Search Results (61)

Background/Objectives: Arsenic (ARS) exposure is a major cause of kidney injury, driven by oxidative stress, inflammation, fibrosis, and apoptosis. This study evaluated the renoprotective effects of morin (MOR) and morin-loaded PLGA nanoparticles (MOR–PGNPs) against ARS-induced nephrotoxicity in rats. Methods: Sixty male Sprague Dawley rats were randomly allocated into six groups (n = 10 per group). The control group received corn oil. The MOR group received MOR (100 mg/kg), and the MOR–PGNPs group received the same dose of MOR encapsulated in PLGA nanoparticles. ARS was administered at 10 mg/kg for 14 days. Co-treated groups received ARS together with either MOR or MOR–PGNPs, with a 28 min interval between administrations. Renal function markers (serum urea, creatinine, uric acid, renal KIM-1), oxidative stress and antioxidant parameters (Nrf2/HO-1, CAT, SOD, GPx, ROS, MDA), inflammatory mediators (TLR4/NF-κB, TNF-α, IL-6, IL-1β), fibrotic markers (TGF-β1, fibronectin), and apoptotic proteins (caspase-3, caspase-8, Bax, Bcl-2) were assessed, alongside histopathological and ultrastructural evaluations. Results: ARS exposure significantly impaired renal function, increased KIM-1, suppressed Nrf2/HO-1 signaling, reduced antioxidant enzyme activities, and elevated ROS and MDA levels. It also activated TLR4/NF-κB signaling, upregulated pro-inflammatory cytokines and fibrotic markers, and increased pro-apoptotic proteins while downregulating Bcl-2. MOR co-treatment partially ameliorated these alterations. MOR–PGNPs produced potentially enhanced protection, restoring kidney function markers, enhancing antioxidant defenses, and markedly attenuating inflammation, fibrosis, and apoptosis. Histopathological and ultrastructural analyses confirmed preservation of glomerular and tubular architecture, mitochondrial integrity, and minimal cytoplasmic vacuolization in the MOR–PGNPs group. Conclusions: MOR–PGNPs at 100 mg/kg effectively mitigated ARS-induced renal damage through antioxidant, anti-inflammatory, antifibrotic, and anti-apoptotic mechanisms, supporting PLGA-based morin nanoparticles as a promising and safe renoprotective strategy. Full article

Polygonum capitatum (PC) is an ethnomedicine with reported antibacterial and anti-inflammatory activities and has been clinically used in urinary tract infection (UTI)-related disorders. However, its in vivo exposure characteristics and metabolically associated therapeutic mechanisms in acute pyelonephritis (AP) remain insufficiently understood. To address this issue, this study aimed to evaluate the therapeutic effects of PC in an Escherichia coli (E. coli)-induced rat model of AP and to explore constituents and metabolic pathways associated with its activity. Different PC extracts were screened for antibacterial and anti-inflammatory activities, and the 70% ethanol extract was selected for further study. Seven major compounds were quantified by HPLC. In AP rats, the pharmacokinetic profiles of these compounds in plasma and the renal cortex were analyzed by microdialysis-coupled HPLC-MS/MS. Pharmacodynamic evaluation included urinary bacterial load, urinalysis, renal function, inflammatory cytokines, and renal histopathology. Exploratory PK–PD analysis, untargeted renal metabolomics, and targeted metabolomics of the tryptophan–kynurenine (Trp–Kyn) pathway were also performed. The 70% ethanol extract of PC exhibited the strongest antibacterial and anti-inflammatory activities. The total content of seven active compounds was 3.85%, with gallic acid being the predominant compound (3.42%). Pharmacokinetic analysis revealed that gallic acid, protocatechuic acid, methyl gallate, and quercitrin achieved relatively high systemic exposure and renal distribution. In AP rats, the pharmacokinetic profiles of several compounds were altered, with increased plasma exposure of protocatechuic acid, vanillic acid, ethyl gallate, and syringic acid, while protocatechuic acid also showed higher exposure in the renal cortex. PC treatment reduced urinary bacterial load, improved renal function and urinalysis parameters, alleviated histopathological injury, and decreased inflammatory mediator levels, particularly in renal tissue. Exploratory PK–PD correlations were observed between several compounds and selected pharmacodynamic indicators. Metabolomic analysis suggested disturbances in glycerophospholipid metabolism and the Trp–Kyn pathway in AP rats, some of which were partially reversed after PC treatment. PC showed antibacterial and anti-inflammatory effects in AP rats. Gallic acid, protocatechuic acid, methyl gallate, and quercitrin may be candidate constituents associated with the therapeutic effects of PC, while modulation of glycerophospholipid metabolism and the Trp–Kyn pathway may be involved in its action against AP. These findings provide preclinical pharmacological evidence supporting the therapeutic potential of PC in AP. Full article

