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Anesthesia Progress 2017Nitrous oxide and midazolam have been used as sedative agents to decrease fear and anxiety associated with dental procedures. Although these agents have been widely used... (Meta-Analysis)
Meta-Analysis Review
Nitrous oxide and midazolam have been used as sedative agents to decrease fear and anxiety associated with dental procedures. Although these agents have been widely used individually, the combination of the two is also commonly used. Four clinical trials were identified that compared the combination technique with the individual use of the drugs. The standardized mean difference (SMD) for each outcome measure was considered for final analysis. Three studies with 534 participants were included in the final meta-analysis, and the SMD [95% CI] was obtained as -0.15 [-0.32, 0.03] and was not statistically significant for cooperation scores. Two studies reported the dose of midazolam required for inducing sedation in 450 participants, and the pooled estimate of SMD [95% CI] was obtained as -0.29 [-0.48, -0.10] and was significant. Two studies with 450 participants reported the time taken to recover from sedation, and the pooled estimate of SMD [95% CI] was obtained as -0.20 [-0.39, -0.01] and favored the combination technique. To conclude, the combination technique combines the pros and cons of both drugs in causing fewer adverse effects due to midazolam by reducing the total dose and also helps to provide better acceptance of nitrous oxide inhalation.
Topics: Anesthesia, Dental; Conscious Sedation; Humans; Hypnotics and Sedatives; Midazolam; Nitrous Oxide; Outcome Assessment, Health Care
PubMed: 28604098
DOI: 10.2344/anpr-63-03-06 -
Environment International Aug 2023The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury... (Meta-Analysis)
Meta-Analysis
The prevalences and levels of occupational exposure to dusts and/or fibres (silica, asbestos and coal): A systematic review and meta-analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.
BACKGROUND
The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large number of individual experts. Evidence from human, animal and mechanistic data suggests that occupational exposure to dusts and/or fibres (silica, asbestos and coal dust) causes pneumoconiosis. In this paper, we present a systematic review and meta-analysis of the prevalences and levels of occupational exposure to silica, asbestos and coal dust. These estimates of prevalences and levels will serve as input data for estimating (if feasible) the number of deaths and disability-adjusted life years that are attributable to occupational exposure to silica, asbestos and coal dust, for the development of the WHO/ILO Joint Estimates.
OBJECTIVES
We aimed to systematically review and meta-analyse estimates of the prevalences and levels of occupational exposure to silica, asbestos and coal dust among working-age (≥ 15 years) workers.
DATA SOURCES
We searched electronic academic databases for potentially relevant records from published and unpublished studies, including Ovid Medline, PubMed, EMBASE, and CISDOC. We also searched electronic grey literature databases, Internet search engines and organizational websites; hand-searched reference lists of previous systematic reviews and included study records; and consulted additional experts.
STUDY ELIGIBILITY AND CRITERIA
We included working-age (≥ 15 years) workers in the formal and informal economy in any WHO and/or ILO Member State but excluded children (< 15 years) and unpaid domestic workers. We included all study types with objective dust or fibre measurements, published between 1960 and 2018, that directly or indirectly reported an estimate of the prevalence and/or level of occupational exposure to silica, asbestos and/or coal dust.
STUDY APPRAISAL AND SYNTHESIS METHODS
At least two review authors independently screened titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, then data were extracted from qualifying studies. We combined prevalence estimates by industrial sector (ISIC-4 2-digit level with additional merging within Mining, Manufacturing and Construction) using random-effects meta-analysis. Two or more review authors assessed the risk of bias and all available authors assessed the quality of evidence, using the ROB-SPEO tool and QoE-SPEO approach developed specifically for the WHO/ILO Joint Estimates.
