bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidative Stress Promotes Instability of Regulatory T Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis
Authors: Shimojima Yasuhiro , Kishida Dai , Ichikawa Takanori , Takamatsu Ryota , Nomura Shun , Sekijima Yoshiki
Published: December 2021

We investigated the characteristics of regulatory T cells (Tregs), focusing on the relationship between their stability and reactive oxygen species (ROS), in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Intracellular expressions of effector cytokines, forkhead box protein 3 (FoxP3), ROS, phosphorylated mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) in Tregs from peripheral blood mononuclear cells (PBMCs) of patients with AAV and healthy controls (HC) were analyzed. The alterations in and functional ability of Tregs were compared before and after resveratrol (RVL) treatment of PBMCs in patients with AAV. Significantly higher expressions of interferon (IFN)-γ, interleukin (IL)-17, IL-4, ROS, and phosphorylated mTOR (pho-mTOR) and lower expression of SIRT1 in CD4+CD25+FoxP3+ cells were found in patients with AAV than in the HC. FoxP3 expression in CD4+CD25+ cells and suppressive function of Tregs were significantly lower in patients with AAV than in the HC. Tregs after RVL treatment demonstrated significant decreases in IFN-γ, ROS, and pho-mTOR levels and increases in FoxP3, SIRT1 levels, and functional activity. Conversely, the direct activation of SIRT1 by SRT1720 resulted in decreased FoxP3 expression, with no reduction in ROS levels. The pho-mTOR levels were significantly higher in Tregs after activation by SRT1720 than in those after RVL treatment. This study suggested that imbalanced changes in Tregs could be attributed to mTOR activation, in which ROS overproduction was predominantly implicated. Therefore, ROS is a key mediator for promoting Tregs instability in AAV.
Pandora’s Box in the Deep Sea –Intraspecific Diversity Patterns and Distribution of Two Congeneric Scavenging Amphipods
Authors: Jażdżewska Anna M. , Horton Tammy , Hendrycks Ed , Mamos Tomasz , Driskell Amy C. , Brix Saskia , Arbizu Pedro Martínez
Published: December 2021

Paralicella tenuipesChevreux, 1908 and Paralicella caperescaShulenberger and Barnard, 1976 are known as widely distributed deep-sea scavenging amphipods. Some recent studies based on genetic data indicated the presence of high intraspecific variation of P. caperesca suggesting it is a species complex. Based on published molecular data from the Pacific and Indian oceans and new material obtained from the North and South Atlantic, we integrated the knowledge on the intraspecific variation and species distribution of the two nominal taxa. The study included analysis of three genes (COI, 16S rRNA, 28S rRNA) and revealed the existence of a single Molecular Operational Taxonomic Unit (MOTU) within P. tenuipes and six different MOTUs forming P. caperesca. The distribution pattern of the recognized lineages varied with three (P. tenuipes, MOTU 1 and MOTU 5 of P. caperesca) being widely distributed. There was evidence of contemporary population connectivity expressed by the share of the same COI haplotypes by individuals from very distant localities. At the same time no signal of recent demographic changes was observed within the studied taxa. The time-calibrated phylogeny suggested the emergence of species to be at the time of Mesozoic/Cenozoic transition that may be associated with global changes of the ocean circulation and deep sea water cooling.
Case Report and Literature Review: Catastrophic Embolism Following Cosmetic Injection of Autologous Fat in the Face
Authors: Liu Chunyu , Cai Zhaolun , Zhang Lingli , Zhou Muke , He Li
Published: December 2021

Injection of autologous fat on the face is a commonly performed procedure in plastic surgery. However, it can lead to rare but devastating complications due to fat embolism. In this study, we presented two cases of cerebral infarction and/or sudden vision loss after cosmetic injections of autologous fat on the face. Two women underwent injections into the temporal and frontal areas, respectively. In case 1, the patient underwent decompressive craniectomy as her condition deteriorated continuously and died. In case 2, the patient's vision had not improved at the 3-month follow-up visit. Imaging examinations showed occlusion of the right external carotid artery in case 1, and multiple retinal arterioles were segmentally occluded in case 2. We also screened relevant studiesviaa systematic search of PubMed (last updated on May 9, 2020) and performed a narrative review due to the significant heterogeneity between the studies. To prevent this catastrophic event, the autologous fat injection should be performed carefully. If embolization does occur, early diagnosis and timely treatment may help improve functional outcomes.
Non-classical Vitamin D Actions for Renal Protection
Authors: Dusso Adriana S. , Bauerle Kevin T. , Bernal-Mizrachi Carlos
Published: December 2021

