bluuebunny/crossref_metadata_2025 huggingface dataset:
Laparoscopic surgery experience does not influence oncological and functional results of robotic-assisted laparoscopic prostatectomy
Authors: Cetin Taha , Yalcin Mehmet Yigit , Karaca Erkin , Ozbilen Mert Hamza , Ergani Batuhan , Koc Gokhan , Boyacioglu Hayal , Ilbey Yusuf Ozlem
Published: March 2021

Introduction:

Surgery is one of the treatment alternatives for prostate cancer, and robotic-assisted laparoscopic prostatectomy (RALP) has become the new trend in the past decade. There is no consensus yet for surgeons who will perform RALP whether they need to be trained or experienced in laparoscopy. In this study, it was aimed to investigate the effectiveness of the surgeon’s laparoscopy experience in the perioperative and postoperative results of RALP patients.

Material and method:

Patients who underwent RALP were retrospectively screened. The first 20 cases done by surgeons in both groups and 40 cases in total were included in the study. Surgeons with laparoscopy training were designated as group 1, and surgeons without laparoscopy training were designated as group 2. Patient’s age, preoperative prostate-specific antigen (PSA) value, prostate biopsy pathology, radical prostatectomy pathology, surgical margin positivity, extracapsular extension, and seminal vesicle invasion status, blood transfusion rate, operation time, length of hospital stay, and 1-year follow-up potency and urinary incontinence rates were compared.

Results:

There was no difference between the two groups in terms of age, preoperative PSA, preoperative biopsy results, blood transfusion rates, operation times, and the length of hospital stay of the patients. When the postoperative oncological and functional results of the patients were examined, there was no difference between the two groups in the prostatectomy pathology ( p = 0.895), extracapsular extension (pT3a) ( p = 0.519), positive surgical margin (pSM) ( p = 0.723), and seminal vesicle invasion (pT3b) ( p = 0.756). Potency and urinary incontinence rates were similar in both groups at the end of one year follow-up ( p = 0.327, 0.500 respectively).

Conclusions:

Based on our study, it is clearly seen that regardless of the surgeon’s experience of laparoscopy, it can be safely preferred when looking at the oncological and functional results of RALP.
A Qualitative Study Describing Pediatric Palliative Care in Non-Metropolitan Areas of Illinois
Authors: Murday Patrick , Downing Kimberly , Gaab Erin , Misasi Jennifer , Michelson Kelly N.
Published: March 2021

Background:

There is little information about providing pediatric palliative care (PPC) in non-metropolitan areas.

Objective:

Describe the strengths of and challenges to delivering PPC in non-metropolitan communities and identify opportunities to improve care delivery.

Design:

A qualitative study involving focus groups (FGs) with PPC stakeholders.

Setting/Participants:

From 4 non-metropolitan areas in Illinois, we recruited 3 stakeholder groups: healthcare providers (HPs); bereaved parents; and parents caring for a seriously ill child (SIC).

Measurements:

At each site, we held an FG with people of the same stakeholder group and then an FG involving all stakeholders. Discussion topics included: availability and strengths of local PPC services, barriers to local PPC, opportunities for improving local PPC access and quality, and clinician educational needs. We analyzed data using phenomenology and directed content analysis.

Results:

Thirty people, 12 parents and 18 HPs, participated in FGs. Identified themes related to: PPC perceptions; availability and use of local resources; and challenges associated with travel, care coordination, and finances. Participants described benefits of and limits to local PPC including pediatric-specific issues such as attending to siblings, creating child peer-support activities, providing school guidance, and financing for PPC. Recommendations included suggestions to enhance care coordination, use existing resources, improve community and provider education, develop community networks, and minimize financial challenges.

Conclusion:

Unique PPC challenges exist in non-metropolitan areas. PPC in non-metropolitan areas would benefit from enhancing local resource utilization and quality. Future work should address the challenges to providing PPC in non-metropolitan areas with a focus on pediatric-specific issues.
Best Interest Standard in School Health: A Concept Analysis
Authors: Grunin Laura , Malone Susan
Published: March 2021

The bioethical concept of best interest standard is cited in courts across America and considered to be an effective method of managing pediatric health care decision-making. Although the best interest standard is referred to in an abundance of nursing, medical, legal, and bioethical literature, refinement and a clear definition of the concept are lacking in the context of school health. An exhaustive and methodical search was conducted across six databases revealing 41 articles from the past decade. The Wilsonian methodology was used to analyze, refine, and clarify the concept of best interest standard by presenting original case vignettes (model, contrary, related, and borderline) and an innovative conceptual model as it applies to school nursing. This concept analysis provides school nurses with a deeper understanding of the best interest standard to navigate the complex nature of making school health care decisions.
Quality assessment of Diflucan® tablets distributed online: Diflucan® distributed online
Authors: Sanada Tomoko , Ohnishi Myu , Yoshida Naoko , Kimura Kazuko , Tsuboi Hirohito
Published: March 2021

Background:

Falsified medical products have been reported worldwide. Falsified medicines with poor quality are a potential health hazard. Some Internet sites advertise fluconazole (Diflucan®), an antifungal medicine used to treat deep mycoses, as “female Viagra®.”

