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Viruses Jun 2024The epidemiology of different respiratory viral infections is believed to be affected by prior viral infections in addition to seasonal effects. This PROSPERO-registered... (Meta-Analysis)
Meta-Analysis Review
The epidemiology of different respiratory viral infections is believed to be affected by prior viral infections in addition to seasonal effects. This PROSPERO-registered systematic review identified 7388 studies, of which six met our criteria to answer the question specifically. The purpose of this review was to compare the prevalence of sequential viral infections in those with previously documented positive versus negative swabs. The pooled prevalence of sequential viral infections over varying periods from 30-1000 days of follow-up was higher following a negative respiratory viral swab at 0.15 than following a positive swab at 0.08, indicating the potential protective effects of prior respiratory viral infections. However, significant heterogeneity and publication biases were noted. There is some evidence, albeit of low quality, of a possible protective effect of an initial viral infection against subsequent infections by a different virus, which is possibly due to broad, nonspecific innate immunity. Future prospective studies are needed to validate our findings.
Topics: Humans; Respiratory Tract Infections; Virus Diseases; Cross Protection; Prevalence
PubMed: 38932273
DOI: 10.3390/v16060982 -
Environment International Jun 2024We aimed to assess evidence of long-term effects of exposure to radiofrequency (RF) electromagnetic fields (EMF) on indicators of cognition, including domains of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
We aimed to assess evidence of long-term effects of exposure to radiofrequency (RF) electromagnetic fields (EMF) on indicators of cognition, including domains of learning and memory, executive function, complex attention, language, perceptual motor ability and social cognition, and of an exposure-response relationship between RF-EMF and cognition.
METHODS
We searched PubMed, Embase, PsycInfo and the EMF-Portal on September 30, 2022 without limiting by date or language of publication. We included cohort or case-control studies that evaluated the effects of RF exposure on cognitive function in one or more of the cognitive domains. Studies were rated for risk of bias using the OHAT tool and synthesised using fixed effects meta-analysis. We assessed the certainty of the evidence using the GRADE approach and considered modification by OHAT for assessing evidence of exposures.
RESULTS
We included 5 studies that reported analyses of data from 4 cohorts with 4639 participants consisting of 2808 adults and 1831 children across three countries (Australia, Singapore and Switzerland) conducted between 2006 and 2017. The main source of RF-EMF exposure was mobile (cell) phone use measured as calls per week or minutes per day. For mobile phone use in children, two studies (615 participants) that compared an increase in mobile phone use to a decrease or no change were included in meta-analyses. Learning and memory. There was little effect on accuracy (mean difference, MD -0.03; 95% CI -0.07 to 0.02) or response time (MD -0.01; 95% CI -0.04 to 0.02) on the one-back memory task; and accuracy (MD -0.02; 95%CI -0.04 to 0.00) or response time (MD -0.01; 95%CI -0.04 to 0.03) on the one card learning task (low certainty evidence for all outcomes). Executive function. There was little to no effect on the Stroop test for the time ratio ((B-A)/A) response (MD 0.02; 95% CI -0.01 to 0.04, very low certainty) or the time ratio ((D-C)/C) response (MD 0.00; 95% CI -0.06 to 0.05, very low certainty), with both tests measuring susceptibility to interference effects. Complex attention. There was little to no effect on detection task accuracy (MD 0.02; 95% CI -0.04 to 0.08), or response time (MD 0.02;95% CI 0.01 to 0.03), and little to no effect on identification task accuracy (MD 0.00; 95% CI -0.04 to 0.05) or response time (MD 0.00;95% CI -0.01 to 0.02) (low certainty evidence for all outcomes). No other cognitive domains were investigated in children. A single study among elderly people provided very low certainty evidence that more frequent mobile phone use may have little to no effect on the odds of a decline in global cognitive function (odds ratio, OR 0.81; 95% CI 0.42 to 1.58, 649 participants) or a decline in executive function (OR 1.07; 95% CI 0.37 to 3.05, 146 participants), and may lead to a small, probably unimportant, reduction in the odds of a decline in complex attention (OR 0.67;95%CI 0.27 to 1.68, 159 participants) and a decline in learning and memory (OR 0.75; 95% CI 0.29 to 1.99, 159 participants). An exposure-response relationship was not identified for any of the cognitive outcomes.