Chronic Kidney Disease (CKD), a disorder that affects 11% of the world's population, is characterized by an acceleration in skeletal, immune, renal, and cardiovascular aging that increases the risk of cardiovascular mortality by 10- to 20-fold, compared to that in individuals with normal renal function. For more than two decades, the progressive impairment in renal capacity to maintain normal circulating levels of the hormonal form of vitamin D (1,25-dihydroxyvitamin D or calcitriol) was considered the main contributor to the reduced survival of CKD patients. Accordingly, calcitriol administration was the treatment of choice to attenuate the progression of secondary hyperparathyroidism (SHPT) and its adverse impact on bone health and vascular calcification. The development of calcitriol analogs, designed to mitigate the resistance to calcitriol suppression of PTH associated with CKD progression, demonstrated survival benefits unrelated to the control of SHPT or skeletal health. The exhaustive search for the pathophysiology behind survival benefits associated with active vitamin D analogs has identified novel anti-inflammatory, anti-hypertensive, anti-aging actions of the vitamin D endocrine system. A major paradigm shift regarding the use of calcitriol or active vitamin D analogs to improve survival in CKD patients emerged upon demonstration of a high prevalence of vitamin D (not calcitriol) deficiency at all stages of CKD and, more significantly, that maintaining serum levels of the calcitriol precursor, 25(OH)vitamin D, above 23 ng/ml delayed CKD progression. The cause of vitamin D deficiency in CKD, however, is unclear since vitamin D bioactivation to 25(OH)D occurs mostly at the liver. Importantly, neither calcitriol nor its analogs can correct vitamin D deficiency. The goals of this chapter are to present our current understanding of the pathogenesis of vitamin D deficiency in CKD and of the causal link between defective vitamin D bioactivation to calcitriol and the onset of molecular pathways that promote CKD progression independently of the degree of SHPT. An understanding of these mechanisms will highlight the need for identification of novel sensitive biomarkers to assess the efficacy of interventions with vitamin D and/or calcitriol(analogs) to ameliorate CKD progression in a PTH-independent manner.
Novel Tyrosine Kinase-Mediated Phosphorylation With Dual Specificity Plays a Key Role in the Modulation of Streptococcus pyogenes Physiology and Virulence
Authors: Kant Sashi , Pancholi Vijay
Published: December 2021

Streptococcus pyogenes (Group A Streptococcus, GAS) genomes do not contain a gene encoding a typical bacterial-type tyrosine kinase (BY-kinase) but contain an orphan gene-encoding protein Tyr-phosphatase (SP-PTP). Hence, the importance of Tyr-phosphorylation is underappreciated and not recognized for its role in GAS pathophysiology and pathogenesis. The fact that SP-PTP dephosphorylates Abl-tyrosine kinase-phosphorylated myelin basic protein (MBP), and SP-STK (S. pyogenes Ser/Thr kinase) also autophosphorylates its Tyr101-residue prompted us to identify a putative tyrosine kinase and Tyr-phosphorylation in GAS. Upon a genome-wide search of kinases possessing a classical Walker motif, we identified a non-canonical tyrosine kinase M5005_Spy_1476, a ∼17 kDa protein (153 aa) (SP-TyK). The purified recombinant SP-TyK autophosphorylated in the presence of ATP. In vitro and in vivo phosphoproteomic analyses revealed two key phosphorylated tyrosine residues located within the catalytic domain of SP-TyK. An isogenic mutant lacking SP-TyK derived from the M1T1 strain showed a retarded growth pattern. It displayed defective cell division and long chains with multiple parallel septa, often resulting in aggregates. Transcriptomic analysis of the mutant revealed 287 differentially expressed genes responsible for GAS pathophysiology and pathogenesis. SP-TyK also phosphorylated GAS CovR, WalR, SP-STP, and SDH/GAPDH proteins with dual specificity targeting their Tyr/Ser/Thr residues as revealed by biochemical and mass-spectrometric-based phosphoproteomic analyses. SP-TyK-phosphorylated CovR bound to PcovR efficiently. The mutant displayed sustained release of IL-6 compared to TNF-α during co-culturing with A549 lung cell lines, attenuation in mice sepsis model, and significantly reduced ability to adhere to and invade A549 lung cells and form biofilms on abiotic surfaces. SP-TyK, thus, plays a critical role in fine-tuning the regulation of key cellular functions essential for GAS pathophysiology and pathogenesis through post-translational modifications and hence, may serve as a promising target for future therapeutic developments.
Identification and Validation of CYBB, CD86, and C3AR1 as the Key Genes Related to Macrophage Infiltration of Gastric Cancer
Authors: Chen Haiyan , Sun Qi , Zhang Cangang , She Junjun , Cao Shuai , Cao Meng , Zhang Nana , Adiila Ayarick Vivian , Zhong Jinjin , Yao Chengyun , Wang Yili , Xia Hongping , Lan Linhua
Published: December 2021

Gastric cancer (GC) is rampant around the world. Most of the GC cases are detected in advanced stages with poor prognosis. The identification of marker genes for early diagnosis is of great significance. Studying the tumor environment is helpful to acknowledge the process of tumorigenesis, development, and metastasis. Twenty-two kinds of immune cells were calculated by CIBERSORT from Gene Expression Omnibus (GEO) database. Subsequently, higher infiltration of macrophages M0 was discovered in GC compared with normal tissues. WGCNA was utilized to construct the network and then identify key modules and genes related to macrophages in TCGA. Finally, 18 hub genes were verified. In the PPI bar chart, the top 3 genes were chosen as hub genes involved in most pathways. On the TIMER and THPA websites, it is verified that the expression levels of CYBB, CD86, and C3AR1 genes in tumor tissues were higher than those in normal tissues. These genes may work as biomarkers or targets for accurate diagnosis and treatment of GC in the future. Our findings may be a new strategy for the treatment of GC.
Crossed Connections From Insular Cortex to the Contralateral Thalamus
Authors: Adeyelu Tolulope , Gandhi Tanya , Lee Charles C.
Published: December 2021