Aim:

The aim of this study was to investigate the authenticity and quality of Diflucan® tablets distributed on the Internet.

Methods:

We ordered Diflucan® tablets via the Internet and evaluated them by visual observation, authenticity investigation, quality evaluation (quantity of the active pharmaceutical ingredient, content uniformity, and dissolution), and near-infrared and Raman scattering spectroscopy.

Results:

We obtained 11 samples of Diflucan® tablets from all 11 Japanese Internet sites identified in our search. Of 11 sites, 7 advertised fluconazole as having effects on female sexual function. Ten of the Diflucan® samples were confirmed as genuine and one sample was falsified. The genuine Diflucan® samples met the specifications of all quality evaluations. The packaging, size, and color of the falsified Diflucan® sample obtained in this study differed from the authentic Diflucan® tablet. The falsified Diflucan® sample obtained in this study did not contain fluconazole and instead contained what appeared to be sildenafil citrate. The spectra of the falsified Diflucan® tablet obtained in this study differed from the authentic Diflucan® tablet in near-infrared and Raman scattering spectroscopy.

Conclusion:

We confirmed that one falsified Diflucan® tablet was distributed online. Thus, continued measures against falsified medicines are required.
Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma
Authors: Facon Thierry , Venner Christopher P. , Bahlis Nizar J. , Offner Fritz , White Darrell J. , Karlin Lionel , Benboubker Lotfi , Rigaudeau Sophie , Rodon Philippe , Voog Eric , Yoon Sung-Soo , Suzuki Kenshi , Shibayama Hirohiko , Zhang Xiaoquan , Twumasi-Ankrah Philip , Yung Godwin , Rifkin Robert M. , Moreau Philippe , Lonial Sagar , Kumar Shaji K. , Richardson Paul G. , Rajkumar S. Vincent
Published: March 2021

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.
Single-cell transcriptomics dissects hematopoietic cell destruction and T-cell engagement in aplastic anemia
Authors: Zhu Caiying , Lian Yu , Wang Chenchen , Wu Peng , Li Xuan , Gao Yan , Fan Sibin , Ai Lanlan , Fang Liwei , Pan Hong , Cheng Tao , Shi Jun , Zhu Ping
Published: March 2021

Aplastic anemia (AA) is a T cell–mediated autoimmune disorder of the hematopoietic system manifested by severe depletion of the hematopoietic stem and progenitor cells (HSPCs). Nonetheless, our understanding of the complex relationship between HSPCs and T cells is still obscure, mainly limited by techniques and the sparsity of HSPCs in the context of bone marrow failure. Here we performed single-cell transcriptome analysis of residual HSPCs and T cells to identify the molecular players from patients with AA. We observed that residual HSPCs in AA exhibited lineage-specific alterations in gene expression and transcriptional regulatory networks, indicating a selective disruption of distinct lineage-committed progenitor pools. In particular, HSPCs displayed frequently altered alternative splicing events and skewed patterns of polyadenylation in transcripts related to DNA damage and repair, suggesting a likely role in AA progression to myelodysplastic syndromes. We further identified cell type–specific ligand-receptor interactions as potential mediators for ongoing HSPCs destruction by T cells. By tracking patients after immunosuppressive therapy (IST), we showed that hematopoiesis remission was incomplete accompanied by IST insensitive interactions between HSPCs and T cells as well as sustained abnormal transcription state. These data collectively constitute the transcriptomic landscape of disrupted hematopoiesis in AA at single-cell resolution, providing new insights into the molecular interactions of engaged T cells with residual HSPCs and render novel therapeutic opportunities for AA.
Nanocell-mediated delivery of miR-34a counteracts temozolomide resistance in glioblastoma
Authors: Khan Muhammad Babar , Ruggieri Rosamaria , Jamil Eesha , Tran Nhan L. , Gonzalez Camila , Mugridge Nancy , Gao Steven , MacDiarmid Jennifer , Brahmbhatt Himanshu , Sarkaria Jann N. , Boockvar John , Symons Marc
Published: March 2021

Background

Glioblastoma is the most common primary brain tumor and remains uniformly fatal, highlighting the dire need for developing effective therapeutics. Significant intra- and inter-tumor heterogeneity and inadequate delivery of therapeutics across blood–brain barrier continue to be significant impediments towards developing therapies which can significantly enhance survival. We hypothesize that microRNAs have the potential to serve as effective therapeutics for glioblastoma as they modulate the activity of multiple signaling pathways, and hence can counteract heterogeneity if successfully delivered.

Methods

Using a computational approach, we identified microRNA-34a as a microRNA that maximally reduces the activation status of the three core signaling networks (the receptor tyrosine kinase, p53 and Rb networks) that have been found to be deregulated in most glioblastoma tumors. Glioblastoma cultures were transfected with microRNA-34a or control microRNA to assess biological function and therapeutic potential in vitro. Nanocells were derived from genetically modified bacteria and loaded with microRNA-34a for intravenous administration to orthotopic patient-derived glioblastoma xenografts in mice.

