma
Authors: Yokota Yuki , Hara Makoto , Oshita Natsuki , Mizoguchi Tomotaka , Nishimaki Haruna , Hao Hiroyuki , Nakajima Hideto
Published: January 2023

Background

We herein detail our experience with a unique patient with a primary central nervous system (PCNS) B-cell lymphoma concomitant with anti-N-methyl-d-aspartate receptor (NMDAR) antibodies that satisfied the criteria of “probable anti-NMDAR encephalitis (ProNMDARE)” based on the Graus criteria 2016.

Case presentation

A 73-year-old Japanese woman presented with acute pyrexia, agitation, and disturbance of consciousness. She gradually developed a reduction in speech frequency and truncal dystonia causing abnormal posture. Brain magnetic resonance imaging (MRI) demonstrated high-intensity lesions in the bilateral frontal lobes, and her cerebrospinal fluid revealed mild pleocytosis. She was diagnosed with acute encephalitis and treated with acyclovir and intravenous dexamethasone; however, no improvement was observed. She was transferred to our hospital 6 weeks after the onset of her symptoms, and anti-NMDAR antibodies were identified in her cerebrospinal fluid through indirect immunolabeling with rat brain frozen sections and cell-based assays with NR1/NR2 transfected HEK cells. Follow-up MRI showed enlargement of the lesions in the right frontal lobe with gadolinium enhancement, suggesting a brain tumor. Stereotactic surgery was implemented, with subsequent pathological examination revealing that the tumor was consistent with diffuse large B-cell lymphoma (DLBCL) without evidence of systemic satellite lesions. Stereotactic irradiative therapies were then added to her treatment regimen, which partly improved her neurological symptoms with only mild cognitive dysfunction still remaining. A decrease in anti-NMDAR antibody titer was also confirmed after immunotherapy and tumor removal.

Conclusions

We herein report our experience with a novel case of PCNS-DLBCL masquerading as anti-NMDAR encephalitis that satisfied the diagnostic criteria of “proNMDARE.” Treatment, including tumor removal, ameliorated disease severity and antibody titers of the patient. Our findings suggest that anti-NMDAR antibody-associated autoimmunity can be triggered by PCNS B-cell tumors, although primary brain tumors need to be excluded before establishing a diagnosis of autoimmune encephalitis.
Feasibility and acceptability of time-restricted eating in a group of adults with multiple sclerosis
Authors: Wingo Brooks C. , Rinker John R. , Green Kathryn , Peterson Courtney M.
Published: January 2023

Introduction

Intermittent fasting (IF) has become a popular dietary pattern for adults with multiple sclerosis (MS), and initial studies in animal models and human trials indicate promising results for improving symptoms and slowing disease progression. Most studies published to date have focused on alternate day fasting or fasting mimicking diets including a 5:2 pattern, in which participants greatly restrict calorie intake on two non-consecutive days and eat regularly on other days; however, time restricted eating (TRE) may be equally effective for improving symptoms and may lead to better long term adherence due to its focus only on the time of day in which calories are consumed with no restriction on number of calories or types of food consumed.

Methods

The purpose of this pilot study was to determine the feasibility and acceptability of a TRE intervention in adults with relapsing remitting MS (RRMS). Participants (n = 12) were instructed to eat all food within an 8-h window every day and fast the remaining 16 h for 8 weeks.

Results

The eating pattern was determined to be feasible based on retention rates (n = 11; 92%) and acceptable based on participant feedback.

Discussion

Exploratory results of changes in cognition, pain, and fatigue, indicate that further study of TRE in this population is warranted.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/NCT04389970; NCT04389970.
Effects of auditory rehabilitation with cochlear implant on tinnitus prevalence and distress, health-related quality of life, subjective hearing and psychological comorbidities: Comparative analysis of patients with asymmetric hearing loss (AHL), double-sided (bilateral) deafness (DSD), and single-sided (unilateral) deafness (SSD)
Authors: Olze Heidi , Ketterer Manuel Christoph , Péus Dominik , Häußler Sophia Marie , Hildebrandt Lynn , Gräbel Stefan , Szczepek Agnieszka J.
Published: January 2023

Introduction

Auditory rehabilitation with a cochlear implant (CI), in many cases, positively impacts tinnitus. However, it is unclear if the tinnitus-related benefit of CI is equal for patients with various indications for CI. Therefore, this study aimed to determine differences in tinnitus prevalence and distress, health-related quality of life, subjective hearing, perceived stress, and psychological comorbidities between patients diagnosed with asymmetric hearing loss (AHL), single-sided (unilateral) deafness (SSD), and double-sided (bilateral) deafness (DSD) before and six months after cochlear implantation.

