bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating metabolomics and network pharmacology to assess the effects of Mahuang Xixin Fuzi decoction on migraine rats induced by nitroglycerin
Authors: Ge Fei , Zhang Yao , Luo Yamin , Wang Chunguo , Lu Yixing , Zhao Yafang , Zhang Di , Meng Fengxian , Zhang Dongmei , Chen Meng , Tao Xiaohua 
Published: March 2024

Abstract

Objectives
This study was designed to investigate the pharmacological activity and therapeutic mechanism of Mahuang Xixin Fuzi decoction (MXFD) on migraine.

Methods
Migraine model rats induced by nitroglycerin were established, and then orally administered with MXFD for 7 days. Blood and urine samples were collected to identify differential metabolites with metabolomics. To integrate the findings from network pharmacology and metabolomics analysis, the metabolites and targets related to MXFD therapy for migraine were filtered.

Key findings
MXFD was found to alleviate the symptoms of migraines in rats. After treatment with MXFD, nine metabolites were found to be regulated and returned to normal levels. MXFD acted directly on nine key targets including MAOB, MAOA, ADRB1, ADRB2, ADRB3, ADORA2A, ADORA2B, DRD5, and HTR4 and regulated two out of nine metabolites, namely deoxycholic acid and 5-methoxyindoleacetate.

Conclusions
The study found that MXFD can alleviate migraines through multitarget and multicomponent interaction networks.
Anticancer Drugs-Related Hypogonadism in Male Patients with Advanced Cancers on Active Treatment: A Systematic Review
Authors: Massa Giacomo , Zambelli Luca , Zecca Ernesto , Shkodra Morena , Tinè Gabriele , Caraceni Augusto 
Published: March 2024

Abstract

Background
In male patients with cancer treated with antineoplastic drug, hypogonadism is a neglected cause of diminished quality of life. This condition may be cancer related as well as toxicity related. The role of antineoplastic drug in causing hypogonadism is poorly understood. The aim of this systematic review was to establish the prevalence, nature (primary/secondary), and impact of hypogonadism on quality of life in male patients with cancer on antineoplastic therapy.

Methods
The search strategy used PubMed, Embase, and Cochrane databases to select articles in English language that described hypogonadism in male patients with cancer. The search period was from January 1, 1945 to February 28, 2023. We included observational studies, case reports or case series and excluded studies concerning hematological malignancies, prostate cancer, female patients, and survivors.

Findings
Of 4488 records identified, 28 studies met inclusion criteria (17 observational studies, 11 case reports or case series). Anti-angiogenic drugs and crizotinib were found to have a role in the development of hypogonadism. Patients treated with immune checkpoint-inhibitors developed secondary hypogonadism due to immune-related hypophysitis or orchitis. As for active chemotherapy, platinum salts were often associated with hypogonadism, followed by antimetabolites and taxanes. Selected studies were heterogeneous for populations, interventions, and outcomes assessments. Thus, a generalization is difficult. Moreover, the role of concurrent etiologies cannot be excluded in most studies.

Conclusion
Our research emphasizes the importance of evaluating the gonadal axis before treatment in patients considered at risk and testing it at regular intervals or in case of clinical suspicion.
Engineered extracellular vesicles enable high-efficient delivery of intracellular therapeutic proteins
Authors: Ma Ding , Xie An , Lv Jiahui , Min Xiaolin , Zhang Xinye , Zhou Qian , Gao Daxing , Wang Enyu , Gao Lei , Cheng Linzhao , Liu Senquan 
Published: March 2024

Abstract
Developing an intracellular delivery system is of key importance in the expansion of protein-based therapeutics acting on cytosolic or nuclear targets. Recently, extracellular vesicles (EVs) have been exploited as next-generation delivery modalities due to their natural role in intercellular communication and biocompatibility. However, fusion of protein of interest to a scaffold represents a widely used strategy for cargo enrichment in EVs, which could compromise the stability and functionality of cargo. Herein, we report intracellular delivery via EV-based approach (IDEA) that efficiently packages and delivers native proteins both in vitro and in vivo without the use of a scaffold. As a proof-of-concept, we applied the IDEA to deliver cyclic GMP-AMP synthase (cGAS), an innate immune sensor. The results showed that cGAS-carrying EVs activated interferon signaling and elicited enhanced antitumor immunity in multiple syngeneic tumor models. Combining cGAS EVs with immune checkpoint inhibition further synergistically boosted antitumor efficacy in vivo. Mechanistically, scRNA-seq demonstrated that cGAS EVs mediated significant remodeling of intratumoral microenvironment, revealing a pivotal role of infiltrating neutrophils in the antitumor immune milieu. Collectively, IDEA, as a universal and facile strategy, can be applied to expand and advance the development of protein-based therapeutics.
Measuring the Size of the “Third Pillar”: A Global Dataset
Authors: Schiltz Fritz , MacKay Kelsey J , Vandekerckhove Philippe 
Published: March 2024