DISCUSSION
This systematic review and meta-analysis found only a few studies that provided very low to low certainty evidence of little to no association between RF-EMF exposure and learning and memory, executive function and complex attention. None of the studies among children reported on global cognitive function or other domains of cognition. Only one study reported a lack of an effect for all domains in elderly persons but this was of very low certainty evidence. Further studies are needed to address all types of populations, exposures and cognitive outcomes, particularly studies investigating environmental and occupational exposure in adults. Future studies also need to address uncertainties in the assessment of exposure and standardise testing of specific domains of cognitive function to enable synthesis across studies and increase the certainty of the evidence.
OTHER
This review was partially funded by the WHO radioprotection programme and prospectively registered on PROSPERO CRD42021257548.
Topics: Humans; Cognition; Radio Waves; Electromagnetic Fields; Observational Studies as Topic; Child; Cell Phone; Environmental Exposure; Adult; Memory
PubMed: 38821015
DOI: 10.1016/j.envint.2024.108779 -
Cureus Apr 2024One of the leading environmental hazards, ionizing radiation, is linked to several detrimental health consequences in the body. RADPAD (Worldwide Innovations &... (Review)
Review
Assessing the Efficacy of RADPAD Protection Drape in Reducing Radiation Exposure to Operators in the Cardiac Catheterization Laboratory: A Systematic Review and Meta-Analysis.
One of the leading environmental hazards, ionizing radiation, is linked to several detrimental health consequences in the body. RADPAD (Worldwide Innovations & Technologies, Inc., Kansas City, Kansas) is a sterile, lead-free, lightweight, disposable radiation protection shield. We conducted a systematic review and meta-analysis to determine the effectiveness of RADPAD protection drapes in the cardiac catheterization lab and how they can aid interventional cardiologists in becoming subjected to less scatter radiation. PubMed, Embase, and Google Scholar were searched for studies discussing the efficacy of RADPAD protection drapes in reducing radiation exposure to operators in the cardiac catheterization laboratory. A random-effects model was used to pool odds ratios (ORs) and 95% confidence intervals (CIs) for endpoints: primary operator exposure dose, dose area product (DAP), relative exposure, and screening time. Our analysis included 892 patients from six studies. Compared to the No-RADPAD group, primary operator exposure dose (E) was significantly lower in the RADPAD group (OR: -0.9, 95% CI: -1.36 to -0.43, I= 80.5%, p = 0.0001). DAP was comparable between both groups (OR: 0.008, 95% CI: -0.12 to -0.14, I= 0%, p = 0.9066). There was no difference in the relative exposure (E/DAP) (OR: -0.47, 95% CI: -0.96 to 0.02, I= 0%, p = 0.90) and screening time (OR: 0.13, 95% CI: 0.08 to 0.35, I= 0%, p = 0.22) between the two groups. The interventional cardiology laboratory is exposed to significantly less scatter radiation during procedures owing to the RADPAD protective drape. Consequently, all catheterization laboratories could be advised to employ RADPAD protective drapes.
PubMed: 38807800
DOI: 10.7759/cureus.59215 -
Environment International May 2024The technological applications of radiofrequency electromagnetic fields (RF-EMF) have been steadily increasing since the 1950s exposing large proportions of the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The technological applications of radiofrequency electromagnetic fields (RF-EMF) have been steadily increasing since the 1950s exposing large proportions of the population. The World Health Organization (WHO) is assessing the potential health effects of exposure to RF-EMF.
OBJECTIVES
To systematically assess the effects of exposure to RF-EMF on self-reported non-specific symptoms in human subjects and to assess the accuracy of perceptions of presence or absence of RF-EMF exposure.
METHODS
Eligibility criteria: experimental studies carried out in the general population and in individuals with idiopathic environmental intolerance attributed to EMF (IEI-EMF), in any language.
INFORMATION SOURCES
Medline, Web of Science, PsycInfo, Cochrane Library, Epistemonikos, Embase and EMF portal, searched till April 2022. Risk of Bias (ROB): we used the RoB tool developed by OHAT adapted to the topic of this review.
SYNTHESIS OF RESULTS
we synthesized studies using random effects meta-analysis and sensitivity analyses, where appropriate.