Methods

One hundred-one CI candidates were included in this prospective study (39 AHL patients, 23 DSD patients, and 39 SSD patients). The patients completed questionnaires measuring tinnitus distress, health-related quality of life, subjective hearing, perceived stress, and psychological comorbidities before and 6 months after CI.

Results

The prevalence of tinnitus in the entire cohort (80.2% before CI) decreased 6 months after CI to 71.3%. The DSD group had the lowest tinnitus prevalence at both time points. The degree of tinnitus-induced distress decreased significantly in all three groups after CI. Differences in quality of life, subjective hearing, and psychological comorbidities between the groups at the study onset disappeared after CI. Significant correlations existed between anxiety, depression, and tinnitus distress in AHL and SSD but not in DSD patients before and after CI.

Discussion

Our results demonstrate significant differences between the three groups of CI candidates, which might affect the implantation outcome. These differences suggest a need for personalized psychological counseling during the auditory rehabilitation process, focusing on anxiety and depressive symptoms for SSD and AHL patients.
Utility of serum amyloid A as a potential prognostic biomarker of aneurysmal subarachnoid hemorrhage
Authors: Sun Zhongbo , Li Yaqiang , Chang Fu , Jiang Ke
Published: January 2023

Objectives

Inflammation plays a vital role in the aneurysmal subarachnoid hemorrhage (aSAH), while serum amyloid A (SAA) has been identified as an inflammatory biomarker. The present study aimed to elucidate the relationship between SAA concentrations and prognosis in aSAH.

Methods

From prospective analyses of patients admitted to our department between March 2016 and August 2022, aSAH patients with complete medical records were evaluated. Meanwhile, the healthy control group consisted of the age and sex matched individuals who came to our hospital for healthy examination between March 2018 and August 2022. SAA level was measured by enzyme-linked immunosorbent assay kit (Invitrogen Corp). The Glasgow Outcome Scale (GOS) was used to classify patients into good (GOS score of 4 or 5) and poor (GOS score of 1, 2, or 3) outcome.

Results

456 patients were enrolled in the study, thereinto, 200 (43.86%) patients had a poor prognosis at the 3-months follow-up. Indeed, the SAA of poor outcome group were significantly increased compared to good outcome group and healthy control group [36.44 (32.23–41.00) vs. 28.99 (14.67–34.12) and 5.64 (3.43–7.45), P < 0.001]. In multivariate analyses, SAA served for independently predicting the poor outcome after aICH at 3 months [OR:1.129 (95% CI, 1.081–1.177), P < 0.001]. After adjusting the underlying confounding factors, the odds ratio (OR) of depression after aSAH was 2.247 (95% CI: 1.095–4.604, P = 0.021) for the highest tertile of SAA relative to the lowest tertile. With an AUC of 0.807 (95% CI, 0.623–0.747), SAA demonstrated an obviously better discriminatory ability relative to CRP, WBC, and IL-6. SAA as an indicator for predicting poor outcome after aSAH had an optimal cut-off value of 30.28, and the sensitivity and specificity were 61.9 and 78.7%, respectively.

Conclusions

Elevated level of SAA was associated with poor outcome at 3 months, suggesting that SAA might be a useful inflammatory markers to predict prognosis after aSAH.
Audiological and psychological assessment of tinnitus patients with normal hearing
Authors: Park Yelin , Shin Seung-Ho , Byun Sung Wan , Lee Zoo Young , Lee Ho Yun
Published: January 2023

Introduction

This study was performed to assess identifiable abnormalities in tinnitus patients with normal hearing.

Methods

The medical records of subjective non-pulsatile tinnitus patients with normal hearing confirmed by conventional pure-tone audiometry who visited our tinnitus clinic between March 2020 and May 2022 were reviewed. The loudness discomfort level (LDL), extended high-frequency hearing loss (EHFHL), summating potential (SP)/action potential (AP) ratio, distortion product otoacoustic emission (DPOAE), thresholds of auditory brainstem response (ABR) wave V, somatic modulation, and psychiatric symptoms, such as anxiety, depression, and stress were evaluated by questionnaires.

Results

Decreased LDL (n = 48, 59.8%) was the most frequent finding, followed by EHFHL (n = 29, 35.4%), increased SP/AP ratio (n = 27, 32.9%), psychiatric symptoms (n = 24, 29.3%), decreased DPOAE (n = 17, 20.7%), somatic modulation (n = 8, 9.8%), and increased ABR threshold (n = 3, 3.7%); 75.6% of patients had one or more of these findings. The presence of psychiatric symptoms was independently associated with the Tinnitus Handicap Inventory (THI) score.

