bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of Energy-Efficient Seizure Detectors for Implantable Neurostimulation Devices
Authors: Manzouri Farrokh , Zöllin Marc , Schillinger Simon , Dümpelmann Matthias , Mikut Ralf , Woias Peter , Comella Laura Maria , Schulze-Bonhage Andreas
Published: March 2022

Introduction

About 30% of epilepsy patients are resistant to treatment with antiepileptic drugs, and only a minority of these are surgical candidates. A recent therapeutic approach is the application of electrical stimulation in the early phases of a seizure to interrupt its spread across the brain. To accomplish this, energy-efficient seizure detectors are required that are able to detect a seizure in its early stages.

Methods

Three patient-specific, energy-efficient seizure detectors are proposed in this study: (i) random forest (RF); (ii) long short-term memory (LSTM) recurrent neural network (RNN); and (iii) convolutional neural network (CNN). Performance evaluation was based on EEG data (n = 40 patients) derived from a selected set of surface EEG electrodes, which mimic the electrode layout of an implantable neurostimulation system. As for the RF input, 16 features in the time- and frequency-domains were selected. Raw EEG data were used for both CNN and RNN. Energy consumption was estimated by a platform-independent model based on the number of arithmetic operations (AOs) and memory accesses (MAs). To validate the estimated energy consumption, the RNN classifier was implemented on an ultra-low-power microcontroller.

Results

The RNN seizure detector achieved a slightly better level of performance, with a median area under the precision-recall curve score of 0.49, compared to 0.47 for CNN and 0.46 for RF. In terms of energy consumption, RF was the most efficient algorithm, with a total of 67k AOs and 67k MAs per classification. This was followed by CNN (488k AOs and 963k MAs) and RNN (772k AOs and 978k MAs), whereby MAs contributed more to total energy consumption. Measurements derived from the hardware implementation of the RNN algorithm demonstrated a significant correlation between estimations and actual measurements.

Discussion

All three proposed seizure detection algorithms were shown to be suitable for application in implantable devices. The applied methodology for a platform-independent energy estimation was proven to be accurate by way of hardware implementation of the RNN algorithm. These findings show that seizure detection can be achieved using just a few channels with limited spatial distribution. The methodology proposed in this study can therefore be applied when designing new models for responsive neurostimulation.
Cerebellar and Cerebral Amyloid Visualized by [18F]flutemetamol PET in Long-Term Hereditary V30M (p.V50M) Transthyretin Amyloidosis Survivors
Authors: Uneus Erica Irene , Wilhelmsson Christer , Bäckström David , Anan Intissar , Wixner Jonas , Pilebro Björn , Riklund Katrine , Ögren Mattias , Ögreen Margareta , Axelsson Jan , Suhr Ole B. , Sundström Torbjörn
Published: March 2022

Introduction

Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS.

Methods

A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8–25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls.

Result

60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD.

Conclusion

Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.
Adherence to the Chinese Food Pagoda in the High-Risk Population of Non-communicable Diseases Aged 35–59 in Central China
Authors: Jiang Qingqing , You Qiqi , Lou Yiling , Wang Shiqi , Cao Shiyi
Published: March 2022

Objectives

A healthy dietary habit is essential for preventing non-communicable diseases (NCDs). We aimed to assess the adherence to the Chinese Food Pagoda (CFP) proposed in the Chinese Dietary Guidelines 2016 in the high-risk population of NCDs in central China.

Methods

A cross-sectional study was conducted in two large enterprises (totally 3,016 employees) from October to December 2019 in Hubei Province (central China). The high-risk population of NCDs was identified by physical examination, laboratory test and face-to-face questionnaire survey according to the National Norms for Prevention and Control of Non-communicable Diseases issued by the Chinese government. We assessed the deviation of real diet from the CFP recommended diet in the high-risk population of NCDs.

Results

A total of 821 participants aged 35–59 years old with at least one high-risk factor of NCDs were enrolled in our study. Of them, 53.8% were daily smokers, 49.6% had elevated blood cholesterol, 31.4% were centrally obese, 23.3% had high normal blood pressure, and 3.5% had impaired fasting glucose. Significant disparity was detected in the high-risk population of NCDs between real food consumption and the CFP's recommendation (P < 0.05), such as the deficient intake of nuts and milk and dairy products, and the over-consumption of cereals, meat and poultry, oil, and salt. Participants with impaired fasting glucose had the highest intake of cereals and vegetables on average. Participants with central obesity were more likely to consume meat and poultry (P < 0.05). The lowest average intake of eggs and the highest average intake of milk and dairy products were found in participants with high blood cholesterol (P < 0.05). The daily smokers were more likely to consume beans and nuts (P < 0.05). The lowest average intake of fruits and the highest average intake of tubers were found in participants with high normal blood pressure (P < 0.05).