Results

Overexpression of microRNA-34a strongly reduced the activation status of the three core signaling networks. microRNA-34a transfection also inhibited the survival of multiple established glioblastoma cell lines, as well as primary patient-derived xenograft cultures representing the proneural, mesenchymal and classical subtypes. Transfection of microRNA-34a enhanced temozolomide (TMZ) response in in vitro cultures of glioblastoma cells with primary TMZ sensitivity, primary TMZ resistance and acquired TMZ resistance. Mechanistically, microRNA-34a downregulated multiple therapeutic resistance genes which are associated with worse survival in glioblastoma patients and are enriched in specific tumor spatial compartments. Importantly, intravenous administration of nanocells carrying miR-34a and targeted to epidermal growth factor receptor (EGFR) strongly enhanced TMZ sensitivity in an orthotopic patient-derived xenograft mouse model of glioblastoma.

Conclusions

Targeted bacterially-derived nanocells are an effective vehicle for the delivery of microRNA-34a to glioblastoma tumors. microRNA-34a inhibits survival and strongly sensitizes a wide range of glioblastoma cell cultures to TMZ, suggesting that combination therapy of TMZ with microRNA-34a loaded nanocells may serve as a novel therapeutic approach for the treatment of glioblastoma tumors.
Early onset of effect following galcanezumab treatment in patients with previous preventive medication failures
Authors: Schwedt Todd J. , Kuruppu Dulanji K. , Dong Yan , Standley Katherine , Yunes-Medina Laura , Pearlman Eric
Published: March 2021

Background

Galcanezumab is a monoclonal antibody (mAb) that binds calcitonin gene-related peptide (CGRP) and is indicated for the preventive treatment of migraine. Galcanezumab demonstrated early onset of effect in patients with migraine but it is unknown whether the same holds true for patients who have not benefited from multiple prior migraine preventives.

Methods

Patients with episodic or chronic migraine from a 3-month, randomized, double-blind, placebo-controlled, phase 3b study (CONQUER) who had 2 to 4 migraine preventive medication category failures in the past 10 years were randomized 1:1 to placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). In this post-hoc analysis, change from baseline in number of monthly and weekly migraine headache days was assessed. Monthly onset of effect was the earliest month at which significant improvement with galcanezumab compared to placebo was achieved and maintained at all subsequent months. Weekly onset was the initial week at which statistical separation was achieved and maintained at all subsequent weeks during that month. Proportion of patients with migraine headache days in the first week of treatment, and patients achieving ≥50%, ≥75%, and 100% response by month and week were also assessed.

Results

Galcanezumab-treated patients had a significantly greater reduction in monthly migraine headache days starting at month 1, which remained significant for all subsequent months compared to placebo (all p ≤ 0.0001, month 1 mean change from baseline: placebo − 0.7; galcanezumab − 4.0). Weekly migraine headache days was significantly reduced in galcanezumab-treated patients starting at week 1 and continued for each subsequent week of month 1 compared to placebo (all p < 0.01, week 1 mean change from baseline: placebo − 0.2; galcanezumab − 1.1). A significantly smaller percentage of patients had a migraine headache on the first day after galcanezumab treatment compared to placebo (28.4% vs 39.2%) and at each subsequent day during week 1 (all p < 0.05). A greater proportion of galcanezumab-treated patients achieved ≥50%, ≥75%, and 100% response at months 1–3 (all p < 0.05) and at weeks 1–4 of month 1 compared to placebo (all p < 0.01).

Conclusion

Galcanezumab showed early onset of effect beginning the day after treatment initiation in patients who had not previously benefited from migraine preventive treatments.

Trial registration

ClinicalTrials.gov, NCT03559257. Registered 18 June 2018.
Quantitative analysis of cadmium in rice roots based on LIBS and chemometrics methods
Authors: Wang Wei , Kong Wenwen , Shen Tingting , Man Zun , Zhu Wenjing , He Yong , Liu Fei
Published: March 2021

Background

Excessive cadmium can damage cell structure, inhibit enzyme activity, and affect metabolic process, thus, leading to decline of rice yield and quality. Root is an important organ of crops, the detection of cadmium in root is essential for limitation of cadmium in rice grains.

Results

In this study, laser-induced breakdown spectroscopy (LIBS) was applied for cadmium quantitative analysis. Pretreatment methods, including median absolute deviation, wavelet transform, area normalization, were used to improve spectral stability. Scanning electron microscope and energy-dispersive X-ray spectrometer (SEM/EDS) was first used to analyze ablation pit surface characteristics and the results showed significant positive correlation with spectral lines of Cd II 214.44, Cd II 226.50 and Cd I 228.80 nm. Univariable models of spectral lines showed that three Cd spectral lines have good prediction for cadmium. Fitting methods including linear, logarithmic, and polynomial were used to propose characteristic input variables, and univariable models based on variable of polynomial fitting of I214.44 nm have achieved the best effect (Rp = 0.9821 and RMSEP = 31.1 mg/kg). Besides, partial least squares regression (PLSR), least squares support vector machine (LS-SVM) and extreme learning machine (ELM) were used for multivariate analysis. Compared with univariate analysis, ELM model based on the full spectrum (Rp = 0.9896 and RMSEP = 26.0 mg/kg) had more advantages for cadmium detection.