Sensory information in all modalities, except olfaction, is processed at the level of the thalamus before subsequent transmission to the cerebral cortex. This incoming sensory stream is refined and modulated in the thalamus by numerous descending corticothalamic projections originating in layer 6 that ultimately alter the sensitivity and selectivity for sensory features. In general, these sensory thalamo-cortico-thalamic loops are considered strictly unilateral, i.e., no contralateral crosstalk between cortex and thalamus. However, in contrast to this canonical view, we characterize here a prominent contralateral corticothalamic projection originating in the insular cortex, utilizing both retrograde tracing and cre-lox mediated viral anterograde tracing strategies with the Ntsr1-Cre transgenic mouse line. From our studies, we find that the insular contralateral corticothalamic projection originates from a separate population of layer 6 neurons than the ipsilateral corticothalamic projection. Furthermore, the contralateral projection targets a topographically distinct subregion of the thalamus than the ipsilateral projection. These findings suggest a unique bilateral mechanism for the top-down refinement of ascending sensory information.
A New Implantable Closed-Loop Clinical Neural Interface: First Application in Parkinson’s Disease
Authors: Arlotti Mattia , Colombo Matteo , Bonfanti Andrea , Mandat Tomasz , Lanotte Michele Maria , Pirola Elena , Borellini Linda , Rampini Paolo , Eleopra Roberto , Rinaldo Sara , Romito Luigi , Janssen Marcus L. F. , Priori Alberto , Marceglia Sara
Published: December 2021

Deep brain stimulation (DBS) is used for the treatment of movement disorders, including Parkinson’s disease, dystonia, and essential tremor, and has shown clinical benefits in other brain disorders. A natural path for the improvement of this technique is to continuously observe the stimulation effects on patient symptoms and neurophysiological markers. This requires the evolution of conventional deep brain stimulators to bidirectional interfaces, able to record, process, store, and wirelessly communicate neural signals in a robust and reliable fashion. Here, we present the architecture, design, and first use of an implantable stimulation and sensing interface (AlphaDBSR System) characterized by artifact-free recording and distributed data management protocols. Its application in three patients with Parkinson’s disease (clinical trial n. NCT04681534) is shown as a proof of functioning of a clinically viable implanted brain-computer interface (BCI) for adaptive DBS. Reliable artifact free-recordings, and chronic long-term data and neural signal management are in place.
Comprehensive Imaging Characterization of Colorectal Liver Metastases
Authors: Maclean Drew , Tsakok Maria , Gleeson Fergus , Breen David J. , Goldin Robert , Primrose John , Harris Adrian , Franklin James
Published: December 2021

Colorectal liver metastases (CRLM) have heterogenous histopathological and immunohistochemical phenotypes, which are associated with variable responses to treatment and outcomes. However, this information is usually only available after resection, and therefore of limited value in treatment planning. Improved techniques for in vivo disease assessment, which can characterise the variable tumour biology, would support further personalization of management strategies. Advanced imaging of CRLM including multiparametric MRI and functional imaging techniques have the potential to provide clinically-actionable phenotypic characterisation. This includes assessment of the tumour-liver interface, internal tumour components and treatment response. Advanced analysis techniques, including radiomics and machine learning now have a growing role in assessment of imaging, providing high-dimensional imaging feature extraction which can be linked to clinical relevant tumour phenotypes, such as a the Consensus Molecular Subtypes (CMS). In this review, we outline how imaging techniques could reproducibly characterize the histopathological features of CRLM, with several matched imaging and histology examples to illustrate these features, and discuss the oncological relevance of these features. Finally, we discuss the future challenges and opportunities of CRLM imaging, with a focus on the potential value of advanced analytics including radiomics and artificial intelligence, to help inform future research in this rapidly moving field.
Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis
Authors: Taslimi Shervin , Brar Karanbir , Ellenbogen Yosef , Deng Jiawen , Hou Winston , Moraes Fabio Y. , Glantz Michael , Zacharia Brad E. , Tan Aaron , Ahluwalia Manmeet S. , Khasraw Mustafa , Zadeh Gelareh , Mansouri Alireza
Published: December 2021

Background

Brain metastases (BM) from non-small-cell lung cancer (NSCLC) are frequent and carry significant morbidity, and current management options include varying local and systemic therapies. Here, we performed a systematic review and network meta-analysis to determine the ideal treatment regimen for NSCLC BMs with targetable EGFR-mutations/ALK-rearrangements.

Methods

We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs including ≥10 patients were selected. We used a frequentist random-effects model for network meta-analysis (NMA) and assessed the certainty of evidence using the GRADE approach. Our primary outcome of interest was intracranial progression-free survival (iPFS).