Abstract
Balancing the state and the market, the “third pillar” (i.e., any association of people that is neither public nor private) is a key sector in society. In contrast to the first two pillars (the public sector and the private sector), the third pillar has received very little attention in academic and policy debates. This paper aims to facilitate research on the third pillar's relevance by constructing the first global dataset on the size of the third pillar, including estimates for 120 countries. Results show that the size of the third pillar is substantial, both when measured as third pillar time (TPT) or third pillar participation (TPP). Global TPT is equivalent to 5.1 percent of total employment, more than half of the global agricultural sector. Moreover, findings indicate that TPP equals 13.4 percent, suggesting that more than one person in eight of the world's adult population is active as a volunteer in the third pillar.
Effectiveness of Lumbar Segmental Stabilization Exercises in Managing Disability and Pain Intensity Among Patients With Lumbar Spondylolysis and Spondylolisthesis
Authors: Lin Long-Huei , Lin Ting-Yu , Chang Ke-Vin , Wu Wei-Ting , Özçakar Levent 
Published: March 2024

Study Design.
Systematic review and meta-analysis.

Objective.
This study aims to assess the effectiveness of lumbar segmental stabilization exercise (LSSE) in managing spondylolysis and spondylolisthesis.

Summary of Background Data.
Spondylolysis and spondylolisthesis are spinal disorders associated with lumbar segmental instability. LSSE has shown positive effects in treating these conditions; however, systematic reviews and meta-analyses are lacking.

Materials and Methods.
A systematic search adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, including studies from the inception of the databases used up to January 2024, was conducted. Disability improvement and pain intensity change were the primary and secondary outcomes, respectively, standardized using Hedges g. Eligible articles underwent independent scrutiny by two authors, who also performed data extraction and quality assessment. Data pooling was accomplished using a random-effects model.

Results.
In total, five randomized controlled trials comprising 198 participants were included, revealing a trend effect toward disability improvement in the LSSE group (Hedges g=−0.598, 95% CI: −1.211 to 0.016, P=0.056, I
2=75.447%). When the LSSE was administered as a single treatment, disability improvement became significant (Hedge g=−1.325, 95% CI: −2.598 to −0.053, P=0.041, I
2=80.020%). No significant effect of LSSE on pain reduction was observed (Hedges g=−0.496, 95% CI: −1.082 to 0.090, P=0.097, I
2=73.935%).

Conclusions.
In summary, our meta-analysis suggests that LSSE can potentially improve disability, especially when used as a single treatment. LSSE appears more beneficial in reducing disability than alleviating pain. Future research on different patient groups is needed to understand comprehensively LSSE’s effects on other musculoskeletal disorders.
Fezolinetant treatment of moderate-to-severe vasomotor symptoms due to menopause: effect of intrinsic and extrinsic factors in two phase 3 studies (SKYLIGHT 1 and 2)
Authors: Santoro Nanette , Nappi Rossella E. , Neal-Perry Genevieve , English Marci , King Deanna D. , Yamaguchi Yusuke , Ottery Faith D. 
Published: March 2024