Conclusion

Tinnitus in patients with normal hearing may be accompanied by a combination of various subclinical abnormal audiological findings. However, the presence of psychiatric symptoms alone was independently associated with tinnitus distress.
ERCC1 polymorphism and its expression associated with ischemic stroke in Chinese population
Authors: Deng Xiao-Dong , Ke Jian-Lin , Chen Tai-Yu , Gao Qin , Zhao Zhuo-Lin , Zhang Wei , Liu Huan , Xiang Ming-Liang , Wang Li-Zhen , Ma Ying , Liu Yun
Published: January 2023

Background

Excision repair cross-complementing group 1 (ERCC1) was considered a potential candidate gene for ischemic stroke, and its polymorphisms might be associated with the susceptibility to ischemic stroke.

Methods

A total of 513 patients with ischemic stroke and 550 control subjects were recruited. The expression levels of ERCC1 messenger RNA (mRNA) in peripheral blood mononuclear cells and its protein in plasma were detected by quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Rs3212986 polymorphism of ERCC1 was detected by PCR-restriction fragment length polymorphism (RFLP-PCR) and was confirmed by sequencing. The association between the ERCC1 rs3212986 polymorphism or its expression and ischemic stroke was further analyzed.

Results

The ERCC1 mRNA level in patients with ischemic stroke was lower than that in the control group (P < 0.05). However, the ERCC1 protein level in patients with ischemic stroke was higher than that in the control group (P < 0.05). The A allele of rs3212986 was associated with increased ischemic stroke risk (OR = 1.287, 95% CI = 1.076–1.540, P = 0.006). The association between rs3212986 polymorphism and ischemic stroke susceptibility was found in both recessive (OR = 2.638, 95% CI = 1.744–3.989, P < 0.001) and additive models (OR = 1.309, 95% CI = 1.028–1.667, P = 0.031), respectively. Similar results were obtained in the recessive model (OR = 2.015, 95% CI = 1.087–3.704, P = 0.026) after adjusting for demographic information and other variables. Additionally, the level of ERCC1 mRNA in the CC/CA genotype was higher than that in the AA genotype (P < 0.05).

Conclusion

It was suggested that the ERCC1 rs3212986 polymorphism was associated with ischemic stroke susceptibility in a Chinese Han population and that an A allele of rs3212986 was related to increased ischemic stroke risk. The altered ERCC1 expression level caused by the rs3212986 polymorphism might participate in the pathophysiological process of ischemic stroke.
A structural connectivity atlas of limbic brainstem nuclei
Authors: Levinson Simon , Miller Michelle , Iftekhar Ahmed , Justo Monica , Arriola Daniel , Wei Wenxin , Hazany Saman , Avecillas-Chasin Josue M. , Kuhn Taylor P. , Horn Andreas , Bari Ausaf A.
Published: January 2023

Background

Understanding the structural connectivity of key brainstem nuclei with limbic cortical regions is essential to the development of therapeutic neuromodulation for depression, chronic pain, addiction, anxiety and movement disorders. Several brainstem nuclei have been identified as the primary central nervous system (CNS) source of important monoaminergic ascending fibers including the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, and dopaminergic ventral tegmental area. However, due to practical challenges to their study, there is limited data regarding their in vivo anatomic connectivity in humans.

Objective

To evaluate the structural connectivity of the following brainstem nuclei with limbic cortical areas: locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius. Additionally, to develop a group average atlas of these limbic brainstem structures to facilitate future analyses.

Methods

Each nucleus was manually masked from 197 Human Connectome Project (HCP) structural MRI images using FSL software. Probabilistic tractography was performed using FSL's FMRIB Diffusion Toolbox. Connectivity with limbic cortical regions was calculated and compared between brainstem nuclei. Results were aggregated to produce a freely available MNI structural atlas of limbic brainstem structures.

Results

A general trend was observed for a high probability of connectivity to the amygdala, hippocampus and DLPFC with relatively lower connectivity to the orbitofrontal cortex, NAc, hippocampus and insula. The locus coeruleus and nucleus tractus solitarius demonstrated significantly greater connectivity to the DLPFC than amygdala while the periaqueductal grey, dorsal raphe nucleus, and ventral tegmental area did not demonstrate a significant difference between these two structures.

Conclusion

Monoaminergic and other modulatory nuclei in the brainstem project widely to cortical limbic regions. We describe the structural connectivity across the several key brainstem nuclei theorized to influence emotion, reward, and cognitive functions. An increased understanding of the anatomic basis of the brainstem's role in emotion and other reward-related processing will support targeted neuromodulatary therapies aimed at alleviating the symptoms of neuropsychiatric disorders.
Quality control in functional MRI studies with MRIQC and fMRIPrep
Authors: Provins Céline , MacNicol Eilidh , Seeley Saren H. , Hagmann Patric , Esteban Oscar
Published: January 2023