RESULTS
Eighty-eight studies (82 cross-sectional studies and 6 longitudinal studies) met the inclusion criteria, comprising > 2.4 million measurements covering 23 countries from all WHO regions (Africa, Americas, Eastern Mediterranean, South-East Asia, Europe, and Western Pacific). The target population in all 88 included studies was from major ISCO groups 3 (Technicians and Associate Professionals), 6 (Skilled Agricultural, Forestry and Fishery Workers), 7 (Craft and Related Trades Workers), 8 (Plant and Machine Operators and Assemblers), and 9 (Elementary Occupations), hereafter called manual workers. Most studies were performed in Construction, Manufacturing and Mining. For occupational exposure to silica, 65 studies (61 cross-sectional studies and 4 longitudinal studies) were included with > 2.3 million measurements collected in 22 countries in all six WHO regions. For occupational exposure to asbestos, 18 studies (17 cross-sectional studies and 1 longitudinal) were included with > 20,000 measurements collected in eight countries in five WHO regions (no data for Africa). For occupational exposure to coal dust, eight studies (all cross-sectional) were included comprising > 100,000 samples in six countries in five WHO regions (no data for Eastern Mediterranean). Occupational exposure to silica, asbestos and coal dust was assessed with personal or stationary active filter sampling; for silica and asbestos, gravimetric assessment was followed by technical analysis. Risk of bias profiles varied between the bodies of evidence looking at asbestos, silica and coal dust, as well as between industrial sectors. However, risk of bias was generally highest for the domain of selection of participants into the studies. The largest bodies of evidence for silica related to the industrial sectors of Construction (ISIC 41-43), Manufacturing (ISIC 20, 23-25, 27, 31-32) and Mining (ISIC 05, 07, 08). For Construction, the pooled prevalence estimate was 0.89 (95% CI 0.84 to 0.93, 17 studies, I 91%, moderate quality of evidence) and the level estimate was rated as of very low quality of evidence. For Manufacturing, the pooled prevalence estimate was 0.85 (95% CI 0.78 to 0.91, 24 studies, I 100%, moderate quality of evidence) and the pooled level estimate was rated as of very low quality of evidence. The pooled prevalence estimate for Mining was 0.75 (95% CI 0.68 to 0.82, 20 studies, I 100%, moderate quality of evidence) and the pooled level estimate was 0.04 mg/m (95% CI 0.03 to 0.05, 17 studies, I 100%, low quality of evidence). Smaller bodies of evidence were identified for Crop and animal production (ISIC 01; very low quality of evidence for both prevalence and level); Professional, scientific and technical activities (ISIC 71, 74; very low quality of evidence for both prevalence and level); and Electricity, gas, steam and air conditioning supply (ISIC 35; very low quality of evidence for both prevalence and level). For asbestos, the pooled prevalence estimate for Construction (ISIC 41, 43, 45,) was 0.77 (95% CI 0.65 to 0.87, six studies, I 99%, low quality of evidence) and the level estimate was rated as of very low quality of evidence. For Manufacturing (ISIC 13, 23-24, 29-30), the pooled prevalence and level estimates were rated as being of very low quality of evidence. Smaller bodies of evidence were identified for Other mining and quarrying (ISIC 08; very low quality of evidence for both prevalence and level); Electricity, gas, steam and air conditioning supply (ISIC 35; very low quality of evidence for both prevalence and level); and Water supply, sewerage, waste management and remediation (ISIC 37; very low quality of evidence for levels). For coal dust, the pooled prevalence estimate for Mining of coal and lignite (ISIC 05), was 1.00 (95% CI 1.00 to 1.00, six studies, I 16%, moderate quality of evidence) and the pooled level estimate was 0.77 mg/m (95% CI 0.68 to 0.86, three studies, I 100%, low quality of evidence). A small body of evidence was identified for Electricity, gas, steam and air conditioning supply (ISIC 35); with very low quality of evidence for prevalence, and the pooled level estimate being 0.60 mg/m (95% CI -6.95 to 8.14, one study, low quality of evidence).
CONCLUSIONS
Overall, we judged the bodies of evidence for occupational exposure to silica to vary by industrial sector between very low and moderate quality of evidence for prevalence, and very low and low for level. For occupational exposure to asbestos, the bodies of evidence varied by industrial sector between very low and low quality of evidence for prevalence and were of very low quality of evidence for level. For occupational exposure to coal dust, the bodies of evidence were of very low or moderate quality of evidence for prevalence, and low for level. None of the included studies were population-based studies (i.e., covered the entire workers' population in the industrial sector), which we judged to present serious concern for indirectness, except for occupational exposure to coal dust within the industrial sector of mining of coal and lignite. Selected estimates of the prevalences and levels of occupational exposure to silica by industrial sector are considered suitable as input data for the WHO/ILO Joint Estimates, and selected estimates of the prevalences and levels of occupational exposure to asbestos and coal dust may perhaps also be suitable for estimation purposes. Protocol identifier: https://doi.org/10.1016/j.envint.2018.06.005. PROSPERO registration number: CRD42018084131.