Conclusion

Adherence to CFP in the high-risk population of NCDs appeared to be challenging. It is necessary to adopt dietary education campaign focusing on the high-risk population of NCDs to prevent or delay the occurrence of NCDs.
Phytochemicals From Vicia faba Beans as Ligands of the Aryl Hydrocarbon Receptor to Regulate Autoimmune Diseases
Authors: Méndez-López Luis Fernando , Sosa de León Deisy , López-Cabanillas Lomelí Manuel , González-Martínez Blanca Edelia , Vázquez-Rodríguez Jesús Alberto
Published: March 2022

Legumes are associated with gut health benefits, and increasing evidence indicates that their consumption reduces the risk of chronic diseases that include autoimmunity. Beans are rich sources of compounds with health-promoting effects, and recent metabolomic approaches have enabled the comprehensive characterization of the chemical composition of Vicia faba L. This article reviewed whether the phytocompounds in broad beans might modulate the aryl hydrocarbon receptor (AhR), which plays an essential role in autoantigen tolerance as a potential dietary strategy for autoimmune disease management. Therefore, thirty molecules present in Vicia faba of the chemical classes of flavonoids, chalcones, stilbenes, jasmonates, alkaloids, and amino acids, and either a human- or microbiome-derived product of biotransformation, retrieved from the literature or predicted in silico were evaluated by docking for affinity against the ligand-binding domain of AhR. Most analyzed compounds showed high affinity even after their metabolism which indicate that some AhR modulators remain active despite several steps in their biotransformation. Hence, our results suggest that in similitude with the gut metabolism of the tryptophan, phytocompounds mainly polyphenols also lead to metabolites that induce the AhR pathway. Furthermore, wyerone acid, wyerone epoxide, jasmonic acid, stizolamine, vicine, and convicine and their metabolite derivatives are reported for the first time as potential AhR ligands. Overall, chronic consumption of phytochemicals in Vicia faba L. and their gut biotransformation may protect against autoimmune disease pathogenesis by AhR modulation.
Nutrition and Congruent Care Improve Wellbeing of Residents With Dementia in Slovenian Care Homes
Authors: KejŽar Anamarija , Rihter Liljana , Sajovic Jakob , Drevenšek Gorazd
Published: March 2022

Introduction

Current nutritional strategies for people with dementia focus on nutritional diets and regimens, although in recent years congruent care for people with dementia has been increasingly recognized to improve their wellbeing. This includes consistency of care, respecting the variability of psycho-sociological factors, emphasizing the importance of participation in activities, and congruence with the individual's needs and capabilities. When applied to the nutritional aspects of care, it aims to empower people with dementia to have an active role in their care and during meals. Congruent care has previously shown promising results in improving the quality of life of residents, reducing the incidence of negative social interactions and daily intake of medicines.

Methods

A mixed methods qualitative-quantitative study was carried out. Out of 102 residential care homes for the elderly in Slovenia, a non-random sample of homes was selected. Seven homes that have implemented congruent care and five who have not implemented it agreed to participate. Content analysis of the transcripts of focus group interviews was carried out, to establish how the congruent care model was included into their everyday practice of care for people with dementia. Qualitative comparative analysis was used to describe the differences in the practice of care between the two groups of homes, in the fields of nutritional and general care. Frequencies and assigned importance of statements relating to different aspects of nutritional care were statistically compared.

Results

The introduction of congruent care improved the wellbeing of the people with dementia, as observed by caregivers. The homes that had implemented congruent care gave more attention to the food choice aspects of nutritional care (p = 0.0474, 95%CICongruent = 50.77–72.35%, 95%CINon−congruent = 27.65–49.23%), while the homes that had not were more attentive to the dietary intake aspects (p = 0.0067, 95%CICongruent = 22.79–44.74%, 95%CINon−congruent = 55.26–77.21%). In the homes for the elderly that had implemented congruent care, both caregivers and management reported that the frequency of use of pro re nata medication decreased, which is supported by the results of the linear regression (R2adjusted =78.4, p = 0.005), although the data available is limited.

Conclusion

First, the people with dementia in the care homes that had implemented congruent care were observed to have improved in mood, attitudes toward eating and wellbeing, as reported by caregivers. Second, the implementation of congruent care was well received by the management and caregivers of the care homes. A model of implementation of congruent nutritional care for people with dementia is presented.
Profiles of Behavioral Self-Regulation and Appetitive Traits in Preschool Children: Associations With BMI and Food Parenting Practices
Authors: Francis Lori A. , Rollins Brandi Y. , Keller Kathleen L. , Nix Robert L. , Savage Jennifer S.
Published: March 2022