RESULTS
Included studies: 41 studies were included, mostly cross over trials and from Europe, with a total of 2,874 participants.
SYNTHESIS OF RESULTS
considering the primary outcomes, we carried out meta-analyses of 10 exposure-outcomes pairs. All evidence suggested no or small non-significant effects of exposure on symptoms with high (three comparisons), moderate (four comparisons), low (one comparison) and very low (two comparisons) certainty of evidence. The effects (standard mean difference, where positive values indicate presence of symptom being exposed) in the general population for head exposure were (95% confidence intervals) 0.08 (-0.07 to 0.22) for headache, -0.01 (-0.22 to 0.20) for sleeping disturbances and 0.13 (-0.51 to 0.76) for composite symptoms; and for whole-body exposure: 0.09 (-0.35 to 0.54), 0.00 (-0.15 to 0.15) for sleeping disturbances and -0.05 (-0.17 to 0.07) for composite symptoms. For IEI-EMF individuals SMD ranged from -0.19 to 0.11, all of them with confidence intervals crossing the value of zero. Further, the available evidence suggested that study volunteers could not perceive the EMF exposure status better than what is expected by chance and that IEI-EMF individuals could not determine EMF conditions better than the general population.
DISCUSSION
Limitations of evidence: experimental conditions are substantially different from real-life situations in the duration, frequency, distance and position of the exposure. Most studies were conducted in young, healthy volunteers, who might be more resilient to RF-EMF than the general population. The outcomes of interest in this systematic review were symptoms, which are self-reported. The available information did not allow to assess the potential effects of exposures beyond acute exposure and in elderly or in chronically ill people. It cannot be ruled out that a real EMF effect in IEI-EMF groups is masked by a mix with insensitive subjects. However, studies on symptoms reporting and/or field perceptions did not find any evidence that there were particularly vulnerable individuals in the IEI-EMF group, although in open provocation studies, when volunteers were informed about the presence or absence of EMF exposure, such differences were consistently observed.
INTERPRETATION
available evidence suggests that acute RF-EMF below regulatory limits does not cause symptoms and corresponding claims in the everyday life are related to perceived and not to real EMF exposure status.
Topics: Humans; Electromagnetic Fields; Self Report; Environmental Exposure; Radio Waves
PubMed: 38640611
DOI: 10.1016/j.envint.2024.108612 -
Frontiers in Oncology 2024This systematic review and meta-analysis aimed to examine the risk of second primary cancers (SPCs) among retinoblastoma (Rb) patients, both hereditary and...
INTRODUCTION
This systematic review and meta-analysis aimed to examine the risk of second primary cancers (SPCs) among retinoblastoma (Rb) patients, both hereditary and nonhereditary. Previous studies have reported on the long-term risk of SPCs in these patient populations, but a comprehensive synthesis of the existing evidence is lacking.
METHODS
A systematic search was conducted in PubMed, EMBASE, and Cochrane Library from inception to 12 March 2023, supplemented by manual screening. Eligible studies were identified, and data were extracted. The primary outcome measure was the standardized incidence ratios (SIRs) of SPCs in Rb patients. Summary estimates were calculated using random or fixed effects models. The quality of included studies was assessed using the Newcastle-Ottawa Scale.
RESULTS
Ten studies, including nine high-quality studies, were included in this review. The summary estimate of SIR for SPCs among hereditary Rb patients was 17.55 (95% CI=13.10-23.51), while the pooled estimate of SIR for SPCs among nonhereditary Rb patients was 1.36 (95% CI=0.90-2.04). Significant differences in SIRs for different SPC types were observed (P=0.028), including nasal cavity tumor (SIR=591.06, 95% CI=162.79-2146.01), bone tumor (SIR=442.91, 95% CI=191.63-1023.68), soft tissue sarcoma (SIR=202.93, 95% CI=114.10-360.93), CNS (SIR=12.84, 95% CI=8.80-18.74), and female breast cancer (SIR=3.68, 95% CI=2.52-5.37). Chemotherapy and radiation therapy were associated with an increased risk of SPCs among hereditary Rb patients.