Topics: Humans; Adolescent; Occupational Diseases; Dust; Prevalence; Silicon Dioxide; Cross-Sectional Studies; Coal; Steam; Asbestos; Occupational Exposure; World Health Organization; Cost of Illness
PubMed: 37487377
DOI: 10.1016/j.envint.2023.107980 -
Scientific Reports Mar 2017Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), impairs the beneficial effect of NO. The predictive value of ADMA for... (Meta-Analysis)
Meta-Analysis Review
Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), impairs the beneficial effect of NO. The predictive value of ADMA for all-cause mortality remains controversial, though it is important in the development of cardiovascular disease (CVD) and progression to dialysis in renal disease. This systematic review and meta-analysis was conducted to investigate the association between circulating ADMA and all-cause mortality. Studies with data pertinent to the association between circulating ADMA and all-cause mortality were reviewed and OR, HR or RR with 95% CI derived from multivariate Cox's proportional-hazards analysis were extracted. A total of 34 studies reporting 39137 participants were included in final analysis. The results demonstrated that circulating ADMA was independently associated with all-cause mortality (RR = 1.27, 95% CI: 1.20-1.34). The association was still statistically significant in patients with pre-existing renal disease (RR = 1.30, 95% CI: 1.19-1.43) and pre-existing CVD (RR = 1.26, 95% CI: 1.16-1.37). In those without pre-existing renal or CVD, ADMA also predicted all-cause mortality (RR = 1.31, 95% CI: 1.13-1.53). The present study suggests a positive association of circulating ADMA with all-cause mortality. Further studies are needed to investigate the effects of interventions on ADMA, and the value of ADMA as a biomarker.
Topics: Arginine; Biomarkers; Cardiovascular Diseases; Humans; Nitric Oxide; Nitric Oxide Synthase; Proportional Hazards Models; Renal Dialysis; Risk Factors
PubMed: 28294182
DOI: 10.1038/srep44692 -
Fluids and Barriers of the CNS Dec 2023The neurovascular unit (NVU) is a complex structure that facilitates nutrient delivery and metabolic waste clearance, forms the blood-brain barrier (BBB), and supports... (Review)
Review
The neurovascular unit (NVU) is a complex structure that facilitates nutrient delivery and metabolic waste clearance, forms the blood-brain barrier (BBB), and supports fluid homeostasis in the brain. The integrity of NVU subcomponents can be measured in vivo using magnetic resonance imaging (MRI), including quantification of enlarged perivascular spaces (ePVS), BBB permeability, cerebral perfusion and extracellular free water. The breakdown of NVU subparts is individually associated with aging, pathology, and cognition. However, how these subcomponents interact as a system, and how interdependencies are impacted by pathology remains unclear. This systematic scoping review identified 26 studies that investigated the inter-relationships between multiple subcomponents of the NVU in nonclinical and neurodegenerative populations using MRI. A further 112 studies investigated associations between the NVU and white matter hyperintensities (WMH). We identify two putative clusters of NVU interdependencies: a 'vascular' cluster comprising BBB permeability, perfusion and basal ganglia ePVS; and a 'fluid' cluster comprising ePVS, free water and WMH. Emerging evidence suggests that subcomponent coupling within these clusters may be differentially related to aging, neurovascular injury or neurodegenerative pathology.
Topics: Magnetic Resonance Imaging; Brain; Blood-Brain Barrier; Water
PubMed: 38129925
DOI: 10.1186/s12987-023-00499-0 -
International Journal of Environmental... Jul 2021Given health threats of climate change, a comprehensive review of the impacts of ambient temperature and ar pollution on suicide is needed. We performed systematic... (Meta-Analysis)
Meta-Analysis Review
Given health threats of climate change, a comprehensive review of the impacts of ambient temperature and ar pollution on suicide is needed. We performed systematic literature review and meta-analysis of suicide risks associated with short-term exposure to ambient temperature and air pollution. Pubmed, Scopus, and Web of Science were searched for English-language publications using relevant keywords. Observational studies assessing risks of daily suicide and suicide attempts associated with temperature, particulate matter with aerodynamic diameter ≤10 μm (PM) and ≤2.5 mm (PM), ozone (O), sulfur dioxide (SO), nitrogen dioxide (NO), and carbon monoxide (CO) were included. Data extraction was independently performed in duplicate. Random-effect meta-analysis was applied to pool risk ratios (RRs) for increases in daily suicide per interquartile range (IQR) increase in exposure. Meta-regression analysis was applied to examine effect modification by income level based on gross national income (GNI) per capita, national suicide rates, and average level of exposure factors. In total 2274 articles were screened, with 18 studies meeting inclusion criteria for air pollution and 32 studies for temperature. RRs of suicide per 7.1 °C temperature was 1.09 (95% CI: 1.06, 1.13). RRs of suicide per IQR increase in PM, PM, and NO were 1.02 (95% CI: 1.00, 1.05), 1.01 (95% CI: 1.00, 1.03), and 1.03 (95% CI: 1.00, 1.07). O, SO, and CO were not associated with suicide. RR of suicide was significantly higher in higher-income than lower-income countries (1.09, 95% CI: 1.07, 1.11 and 1.20, 95% CI: 1.14, 1.26 per 7.1 °C increased temperature, respectively). Suicide risks associated with air pollution did not significantly differ by income level, national suicide rates, or average exposure levels. Research gaps were found for interactions between air pollution and temperature on suicide risks.