The implementation of adequate quality assessment (QA) and quality control (QC) protocols within the magnetic resonance imaging (MRI) research workflow is resource- and time-consuming and even more so is their execution. As a result, QA/QC practices highly vary across laboratories and “MRI schools”, ranging from highly specialized knowledge spots to environments where QA/QC is considered overly onerous and costly despite evidence showing that below-standard data increase the false positive and false negative rates of the final results. Here, we demonstrate a protocol based on the visual assessment of images one-by-one with reports generated by MRIQC and fMRIPrep, for the QC of data in functional (blood-oxygen dependent-level; BOLD) MRI analyses. We particularize the proposed, open-ended scope of application to whole-brain voxel-wise analyses of BOLD to correspondingly enumerate and define the exclusion criteria applied at the QC checkpoints. We apply our protocol on a composite dataset (n = 181 subjects) drawn from open fMRI studies, resulting in the exclusion of 97% of the data (176 subjects). This high exclusion rate was expected because subjects were selected to showcase artifacts. We describe the artifacts and defects more commonly found in the dataset that justified exclusion. We moreover release all the materials we generated in this assessment and document all the QC decisions with the expectation of contributing to the standardization of these procedures and engaging in the discussion of QA/QC by the community.
Optimizing NV magnetometry for Magnetoneurography and Magnetomyography applications
Authors: Zhang Chen , Zhang Jixing , Widmann Matthias , Benke Magnus , Kübler Michael , Dasari Durga , Klotz Thomas , Gizzi Leonardo , Röhrle Oliver , Brenner Philipp , Wrachtrup Jörg
Published: January 2023

Magnetometers based on color centers in diamond are setting new frontiers for sensing capabilities due to their combined extraordinary performances in sensitivity, bandwidth, dynamic range, and spatial resolution, with stable operability in a wide range of conditions ranging from room to low temperatures. This has allowed for its wide range of applications, from biology and chemical studies to industrial applications. Among the many, sensing of bio-magnetic fields from muscular and neurophysiology has been one of the most attractive applications for NV magnetometry due to its compact and proximal sensing capability. Although SQUID magnetometers and optically pumped magnetometers (OPM) have made huge progress in Magnetomyography (MMG) and Magnetoneurography (MNG), exploring the same with NV magnetometry is scant at best. Given the room temperature operability and gradiometric applications of the NV magnetometer, it could be highly sensitive in the pT/Hz-range even without magnetic shielding, bringing it close to industrial applications. The presented work here elaborates on the performance metrics of these magnetometers to the state-of-the-art techniques by analyzing the sensitivity, dynamic range, and bandwidth, and discusses the potential benefits of using NV magnetometers for MMG and MNG applications.
Probabilistic deconvolution of PET images using informed priors
Authors: Hansen Thomas Mejer , Mosegaard Klaus , Holm Søren , Andersen Flemming Littrup , Fischer Barbara Malene , Hansen Adam Espe
Published: January 2023

Purpose

We present a probabilistic approach to medical image analysis that requires, and makes use of, explicit prior information provided by a medical expert. Depending on the choice of prior model the method can be used for image enhancement, analysis, and segmentation.

Methods

The methodology is based on a probabilistic approach to medical image analysis, that allows integration of 1) arbitrarily complex prior information (for which realizations can be generated), 2) information about a convolution operator of the imaging system, and 3) information about the noise in the reconstructed image into a posterior probability density. The method was demonstrated on positron emission tomography (PET) images obtained from a phantom and a patient with lung cancer. The likelihood model (multivariate log-normal) and the convolution operator were derived from phantom data. Two examples of prior information were used to show the potential of the method. The extended Metropolis-Hastings algorithm, a Markov chain Monte Carlo method, was used to generate realizations of the posterior distribution of the tracer activity concentration.

Results

A set of realizations from the posterior was used as the base of a quantitative PET image analysis. The mean and variance of activity concentrations were computed, as well as the probability of high tracer uptake and statistics on the size and activity concentration of high uptake regions. For both phantom and in vivo images, the estimated images of mean activity concentrations appeared to have reduced noise levels, and a sharper outline of high activity regions, as compared to the original PET. The estimated variance of activity concentrations was high at the edges of high activity regions.

Conclusions

The methodology provides a probabilistic approach for medical image analysis that explicitly takes into account medical expert knowledge as prior information. The presented first results indicate the potential of the method to improve the detection of small lesions. The methodology allows for a probabilistic measure of the size and activity level of high uptake regions, with possible long-term perspectives for early detection of cancer, as well as treatment, planning, and follow-up.
Pancreatic cancer derived 3D organoids as a clinical tool to evaluate the treatment response
Authors: Shukla Hem D , Dukic Tijana , Roy Sanjit , Bhandary Binny , Gerry Andrew , Poirier Yannick , Lamichhane Narottam , Molitoris Jason , Carrier France , Banerjee Aditi , Regine William F. , Polf Jerimy C.
Published: January 2023

Background and purpose

Pancreatic cancer (PC) is the fourth leading cause of cancer death in both men and women. The standard of care for patients with locally advanced PC of chemotherapy, stereotactic radiotherapy (RT), or chemo-radiation-therapy has shown highly variable and limited success rates. However, three-dimensional (3D) Pancreatic tumor organoids (PTOs) have shown promise to study tumor response to drugs, and emerging treatments under in vitro conditions. We investigated the potential for using 3D organoids to evaluate the precise radiation and drug dose responses of in vivo PC tumors.