DISCUSSION
The findings of this review indicate that hereditary Rb patients have a significantly elevated risk of developing SPCs, whereas nonhereditary Rb patients do not show the same risk. Furthermore, significant differences were observed in the SIRs of different SPC types. Treatment techniques, specifically chemotherapy and radiation therapy, were associated with an increased risk of SPCs among hereditary Rb patients. These findings highlight the importance of radiation protection for Rb patients and the need for further research and tailored management strategies for this high-risk population.
PubMed: 38606112
DOI: 10.3389/fonc.2024.1372548 -
Imaging Science in Dentistry Mar 2024This study was conducted to investigate the safety of dental imaging in pregnant women with respect to fetal health. (Review)
Review
PURPOSE
This study was conducted to investigate the safety of dental imaging in pregnant women with respect to fetal health.
MATERIALS AND METHODS
Searches were conducted of the PubMed, Scopus, and Web of Science databases in May 2023. The inclusion criteria encompassed cross-sectional and longitudinal studies that focused on the analysis of diagnostic dental imaging in pregnant women, as well as studies utilizing phantoms to simulate imaging examinations. The exclusion criteria consisted of reviews, letters to the editor, book chapters, and abstracts from scientific conferences and seminars.
RESULTS
A total of 3,913 articles were identified. Based on a review of the titles and abstracts, 3,892 articles were excluded, leaving 21 articles remaining for full-text review. Of these, 18 were excluded, and 4 additional articles were included as cross-references. Ultimately, 7 articles underwent quantitative-qualitative analysis. Three retrospective studies were focused on pregnant women who underwent dental imaging procedures. The remaining 4 studies utilized female phantoms to simulate imaging examinations and represent the radiation doses absorbed by the uterus or thyroid.
CONCLUSION
Few dental radiology studies have been conducted to determine the safe radiation threshold for pregnant women. Additionally, the reviewed articles did not provide numbers of dental examinations, by type, corresponding to this dose. Dental imaging examinations of pregnant women should not be restricted if clinically indicated. Ultimately, practitioners must be able to justify the examination and should adhere to the "as low as diagnostically acceptable, being indication-oriented and patient-specific" (ALADAIP) principle of radioprotection.
PubMed: 38571778
DOI: 10.5624/isd.20230177 -
Environment International Mar 2024The World Health Organization is coordinating an international project aimed at systematically reviewing the evidence regarding the association between radiofrequency... (Meta-Analysis)
Meta-Analysis
Effects of radiofrequency electromagnetic field (RF-EMF) exposure on male fertility: A systematic review of experimental studies on non-human mammals and human sperm in vitro.
BACKGROUND
The World Health Organization is coordinating an international project aimed at systematically reviewing the evidence regarding the association between radiofrequency electromagnetic field (RF-EMF) exposure and adverse health effects. Reproductive health outcomes have been identified among the priority topics to be addressed.
OBJECTIVES
To evaluate the effect of RF-EMF exposure on male fertility of experimental mammals and on human sperm exposed in vitro.
METHODS
Three electronic databases (PubMed, Scopus and EMF Portal) were last searched on September 17, 2022. Two independent reviewers screened the studies, which were considered eligible if met the following criteria: 1) Peer-reviewed publications of sham controlled experimental studies, 2) Non-human male mammals exposed at any stage of development or human sperm exposed in vitro, 3) RF-EMF exposure within the frequency range of 100 kHz-300 GHz, including electromagnetic pulses (EMP), 4) one of the following indicators of reproductive system impairment:Two reviewers extracted study characteristics and outcome data. We assessed risk of bias (RoB) using the Office of Health Assessment and Translation (OHAT) guidelines. We categorized studies into 3 levels of overall RoB: low, some or high concern. We pooled study results in a random effects meta-analysis comparing average exposure to no-exposure and in a dose-response meta-analysis using all exposure doses. For experimental animal studies, we conducted subgroup analyses for species, Specific Absorption Rate (SAR) and temperature increase. We grouped studies on human sperm exposed in vitro by the fertility status of sample donors and SAR. We assessed the certainty of the evidence using the GRADE approach after excluding studies that were rated as "high concern" for RoB.