Topics: Air Pollutants; Air Pollution; Environmental Exposure; Humans; Nitrogen Dioxide; Ozone; Particulate Matter; Sulfur Dioxide; Temperature
PubMed: 34300149
DOI: 10.3390/ijerph18147699 -
International Journal of Environmental... Apr 2023The present systematic review is aimed at evaluating the diuretic effects determined according to the natural mineral water consumption on healthy individuals. This... (Review)
Review
The present systematic review is aimed at evaluating the diuretic effects determined according to the natural mineral water consumption on healthy individuals. This systematic review has been performed following the guidelines of the PRISMA (preferred reporting items for systematic reviews and meta-analyses) Statement, investigating PubMed, Scopus, Web of Science and Cochrane Library from inception to November 2022. Studies performed both on animals and on humans were considered. After screening, a total of 12 studies have been identified. Of these, 11 studies were performed in Italy and 1 in Bulgaria. The time range of publication is very wide, ranging from 1962 to 2019 for human studies and from 1967 to 2001 for animal studies. All the included studies found an increase in diuresis determined according to the consumption of natural mineral water, in some cases after just one administration of the tested water. However, the quality of the studies is not so high, especially for the research conducted many years ago. Thus, it would be desirable to carry out new clinical studies using more appropriate methodological approaches and more refined methods of statistical data processing.
Topics: Humans; Mineral Waters; Diuresis; Bulgaria; Italy
PubMed: 37107810
DOI: 10.3390/ijerph20085527 -
Cells Apr 2023Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline -oxide (ANO) is...
Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline -oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with -acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial-mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.
Topics: Arecoline; Cyclic N-Oxides; Mouth Neoplasms; Carcinogenesis; Humans; Animals; Mice; Areca; Oxygenases; Oxidation-Reduction; Acetylcysteine; Epigenesis, Genetic; Carcinogens
PubMed: 37190117
DOI: 10.3390/cells12081208 -
The Journal of Hospital Infection Sep 2023This systematic review and network meta-analysis (NMA) comprehensively compared the effectiveness of different mouth rinses in reducing the viral load/infectivity of... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This systematic review and network meta-analysis (NMA) comprehensively compared the effectiveness of different mouth rinses in reducing the viral load/infectivity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (Part I), alleviating clinical symptoms or severity of disease (Part II), and decreasing the incidence of SARS-CoV-2 infection (Part III).
METHODS
Randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs) with restrictions were searched up to 3 March 2023. Twenty-three studies (22 RCTs and one NRCT) met the inclusion criteria for this systematic review.
RESULTS
Five RCTs (454 patients and nine interventions) in Part I were eligible for NMA. The NMA results showed that, in comparison with no rinse, sodium chloride (NaCl) was the most effective mouth rinse for reducing the viral load, followed by povidone-iodine (PVP-I), ß-cyclodextrin + citrox (CDCM), hydrogen peroxide (HP), chlorhexidine gluconate (CHX), cetylpyridinium chloride (CPC), placebo and hypochlorous acid (HClO). However, these results were not significant. Based on surface under the cumulative ranking curve scores, PVP-I was likely to be the most efficacious mouth rinse for reducing SARS-CoV-2 viral load, followed by CDCM, HP, NaCl, CHX, CPC, placebo, no rinse and HClO.
CONCLUSION
Due to heterogeneity of the primary studies, the effectiveness of different mouth rinses to reduce viral infectivity, improve clinical symptoms or prevent SARS-CoV-2 infection remains inconclusive.
Topics: Humans; COVID-19; Mouthwashes; Povidone-Iodine; SARS-CoV-2; Sodium Chloride; Network Meta-Analysis; Hydrogen Peroxide; Mouth
PubMed: 37419189
DOI: 10.1016/j.jhin.2023.06.022 -
EBioMedicine Dec 2022A growing number of studies have reported an increased risk of cardiovascular disease (CVD) and respiratory disease (RD) within hours after exposure to ambient air... (Meta-Analysis)
Meta-Analysis
A systematic review and meta-analysis of intraday effects of ambient air pollution and temperature on cardiorespiratory morbidities: First few hours of exposure matters to life.
BACKGROUND
A growing number of studies have reported an increased risk of cardiovascular disease (CVD) and respiratory disease (RD) within hours after exposure to ambient air pollution or temperature. We assemble published evidence on the sub-daily associations of CVD and RD with ambient air pollution and temperature.