Methods

PTOs were created from mouse pancreatic tumor tissues, and their microenvironment was compared to that of in vivo tumors using immunohistochemical and immunofluorescence staining. The organoids and in vivo PC tumors were treated with fractionated X-ray RT, 3-bromopyruvate (3BP) anti-tumor drug, and combination of 3BP + fractionated RT.

Results

Pancreatic tumor organoids (PTOs) exhibited a similar fibrotic microenvironment and molecular response (as seen by apoptosis biomarker expression) as in vivo tumors. Untreated tumor organoids and in vivo tumor both exhibited proliferative growth of 6 folds the original size after 10 days, whereas no growth was seen for organoids and in vivo tumors treated with 8 (Gray) Gy of fractionated RT. Tumor organoids showed reduced growth rates of 3.2x and 1.8x when treated with 4 and 6 Gy fractionated RT, respectively. Interestingly, combination of 100 µM of 3BP + 4 Gy of RT showed pronounced growth inhibition as compared to 3-BP alone or 4 Gy of radiation alone. Further, positive identification of SOX2, SOX10 and TGFβ indicated presence of cancer stem cells in tumor organoids which might have some role in resistance to therapies in pancreatic cancer.

Conclusions

PTOs produced a similar microenvironment and exhibited similar growth characteristics as in vivo tumors following treatment, indicating their potential for predicting in vivo tumor sensitivity and response to RT and combined chemo-RT treatments.
Adherence and treatment patterns of disease-specific drugs among patients with pulmonary arterial hypertension: A nationwide, new-user cohort study
Authors: Tsai Cheng-Yu , Shen Chuan-Wei , Lai Hsuan-Lin , Chen Chung-Yu
Published: January 2023

Background: Pulmonary arterial hypertension (PAH) is an incurable pulmonary disease that might result in right heart failure and death. Treatment guidelines recommend upfront or sequential combination therapy for patients with PAH. Recently, several PAH-targeted medications have been approved in Taiwan. This study aimed to investigate treatment patterns and medication adherence in real-world settings.

Method: This was a new-user design study on patients treated with PAH-specific medication between 1 January 2014, and 31 December 2019. Data were extracted from the National Health Insurance Research Database. Medication adherence was evaluated by the proportion of days covered (PDC). Adherence was defined as PDC ≥ .8. Statistical analyses were performed to compare the study outcomes. Logistic regression analysis was performed to identify the association between baseline characteristics and adherence. P < .05 indicated statistical significance.

Results: A total of 1,900 patients with PAH were identified, and 75.3% of them were females. The mean (standard deviation (SD)) age was 57.2 (17.5) years. Only 23 (1.2%) patients began the initial combination therapy. A total of 148 (7.8%) patients switched their initial treatment to another treatment, and 159 (8.4%) patients had sequential combination therapy. The most common combination therapy was endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitor (PDE5i), mostly macitentan plus sildenafil, for initial or sequential combination. The mean (SD) PDC was .71 (.33), and 1,117 (58.8%) patients were adherent. A significant difference in mean PDC was observed between initial ERA users and PDE5i users (p < .0001). No factor was significantly associated with medication adherence.

Conclusion: Patients with PAH mostly initiated sildenafil as monotherapy, and macitentan was added as a sequential combination therapy. The initial ERA and combination groups showed higher medication adherence. Further investigations are needed to identify other factors associated with adherence.
Factors associated with the uptake of biosimilars for breast cancer treatment from the perspectives of physicians and patients-Evidence from China
Authors: Wu Qiyou , Lian Zhiwei , Wang Xin , Cheng Hanchao , Sun Jing , Yu Hui , Zhang Gong , Wu Fan , Liu Jian , Chen Chuanben
Published: January 2023

Objective: To investigate the factors associated with the treatment of breast cancer with biosimilars from the perspectives of physicians and patients, and to generate evidence for promoting the uptake of biosimilars.

Methods: This study targeted trastuzumab and its indicated human epidermal growth factor receptor 2 (HER2) positive breast cancer and included female HER2 positive breast cancer patients under treatment of trastuzumab at a provincial oncology medical center in southern China from 1 January 2021, to 31 December 2021. The study extracted patients’ demographic, socioeconomic and clinical information and the basic information of their attending physicians from the hospital information system. We performed a bivariate multiple logistic regression analysis of predictive factors of the use of trastuzumab biosimilar.