RESULTS
One-hundred and seventeen papers on animal studies and 10 papers on human sperm exposed in vitro were included in this review. Only few studies were rated as "low concern" because most studies were at RoB for exposure and/or outcome assessment. Subgrouping the experimental animal studies by species, SAR, and temperature increase partly accounted for the heterogeneity of individual studies in about one third of the meta-analyses. In no case was it possible to conduct a subgroup analysis of the few human sperm in vitro studies because there were always 1 or more groups including less than 3 studies. Among all the considered endpoints, the meta-analyses of animal studies provided evidence of adverse effects of RF-EMF exposure in all cases but the rate of infertile males and the size of the sired litters. The assessment of certainty according to the GRADE methodology assigned a moderate certainty to the reduction of pregnancy rate and to the evidence of no-effect on litter size, a low certainty to the reduction of sperm count, and a very low certainty to all the other meta-analysis results. Studies on human sperm exposed in vitro indicated a small detrimental effect of RF-EMF exposure on vitality and no-effect on DNA/chromatin alterations. According to GRADE, a very low certainty was attributed to these results. The few studies that used EMP exposure did not show effects on the outcomes. A low to very low certainty was attributed to these results.
DISCUSSION
Many of the studies examined suffered of severe limitations that led to the attribution of uncertainty to the results of the meta-analyses and did not allow to draw firm conclusions on most of the endpoints. Nevertheless, the associations between RF-EMF exposure and decrease of pregnancy rate and sperm count, to which moderate and low certainty were attributed, are not negligible, also in view of the indications that in Western countries human male fertility potential seems to be progressively declining. It was beyond the scope of our systematic review to determine the shape of the dose-response relationship or to identify a minimum effective exposure level. The subgroup and the dose-response fitting analyses did not show a consistent relationship between the exposure levels and the observed effects. Notably, most studies evaluated RF-EMF exposure levels that were higher than the levels to which human populations are typically exposed, and the limits set in international guidelines. For these reasons we cannot provide suggestions to confirm or reconsider current human exposure limits. Considering the outcomes of this systematic review and taking into account the limitations found in several of the studies, we suggest that further investigations with better characterization of exposure and dosimetry including several exposure levels and blinded outcome assessment were conducted.
PROTOCOL REGISTRATION
Protocols for the systematic reviews of animal studies and of human sperm in vitro studies were published in Pacchierotti et al., 2021. The former was also registered in PROSPERO (CRD42021227729 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID = 227729) and the latter in Open Science Framework (OSF Registration DOI https://doi.org/10.17605/OSF.IO/7MUS3).
Topics: Animals; Humans; Male; Electromagnetic Fields; Mammals; Radio Waves; Reproduction; Semen; Infertility, Male
PubMed: 38492496
DOI: 10.1016/j.envint.2024.108509 -
Radiography (London, England : 1995) Mar 2024According to World Health Organization (WHO), workplace violence (WPV) is a significant issue in healthcare. However, no systematic review on WPV in medical radiation...
INTRODUCTION
According to World Health Organization (WHO), workplace violence (WPV) is a significant issue in healthcare. However, no systematic review on WPV in medical radiation science (MRS) has been published yet. The purpose of this paper is to systematically review prevalence of WPV in MRS and its risk factors.
METHODS
Electronic scholarly publication databases, namely EBSCOhost/Cumulative Index of Nursing and Allied Health Literature Ultimate, PubMed/Medline, ScienceDirect, Scopus, and Wiley Online Library were used for literature search to identify articles about WPV in MRS published over last 10 years as per preferred reporting items for systematic reviews and meta-analyses guidelines. To facilitate comparisons of the WPV prevalence and relative importance of individual risk factors across the included studies, their reported absolute figures of findings were used to synthesize respective percentages (if not stated).
RESULTS
Twelve papers met the selection criteria and were included. This review shows that the WPV prevalence were 69.2-100 % (whole career) and 46.1-83.0 % (last 12 months) in diagnostic radiography, 63.0-84.0 % (whole career) in radiation therapy, 57.6 % in medical sonography (last 12 months), and 46.8 % (last 6 months) in nuclear medicine. The identified WPV risk factors included intoxicated patients, staff stress, feeling of inadequacy resulting in self-protection, more vulnerable practitioners (female, <40 years old and <5-year experience), working in radiation therapy treatment room, emergency department, examination room, general radiography, public hospital, and non-examination and waiting areas, long patient waiting time, night shift, overcrowding environment, unable to meet patients'/family members' expectations, miscommunication, patient handling, inadequate staff and security measures, interaction with colleagues, and lone working.