Conclusion

Compared with traditional methods (150 min), the quantitative detection method based on LIBS technology (less than 5 min) greatly reduces the detection time of heavy metals. The results showed that LIBS has proved to be a reliable method for quantitative detection of cadmium in rice roots. The research can provide theoretical support for timely detection of heavy metals in crop and food production.
SLR-superscaffolder: a de novo scaffolding tool for synthetic long reads using a top-to-bottom scheme
Authors: Guo Lidong , Xu Mengyang , Wang Wenchao , Gu Shengqiang , Zhao Xia , Chen Fang , Wang Ou , Xu Xun , Seim Inge , Fan Guangyi , Deng Li , Liu Xin
Published: March 2021

Background

Synthetic long reads (SLR) with long-range co-barcoding information are now widely applied in genomics research. Although several tools have been developed for each specific SLR technique, a robust standalone scaffolder with high efficiency is warranted for hybrid genome assembly.

Results

In this work, we developed a standalone scaffolding tool, SLR-superscaffolder, to link together contigs in draft assemblies using co-barcoding and paired-end read information. Our top-to-bottom scheme first builds a global scaffold graph based on Jaccard Similarity to determine the order and orientation of contigs, and then locally improves the scaffolds with the aid of paired-end information. We also exploited a screening algorithm to reduce the negative effect of misassembled contigs in the input assembly. We applied SLR-superscaffolder to a human single tube long fragment read sequencing dataset and increased the scaffold NG50 of its corresponding draft assembly 1349 fold. Moreover, benchmarking on different input contigs showed that this approach overall outperformed existing SLR scaffolders, providing longer contiguity and fewer misassemblies, especially for short contigs assembled by next-generation sequencing data. The open-source code of SLR-superscaffolder is available at https://github.com/BGI-Qingdao/SLR-superscaffolder.

Conclusions

SLR-superscaffolder can dramatically improve the contiguity of a draft assembly by integrating a hybrid assembly strategy.
Extensive structural variation in the Bowman-Birk inhibitor family in common wheat (Triticum aestivum L.)
Authors: Xie Yucong , Ravet Karl , Pearce Stephen
Published: March 2021

Background

Bowman-Birk inhibitors (BBI) are a family of serine-type protease inhibitors that modulate endogenous plant proteolytic activities during different phases of development. They also inhibit exogenous proteases as a component of plant defense mechanisms, and their overexpression can confer resistance to phytophagous herbivores and multiple fungal and bacterial pathogens. Dicot BBIs are multifunctional, with a “double-headed” structure containing two separate inhibitory loops that can bind and inhibit trypsin and chymotrypsin proteases simultaneously. By contrast, monocot BBIs have a non-functional chymotrypsin inhibitory loop, although they have undergone internal duplication events giving rise to proteins with multiple BBI domains.

Results

We used a Hidden Markov Model (HMM) profile-based search to identify 57 BBI genes in the common wheat (Triticum aestivum L.) genome. The BBI genes are unevenly distributed, with large gene clusters in the telomeric regions of homoeologous group 1 and 3 chromosomes that likely arose through a series of tandem gene duplication events. The genomes of wheat progenitors also contain contiguous clusters of BBI genes, suggesting this family underwent expansion before the domestication of common wheat. However, the BBI gene family varied in size among different cultivars, showing this family remains dynamic. Because of these expansions, the BBI gene family is larger in wheat than other monocots such as maize, rice and Brachypodium.

We found BBI proteins in common wheat with intragenic homologous duplications of cysteine-rich functional domains, including one protein with four functional BBI domains. This diversification may expand the spectrum of target substrates. Expression profiling suggests that some wheat BBI proteins may be involved in regulating endogenous proteases during grain development, while others were induced in response to biotic and abiotic stresses, suggesting a role in plant defense.

Conclusions

Genome-wide characterization reveals that the BBI gene family in wheat is subject to a high rate of homologous tandem duplication and deletion events, giving rise to a diverse set of encoded proteins. This information will facilitate the functional characterization of individual wheat BBI genes to determine their role in wheat development and stress responses, and their potential application in breeding.
Transcriptional profiling of identified neurons in leech
Authors: Heath-Heckman Elizabeth , Yoo Shinja , Winchell Christopher , Pellegrino Maurizio , Angstadt James , Lammardo Veronica B. , Bautista Diana , De-Miguel Francisco F. , Weisblat David
Published: March 2021

Background

While leeches in the genusHirudohave long been models for neurobiology, the molecular underpinnings of nervous system structure and function in this group remain largely unknown. To begin to bridge this gap, we performed RNASeq on pools of identified neurons of the central nervous system (CNS): sensory T (touch), P (pressure) and N (nociception) neurons; neurosecretory Retzius cells; and ganglia from which these four cell types had been removed.