AbstractObjectiveThis study aimed to assess the efficacy of the neurokinin 3 receptor antagonist, fezolinetant, according to several intrinsic (individual related) and extrinsic (external influence) factors that may influence the frequency and severity of moderate-to-severe vasomotor symptoms (VMS) using pooled 12-week data from SKYLIGHT 1 and 2.MethodsSKYLIGHT 1 and 2 were two phase 3, randomized, double-blind studies conducted from July 2019 to August 2021 (SKYLIGHT 1) or April 2021 (SKYLIGHT 2). Participants were initially randomized to receive daily doses of placebo, fezolinetant 30 mg, or fezolinetant 45 mg. After 12 weeks, placebo participants were rerandomized to receive fezolinetant 30 mg or 45 mg, whereas those receiving fezolinetant continued on the same dose. Change in VMS frequency from baseline to week 12 was used to assess efficacy according to several intrinsic and extrinsic factors. Overall efficacy and safety were also investigated.ResultsOverall, 1,022 individuals were included. Fezolinetant was efficacious in reducing VMS frequency across all intrinsic and extrinsic factors. Efficacy was most notable for participants who self-identify as Black (least squares mean difference for fezolinetant 45 mg versus placebo, −3.67; 95% CI, −5.32 to −2.01), current smokers (−3.48; −5.19 to −1.77), and current alcohol users (−3.48; −4.42 to −2.54). Overall efficacy was −2.51 (95% CI, −3.20 to −1.82) for fezolinetant 45 mg versus placebo. Similar findings were observed for the fezolinetant 30 mg dose. Comparable incidences of treatment-emergent adverse events were observed for placebo (132 of 342 individuals [38.6%]), fezolinetant 30 mg (132 of 340 individuals [38.8%]), and fezolinetant 45 mg (135 of 340 individuals [39.7%]).ConclusionsNone of the intrinsic and extrinsic factors analyzed substantially reduced the efficacy response to fezolinetant in SKYLIGHT 1 and 2. These data provide additional confidence for using fezolinetant in a diverse population of individuals with VMS.
Velacur ACE outperforms FibroScan CAP for diagnosis of MASLD
Authors: Loomba Rohit , Ramji Alnoor , Hassanein Tarek , Yoshida Eric M. , Pang Emily , Schneider Caitlin , Curry Michael P. , Afdhal Nezam H. 
Published: March 2024

Background:
As the prevalence of metabolic dysfunction-associated steatotic liver disease increases, it is imperative to have noninvasive alternatives to liver biopsy. Velacur offers a non-invasive, point-of-care ultrasound-based method for the assessment of liver stiffness and attenuation. The aim of this study was to perform a head-to-head comparison of liver stiffness and liver fat determined by Velacur and FibroScan using MRI-based measurements as the reference standard.

Methods:
This prospective cross-sectional study included 164 adult participants with well-characterized metabolic dysfunction-associated steatotic liver disease. Patients underwent a research exam including Velacur, FibroScan and contemporaneous magnetic resonance elastography, and magnetic resonance imaging proton density fat fraction (MRI-PDFF) scans. The primary outcome was the presence of advanced fibrosis (>F2) as measured by magnetic resonance elastography and the presence of liver fat (>5%) as measured by MRI-PDFF.

Results:
The mean age and body mass index were 57±12 years and 30.6±4.8 kg/m2, respectively. The mean liver stiffness on magnetic resonance elastography was 3.22±1.39 kPa and the mean liver fat on MRI-PDFF was 14.2±8%. The liver stiffness assessments by Velacur and FibroScan were similar for the detection of advanced fibrosis (AUC 0.95 vs. 0.97) and were not statistically different (p=0.43). Velacur was significantly better than FibroScan (AUC 0.94 vs. 0.79, p=0.01), for the detection of MRI-PDFF >5% (diagnosis of metabolic dysfunction–associated liver disease).

Conclusions:
Velacur was superior to FibroScan for liver fat detection with MRI-PDFF as the reference. Velacur and FibroScan were not statistically different for liver stiffness assessment as defined by magnetic resonance elastography.
Impaired systemic proteostasis and peripheral immune cell dysfunction in kidney diseases
Authors: Desirée Bartolini , Anna Migni , Roberta Russo , Francesco Galli 
Published: March 2024

ABSTRACT
Kidney diseases, encompassing a spectrum of either acute or chronic disorders, manifest complex systemic repercussions beyond renal dysfunction. These include a reduced efficacy of tissue proteostasis mechanisms to control protein synthesis, folding, and degradation in both the renal and extra-renal compartments. Emerging research has revealed a pivotal interplay between proteostasis and immune regulation in the pathogenesis of kidney diseases, along with their cardiovascular, immunometabolic, and organ dysfunction symptoms. This review outlines the multifaceted connections between proteostasis dysregulation and immune dysfunction in kidney disease onset and progression. The crosstalk between the proteostasis network and immune cells orchestrates a bidirectional communication that amplifies pathological cascades, exacerbating kidney injury and impairing organ resilience. Furthermore, the article focuses on the implications of systemic proteostasis defects in modulating immune responses in extra-renal tissues underscore the systemic nature of kidney diseases. The disruption of proteostasis mechanisms triggers the release of damage-associated molecular patterns (DAMPs) and inflammatory mediators, perpetuating a state of heightened immune activation, contributing to systemic complications in affected individuals. Understanding the intricate interaction between proteostasis and immune regulation in kidney diseases, including both chronic and acute forms, promises novel therapeutic interventions. Targeting proteostasis pathways to restore cellular homeostasis and modulating immune responses could offer innovative strategies to mitigate renal damage and ameliorate systemic complications associated with kidney diseases. Harnessing this knowledge may also pave the way for the development of more efficient dialysis therapies and interventions with sorbents and hemoperfusion methods, to improve the clinical outcome of the patients.
Psychedelic Therapy: A Primer for Primary Care Clinicians—3,4-Methylenedioxy-methamphetamine (MDMA)
Authors: Shinozuka Kenneth , Tabaac Burton J. , Arenas Alejandro , Beutler Bryce D. , Cherian Kirsten , Evans Viviana D. , Fasano Chelsey , Muir Owen S. 
Published: March 2024