CONCLUSION
The WPV risk in diagnostic radiography and radiation therapy appears extremely high as a result of the aforementioned risk factors. Nevertheless, these study findings should be used with caution due to potential non-response bias.
IMPLICATIONS FOR PRACTICE
A WPV policy should be developed in every clinical workplace. Even if such policy is available, its enforcement including policy awareness boosting, and encouraging incident reporting and support seeking will be essential for reducing WPV. More survey studies based on WHO WPV questionnaire should be conducted for strengthening evidence base.
Topics: Humans; Risk Factors; Workplace; Workplace Violence; Radiology
PubMed: 38199160
DOI: 10.1016/j.radi.2023.12.018 -
Effect of low-frequency noise exposure on cognitive function: a systematic review and meta-analysis.BMC Public Health Jan 2024Low-frequency noise may cause changes in cognitive function. However, there is no established consensus on the effect of low-frequency noise on cognitive function.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Low-frequency noise may cause changes in cognitive function. However, there is no established consensus on the effect of low-frequency noise on cognitive function. Therefore, this systematic review and meta-analysis aimed to explore the relationship between low-frequency noise exposure and cognitive function.
METHODS
We conducted a systematic review and identified original studies written in English on low-frequency noise and cognition published before December 2022 using the PsycINFO, PubMed, Medline, and Web of Science databases. The risk of bias was evaluated according to established guidelines. A random-effects meta-analysis was performed where appropriate. To explore the association between low-frequency noise exposure and cognitive function, we reviewed eight relevant studies. These studies covered cognitive functions grouped into four domains: attention, executive function, memory, and higher-order cognitive functions. The data extraction process was followed by a random-effects meta-analysis for each domain, which allowed us to quantify the overall effect.
RESULTS
Our analysis of the selected studies suggested that interventions involving low-frequency noise only had a negative impact on higher-order cognitive functions (Z = 2.42, p = 0.02), with a standardized mean difference of -0.37 (95% confidence interval: -0.67, -0.07). A moderate level of heterogeneity was observed among studies (p = 0.24, I = 29%, Tau = 0.03).
CONCLUSIONS
Our study findings suggest that low-frequency noise can negatively impact higher-order cognitive functions, such as logical reasoning, mathematical calculation, and data processing. Therefore, it becomes important to consider the potential negative consequences of low-frequency noise in everyday situations, and proactive measures should be taken to address this issue and mitigate the associated potential adverse outcomes.
Topics: Humans; Cognition; Executive Function; Problem Solving; Consensus; Databases, Factual
PubMed: 38195479
DOI: 10.1186/s12889-023-17593-5 -
Journal of Cancer 2024Cancer imposes a substantial burden and its incidence is persistently increasing in recent years. Cancer treatment has been difficult due to its inherently complex... (Review)
Review
Cancer imposes a substantial burden and its incidence is persistently increasing in recent years. Cancer treatment has been difficult due to its inherently complex nature. The tumor microenvironment (TME) includes a complex interplay of cellular and noncellular constituents surrounding neoplastic cells, intricately contributing to the tumor initiation and progression. This critical aspect of tumors involves a complex interplay among cancer, stromal, and inflammatory cells, forming an inflammatory TME that promotes tumorigenesis across all stages. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is implicated in modulating various critical processes linked to tumor pathogenesis, including but not limited to the regulation of tumor cell proliferation, invasion, migration, and survival. Furthermore, TRAF6 prominently contributes to various immune and inflammatory pathways. The TRAF6-mediated activation of nuclear factor (NF)-κB in immune cells governs the production of proinflammatory cytokines. These cytokines sustain inflammation and stimulate tumor growth by activating NF-κB in tumor cells. In this review, we discuss various types of tumors, including gastrointestinal cancers, urogenital cancers, breast cancer, lung cancer, head and neck squamous cell carcinoma, uterine fibroids, and glioma. Employing a rigorous and systematic approach, we comprehensively evaluate the functional repertoire and potential roles of TRAF6 in various cancer types, thus highlighting TRAF6 as a compelling and emerging therapeutic target worthy of further investigation and development.
PubMed: 38169510
DOI: 10.7150/jca.90059