Results

We included 24 studies representing 19 trials with 1623 total patients. Targeted tyrosine kinase inhibitors (TKIs) significantly improved iPFS, with second-and third- generation TKIs showing the greatest benefit (HR=0.25, 95%CI 0.15-0.40). Overall PFS was also improved compared to conventional chemotherapy (HR=0.47, 95%CI 0.36-0.61). In EGFR-mutant patients, osimertinib showed the greatest benefit in iPFS (HR=0.32, 95%CI 0.15-0.69) compared to conventional chemotherapy, while gefitinib + chemotherapy showed the greatest overall PFS benefit (HR=0.26, 95%CI 0.10-0.70). All ALKi improved overall PFS compared to conventional chemotherapy, with alectinib having the greatest benefit (HR=0.13, 95%CI 0.07-0.24).

Conclusions

In patients with NSCLC BMs and EGFR/ALK mutations, targeted TKIs improve intracranial and overall PFS compared to conventional modalities such as chemotherapy, with greater efficacy seen using newer generations of TKIs. This data is important for treatment selection and patient counseling, and highlights areas for future RCT research.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=179060.
TMB and TCR Are Correlated Indicators Predictive of the Efficacy of Neoadjuvant Chemotherapy in Breast Cancer
Authors: Liang Hongling , Huang Jia , Ao Xiang , Guo Weibang , Chen Yu , Lu Danxia , Lv Zhiyi , Tan Xiaojun , He Weixing , Jiang Ming , Xia Haoming , Zhan Yongtao , Guo Weiling , Ye Zhiqing , Jiao Lei , Ma Jie , Wang Changxi , Li Hongsheng , Zhang Xuchao , Huang Jianqing
Published: December 2021

Immune characteristics were reported correlated to benefit neoadjuvant chemotherapy (NAC) in breast cancer, yet integration of comprehensive genomic alterations and T-cell receptors (TCR) to predict efficacy of NAC needs further investigation. This study simultaneously analyzed TMB (Tumor Mutation Burden), TCRs, and TILs (tumor infiltrating lymphocyte) in breast cancers receiving NAC was conducted in a prospective cohort (n = 22). The next-generation sequencing technology-based analysis of genomic alterations and TCR repertoire in paired breast cancer samples before and after NAC was conducted in a prospective cohort (n = 22). Fluorescent multiplex immunohistochemistry was used to stain CD4, CD8, PD1, TIM3, and cytokeratins simultaneously in those paired samples. TMB in pretreatment tumor tissues and TCR diversity index are higher in non-pCR patients than in pCR patients (10.6 vs. 2.3; p = 0.043) (2.066 vs. 0.467; p = 0.010). TMB and TCR diversity index had linear correlation (y = 5.587x − 0.881; r = 0.522, p = 0.012). Moreover, infiltrating T cells are significantly at higher presence in pCR versus non-pCR patients. Dynamically, the TMB reduced significantly after therapy in non-pCR patients (p = 0.010) but without TCR index change. The CDR3 peptide AWRSAGNYNEQF is the most highly expressed in pre-NAC samples of pCR patients and in post-NAC samples of non-pCR patients. In addition to pCR, high clonality of TCR and high level of CD8+ expression are associated with disease-free survival (DFS). TCR index and TMB have significant interaction and may guide neo-adjuvant treatment in operable breast cancers. Response to NAC in tumors with high TCR clonality may be attributable to high infiltration and expansion of tumor-specific CD8 positive effector cells.
Long-Term Mixed Chimerism After Ex Vivo/In Vivo T Cell-Depleted Allogeneic Hematopoietic Cell Transplantation in Patients With Myeloid Neoplasms
Authors: Ruhnke Leo , Stölzel Friedrich , Oelschlägel Uta , von Bonin Malte , Sockel Katja , Middeke Jan Moritz , Röllig Christoph , Jöhrens Korinna , Schetelig Johannes , Thiede Christian , Bornhäuser Martin
Published: December 2021

In patients who have undergone allogeneic hematopoietic cell transplantation (HCT), myeloid mixed donor chimerism (MC) is a risk factor for disease relapse. In contrast, several studies found favorable outcome in patients with lymphoid MC. Thus far, most studies evaluating MC focused on a short-term follow-up period. Here, we report the first case series of long-term survivors with MC. We screened 1,346 patients having undergone HCT for myeloid neoplasms at our center from 1996 to 2016; 443 patients with data on total peripheral blood mononuclear cells (PBMC)/CD4+/CD34+ short tandem repeat (STR) donor chimerism (DC) and follow-up ≥24 months post-HCT were included. We identified 10 patients with long-term MC (PBMC DC <95% at ≥12 months post-HCT). Median follow-up was 11 years. All patients had received combined ex vivo/in vivo T cell-depleted (TCD) peripheral blood stem cells; none experienced ≥grade 2 acute graft-versus-host disease (GVHD). The mean total PBMC, CD4+, and CD34+ DC of all patients were 95.88%, 85.84%, and 90.15%, respectively. Reduced-intensity conditioning (RIC) was associated with a trend to lower mean total DC. Of note, two patients who experienced relapse had lower CD34+ DC but higher CD4+ DC as compared with patients in continuous remission. Bone marrow evaluation revealed increased CD4+/FOXP3+ cells in patients with MC, which might indicate expansion of regulatory T cells (Tregs). Our results support known predictive factors associated with MC such as RIC and TCD, promote the value of CD34+ MC as a potential predictor of relapse, highlight the potential association of CD4+ MC with reduced risk of GVHD, and indicate a possible role of Tregs in the maintenance of immune tolerance post-HCT.
Case Report: Early 68Ga-PSMA-PET Metabolic Assessment and Response to Systemic Treatment for First-Line Metastatic Clear Cell Renal Cell Carcinoma; About Two Clinical Cases
Authors: Seront Emmanuel , Lhommel Renaud , Tombal Bertrand
Published: December 2021