Results: A total of 446 patients (aged ranging between 26 and 74, 51.4 ± 9.06) were included in the analysis, and 19.1% chose biosimilar trastuzumab. Older patients, patients enrolled in the urban and rural resident health insurance program compared with those enrolled in the urban employee health insurance program, patients who initiated treatment after January 2021 when biosimilar entered clinical use compared with those who initiated treatment before, patients with female attending physicians, younger attending physicians and with chief attending physicians compared with deputy chief attending physicians were more likely to adopt biosimilar trastuzumab for treatment (p < 05). Controlling the other factors unchanged, when the patient’s attending physician was deputy chief physician, increasing 1 year age of the patient was associated with an increased probability of adopting biosimilar by .8% (dy/dx = .008, 95%CI: .002–.01, p = .01). When the patient was aged between 26 and 60, the probability of adopting biosimilar for the patient whose attending physician was a chief physician was higher than for those whose attending physician was a deputy chief physician, and the gap was the largest when the patient was at the age of 45 (dy/dx = .20, 95%CI: .13–.27, p < .01).

Conclusion: The uptake rate of biosimilars is still low at its initial development stage in China. Educational policies and physicians making recommendations to the indicated patients at the initiation stage of treatment are helpful to avoid reduced willingness to switch to biosimilars due to non-clinical reasons. Patients with lower ability-to-pay will have better accessibility to biologic regimens through the uptake of biosimilars. Official guidelines and professional training are critical to enhancing physicians’ willingness and confidence in adopting biosimilars.
Anticancer applications of phytochemicals in gastric cancer: Effects and molecular mechanism
Authors: Liang Zhaofeng , Xu Yumeng , Zhang Yue , Zhang Xinyi , Song Jiajia , Qian Hui , Jin Jianhua
Published: January 2023

Gastric cancer (GC) is the fourth most common malignant cancer and is a life-threatening disease worldwide. Phytochemicals have been shown to be a rational, safe, non-toxic, and very promising approach to the prevention and treatment of cancer. It has been found that phytochemicals have protective effects against GC through inhibiting cell proliferation, inducing apoptosis and autophagy, suppressing cell invasion and migration, anti-angiogenesis, inhibit Helicobacter pylori infection, regulating the microenvironment. In recent years, the role of phytochemicals in the occurrence, development, drug resistance and prognosis of GC has attracted more and more attention. In order to better understand the relationship between phytochemicals and gastric cancer, we briefly summarize the roles and functions of phytochemicals in GC tumorigenesis, development and prognosis. This review will probably help guide the public to prevent the occurrence and development of GC through phytochemicals, and develop functional foods or drugs for the prevention and treatment of gastric cancer.
Fast cycling of intermittent hypoxia in a physiomimetic 3D environment: A novel tool for the study of the parenchymal effects of sleep apnea
Authors: Jurado Alicia , Ulldemolins Anna , Lluís Helena , Gasull Xavier , Gavara Núria , Sunyer Raimon , Otero Jorge , Gozal David , Almendros Isaac , Farré Ramon
Published: January 2023

Background: Patients with obstructive sleep apnea (OSA) experience recurrent hypoxemic events with a frequency sometimes exceeding 60 events/h. These episodic events induce downstream transient hypoxia in the parenchymal tissue of all organs, thereby eliciting the pathological consequences of OSA. Whereas experimental models currently apply intermittent hypoxia to cells conventionally cultured in 2D plates, there is no well-characterized setting that will subject cells to well-controlled intermittent hypoxia in a 3D environment and enable the study of the effects of OSA on the cells of interest while preserving the underlying tissue environment.

Aim: To design and characterize an experimental approach that exposes cells to high-frequency intermittent hypoxia mimicking OSA in 3D (hydrogels or tissue slices).

Methods: Hydrogels made from lung extracellular matrix (L-ECM) or brain tissue slices (300–800-μm thickness) were placed on a well whose bottom consisted of a permeable silicone membrane. The chamber beneath the membrane was subjected to a square wave of hypoxic/normoxic air. The oxygen concentration at different depths within the hydrogel/tissue slice was measured with an oxygen microsensor.

Results: 3D-seeded cells could be subjected to well-controlled and realistic intermittent hypoxia patterns mimicking 60 apneas/h when cultured in L-ECM hydrogels ≈500 μm-thick or ex-vivo in brain slices 300–500 μm-thick.