Background:
After becoming notorious for its use as a party drug in the 1980s, 3,4-methylenedioxy-methampetamine (MDMA), also known by its street names “molly” and “ecstasy,” has emerged as a powerful treatment for post-traumatic stress disorder (PTSD).

Areas of Uncertainty:
There are extensive data about the risk profile of MDMA. However, the literature is significantly biased. Animal models demonstrating neurotoxic or adverse effects used doses well beyond the range that would be expected in humans (up to 40 mg/kg in rats compared with roughly 1–2 mg/kg in humans). Furthermore, human samples often comprise recreational users who took other substances in addition to MDMA, in uncontrolled settings.

Therapeutic Advances:
Phase III clinical trials led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have shown that MDMA-assisted psychotherapy has an effect size of d = 0.7–0.91, up to 2–3 times higher than the effect sizes of existing antidepressant treatments. 67%–71% of patients who undergo MDMA-assisted psychotherapy no longer meet the diagnostic criteria for PTSD within 18 weeks. We also describe other promising applications of MDMA-assisted psychotherapy for treating alcohol use disorder, social anxiety, and other psychiatric conditions.

Limitations:
Thus far, almost all clinical trials on MDMA have been sponsored by a single organization, MAPS. More work is needed to determine whether MDMA-assisted therapy is more effective than existing nonpharmacological treatments such as cognitive behavioral therapy.

Conclusions:
Phase III trials suggest that MDMA is superior to antidepressant medications for treating PTSD. Now that MAPS has officially requested the Food and Drug Administration to approve MDMA as a treatment for PTSD, legal MDMA-assisted therapy may become available as soon as 2024.
Psychedelic Therapy: A Primer for Primary Care Clinicians—Ibogaine
Authors: Cherian Kirsten , Shinozuka Kenneth , Tabaac Burton J. , Arenas Alejandro , Beutler Bryce D. , Evans Viviana D. , Fasano Chelsey , Muir Owen S. 
Published: March 2024

Background:
Ibogaine is a plant-derived alkaloid that has been used for thousands of years in rites of passage and spiritual ceremonies in West-Central Africa. In the West, it has primarily been used and studied for its anti-addictive properties and more recently for other neuropsychiatric indications, including post-traumatic stress disorder, depression, anxiety, and traumatic brain injury.

Areas of Uncertainty:
Ibogaine requires careful patient screening and monitoring because of significant safety issues. There is potential for cardiotoxicity (prolonged QT interval); without rigorous screening, fatal arrhythmias may occur. However, preliminary research suggests that co-administration of ibogaine with magnesium may mitigate cardiotoxicity. Additionally, ibogaine may have dangerous interactions with opiates, so patients who receive ibogaine treatment for opioid use disorder must withdraw from long-acting opioids. Other potential concerning effects of ibogaine include rare incidences of mania or psychosis. Anticipated transient effects during ibogaine treatment can include ataxia, tremors, and gastrointestinal symptoms.

Therapeutic Advances:
Robust effects after a single treatment with ibogaine have been reported. In open-label and randomized controlled trials (RCTs), ibogaine reduces heroin and opioid cravings by upwards of 50%, up to 24 weeks after the treatment. An observational study of 30 Special Operations Forces veterans with mild traumatic brain injury reported that 86% were in remission from post-traumatic stress disorder, 83% from depression, and 83% from anxiety, one month after a single-dose ibogaine treatment.

Limitations:
Although there are several observational and open-label studies, there is only a single double-blind, placebo-controlled RCT on ibogaine. More RCTs with large sample sizes must be conducted to support ibogaine's safety and efficacy.