Early evaluation of response to anticancer treatment in metastatic renal cell carcinoma (RCC) is challenging as responses are sometimes delayed, as mixed responses can occur, and as conventional imaging have some limitations. As PSMA has been previously identified in neovasculature of clear cell RCC (ccRCC), 68Ga-PSMA-Positron Emitted Tomography (PET) could appear as an interesting tool to evaluate therapeutic response. We describe the association of an early decrease in 68Ga metabolism (at 8 weeks after treatment onset) and further radiological response (at 12 weeks after treatment onset) to treatment in two patients with different sensitivity to axitinib–pembrolizumab combination. Interestingly, one of these patients presented an initial progressive disease on pembrolizumab alone and a subsequent response to axitinib alone in the disease course; these response profiles were associated with absence of decrease and subsequent decrease in the 68Ga metabolism, respectively. Even if further prospective trials are needed, 68Ga-PSMA-PET may appear as a promising way for early prediction of response to ccRCC systemic treatment.
Synthesizing the First Phase of Dynamic Sequences of Breast MRI for Enhanced Lesion Identification
Authors: Wang Pingping , Nie Pin , Dang Yanli , Wang Lifang , Zhu Kaiguo , Wang Hongyu , Wang Jiawei , Liu Rumei , Ren Jialiang , Feng Jun , Fan Haiming , Yu Jun , Chen Baoying
Published: December 2021

Objective

To develop a deep learning model for synthesizing the first phases of dynamic (FP-Dyn) sequences to supplement the lack of information in unenhanced breast MRI examinations.

Methods

In total, 97 patients with breast MRI images were collected as the training set (n = 45), the validation set (n = 31), and the test set (n = 21), respectively. An enhance border lifelike synthesize (EDLS) model was developed in the training set and used to synthesize the FP-Dyn images from the T1WI images in the validation set. The peak signal-to-noise ratio (PSNR), structural similarity (SSIM), mean square error (MSE) and mean absolute error (MAE) of the synthesized images were measured. Moreover, three radiologists subjectively assessed image quality, respectively. The diagnostic value of the synthesized FP-Dyn sequences was further evaluated in the test set.

Results

The image synthesis performance in the EDLS model was superior to that in conventional models from the results of PSNR, SSIM, MSE, and MAE. Subjective results displayed a remarkable visual consistency between the synthesized and original FP-Dyn images. Moreover, by using a combination of synthesized FP-Dyn sequence and an unenhanced protocol, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MRI were 100%, 72.73%, 76.92%, and 100%, respectively, which had a similar diagnostic value to full MRI protocols.

Conclusions

The EDLS model could synthesize the realistic FP-Dyn sequence to supplement the lack of enhanced images. Compared with full MRI examinations, it thus provides a new approach for reducing examination time and cost, and avoids the use of contrast agents without influencing diagnostic accuracy.
Placebo Responses and Their Clinical Implications in Fibromyalgia: A Meta-Analysis Using SSRI and SNRI Trials
Authors: Koechlin Helen , Kharko Anna , Probst Tamara , Pradela Julia , Buechi Stefan , Locher Cosima
Published: December 2021

Background: Fibromyalgia (FM) is a chronic primary pain condition, associated with widespread musculoskeletal pain, disturbed sleep, fatigue, cognitive dysfunction, and a range of comorbid conditions such as irritable bowel syndrome, and depression. Despite its high prevalence of 2% in the general population, FM continues to pose scientific and clinical challenges in definition, etiology, and day-to-day management. In terms of treatment, FM can be treated with selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs).

Objective: Patients with FM and other chronic primary pain syndromes are known to experience substantial and clinically relevant placebo effects. An update of the placebo responses for various outcomes in the FM population and especially a discussion about clinical implications is therefore needed.

Methods: We used data from a large data pool that includes randomized controlled trials (RCTs) examining within-placebo mean change scores of baseline vs. follow-up assessments in FM trials of SSRIs and SNRIs. The primary outcomes were pain, functional disability, and depression and using different scales. We assessed heterogeneity of included trials.

Results: A total of 29 RCTs with N = 8,453 patients suffering from FM were included in our analysis. Within-placebo mean change scores of baseline vs. follow-up assessments were large for pain (mean change = 2.31, 95% CI: 0.42–4.21, p = 0.017), functional disability (mean change = 3.31, 95% CI: 2.37–4.26, p < 0.000), and depression (mean change = 1.55, 95% CI: 0.92–2.18, p < 0.000). Heterogeneity was found to be large for all outcomes.