Results

Bioinformatic analyses identified 3565 putative genes whose expression differed significantly among the samples. These genes clustered into 9 groups which could be associated with one or more of the identified cell types. We verified predicted expression patterns through in situ hybridization on whole CNS ganglia, and found that orthologous genes were for the most part similarly expressed in a divergent leech genus, suggesting evolutionarily conserved roles for these genes. Transcriptional profiling allowed us to identify candidate phenotype-defining genes from expanded gene families. Thus, we identified one of eight hyperpolarization-activated cyclic-nucleotide gated (HCN) channels as a candidate for mediating the prominent sag current in P neurons, and found that one of five inositol triphosphate receptors (IP3Rs), representing a sub-family of IP3Rs absent from vertebrate genomes, is expressed with high specificity in T cells. We also identified one of twopiezogenes, two of ~ 65 deg/enacgenes, and one of at least 16transient receptor potential(trp) genes as prime candidates for involvement in sensory transduction in the three distinct classes of leech mechanosensory neurons.

Conclusions

Our study defines distinct transcriptional profiles for four different neuronal types within the leech CNS, in addition to providing a second ganglionic transcriptome for the species. From these data we identified five gene families that may facilitate the sensory capabilities of these neurons, thus laying the basis for future work leveraging the strengths of the leech system to investigate the molecular processes underlying and linking mechanosensation, cell type specification, and behavior.
Expression characteristics of pineal miRNAs at ovine different reproductive stages and the identification of miRNAs targeting the AANAT gene
Authors: Di Ran , Liu Qiu-Yue , Song Shu-Hui , Tian Dong-Mei , He Jian-Ning , Ge Ying , Wang Xiang-Yu , Hu Wen-Ping , Mwacharo Joram-Mwashigadi , Pan Zhang-Yuan , Wang Jian-Dong , Ma Qing , Cao Gui-Ling , Jin Hui-Hui , Liang Xiao-Jun , Chu Ming-Xing
Published: March 2021

Background

Many recent studies have shown that miRNAs play important roles in the regulation of animal reproduction, including seasonal reproduction. The pineal gland is a crucial hub in the regulation of seasonal reproduction. However, little is known about the expression characteristics of pineal miRNAs in different reproductive seasons (anestrus and breeding season). Therefore, the expression profiles and regulatory roles of ovine pineal miRNAs were investigated during different reproductive stages using Solexa sequencing technology and dual luciferase reporter assays.

Results

A total of 427 miRNAs were identified in the sheep pineal gland. Significant differences in miRNA expression were demonstrated between anestrus and the breeding season in terms of the frequency distributions of miRNA lengths, number of expressed miRNAs, and specifically and highly expressed miRNAs in each reproductive stage. KEGG analysis of the differentially expressed (DE) miRNAs between anestrus and the breeding season indicated that they are significantly enriched in pathways related to protein synthesis, secretion and uptake. Furthermore, transcriptome analysis revealed that many target genes of DE miRNAs in the ribosome pathway showed relatively low expression in the breeding season. On the other hand, analyses combining miRNA-gene expression data with target relationship validation in vitro implied that miR-89 may participate in the negative regulation of aralkylamine N-acetyltransferase (AANAT) mRNA expression by targeting its 3’UTR at a unique binding site.

Conclusions

Our results provide new insights into the expression characteristics of sheep pineal miRNAs at different reproductive stages and into the negative regulatory effects of pineal miRNAs onAANATmRNA expression.
Ammonia induced microglia activation was associated with limited effects on connexin 43 and aquaporin 4 expression in an astrocyte-microglia co-culture model
Authors: Ismail Fatme Seval , Faustmann Timo Jendrik , Corvace Franco , Tsvetanova Anamariya , Moinfar Zahra , Faustmann Pedro M.
Published: March 2021

Background

Hepatic encephalopathy (HE) is a neurological complication resulting from acute or chronic liver disease. Hyperammonemia leading to astrocyte swelling and cerebral edema in combination with neuroinflammation including microglia activation, mainly contribute to the pathogenesis of HE. However, little is known about microglia and their inflammatory response, as well as their influence on astrocytic channels and astrocyte swelling under hyperammonemia.

Objective

To investigate the effects of ammonia on the microglial activation and morphology in different set-ups of an in vitro astrocyte-microglia co-culture model. Further, potential effects on glial viability, connexin 43 (Cx43) and aquaporin 4 (AQP4) expression were tested.

Methods

Primary rat glial co-cultures of astrocytes containing 5% (M5, representing "physiological" conditions) or 30% (M30, representing "pathological" conditions) of microglia were incubated with 3 mM, 5 mM, 10 mM and 20 mM ammonium chloride (NH4Cl) for 6 h and 24 h in order to mimic the conditions of HE. An MTT assay was performed to measure the viability, proliferation and cytotoxicity of cells. The microglial phenotypes were analyzed by immunocytochemistry. The expression of Cx43 and AQP4 were quantified by immunoblot analysis.