Conclusion: This novel approach will facilitate the investigation of the effects of intermittent hypoxia simulating OSA in 3D-residing cells within the parenchyma of different tissues/organs.
Gel formulated with Bryophyllum pinnatum leaf extract promotes skin wound healing in vivo by increasing VEGF expression: A novel potential active ingredient for pharmaceuticals
Authors: Araújo Edilane Rodrigues Dantas , Xavier-Santos Jacinthia Beatriz , da Silva Valéria Costa , de Lima Juliana Bessa Figueiredo , Schlamb Jade , Fernandes-Pedrosa Matheus de Freitas , da Silva Júnior Arnóbio Antônio , de Araújo Júnior Raimundo Fernandes , Rathinasabapathy Thirumurugan , Moncada Marvin , Esposito Debora , Guerra Gerlane Coelho Bernardo , Zucolotto Silvana Maria
Published: January 2023

Bryophyllumpinnatum(Crassulaceae) is used in traditional medicine for treating skin wounds. In our previous study, a topical gel containingB. pinnatumaqueous leaf extract showed a preclinical anti-inflammatory effect inin vivoacute edema models. In continuation, the present study aims to evaluate the phytochemical content and the stability of a formulation in gel containingB. pinnatumaqueous leaf extract and its healing properties and mechanism of action through an experimental model of induction of skin wounds in rats andin vitroassays. The animals were treated topically for 7 or 14 days with a formulation in gel containing extract at 5% or a placebo or Fibrinase®in cream. In addition, to establish some quality control parameters, the total phenolic content (TPC), total flavonoid content (TFC), and a study focusing on the phytochemical and biological stability of a gel for 30 days at two different conditions (room temperature and 40°C/75% RH) were performed. Gel formulation containing extract showed a TPC and TFC of 2.77 ± 0.06 mg of gallic acid/g and 1.58 ± 0.03 mg of quercetin/g, respectively. Regarding the stability study, the formulation in gel showed no significant change in the following parameters: pH, water activity, chromatographic profile, and the content of the major compound identified in the extract. The gel formulation containing extract stimulated skin wound healing while reducing the wound area, as well as decreasing the inflammatory infiltrate, reducing the levels of IL-1β and TNF-α, and stimulating angiogenesis with increased expression of VEGF, an effect similar to Fibrinase. In conclusion, the gel formulation containing extract exhibited relevant skin wound healing properties and, therefore, has the potential to be applied as a novel active ingredient for developing wound healing pharmaceuticals.
Whole β-glucan particle attenuates AOM/DSS-induced colorectal tumorigenesis in mice via inhibition of intestinal inflammation
Authors: Xie Yewen , Shao Fang , Duan Xuehan , Ding Jun , Ning Yongling , Sun Xiao , Xia Lei , Pan Jie , Chen Jie , He Shuyan , Shen Dong , Qi Chunjian
Published: January 2023

Yeast β-glucan is a polysaccharide purified from the Saccharomyces cerevisiae cell wall, and its multiple biological activities are essential for immune regulation. However, the effect of β-glucan on the intestinal immune response during colitis-associated colorectal cancer (CAC) is unclear. Here, we explore the possible role of β-glucan in the development of CAC. Wild type (WT) mice with CAC induced by azoxmethane (AOM) and dextran sodium sulfate (DSS) had fewer tumors than untreated mice after oral β-glucan because of increased antitumor dendritic cells (DCs) in the tumor microenvironment, resulting in more CD8+ T cells and the production of related cytokines. β-glucan also increased resistance to DSS-induced chronic colitis by reshaping the inflammatory microenvironment. These data suggest that β-glucan improves experimental intestinal inflammation and delays the development of CAC. Therefore, β-glucan is feasible for treating chronic colitis and CAC in clinical practice.
Comprehensive in vitro and in silico assessments of metabolic capabilities of 24 genomic variants of CYP2C19 using two different substrates
Authors: Seo Myung-Eui , Min Byung-Joo , Heo Nayoon , Lee Kye Hwa , Kim Ju Han
Published: January 2023

Introduction: Most hepatically cleared drugs are metabolized by cytochromes P450 (CYPs), and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide curated clinical references for CYPs to apply individual genome data for optimized drug therapy. However, incorporating novel pharmacogenetic variants into guidelines takes considerable time.

Methods: We comprehensively assessed the drug metabolizing capabilities of CYP2C19 variants discovered through population sequencing of two substrates, S-mephenytoin and omeprazole.

Results: Based on established functional assays, 75% (18/24) of the variants not yet described in Pharmacogene Variation (PharmVar) had significantly altered drug metabolizing capabilities. Of them, seven variants with inappreciable protein expression were evaluated as protein damaging by all three in silico prediction algorithms, Sorting intolerant from tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Combined annotation dependent depletion (CADD). The five variants with decreased metabolic capability (<50%) of wild type for either substrates were evaluated as protein damaging by all three in silico prediction algorithms, except CADD exact score of NM_000769.4:c.593T>C that was 19.68 (<20.0). In the crystal structure of the five polymorphic proteins, each altered residue of all those proteins was observed to affect the key structures of drug binding specificity. We also identified polymorphic proteins indicating different tendencies of metabolic capability between the two substrates (5/24).