Appetitive traits that contribute to appetite self-regulation have been shown to relate to non-food-related regulation in general domains of child development. Latent profile analysis (LPA) was used to identify typologies of preschool children's behavioral self-regulation (BSR) and appetitive traits related to appetite self-regulation (ASR), and we examined their relation with children's BMIz and food parenting practices. Participants included 720 children and their parents (90% mothers), drawn from the baseline assessment of a childhood obesity preventive intervention. BSR measures included teacher reports of children's inhibitory control, impulsivity and attentional focusing, as well as an observed measure of inhibitory control. ASR was assessed using parents' reports of children's appetitive traits related to food avoidance (e.g., satiety responsiveness, slowness in eating) and food approach (e.g., enjoyment of food, food responsiveness). Children's body mass index z-score (BMIz) was calculated from measured height and weight. Parents' BMI and food parenting practices were also measured. Four profiles were identified that characterized children with dysregulated behavior, higher food approach and lower food avoidance (16%), dysregulated behavior but lower food approach and higher food avoidance (33%), regulated behavior but highest food approach and lowest food avoidance (16%), and highly-regulated behavior, lowest food approach and highest food avoidance (35%). Children's BMIz was highest in the profile consisting of children with dysregulated behavior, higher food approach and lower food avoidance. BMI was similar in the profile with children with regulated behavior but highest food approach and lowest food avoidance; children in this profile also had parents who reported the highest levels of controlling food parenting practices, and the lowest levels of parental modeling of healthy eating. Compared to all other profiles, children in the profile characterized by highly-regulated behavior, lowest food approach and highest food avoidance had the lowest BMIz and had parents who reported food parenting practices characterized by the highest levels of child control in feeding and the lowest levels of pressure to eat. These findings provide evidence of differing patterns of relations between self-regulation across behavioral and eating domains, and children's obesity risk may vary based on these different patterns.
RETRACTED: Hydrodynamic Cavitation: A Novel Non-Thermal Liquid Food Processing Technology
Authors: Sun Xun , You Weibin , Wu Yue , Tao Yang , Yoon Joon Yong , Zhang Xinyan , Xuan Xiaoxu
Published: March 2022

Hydrodynamic cavitation (HC), as a novel non-thermal processing technology, has recently shown unique effects on the properties of various liquid foods. The extreme conditions of pressure at ~500 bar, local hotspots with ~5,000 K, and oxidation created by HC can help obtain characteristic products with high quality and special taste. Moreover, compared with other emerging non-thermal approaches, the feature of the HC phenomenon and its generation mechanism helps determine that HC is more suitable for industrial-scale processing. This mini-review summarizes the current knowledge of the recent advances in HC-based liquid food processing. The principle of HC is briefly introduced. The effectiveness of HC on the various physical (e.g., particle size, viscosity, temperature, and stability), chemical (nutrition loss), and biological characteristics (microorganism inactivation) of various liquid foods are evaluated. Finally, several recommendations for future research on the HC technique are provided.
Benefits of Targeted Molecular Therapy to Immune Infiltration and Immune-Related Genes Predicting Signature in Breast Cancer
Authors: Chen Fahai , Fang Jianmin
Published: March 2022

Background

This study aimed to investigate the tumor-related infiltrating lymphocytes (TILs) affecting the response of trastuzumab and identify potential biomarkers based on immune-related genes to improve prognosis and clinical outcomes of targeted therapies in breast cancer.

Methods

Estimation of stromal and immune cells in malignant tumors using expression data (ESTIMATE) was adopted to infer the fraction of stromal and immune cells through utilizing gene expression signatures in breast tumor samples. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) algorithm was applied to characterize cell composition of 22 lymphocytes from breast cancer tissues using their gene expression profiles. Immune-related genes were collected from the Immunology Database and Analysis (ImmPort). Univariate and multivariate Cox regression analyses were performed to identify the significant independent risk factors associated with poor overall survival (OS) and breast cancer-specific survival (BCSS) of breast cancer patients. Hub genes were identified based on the protein–protein interaction (PPI) network analysis.

Results

Based on the ESTIMATE algorithm, a significant reduction of stromal scores was observed in tumor tissues and pretreated tumor tissues compared with nontumor and posttreated tumor tissues, respectively, while immune scores failed to present notably statistical differences between both groups. However, from the results of the univariate Cox regression analysis, the immune score was identified to be remarkably associated with the poor OS for breast cancer patients. Subsequently, the infiltrating lymphocytes were evaluated in tumor tissues based on the CIBERSORT algorithm. Furthermore, significance analysis identified 1,244 differentially expressed genes (DEGs) from the GSE114082 dataset, and then 91 overlapping immune-related DEGs were screened between GSE114082 and ImmPort datasets. Subsequently, 10 top hub genes were identified and five (IGF1, ADIPOQ, PPARG, LEP, and NR3C1) significantly correlated with worse OS and BCSS on response to trastuzumab in breast cancer patients.

Conclusions

This study provided an insight into the immune score based on the tumor-related infiltrating lymphocytes in breast cancer tissues and demonstrates the benefits of immune infiltration on the treatment of trastuzumab. Meanwhile, the study established a novel five immune-related gene signature to predict the OS and BCSS of breast cancer treated by trastuzumab.
New Advances in Targeted Therapy of HER2-Negative Breast Cancer
Authors: An Junsha , Peng Cheng , Xie Xiaofang , Peng Fu
Published: March 2022

Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of molecular biology and genomics, molecular targeted therapy has become one of the most active areas in breast cancer treatment research and has also achieved remarkable achievements. However, molecular targeted therapy is mainly aimed at HER2-positive breast cancer and has not yet achieved satisfactory curative effect on HER2-negative breast cancer. This article describes the potential targets that may be used for breast cancer treatment from the aspects of PI3K/AKT signaling pathway, DDR, angiogenesis, the cell cycle, breast cancer stem cells, etc., and explores possible inhibitors for the treatment of HER2-negative breast cancer, such as PI3K inhibitors, AKT inhibitors and m-TOR inhibitors that inhibit the PI3K/AKT signaling pathway, small molecule tyrosine kinase inhibitors that restrain angiogenesis, CDK inhibitors, aurora kinase inhibitors and HDAC inhibitors that block cell cycle, as well as the drugs targeting breast cancer stem cells which have been a hit, aiming to provide a new idea and strategy for the treatment of HER2-negative breast cancer.
Prognostic Value of Postoperative Circulating Tumor DNA in Patients With Early- and Intermediate-Stage Hepatocellular Carcinoma
Authors: Ye Ke , Fan Qinqiao , Yuan Mingming , Wang Dong , Xiao Liang , Long Guo , Chen Rongrong , Fang Tongdi , Li Zengbo , Zhou Ledu
Published: March 2022

Majority of patients with resected early- and intermediate-stage liver cancer will experience postoperative recurrence. This study aimed to investigate the application of ctDNA sequencing in the postoperative period of hepatocellular carcinoma. A total of 96 patients with liver cancer were enrolled in this study. Postoperative peripheral blood samples were collected from all patients after surgery and analyzed using hybridization capture-based next-generation sequencing. Identification of at least one somatic mutation in the peripheral blood was defined as ctDNA+. Five genetic features in tumor tissues were associated with disease-free survival (DFS) using Lasso-Cox model. The area under the receiver operating characteristic curve was 0.813 and 0.882 in training and validation cohorts, respectively. The recurrence rate in ctDNA+ and ctDNA- groups was 60.9% and 27.8%, respectively. Multivariate Cox regression analysis showed that the postoperative ctDNA was an independent prognostic predictor of DFS (HR [hazard ratio]: 6.074, 95% Cl [confidence interval]: 2.648-13.929, P<0.001) and overall survival (OS) (HR: 4.829, 95% CI: 1.508-15.466, P=0.008). Combined ctDNA with AFP improved prediction performance. The median DFS was 2.0, and 8.0 months in ctDNA+/AFP-H and ctDNA+/AFP-L groups, respectively; while ctDNA-/AFP-H and ctDNA-/AFP-L groups had not reached the median time statistically (Log-rank test, P < 0.0001). Furthermore, ctDNA- patients had better prognosis than ctDNA+ patients irrespective of tumor stage. Postoperative ctDNA sequencing has great prognostic value in patients with liver cancer. Patients with positive ctDNA should receive more intensive disease monitoring and more aggressive treatment strategies to improve the survival time.
The Emerging Role of PRMT6 in Cancer
Authors: Chen Zhixian , Gan Jianfeng , Wei Zhi , Zhang Mo , Du Yan , Xu Congjian , Zhao Hongbo
Published: March 2022

Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that is involved in epigenetic regulation of gene expression through methylating histone or non-histone proteins, and other processes such as alternative splicing, DNA repair, cell proliferation and senescence, and cell signaling. In addition, PRMT6 also plays different roles in various cancers via influencing cell growth, migration, invasion, apoptosis, and drug resistant, which make PRMT6 an anti-tumor therapeutic target for a variety of cancers. As a result, many PRMT6 inhibitors are being utilized to explore their efficacy as potential drugs for various cancers. In this review, we summarize the current knowledge on the function and structure of PRMT6. At the same time, we highlight the role of PRMT6 in different cancers, including the differentiation of its promotive or inhibitory effects and the underlying mechanisms. Apart from the above, current research progress and the potential mechanisms of PRMT6 behind them were also summarized.
Expression of GPR68, an Acid-Sensing Orphan G Protein-Coupled Receptor, in Breast Cancer
Authors: Elemam Noha Mousaad , Youness Rana A. , Hussein Amal , Shihab Israa , Yakout Nada M. , Elwany Yasmine Nagy , Manie Tamer M. , Talaat Iman M. , Maghazachi Azzam A.
Published: March 2022

Background

Breast cancer (BC) is the most diagnosed cancer and the leading cause of global cancer incidence in 2020. It is quite known that highly invasive cancers have disrupted metabolism that leads to the creation of an acidic tumor microenvironment. Among the proton-sensing G protein-coupled receptors is GPR68. In this study, we aimed to explore the expression pattern of GPR68 in tissues from BC patients as well as different BC cell lines. Methods: In-silico tools were used to assess the expression of GPR68 in BC patients. The expression pattern was validated in fresh and paraffin-embedded sections of BC patients using qPCR and immunohistochemistry (IHC), respectively. Also, in-silico tools investigated GPR68 expression in different BC cell lines. Validation of GPR68 expression was performed using qPCR and immunofluorescence techniques in four different BC cell lines (MCF-7, MDA-MB-231, BT-549 and SkBr3). Results: GPR68 expression was found to be significantly increased in BC patients using the in-silico tools and validation using qPCR and IHC. Upon classification according to the molecular subtypes, the luminal subtype showed the highest GPR68 expression followed by triple-negative and Her2-enriched cells. However, upon validation in the recruited cohort, the triple-negative molecular subtype of BC patients showed the highest GPR68 expression. Also, in-silico and validation data revealed that the triple-negative breast cancer cell line MDA-MB-231 showed the highest expression of GPR68. Conclusion: Therefore, this study highlights the potential utilization of GPR68 as a possible diagnostic and/or prognostic marker in BC.
Acute Promyelocytic Leukemia Presenting With a Myeloid Sarcoma of the Spine: A Case Report and Literature Review
Authors: Shu Xuemei , Wu Qiuling , Guo Tao , Yin Hua , Liu Jingdi
Published: March 2022