Conclusions:
Given the promising preliminary findings, ibogaine could potentially fill a much-needed gap in treatments for challenging conditions, including opioid dependence. Ibogaine's remarkable effects in traditionally treatment-resistant, combat-exposed individuals hints at its potential in broader populations with physical and psychological trauma.
Psychedelic Therapy: A Primer for Primary Care Clinicians—Psilocybin
Authors: Tabaac Burton J. , Shinozuka Kenneth , Arenas Alejandro , Beutler Bryce D. , Cherian Kirsten , Evans Viviana D. , Fasano Chelsey , Muir Owen S. 
Published: March 2024

Background:
The primary psychoactive drug in magic mushrooms, psilocybin, induces profound alterations in consciousness through the 5-HT2A receptor. This review consolidates current research findings to elucidate the pharmacology, safety profile, and clinical applications of psilocybin.

Areas of Uncertainty:
Despite initial concerns that psilocybin could cause psychosis, contemporary research has demonstrated that psilocybin is generally safe. The most common adverse effects are nausea and headache, yet both tend to be transient. Serious adverse events can generally be avoided in controlled settings such as clinical trials. However, in the largest clinical trial to date, there were a total of 7 reported cases of suicidal ideation, up to 12 weeks after receiving a single 25 mg dose of psilocybin. That being said, all 7 cases did not respond to the treatment. Although selective serotonin reuptake inhibitors may blunt the hallucinogenic qualities of psilocybin, preliminary research suggests that they may enhance its antidepressant effects.

Therapeutic Advances:
In clinical trials, psilocybin has shown promise for treating major depressive disorder and treatment-resistant depression. Initial studies indicated that 42%–57% of patients underwent remission after psilocybin-assisted therapy, which suggests that psilocybin is more effective than existing antidepressant medications. Clinical data have also demonstrated that psilocybin can manage substance use disorders and end-of-life anxiety with clinical outcomes that are sustained for months and sometimes years after 1 or 2 doses.

Limitations:
However, larger Phase II trials with more than 100 depressed participants have shown a much smaller remission rate of 25%–29%, though these studies still observed that psilocybin causes a significant reduction in depressive symptoms.

Conclusions:
Aside from ketamine, psilocybin is the most clinically well-researched psychedelic drug, with trials that have enrolled hundreds of participants and multiple therapeutic applications. Phase III trials will determine whether psilocybin lives up to the promise that it showed in previous clinical trials.
Comparison of two different orthoses used in the treatment of lateral epicondylitis
Authors: Sarı Mustafa , Öztürk Demet , Bek Nilgün 
Published: March 2024

Background:
Lateral epicondylitis (LE) is one of the most common causes of lateral elbow pain, and orthoses are often used in its conservative treatment. However, the number of studies examining the effectiveness of the orthoses used and their differences compared to each other is limited.

Objective:
To determine the effects of 2 orthoses types, wrist orthosis (WO) and counterforce brace (CB), commonly used in the treatment of lateral epicondylitis on muscle activation, grip strength, hand function, and satisfaction level in healthy individuals.

Study Design:
Quasi-experimental study.

Methods:
Thirty-seven healthy individuals were recruited. Muscle activation was evaluated by surface electromyography, and maximum grip strength was evaluated with a handheld dynamometer. Hand function and satisfaction level were evaluated with Jebsen Taylor Hand Function Test and Orthotics and Prosthetics Users Survey, respectively. All evaluations were conducted for each individual in 3 conditions (no orthosis, WO, and CB).

Results:
Extensor carpi radialis (ECR) muscle activation was greater when using CB compared with that when without orthosis (p = 0.036). There was no significant difference in extensor digitorum communis (EDC) muscle activation and maximum grip strength among the conditions (p > 0.05). Hand function was worse when using the WO compared with the other conditions (p < 0.001). In terms of orthosis satisfaction, individuals were found to be significantly more satisfied with the use of CB (p = 0.001).

Conclusions:
In our study highlight the use of CB in terms of EDC muscle activity, grip strength, hand function, and satisfaction, while the use of WO is prominent in terms of keeping extensor carpi radialis muscle activity low, which has been shown to be important for LE. To obtain definitive results on the effectiveness of different orthoses in the treatment of LE, more research is needed to compare the muscular activation in the extensor carpi radialis brevis (ECRB) and EDC muscles with objective methods.