Results

A significant reduction of glial viability was observed in M30 co-cultures after incubation with 20 mM NH4Cl for 6 h, whereas in M5 co-cultures the viability remained unchanged. Microglial activation was detected by immunocytochemistry after incubation with 3 mM, 5 mM and 10 mM NH4Cl for 6 h and 24 h in M5 as well as in M30 co-cultures. The Cx43 expression was slightly increased in M30 co-cultures after 6 h incubation with 5 mM NH4Cl. Also, the AQP4 expression was slightly increased only in M5 co-cultures treated with 10 mM NH4Cl for 6 h. Under the other conditions, Cx43 and AQP4 expression was not affected by NH4Cl.

Conclusions

The novel aspect of our study was the significant microglial activation and decrease of viability after NH4Cl incubation in different set-ups of an in vitro astrocyte-microglia co-culture model, contributing to better understanding of pathophysiological mechanisms of HE. Hyperammonemia led to limited effects on Cx43 and AQP4 expression, the relevance of these minimal changes should be viewed with caution.
Bilateral posterior Quadratus Lumborum block for pain relief after cesarean delivery: a randomized controlled trial
Authors: Pangthipampai Pawinee , Dejarkom Sukanya , Poolsuppasit Suppachai , Luansritisakul Choopong , Tangchittam Suwida
Published: March 2021

Background

Achieving optimal analgesia with few side effects is the goal of pain management after cesarean delivery. Intrathecal (IT) morphine is the current standard but ultrasound-guided quadratus lumborum block (QLB) may offer superior pain control with fewer side effects. This study compared the pain-free period after cesarean delivery among parturients who received spinal block with IT morphine, with IT morphine and bilateral QLB, or only bilateral QLB.

Methods

Parturients having elective cesarean delivery under spinal block were randomized and allocated into IT morphine 0.2 mg with sham QLB (Group IT), IT morphine 0.2 mg and bilateral QLB with 0.25% bupivacaine 25 ml in each side (Group IT+QLB), or bilateral QLB with 0.25% bupivacaine 25 ml in each side (Group QLB). A PCA pump was connected after completion of the QLB or sham block. The first time to PCA morphine requirement was recorded and compared.

Results

Eighty parturients were included. Analysis of Group QLB was terminated early because at the second interim analysis, median pain-free period was significantly shorter in Group QLB [hours (95%CI): 2.50 (1.04–3.96) in Group IT vs. 7.75 (5.67–9.83) in IT+QLB vs. 1.75 (0.75–2.75) in QLB (p < 0.001)]. The median (min, max) amount of morphine required during 24 h was 5.5 (0–25) in Group IT vs. 5.0 (0–36) in IT+QLB vs. 17.5 (1–40) mg in Group QLB (p < 0.001). In the final analysis the median pain-free period was 2.50 (1.23–3.77) hours (95%CI) in Group IT (n = 27) vs. 8.02 (5.96–10.07) in IT+QLB (n = 28). (p = 0.027).

Conclusion

US-QLB used in conjunction with IT morphine yielded a statistically significant longer median pain-free period compared with standard IT morphine alone. However, QLB alone provided inferior pain control compared with standard IT morphine. When combined with IT morphine, QLB could provide additional analgesic benefit as a part of multimodal analgesic regimen, especially during the early postoperative period.

Trial registration

ClinicalTrials.gov no. NCT03199170 Date registered on June 22, 2017. Prospectively registered.
Beliefs about medication as predictors of medication adherence in a prospective cohort study among persons with multiple sclerosis
Authors: Neter Efrat , Glass-Marmor Lea , Wolkowitz Anat , Lavi Idit , Miller Ariel
Published: March 2021

Background

Though adherence to disease-modifying therapies (DMTs) among persons with multiple sclerosis (PwMS) varies and is often below 80%, only few prospective studies on adherence examined predictors beyond demographic and clinical characteristics.

Objectives

Identify antecedents to adherence and persistence to DMT in a prospective design among PwMS.

Methods

PwMS (n = 186) were prospectively assessed at three time points: baseline, 6 (Time 1) and 12 months later (Time 2). Clinical, demographic information and patient-reported medication beliefs, illness perceptions, medication habits, perceived health and affect were surveyed in-person. Adherence and persistence were assessed by a combination of self-reports and retrospective review of medication claims.

Findings

PwMS were 69.9% (Time 1) and 71% (Time 2) adherent to their DMTs and 64.5.9% were persistent. Beliefs about Medications were consistently predictive at both time points (baseline to Time 1 and Time 1 to Time 2) of medication adherence and persistence whereas other perceptions were predictive in some analyses; clinical and demographic characteristics were mostly not predictive of adherence nor persistence. The prospective association of beliefs about medication with adherence held also in multivariate analyses (OR = 0.88, 95% CI 0.78–0.99, p = 0.029).

Conclusions

Adherence and persistence are predicted by medication beliefs of PwMS. As medication beliefs are modifiable, they should be assessed periodically and targeted as a focus of tailored interventions aimed to improve adherence and consequently health outcomes in PwMS.