Myeloid sarcoma is a rare extramedullary tumor of immature myeloid cells. Certain known acute myeloid leukemia cytogenetic abnormalities, in particular t(8,21), has been associated with a higher incidence. Myeloid sarcoma, which rarely happens in acute promyelocytic leukemias, is more common in recurrent patients after the advent of all-trans retinoic acid (ATRA) and are rare in untreated acute promyelocytic leukemia. We described a case of, to our knowledge, de novo myeloid sarcoma of the spine confirmed as acute promyelocytic leukemia. Myeloid sarcoma is diagnosed by spinal tumor biopsy, and microscopic examination of a bone marrow smear and cytogenetic analysis led to a confirmed diagnosis of acute promyelocytic leukemia.
Lynch Syndrome-Associated Endometrial Cancer With Combined EPCAM-MSH2 Deletion: A Case Report
Authors: Huang Rong , Deng Xiangyu , Zhang Zhenhua , Wen Qinglian , Li Dan
Published: March 2022

Background

Lynch syndrome (LS), an autosomal dominant disorder, is characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes like MSH2. EPCAM deletions cause a minority (3%) of LS cases. However, there are only a few reports of LS-associated endometrial cancer (LS-EC) induced by the inactivation of the MSH2 gene due to EPCAM deletions.

Case Presentation

We present the case of a 45-years old woman diagnosed with endometrial cancer (EC). Definitive surgery revealed meso-differentiated endometrioid adenocarcinoma, stage IA without lymph-vascular space invasion. Four months later, she received radiation therapy (125I radioactive seeds implantation), and platinum-containing regimen combined chemotherapy because of vaginal stump metastasis of EC. After five years, we performed immunohistochemistry (IHC) on pelvic mass because of presacral metastatic lymph node. IHC showed the absence of MSH2 and MSH6 protein expression in the pelvic mass tissue. Peripheral blood was used for genetic testing based on her cancer diagnosis and family history of cancer in close relatives. Genetic testing revealed deletions of exon 8 and 9 in EPCAM and deletions of exon 1 and 8 in MSH2; thus, we diagnosed the presence of LS. The patient underwent interstitial brachytherapy (BT) of the presacral metastatic lymph node.

Conclusion

This case highlights that patients with LS-EC who are carriers of combined EPCAM-MSH2 deletion might experience better oncologic outcomes even with early recurrence.
Using Aggregate Vasoactive-Inotrope Scores to Predict Clinical Outcomes in Pediatric Sepsis
Authors: Shah Palak , Petersen Tara L. , Zhang Liyun , Yan Ke , Thompson Nathan E.
Published: March 2022

Objectives

The heterogeneity of sepsis makes it difficult to predict outcomes using existing severity of illness tools. The vasoactive-inotrope score (VIS) is a quantitative measure of the amount of vasoactive support required by patients. We sought to determine if a higher aggregate VIS over the first 96 h of vasoactive medication initiation is associated with increased resource utilization and worsened clinical outcomes in pediatric patients with severe sepsis.

Design

Retrospective cohort study.

Setting

Single-center at Children's Wisconsin in Milwaukee, WI.

Patients

One hundred ninety-nine pediatric patients, age less than 18 years old, diagnosed with severe sepsis, receiving vasoactive medications between January 2017 and July 2019.

Interventions

Retrospective data obtained from the electronic medical record, calculating VIS at 2 h intervals from 0–12 h and at 4 h intervals from 12–96 h from Time 0.

Measurements

Aggregate VIS derived from the hourly VIS area under the curve (AUC) calculation based on the trapezoidal rule. Data were analyzed using Pearson's correlations, Mann-Whitney test, Wilcoxon signed rank test, and classification, and regression tree (CART) analyses.

Main Results

Higher aggregate VIS is associated with longer hospital LOS (p < 0.0001), PICU LOS (p < 0.0001), MV days (p = 0.018), increased in-hospital mortality (p < 0.0001), in-hospital cardiac arrest (p = 0.006), need for ECMO (p < 0.0001), and need for CRRT (p < 0.0001). CART analyses found that aggregate VIS >20 is an independent predictor for in-hospital mortality (p < 0.0001) and aggregate VIS >16 for ECMO use (p < 0.0001).

Conclusions

There is a statistically significant association between aggregate VIS and many clinical outcomes, allowing clinicians to utilize aggregate VIS as a physiologic indicator to more accurately predict disease severity/trajectory in pediatric sepsis.
Do GnRH Agonists Really Increase Body Weight Gain? Evaluation of a Multicentric Portuguese Cohort of Patients With Central Precocious Puberty
Authors: Leite Ana Luísa , Galo Elisa , Antunes Ana , Robalo Brígida , Amaral Daniela , Espada Filipa , Castro Sofia , Simões Dias Sara , Limbert Catarina
Published: March 2022

Introduction

There are several concerns associated with gonadotropin-releasing hormone agonist (GnRHa) treatment for central precocious puberty (CPP), such as obesity and changes in body mass index (BMI). We aimed to investigate whether any anthropometric differences exist and if they persist over time.