Impact: Our results provide preliminary evidence that placebo responses, which also consist of non-specific effects, might play a role in the treatment of FM. Furthermore, we highlight limitations of our analyses and make suggestions for future studies.
A Model in Female Rats With Phenotypic Features Similar to Interstitial Cystitis/Bladder Pain Syndrome
Authors: Ness Timothy J. , DeWitte Cary , DeBerry Jennifer J. , Hart Morgan P. , Clodfelder-Miller Buffie , Gu Jianguo G. , Ling Jennifer , Randich Alan
Published: December 2021

This report describes methodological and exploratory investigations of the zymosan-induced neonatal bladder inflammation (NBI) model of interstitial cystitis/bladder pain syndrome (IC/BPS) in female rats. These results validate and extend the currently employed model by evaluating critical timepoints for obtaining treatment effects and identified that a second insult as an adult including repeat intravesical zymosan, intravesical lipopolysaccharide, acute footshock stress, neuropathic nociception (facial) or somatic inflammation (hindpaw) all resulted in magnified visceromotor responses to urinary bladder distension (UBD) in rats which had experienced NBI when compared with their controls. NBI also resulted in increased tone and reactivity of pelvic floor musculature to UBD, as well as increased responsiveness to intravesical potassium chloride solutions, abnormal anxiety measures (elevated plus maze) and an increased number of submucosal petechial hemorrhages following 30 min of hydrodistension of the bladder. These phenotypic findings have correlates to the clinical features of IC/BPS in humans and so support use of this model system to examine mechanisms of and treatments for IC/BPS.
Hydrogen Sulfide Ameliorates Angiotensin II-Induced Atrial Fibrosis Progression to Atrial Fibrillation Through Inhibition of the Warburg Effect and Endoplasmic Reticulum Stress
Authors: Hu Heng-Jing , Wang Xiu-Heng , Liu Yao , Zhang Tian-Qing , Chen Zheng-Rong , Zhang Chi , Tang Zhi-Han , Qu Shun-Lin , Tang Hui-Fang , Jiang Zhi-Sheng
Published: December 2021

Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-β-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.
Cost-Related Medication Nonadherence (CRN) on Healthcare Utilization and Patient-Reported Outcomes: Considerations in Managing Medicare Beneficiaries on Antidepressants
Authors: Alnijadi Abdulrahman A. , Yuan Jing , Wu Jun , Li Minghui , Lu Z. Kevin
Published: December 2021

Background: Many patients face a financial burden due to their medications, which may lead to poor health outcomes. The behaviors of non-adherence due to financial difficulties, known as cost-related medication non-adherence (CRN), include taking smaller doses of drugs, skipping doses to make prescriptions last longer, or delaying prescriptions. To date, the prevalence of CRN remains unknown, and there are few studies about the association of CRN on self-reported healthcare utilization (Emergency room (ER) visits and outpatient visits) and self-reported health outcomes (health status and disability status) among older adults taking antidepressants.

Objectives: The objectives were to 1) examine the CRN prevalence, and 2) determine the association of CRN on self-reported healthcare utilization and self-reported health outcomes.

Methods: This study was a cross-sectional study of a sample of older adults from the Medicare Current Beneficiary Survey (MCBS) who reported having used antidepressants in 2017. Four logistic regressions were implemented to evaluate the association of CRN, and self-reported healthcare utilization and self-reported health outcomes.

Results: The study identified 602 participants who were Medicare beneficiaries on antidepressants. The prevalence of CRN among antidepressant users was (16.61%). After controlling for covariates, CRN was associated with poorer self-reported outcomes but not statistically significant: general health status [odds ratio (OR): 0.67; 95% confidence interval (CI): 0.39–1.16] and disability status (OR: 1.34; 95% CI: 0.83–2.14). In addition, CRN was associated with increased outpatient visits (OR: 1.89; 95% CI: 1.19–3.02), but not associated with ER visits (OR: 1.10; 95% CI: 0.69–1.76).

Conclusion: For Medicare beneficiaries on antidepressants, CRN prevalence was high and contributed to more outpatient visits. The healthcare provider needs to define the reasoning for CRN and provide solutions to reduce the financial burden on the affected patient. Also, health care providers need to consider the factors that may enhance patient health status and healthcare efficiency.
Ficus benghalensis as Potential Inhibitor of 5α-Reductase for Hair Growth Promotion: In Vitro, In Silico, and In Vivo Evaluation
Authors: Iltaf Jawaria , Noreen Sobia , Rehman Muhammad Fayyaz ur , Ghumman Shazia Akram , Batool Fozia , Mehdi Muhammad , Hasan Sara , Ijaz Bushra , Akram Muhammad Safwan , Butt Haider
Published: December 2021