Registration

Clinical trials registry #NCT02488343, date: 06/08/2015.
A core outcome set development for a French national prospective study about the effect of mediolateral episiotomy on obstetric anal sphincter injury during operative vaginal delivery (INSTRUMODA)
Authors:   the GROG (Groupe de Recherche en Gynécologie Obstétrique), Gachon Bertrand , Schmitz Thomas , Artzner France , Parant Olivier , De Tayrac Renaud , Ducarme Guillaume , Le Ray Camille , Pizzoferrato Anne Cécile , Garabedian Charles , Riethmuller Didier , Pierre Fabrice , Ragot Stephanie , Fritel Xavier
Published: March 2021

Background

We aimed at developing a core outcome and variables of interest set to investigate the effects of mediolateral episiotomy on Obstetric Anal Sphincter Injury (OASI) during and after operative delivery in nulliparous women in a large-scale one-year observational French study including 15,000 women (INSTRUMODA).

Methods

A list of outcomes and variables of interest was suggested to obstetricians participating in the INSTRUMODA study using online questionnaires divided into 7 categories: the woman’s history and course of pregnancy, course of labor, modalities of operative delivery, episiotomy characteristics, immediate maternal morbidity, one-year maternal morbidity, immediate neonatal morbidity. We used a three-round DELPHI method to reach a consensus. In the first round, outcomes and variables considered as essential by 70% or more of obstetricians were included in the corpus whereas they were excluded when 70% rated them as “not important”. In the second round, non-consensual outcomes and variables were reassessed and excluded or definitively included if considered as “not important” or essential by 50% or more of the obstetricians. During the first round, obstetricians were invited to suggest new outcomes and/or variables that were then assessed in the second and third round. We used the same method to develop a core outcome and variables of interest set in a population of women in the community recruited via an association of patients. At the end of the procedure the core outcome and variables of interest sets were merged to provide the final core outcome set for the INSTRUMODA study.

Results

Fifty-three obstetricians and 16 women filled out questionnaires. After the 3 rounds of Delphi procedure in each population, 74 outcomes and variables were consensually reported by obstetricians and 92 by women in the community. By mixing these two consensual corpora we reported a final consensual list of 114 variables of interest and outcomes for both obstetricians and women.

Conclusion

We established a core outcome and variables of interest set among obstetricians and women in the community to investigate the association between mediolateral episiotomy and OASI during operative delivery.

Trial registration

The INSTRUMODA study was registered on https://clinicaltrials.gov on June 25, 2020 (NCT04446780).
Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma
Authors: Li Hui , Liu Yujuan , Jiang Wei , Xue Junhui , Cheng Yuning , Wang Jiyin , Yang Ruixiang , Zhang Xiaowei
Published: March 2021

Background

Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatment of hepatocellular cancer is under-going, but the specific mechanism of icaritin action was unclear. Alpha-fetoprotein (AFP), an oncofetal protein, produced in the healthy fetal liver and yolk sac. Intracellular AFP promoted cellular proliferation and inhibited cellular apoptosis in hepatocellular carcinoma (HCC). The study was aimed to investigate the effect of icaritin on HCC through p53/AFP pathway.

Methods

Real-time RT PCR and western blot were used to detect p53 and AFP expression levels in HCC cells treated with icaritin. The mechanism of icaritin affecting p53 expression was verified by ubiquitination experiment, and the binding activity of icaritin on p53 in AFP promoter region was verified by luciferase experiment. EdU, MTT and flow cytometry were used to determine whether icaritin affected HCC cellular proliferation and apoptosis through p53/ AFP pathway. Expression levels of p53 and AFP in xenograft mouse model were determined by western blotting.

Results

Our results showed icaritin inhibited AFP expression at mRNA and protein level. AFP was also identified as the target gene of the p53 transcription factor. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Up-regulated p53 protein levels then transcriptionally inhibited the AFP promoter. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis.

Conclusion

Our findings revealed the mechanism of icaritin in promoting apoptosis and inhibiting proliferation in liver cancer cells. The regulatory mechanism of icaritin in AFP protein down-regulation provides a theoretical and experimental basis for further research into new drugs for the treatment of liver cancer.
Factors related to age at depression onset: the role of SLC6A4 methylation, sex, exposure to stressful life events and personality in a sample of inpatients suffering from major depression
Authors: Sanwald Simon , Widenhorn-Müller Katharina , Schönfeldt-Lecuona Carlos ,   GenEmo Research Group, Connemann Bernhard J. , Gahr Maximilian , Kammer Thomas , Montag Christian , Kiefer Markus
Published: March 2021

Background

An early onset of depression is associated with higher chronicity and disability, more stressful life events (SLEs), higher negative emotionality as described by the primary emotion SADNESS and more severe depressive symptomatology compared to depression onset later in life. Additionally, methylation of the serotonin transporter gene (SLC6A4) is associated with SLEs and depressive symptoms.