METHODS
Databases of PubMed and Web of Science were searched for original case-crossover and time-series designs of English articles examining the intra-day effects of ambient air pollution [particulate matter with aerodynamic diameter ≤2.5 μm (PM), ≤10 μm (PM), 2.5-10μm (PM), and < 7 μm (SPM), O, SO, NO, CO, and NO] and temperatures (heat and cold) on cardiorespiratory diseases within 24 h after exposure in the general population by comparing with exposure at different exposure levels or periods. Meta-analyses were conducted to pool excess risks (ERs, absolute percentage increase in risk) of CVD and RD morbidities associated with an increase of 10 μg/m in particulate matters, 0.1 ppm in CO, and 10 ppb in other gaseous pollutants.
FINDINGS
Final analysis included thirty-three papers from North America, Europe, Oceania, and Asia. Meta-analysis found an increased risk of total CVD morbidity within 3 h after exposure to PM [ER%: 2.65% (95% CI: 1.00% to 4.34%)], PM [0.31% (0.02% to 0.59%)], O [1.42% (0.14% to 2.73%)], and CO [0.41% (0.01% to 0.81%)]. The risk of total RD morbidity elevated at lag 7-12 h after exposure to PM [0.69% (0.14% to 1.24%)] and PM [0.38% (0.02% to 0.73%)] and at lag 12-24 h after exposure to SO [2.68% (0.94% to 4.44%)]. Cause-specific CVD analysis observed an increased risk of myocardial infarction morbidity within 6 h after exposure to PM, PM, and NO, and an increased risk of out-of-hospital cardiac arrest morbidity within 12 h after exposure to CO. Risk of total CVD also increased within 24 h after exposure to heat.
INTERPRETATION
This study supports a sudden risk increase of cardiorespiratory diseases within a few hours after exposure to air pollution or heat, and some acute and highly lethal diseases such as myocardial infarction and cardiac arrest could be affected within a shorter time.
FUNDING
The National Natural Science Foundation of China (Grant No. 42105165; 81773518), the High-level Scientific Research Foundation of Anhui Medical University (Grant No. 0305044201), and the Discipline Construction of Anhui Medical University (Grant No. 0301001836).
Topics: Humans; Temperature; Nitrogen Dioxide; Air Pollutants; Air Pollution; Particulate Matter; Respiratory Tract Diseases; Morbidity; Myocardial Infarction; China; Environmental Exposure
PubMed: 36323182
DOI: 10.1016/j.ebiom.2022.104327 -
Neuropsychopharmacology : Official... Jun 2022White-matter abnormalities, including increases in extracellular free-water, are implicated in the pathophysiology of schizophrenia. Recent advances in diffusion... (Meta-Analysis)
Meta-Analysis
White-matter abnormalities, including increases in extracellular free-water, are implicated in the pathophysiology of schizophrenia. Recent advances in diffusion magnetic resonance imaging (MRI) enable free-water levels to be indexed. However, the brain levels in patients with schizophrenia have not yet been systematically investigated. We aimed to meta-analyse white-matter free-water levels in patients with schizophrenia compared to healthy volunteers. We performed a literature search in EMBASE, MEDLINE, and PsycINFO databases. Diffusion MRI studies reporting free-water in patients with schizophrenia compared to healthy controls were included. We investigated the effect of demographic variables, illness duration, chlorpromazine equivalents of antipsychotic medication, type of scanner, and clinical symptoms severity on free-water measures. Ten studies, including five of first episode of psychosis have investigated free-water levels in schizophrenia, with significantly higher levels reported in whole-brain and specific brain regions (including corona radiata, internal capsule, superior and inferior longitudinal fasciculus, cingulum bundle, and corpus callosum). Six studies, including a total of 614 participants met the inclusion criteria for quantitative analysis. Whole-brain free-water levels were significantly higher in patients relative to healthy volunteers (Hedge's g = 0.38, 95% confidence interval (CI) 0.07-0.69, p = 0.02). Sex moderated this effect, such that smaller effects were seen in samples with more females (z = -2.54, p < 0.05), but antipsychotic dose, illness duration and symptom severity did not. Patients with schizophrenia have increased free-water compared to healthy volunteers. Future studies are necessary to determine the pathological sources of increased free-water, and its relationship with illness duration and severity.
Topics: Anisotropy; Antipsychotic Agents; Brain; Diffusion Magnetic Resonance Imaging; Female; Humans; Schizophrenia; Water; White Matter
PubMed: 35034098
DOI: 10.1038/s41386-022-01272-x