Discussion: Therefore, we propose a methodology that combines in silico prediction algorithms and functional assays on polymorphic CYPs with multiple substrates to evaluate the changes in the metabolism of all possible genomic variants in CYP genes. The approach would reinforce existing guidelines and provide information for prescribing appropriate medicines for individual patients.
Pien-tze-huang promotes wound healing in streptozotocin-induced diabetes models associated with improving oxidative stress via the Nrf2/ARE pathway
Authors: Liu Ying , Mo Jiake , Liang Fang , Jiang Siwei , Xiong Jing , Meng Xubiao , Mo Zhaohui
Published: January 2023

Diabetic foot ulcers are a serious complication of diabetes, with high mortality and a lack of effective clinical treatment, which leads to a considerable financial burden. Pien-Tze-Huang (PZH) is a Chinese traditional medicine with a long history that has been found to be an effective and convenient treatment for inflammatory diseases such as skin abscesses and ulcers. In this study, we assessed the effects of PZH on diabetic wounds and the underlying mechanisms. The wounds were established on the backs of streptozotocin-induced type 1 diabetic rats and type 2 diabetic mouse models. We found that PZH treatment used locally or by gavage significantly promoted wound healing, accelerated re-epithelialization and vasculature in the wound tissue, upregulated the expression of the growth factors VEGF-A, PDGF, and EGF, and activated the Nrf2/ARE pathway in the wound tissue. In vitro assays showed that PZH improved the proliferation, migration and angiogenic function of human umbilical vein endothelial cells (HUVECs) cultured in palmitic acid, reduced the expression of the apoptotic proteins p53, Bax, and cleaved-caspase3, and activated Nrf2/ARE signaling; however, these protective effects were abrogated after Nrf2 was knocked down by specific siRNA. In addition, the levels of the serum inflammatory cytokines IL-1β, TNF-α, and IL-6 were reduced after PZH gavage treatment. In conclusion, the positive role of PZH in diabetic wound healing might be related to the activation of the Nrf2/ARE pathway to regulate the level of oxidative stress in vivo and increase the expression of growth factors to improve angiogenesis.
Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux
Authors: Zhang Cheng , Wu Xuewen , Shi Pengmin , Ma Hongyu , Fang Fei , Feng Qianlang , Zhao Shuang , Zhang Ruipu , Huang Jinyuan , Xu Xinting , Xiao Weilie , Cao Guang , Ji Xu
Published: January 2023

Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicarpa rubella Lindl., a traditional Chinese medicine, have been reported to have anti-inflammatory activity. However, little is known about the effects of these diterpenoids on macrophage foam cell formation.

Methods: A macrophage-derived foam cell formation model was established by treating RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) for 24 h. Oil red O staining were used to detect the intracellular lipids. The cholesterol efflux capacity was assayed by labeling cells with 22-NBD-cholesterol. Western blots and real-time PCRs were performed to quantify protein and mRNA expressions.

Results: Two diterpenoid molecules, 14α-hydroxyisopimaric acid (C069002) and isopimaric acid (C069004), extracted from the flowers of Callicarpa rubella Lindl., significantly attenuated ox-LDL-induced foam cell formation in RAW264.7 macrophages. Further investigation showed that these two diterpenoids could promote cholesterol efflux from RAW264.7 macrophages to apolipoprotein A-I or high-density lipoproteins, which was associated with upregulated expression of ATP-binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα), and peroxisome proliferator-activated receptor-γ (PPARγ). Unexpectedly, the diterpenoids C069002 and C069004 failed to enhance the mRNA transcription of the ABCG1 gene in macrophage-derived foam cells induced by ox-LDL. To evaluate the effects of diterpenoids on macrophage foam cell formation and determine the underlying mechanism, two drugs (lovastatin and rosiglitazone) were used as positive controls. Although both drugs could reduce macrophage foam cell formation and promote cholesterol efflux, they each had distinctive abilities to modulate the expression of cholesterol efflux-related genes. In contrast to lovastatin, rosiglitazone showed a similar influence on the expression of cholesterol efflux-related genes (including ABCA1, LXRα, and PPARγ) as the diterpenoids regardless of the presence or absence of ox-LDL, implying a similar mechanism by which they may exert atheroprotective effects.

Conclusion: Our research indicates that diterpenoids effectively inhibit ox-LDL-induced macrophage foam cell formation by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1 pathway. Further investigation of diterpenoids as potential drugs for the treatment of atherosclerosis is warranted.