Methods

We investigated the relation of SLEs, SLC6A4 methylation in peripheral blood, the primary emotions SADNESS and SEEKING (measured by the Affective Neuroscience Personality Scales) as well as depressive symptom severity to age at depression onset in a sample of N = 146 inpatients suffering from major depression.

Results

Depressed women showed higher SADNESS (t (91.05) = − 3.17, p = 0.028, d = − 0.57) and higher SLC6A4 methylation (t (88.79) = − 2.95, p = 0.02, d = − 0.55) compared to men. There were associations between SLEs, primary emotions and depression severity, which partly differed between women and men. The Akaike information criterion (AIC) indicated the selection of a model including sex, SLEs, SEEKING and SADNESS for the prediction of age at depression onset. SLC6A4 methylation was not related to depression severity, age at depression onset or SLEs in the entire group, but positively related to depression severity in women.

Conclusions

Taken together, we provide further evidence that age at depression onset is associated with SLEs, personality and depression severity. However, we found no associations between age at onset and SLC6A4 methylation. The joint investigation of variables originating in biology, psychology and psychiatry could make an important contribution to understanding the development of depressive disorders by elucidating potential subtypes of depression.
Verbal learning impairment in adolescents with methamphetamine use disorder: a cross-sectional study
Authors: Basedow Lukas Andreas , Kuitunen-Paul Sören , Wiedmann Melina Felicitas , Ehrlich Stefan , Roessner Veit , Golub Yulia
Published: March 2021

Background

Methamphetamine (MA) use has been shown to be associated with deficits in impulsivity, verbal learning, and working memory. Additionally, methamphetamine use disorder (MUD) is related to various brain changes, especially in adolescent users who might be more vulnerable to detrimental effects on brain development. However, little is known about the relationship between adolescent MA use and cognitive impairment. This cross-sectional study aims to explore how the presence of a MUD in adolescents is related to impairments of verbal memory, inhibition, and alertness.

Methods

N = 18 psychiatric outpatients with MUD were matched in terms of depressivity, age, and gender ton = 18 adolescents with other substance use disorders (SUDs), as well asn = 18 controls without SUDs. We compared these three groups on the Verbal Learning and Memory Task (VLMT), and the alertness and go/noGo subtests of the Test of Attentional Performance (TAP). Additionally, Spearman’s rank order correlation coefficients were calculated to investigate whether cognitive functioning was directly associated with frequency of past year MA use.

Results

The three groups differed significantly in their verbal learning performance (H(2) = 11.7,p = .003, ηp2 = .19), but not in short-term memory, inhibition, cued recall, or alertness. Post hoc tests revealed significant differences in verbal learning between the MA using group and the control group without a SUD (U = 56.5,p = .001, ηp2 = .31). Frequency of past year MA use correlated negatively with short-term memory (ρ = −.25,p < .01) and verbal learning (ρ = −.41,p < .01). No other cognitive variables correlated significantly with MA use frequency. Significantp-values were considered significant after Bonferroni correction.

Conclusions

Adolescent MUD outpatients with regular MA use show specific impairment in verbal learning performance, but not in other basal cognitive functions when compared to adolescents without a MUD. Verbal learning and short-term memory performance is negatively associated with the frequency of MA use. Future research should apply longitudinal designs to investigate long-term effects of methamphetamine and reversibility of these effects on cognitive functioning.
Social capital and sleep disorders in Tibet, China
Authors: Ciren Wangla , Yu Wanqi , Nima Qucuo , Xiao Xiong , Zhou Junmin , Suolang Deji , Li Yajie , Zhao Xing , Jia Peng , Yang Shujuan
Published: March 2021

Objective

Sleep plays an important role in the health and well-being of middle aged and elderly people, and social capital may be one of the important factors for sleep disorders. This study aimed to understand the relationship between social capital and sleep disorders in a unique region of China –Tibet that generally has the disadvantaged economic status compared to other parts of China.

Methods

The study was based on Tibetan data from The China Multi-Ethnic Cohort (CMEC) and was conducted from May 2018 to September 2019. A total of 3194 Tibetans aged > 50 were selected from the community population by multi-stage stratified cluster sampling. Social capital was measured using two validated health-related social capital scales, family/community and society.. Sleep disorders were measured as the presence of disorders of initiating and maintaining sleep, early morning awakening, or daytime dysfunction. Logistic regression models were applied to examine the association between social capital and sleep disorders.

Results

39.9% (1271/3194) of the participants had sleep disorders. In addition, after controlling for all potential variables, family social capital was significantly negatively associated with sleep disorders (OR = 0.95, P < 0.05), while community and society social capital was not associated with sleep disorders. Then, when we did all the sex-stratified analyses, the significant association between social capital and sleep disorders was found only in women (OR = 0.94, P < 0.05), while no association was found in males; neither males nor females showed any association with community and society social capital.

Conclusion

Our study would help to better understand the extent of health inequality in China, and guide future interventions, strategies and policies to promote sleep quality in low-income areas, taking into account both the role of Tibetan specific cultural traditions, lifestyles and religious beliefs in social capital and the gender differences in social capital.