Methods

We conducted an observational study of Portuguese children (both sexes) diagnosed with CPP between January 2000 and December 2017, using a digital platform, in order to analyze the influence of GnRHa treatment on BMI-SD score (BMI-SDS).

Results

Of the 241 patients diagnosed with CPP, we assessed 92 patients (8% boys) in this study. At baseline, 39% of the patients were overweight. BMI-SDS increased with treatment for girls but then diminished 1 year after stopping GnRHa therapy (p = 0.018). BMI-SDS variation at the end of treatment was negatively correlated with BMI-SDS at baseline (p < 0.001). Boys grew taller and faster during treatment than did girls (p < 0.001), and therefore, their BMI-SDS trajectory might be different.

Conclusions

This study showed an increase of body weight gain during GnRHa treatment only in girls, which reversed just 1 year after stopping treatment. The overall gain in BMI-SDS with treatment is associated with baseline BMI-SDS.
Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of the QX002N anti-IL-17 Monoclonal Antibody: A Phase I, Randomized, Double-Blind, Single Ascending Dose Study in Healthy Chinese Volunteers
Authors: Wu Min , Zhang Hong , Li Qianqian , Chen Hong , Fang Min , Yang Lizhi , Ding Yanhua
Published: March 2022

Background: The innovative injection of interleukin 17 A (IL-17A) monoclonal antibody QX002N is being developed to treat active ankylosing spondylitis and plaque psoriasis in adults.

Objective: This study investigated the pharmacokinetics (PKs), pharmacodynamics (PDs) safety, tolerability, and immunogenicity of single ascending subcutaneous injections of QX002N in healthy Chinese volunteers.

Methods: A total of 65 healthy subjects were enrolled in a randomized, double-blind, placebo-controlled, single ascending dose phase I study (10–320 mg). Ten subjects were allocated to each cohort (containing 8 subjects treated with QX002N and 2 with placebo), except cohort 1 (only 4 subjects treated with QX002N and 1 with placebo). The studies on PKs, PDs, tolerability, and immunogenicity of QX002N were performed.

Results: Our study showed that QX002N injection was well tolerated, without deaths, serious adverse events, or discontinuations due to treatment-emergent adverse events (TEAEs). Neither more frequency nor high severity of the drug-related adverse reaction was observed with increasing QX002N dose. The TEAEs in all subjects were considered Grades 1–2 (CTCAE 5.0) except for one case of Grade 3 (hypertriglyceridemia). Tmax of QX002N was obtained from 168 to 240 h across the dose range after administration. The Cmax and area under the curve of QX002N increased in proportion to dose, and showed linear PKs. Anti-drug antibody positivity was detected in one (1.9%) subject after drug administration.

Conclusion: QX002N was well tolerated in our study. Based on the PKs and safety results of QX002N, 80 mg is recommended as the effective dose for a future phase Ib study.

Clinical Trial Registration: https://www.chinadrugtrials.org.cn/, identifier ChiCTR1900023040.
Maackiain Modulates miR-374a/GADD45A Axis to Inhibit Triple-Negative Breast Cancer Initiation and Progression
Authors: Peng Fu , Wang Li , Xiong Liang , Tang Hailin , Du Junrong , Peng Cheng
Published: March 2022

Breast cancer ranks as the leading cause of death in lethal malignancies among women worldwide, with a sharp increase of incidence since 2008. Triple negative breast cancer (TNBC) gives rise to the largest proportion in breast cancer-related deaths because of its aggressive growth and rapid metastasis. Hence, searching for promising targets and innovative approaches is indispensable for the TNBC treatment. Maackiain (MA), a natural compound with multiple biological activities, could be isolated from different Chinese herbs, such as Spatholobus suberectus and Sophora flavescens. It was the first time to report the anti-cancer effect of MA in TNBC. MA could suppress TNBC cell proliferation, foci formation, migration, and invasion. MA also exerted a significant inhibitory effect on tumor growth of TNBC. Furthermore, MA could induce apoptosis with an increase of GADD45α and a decrease of miR-374a. In contrast, overexpressing miR-374a would result in at least partly affecting the proapoptotic effect of MA and suppressing GADD45α stimulated by MA. These results reveal the anti-TNBC effect of MA in vitro and in vivo, providing evidence for its potential as a drug candidate utilized in TNBC therapy.
Effectiveness and Safety Analysis of PIs/r Based Dual Therapy in Treatment-Naïve, HIV/AIDS Patients: A Network Meta Analysis of Randomized Controlled Trials
Authors: Hui Liu , Xiaoxu Han , Yuqi Wang , Peng Wang , Xin Wang , Yunyun Yi , Xin Li
Published: March 2022

Background: Dual anti-retroviral therapy is the main proven valuable intervention type for treating naïve HIV/AIDS. Currently, no high-quality evidence is available regarding the best dual schemes.