The screening of hair follicles, dermal papilla cells, and keratinocytes through in vitro, in vivo, and histology has previously been reported to combat alopecia. Ficus benghalensis has been used conventionally to cure skin and hair disorders, although its effect on 5α-reductase II is still unknown. Currently, we aim to analyze the phytotherapeutic impact of F. benghalensis leaf extracts (FBLEs) for promoting hair growth in rabbits along with in vitro inhibition of the steroid isozyme 5α-reductase II. The inhibition of 5α-reductase II by FBLEs was assessed by RP-HPLC, using the NADPH cofactor as the reaction initiator and Minoxin (5%) as a positive control. In silico studies were performed using AutoDock Vina to visualize the interaction between 5α-reductase II and the reported phytoconstituents present in FBLEs. Hair growth in female albino rabbits was investigated by applying an oral dose of the FBLE formulation and control drug to the skin once a day. The skin tissues were examined by histology to see hair follicles. Further, FAAS, FTIR, and antioxidants were performed to check the trace elements and secondary metabolites in the FBLEs. The results of RP-HPLC and the binding energies showed that FBLEs reduced the catalytic activity of 5α-reductase II and improved cell proliferation in rabbits. The statistical analysis (p < 0.05 or 0.01) and percentage inhibition (>70%) suggested that hydroalcoholic FBLE has more potential in increasing hair growth by elongating hair follicle’s anagen phase. FAAS, FTIR, and antioxidant experiments revealed sufficient concentrations of Zn, Cu, K, and Fe, together with the presence of polyphenols and scavenging activity in FBLE. Overall, we found that FBLEs are potent in stimulating hair follicle maturation by reducing the 5α-reductase II action, so they may serve as a principal choice in de novo drug designing to treat hair loss.
Investigating the Impact of Isolation During COVID-19 on Family Functioning – An Australian Snapshot
Authors: Sheen Jade , Aridas Anna , Tchernegovski Phillip , Dudley Amanda , McGillivray Jane , Reupert Andrea
Published: December 2021

This study explored possible changes in family functioning from the perspective of parents during the COVID-19 pandemic. Thirty-four parents/guardians of children under 18 years completed a semi-structured interview, average length 47 min. Interviews focussed on changes in different aspects of family functioning including family roles, routines, and rules; parenting practices; communication and relationships; and strengths, challenges, and tensions. Data were analysed using reflexive thematic analysis applied in an idiographic and inductive manner to reduce the loss of individual experiences and perspectives. Four superordinate themes were identified: shifting family roles and boundaries throughout the pandemic; impacts on routines and relationships; opportunities and resourcing; and, experiences of support and unity. Gender differences were evident across some themes, particularly changing roles, workload and work-home boundaries. Challenges and tensions were frequently highlighted, particularly by “vulnerable” family groups such as those with children with disabilities. Parents also described a renewed sense of family and community that underpinned adaptive coping responses. The results highlight the importance of family connectedness in times of need.
Regional Peer Effects of Corporate Tax Avoidance
Authors: Gao Ya , Cai Chang , Cai Yiwei
Published: December 2021

This study empirically demonstrates significant regional peer effects due to tax avoidance. We used peer companies’ idiosyncratic stock returns as an instrumental variable to address potential endogeneity problems. The heterogeneity analysis indicates that for companies with a stronger intensity of regional tax collection and management, a higher degree of informatization, and companies with a low management shareholding ratio, the regional peer effects of enterprise tax avoidance are more significant. Finally, we determined that the managers’ information learning, reputation consideration, and information communication are key mechanisms propagating peer effects. The conclusions of this paper enrich and expand the peer effect theory of corporate tax avoidance, thereby providing a theoretical basis and empirical evidence for tax authorities in supervising corporate tax avoidance.
Preserved Consciousness in Alzheimer’s Disease and Other Dementias: Caregiver Awareness and Communication Strategies
Authors: Warren Alison
Published: December 2021

Alzheimer’s disease is an insidious onset neurodegenerative syndrome without effective treatment or cure. It is rapidly becoming a global health crisis that is overwhelming healthcare, society, and individuals. The clinical nature of neurocognitive decline creates significant challenges in bidirectional communication between caregivers and persons with Alzheimer’s disease (AD) that can negatively impact quality-of-life. This paper sought to understand how and to what extent would awareness training about the levels of consciousness in AD influence the quality-of-life interactions in the caregiver-patient dyad. A literature review of multiple databases was conducted utilizing a transdisciplinary approach. The sum of findings indicates a positive relationship between enhanced caregiver awareness and training, positive interactions, and improved QOL measures among patients and caregivers. A multidirectional relationship was found among healthcare policies, training and education resources, caregivers, and persons with AD. Specifically, the current lack of policy and inadequate training and educational resources has various detrimental effects on patients and caregivers, while improvements in training and education of caregivers yields positive outcomes in communication and QOL. Furthermore, evidence of preserved consciousness in persons with AD was demonstrated from multiple disciplines, including neurobiological, psychological, and biopsychosocial models. The literature further revealed several methods to access the preserved consciousness in persons with AD and related dementias, including sensory, emotional, and cognitive stimulations. The evidence from the literature suggests a reframed approach to our understanding and treatment of persons with AD is not only warranted, but crucial to address the needs of those affected by AD.
A Spectrum of Selves Reinforced in Multilevel Coherence: A Contextual Behavioural Response to the Challenges of Psychedelic-Assisted Therapy Development
Authors: Whitfield Henry J.
Published: December 2021