Objectives: The aim of this study is to evaluate the effectiveness and safety of PIs/r-based dual therapy in treatment-naïve HIV/AIDS patients by using network meta-analysis.

Methods: Randomized controlled trials of PIs/r-based dual therapy in treatment-naïve HIV/AIDS were searched based on Embase, PubMed and Cochrane library database from January 2006 to June 2021. Taking viral suppression rate, CD4+T cell count changes from baseline as the primary indicator and adverse events rate as secondary indicator, the network meta-analysis was performed on Review Manager and STATA software. Heterogeneity was assessed by the Q statistic and I2. We registered our protocol in Prospero with ID CRD42021275466.

Results: Among 15 randomized controlled trials (3,497 patients and 7 PIs/r-based dual therapy) were reviewed in this study. According to the forest map, DRV/r + INSTIs was more effective compared to triple therapy (TT) in viral suppression [OR 0.82, 95% CI (0.61–1.11)], in CD4+T cell count changes from baseline [MD 1.9, 95% CI (0.7, 3.1), I2 86%], in adverse events [OR 0.98, 95% CI (0.68–1.39)]. Furthermore, SUCRA ranking analysis indicated that DRV/r + INSTIs was superior to TT in viral suppression (DRV/r + INSTIs 75.5% > TT 41.2%) and in immune construction (DRV/r + INSTIs 67% > TT 42%). In addition, DRV/r + INSTIs was similar to TT in adverse events (DRV/r + INSTIs 54.9% ≈ TT 54.7%).

Conclusion: DRV/r + INSTIs was obviously superior to TT in viral suppression and immune reconstruction, and was not higher than TT in adverse events.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42021275466
Title: Understanding a Low Vitamin D State in the Context of COVID-19
Authors: Walsh James Bernard , McCartney Daniel M. , Laird Éamon , McCarroll Kevin , Byrne Declan G. , Healy Martin , O’Shea Paula M. , Kenny Rose Anne , Faul John L.
Published: March 2022

While a low vitamin D state has been associated with an increased risk of infection by SARS-CoV-2 in addition to an increased severity of COVID-19 disease, a causal role is not yet established. Here, we review the evidence relating to i) vitamin D and its role in SARS-CoV-2 infection and COVID-19 disease ii) the vitamin D status in the Irish adult population iii) the use of supplemental vitamin D to treat a deficient status and iv) the application of the Bradford-Hill causation criteria. We conclude that reverse causality probably makes a minimal contribution to the presence of low vitamin D states in the setting of COVID-19. Applying the Bradford-Hill criteria, however, the collective literature supports a causal association between low vitamin D status, SARS-CoV-2 infection, and severe COVID-19 (respiratory failure, requirement for ventilation and mortality). A biologically plausible rationale exists for these findings, given vitamin D’s role in immune regulation. The thresholds which define low, deficient, and replete vitamin D states vary according to the disease studied, underscoring the complexities for determining the goals for supplementation. All are currently unknown in the setting of COVID-19. The design of vitamin D randomised controlled trials is notoriously problematic and these trials commonly fail for a number of behavioural and methodological reasons. In Ireland, as in most other countries, low vitamin D status is common in older adults, adults in institutions, and with obesity, dark skin, low UVB exposure, diabetes and low socio-economic status. Physiological vitamin D levels for optimal immune function are considerably higher than those that can be achieved from food and sunlight exposure alone in Ireland. A window exists in which a significant number of adults could benefit from vitamin D supplementation, not least because of recent data demonstrating an association between vitamin D status and COVID-19. During the COVID pandemic, we believe that supplementation with 20-25ug (800–1000 IU)/day or more may be required for adults with apparently normal immune systems to improve immunity against SARS-CoV-2. We expect that higher monitored doses of 37.5–50 ug (1,500–2,000)/day may be needed for vulnerable groups (e.g., those with obesity, darker skin, diabetes mellitus and older adults). Such doses are within the safe daily intakes cited by international advisory agencies.
Cholesterol Sulfate Exerts Protective Effect on Pancreatic β-Cells by Regulating β-Cell Mass and Insulin Secretion
Authors: Zhang Xueping , Deng Dan , Cui Daxin , Liu Yin , He Siyuan , Zhang Hongmei , Xie Yaorui , Yu Xiaoqian , Yang Shanshan , Chen Yulong , Su Zhiguang
Published: March 2022

Rational: Cholesterol sulfate (CS) is the most abundant known sterol sulfate in human plasma, and it plays a significant role in the control of metabolism and inflammatory response, which contribute to the pathogenesis of insulin resistance, β-cell dysfunction and the resultant development of diabetes. However, the role of CS in β-cells and its effect on the development of diabetes remain unknown. Here, we determined the physiological function of CS in pancreatic β-cell homeostasis.

Materials and Methods: Blood CS levels in streptozotocin (STZ)- or high-fat diet-induced diabetic mice and patients with type 1 or 2 diabetes were determined by LC-MS/MS. The impact of CS on β-cell mass and insulin secretion was investigated in vitro in isolated mouse islets and the β-cell line INS-1 and in vivo in STZ-induced diabetic mice. The molecular mechanism of CS was explored by viability assay, EdU incorporation analysis, flow cytometry, intracellular Ca2+ influx analysis, mitochondrial membrane potential and cellular ROS assays, and metabolism assay kits.

Results: Plasma CS levels in mice and humans were significantly elevated under diabetic conditions. CS attenuated diabetes in a low-dose STZ-induced mouse model. Mechanistically, CS promoted β-cell proliferation and protected β-cells against apoptosis under stressful conditions, which in turn preserved β-cell mass. In addition, CS supported glucose transporter-2 (GLUT2) expression and mitochondrial integrity, which then resulted in a less reactive oxygen species (ROS) generation and an increase in ATP production, thereby enabling insulin secretion machinery in the islets to function adequately.

Conclusion: This study revealed a novel dual role of CS in integrating β-cell survival and cell function, suggesting that CS might offer a physiologic approach to preserve β-cells and protect against the development of diabetes mellitus.
Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies
Authors: Pal Soumiya , Rahman Jenat , Mu Shengyu , Rusch Nancy J. , Stolarz Amanda J.
Published: March 2022

The lymphatic circulation is an important component of the circulatory system in humans, playing a critical role in the transport of lymph fluid containing proteins, white blood cells, and lipids from the interstitial space to the central venous circulation. The efficient transport of lymph fluid critically relies on the rhythmic contractions of collecting lymph vessels, which function to “pump” fluid in the distal to proximal direction through the lymphatic circulation with backflow prevented by the presence of valves. When rhythmic contractions are disrupted or valves are incompetent, the loss of lymph flow results in fluid accumulation in the interstitial space and the development of lymphedema. There is growing recognition that many pharmacological agents modify the activity of ion channels and other protein structures in lymph muscle cells to disrupt the cyclic contraction and relaxation of lymph vessels, thereby compromising lymph flow and predisposing to the development of lymphedema. The effects of different medications on lymph flow can be understood by appreciating the intricate intracellular calcium signaling that underlies the contraction and relaxation cycle of collecting lymph vessels. For example, voltage-sensitive calcium influx through long-lasting (“L-type”) calcium channels mediates the rise in cytosolic calcium concentration that triggers lymph vessel contraction. Accordingly, calcium channel antagonists that are mainstay cardiovascular medications, attenuate the cyclic influx of calcium through L-type calcium channels in lymph muscle cells, thereby disrupting rhythmic contractions and compromising lymph flow. Many other classes of medications also may contribute to the formation of lymphedema by impairing lymph flow as an off-target effect. The purpose of this review is to evaluate the evidence regarding potential mechanisms of drug-related lymphedema with an emphasis on common medications administered to treat cardiovascular diseases, metabolic disorders, and cancer. Additionally, although current pharmacological approaches used to alleviate lymphedema are largely ineffective, efforts are mounting to arrive at a deeper understanding of mechanisms that regulate lymph flow as a strategy to identify novel anti-lymphedema medications. Accordingly, this review also will provide information on studies that have explored possible anti-lymphedema therapeutics.
Compressive Interferenceless Coded Aperture Correlation Holography With High Imaging Quality
Authors: Liu Chao , Man Tianlong , Wan Yuhong
Published: March 2022

Interferenceless coded aperture correlation holography (I-COACH) provides an alternative way for the 3D imaging of spatial incoherent illuminated or fluorescent sample. However, the low imaging signal-to-noise ratio (SNR) is one of the bottlenecks that restrict the application of I-COACH. The limitation is mainly originated from the strong bias level that presents in the recorded holograms. Phase shifting methods were implemented in I-COACH to eliminate the background noise while the multiple-exposures recording mechanism significantly reduces the temporal resolution of the system. In this paper, we proposed a compressive I-COACH imaging method with high reconstruction quality and without the sacrifice of the imaging speed. The 3D holographic image reconstruction was implemented under compressive sensing framework while only one single-exposure object hologram and one point spread hologram are necessary. High quality reconstructions were obtained using the proposed method, even for the down-sampled holograms. The imaging SNR of the I-COACH system was improved by a factor of more than 16.5% when comparing with the imaging SNR obtained by the conventional cross-correlation reconstruction method. The proposed method provides a fast and high-fidelity imaging method that can potentially benefit the imaging through scattering medium, partial aperture imaging, and other fields.
Angular-Based Mueller Matrix Polarimetry Parameters for Subwavelength Pore Size Differentiation
Authors: Wan Jiachen , Wang Chuhui , Wang Chunnan , Sun Shuqing , Ma Hui
Published: March 2022

Mueller matrix polarimetry is exploited to find a potential polarization feature sensitive to subwavelength pore size variation in porous alumina samples. After careful analysis using standard machine learning methods, it is observed that existing Mueller matrix decomposition methods and parameters are insufficient to distinguish areas with different pore sizes. Thus, a new angular-based Mueller matrix polarimetry parameter capable of linearly separating areas with varying pore sizes is proposed. Such an angular-based parameter is novel because it is based on angular parameters, it utilizes multi-angle measurements, and it extracts physical information independent of existing decomposition methods or parameters. Hopefully this work should inspire future research on the angular parameters in Mueller matrix polarimetry and their relationships to microstructure information.