Psychedelic-assisted therapy research for depression and PTSD has been fast tracked in the United States with the Food and Drugs Administration (FDA) granting breakthrough designations for MDMA (post-traumatic stress disorder) and psilocybin (major depressive disorder). The psychotherapeutic treatments accompanying these psychedelics have not been well-studied and remain controversial. This article reviews the challenges unique to psychedelic-assisted therapy and introduces a newly optimised psychological flexibility model that adapts Contextual Behavioural Science (CBS)/Acceptance and Commitment Therapy (ACT) to those multiple challenges, including ego inflation, traumatic memories, and the perceived presence ofentities. A methodology aligned with biological mechanisms, psychological processes and therapeutic contexts may be advantageous for improving outcomes. This model expands ACT by integrating practices and data from psychedelic-assisted therapy research into a Contextual Behavioural Science framework, allowing both fields to inform each other. Psychological flexibility processes are questioned and adapted to a psychedelic context, and interventions that operationalise these processes are considered. The principle through-line of the paper is to consider varied constructs of Self, as understood by these fields, and integrates respective elements of varied self-models, interventions and data into a Spectrum of Selves model for psychedelic-assisted therapy. Secondly the paper examines how to select and retain new self-perspectives and their corresponding behaviours systemically, drawing from evolutionary science principles. A case example of such behavioural reinforcement is provided, as well as a psychedelic integration checklist to guide the practical implementation of such an approach. This method can enable a coherent therapeutic framework with clear operational relationships between (1) problematic behaviour patterns that an individual wishes to address (2) the guided psychedelic experiences of that individual, and (3) the barriers to maintaining any changes, thus increasing theoretical-practical coherence, broadening treatment benefits and reducing relapse in psychedelic-assisted therapy. Research questions for further developing a CBS-consistent psychedelic-assisted therapy are offered.
Socio-Demographic, Clinical and Psychological Profile of Frailty Patients Living in the Home Environment and Nursing Homes: A Cross-Sectional Study
Authors: Muszalik Marta , Kotarba Agnieszka , Borowiak Ewa , Puto Grażyna , Cybulski Mateusz , Kȩdziora-Kornatowska Kornelia
Published: December 2021

Introduction: Frailty syndrome, as a physiological syndrome, is characterized by a gradual decline in physiological reserve and a lowered resistance to stress-inducing factors, leading to an increased risk of adverse outcomes. It is significantly connected with dependence on care and frequent hospitalizations.

Objectives: The aim of the study was to describe socio-demographic, clinical and psychological profile of frailty older adults living in their own homes and to nursing homes.

Methods: The study was conducted with 180 patients who were over 60 years of age, the mean (±SD) was 74.1 (±8.8) years. Among the subjects, 90 individuals were community-dwelling older adults. The survey used a list of socio-demographic questions, as well as the following scales: Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), SHARE-FI, and The World Health Organization Quality of Life (WHOQOL-Bref).

Results: Pre-frailty was confirmed in 49 (27.2%) patients, and frailty syndrome was noticed in 47 patients (26.1%). The prevalence of frailty syndrome in the study group was related to: place of living (p < 0.001), age (p < 0.001), widowhood (p < 0.001), a poor economic situation (p < 0.001), basic education level (p < 0.001), living alone (p < 0.001), longer duration of illness (p < 0.001), comorbidities (p < 0.001), more medications taken (p < 0.001), deterioration of hearing (p = 0.003), impairment of cognitive functions (p < 0.001), depression (p < 0.001), and decreased quality of life (p < 0.001).

Discussion: A lot of socio-demographic and medical factors, particularly cognitive and mental functioning were connected with the prevalence and progression of frailty syndrome in the study group. Quality of life was significantly dependent on the presence of frailty syndrome, both in homes and in nursing homes.
Physician's Burnout and the COVID-19 Pandemic—A Nationwide Cross-Sectional Study in Austria
Authors: Kurzthaler Ilsemarie , Kemmler Georg , Holzner Bernhard , Hofer Alex
Published: December 2021

Background: The current study assesses the prevalence of burnout and psychological distress among general practitioners and physicians of various specialities, who are not working in a hospital, during the COVID-19 pandemic. Additionally in this context, contributing factors are registered.

Materials and Methods: Burnout and psychological distress were assessed with the Copenhagen Burnout Inventory (CBI) and the Brief Symptom Inventory (BSI-18). A newly developed self-reporting questionnaire was used to evaluate demographic data and pandemic-associated stress factors.

Results: 252 general practitioners and 229 private practice physicians provided sufficient responses to the outcome variables for analysis. The prevalence of clinically relevant psychological distress was comparable between groups (12.4 vs. 9.2%). A larger proportion of general practitioners than specialists had intermediate (43.8 vs. 39.9%) or high burnout (26.9 vs. 22.0%) without reaching statistical significance for either category. When combining study participants with intermediate and high levels of burnout, the group difference attained significance (70.7 % vs. 61.9%).

Conclusion: Our findings provide evidence that practicing physicians are at high risk of burnout in the context of the pandemic. Being single (standardized beta = 0.134), financial problems (beta = 0.136), and facing violence in patient care (beta = 0.135) were identified as significant predictors for psychological distress. Burnout was predicted by being single (beta = 0.112), financial problems (beta= 0.136), facing violence in patient care (beta = 0.093), stigmatization because of treatment of SARS-CoV-2-positive patients (beta = 0.150), and longer working hours during the pandemic (beta = 0.098).