Acute kidney injury (AKI) is a frequent complication in critically ill patients and is associated with high morbidity, mortality, and an increased risk of progression to chronic kidney disease (CKD). In this context, nutritional management represents a key component of supportive therapy, as AKI is commonly characterized by hypercatabolism, negative nitrogen balance, and protein-energy wasting. Current nutritional strategies primarily focus on the quantity of protein intake required to compensate for catabolic losses, particularly in patients undergoing renal replacement therapy (RRT). However, growing evidence suggests that the quality and metabolic effects of dietary protein sources may also influence renal physiology and recovery. Plant-based proteins have recently gained attention as a potentially advantageous nutritional strategy in kidney disease. Compared with animal-derived proteins, plant-based proteins are associated with a lower dietary acid load, reduced production of gut-derived uremic toxins, and beneficial effects on the intestinal microbiota. In addition, their amino acid profile may modulate oxidative stress, inflammatory pathways, and renal hemodynamics. These characteristics may contribute to a more favorable metabolic environment in patients with AKI, potentially supporting renal recovery and reducing the risk of AKI-to-CKD transition. This review examines the pathophysiological mechanisms linking protein metabolism, renal injury, and nutritional support in AKI. Particular attention is given to the role of plant-based proteins, their amino acid composition, and their potential nephroprotective effects. Understanding the interaction between dietary protein sources, metabolic pathways, and the gut–kidney axis may help guide future nutritional strategies aimed at improving outcomes in critically ill patients with AKI. Full article

Background/Objectives: This study examined the association between dietary acid load (DAL) and metabolic syndrome (MetS)-related parameters in Korean adults undergoing eating habit modification. Methods: Forty-eight Korean adults (≥19 years) with at least one MetS risk factor were recruited via public advertisement. Anthropometric and biochemical parameters, Nutrition Quotient (NQ) scores, and nutrient intake were assessed. The DAL was calculated and expressed as the potential renal acid load (PRAL) and the net endogenous acid production (NEAP). Results: Forty participants completed the 8-week intervention. Overall improvements were observed in total and domain-specific NQ scores, along with improvements in body composition, blood pressure, and glycemic parameters. Among all participants, the mean DAL scores did not change significantly after FDR correction, although the NEAP showed a modest non-significant decrease. Baseline PRAL and NEAP values did not differ between participants with and without MetS risk improvement. At weeks 4 and 8, DAL indices tended to decrease in the improved group and increase in the non-improved group, with a significant between-group difference observed only for the 8-week change in NEAP after FDR correction. While no significant associations were detected at baseline after FDR adjustment, cross-sectional associations between DAL indices and adiposity-related parameters were observed at week 8, particularly when DAL was expressed as NEAP. However, change-to-change analyses did not remain significant after FDR correction. Conclusions: In this exploratory study, DAL levels, especially NEAP, were associated with anthropometric and metabolic status at week 8; however, the absence of significant change-to-change correlations limits causal interpretation. Larger randomized controlled trials are needed to determine whether modification of DAL independently contributes to metabolic improvement (Trial registration number: KCT0011528). Full article

Background: While intravenous administration of nanoparticles (NPs) is effective for targeting the lungs and liver, directing them to other organs and tissues remains challenging. Methods: Here, we report alternative administration routes that improve organ-specific accumulation of poly (lactic-co-glycolic acid) (PLGA) NPs (100 nm, negatively charged) loaded with the near-infrared dye Cyanine 7 (Cy7). NP cytotoxicity was evaluated in HEK293, mMSCs, C2C12, L929, and RAW264.7 cells. Hemocompatibility was assessed using WBCs and RBCs. NPs were administered via the tail vein, carotid, renal, and femoral arteries in BALB/c mice. Administration safety was evaluated by laser speckle contrast imaging and histological analysis. NP biodistribution and accumulation were assessed using in vivo and ex vivo fluorescence tomography and confocal microscopy of cryosections. Results: PLGA-Cy7 NPs demonstrate low cytotoxicity even at high doses and exhibit good hemocompatibility. Administration of NPs through the mouse carotid, renal, and femoral arteries significantly increases accumulation in the target ipsilateral brain hemisphere (31.7-fold) and salivary glands (28.3-fold), kidney (13.7-fold), and hind paw (3.6-fold), respectively, compared to intravenous administration. Injection of NPs through arteries supplying the target organs and tissues does not result in significant changes in blood flow, morphological alterations, or irreversible embolization of vessels, provided the procedure is performed correctly and the optimal dosage is used. Conclusions: These results highlight the potential of intra-arterial delivery of NPs for organ-specific drug targeting, underscoring the synergistic impact of advances in materials science, minimally invasive endovascular surgery, and nanomedicine. Full article

Background: the primary challenge with implant infections is the formation of biofilm, which harbors dormant bacteria that reduce the effectiveness of antibiotics and amplify antibiotic resistance, exacerbating the global antimicrobial resistance crisis. A potential novel treatment strategy is radioimmunotherapy, which uses antibodies linked to radioisotopes to deliver targeted radiation to the bacteria and biofilm. We describe the first in vivo use of targeted radiation therapy, employing Actinium-225 (α-radiation) and Lutetium-177 (β-radiation) labeled antibodies to treat a Staphylococcus aureus biofilm-associated intramedullary implant infection. Untargeted radiation in the form of unbound radionuclide treatment was also evaluated. Methods: to assess therapeutic efficacy, bacterial counts were performed on implant and surrounding bone after seven days of follow-up. Biodistribution was evaluated using SPECT/CT and ex vivo gamma counting. Results: radioimmunotherapy using an antibody against wall teichoic acid which was labeled with Actinium-225 and Lutetium-177 achieved bacterial reductions between 45% and 93% on the implant and surrounding bone. Surprisingly, a similar antimicrobial effect was observed with unbound Actinium-225 treatment reducing the bacterial load by 80% on the implant and 98% in the surrounding bone. Indications of maximum tolerated dose (MTD) with Lutetium-177 labeled antibodies were observed through hepatic and renal function evaluations. Conclusions: These results should be interpreted in the context of the study’s constraints, particularly the limited animal sample size. Nonetheless, the results suggest that in vivo applied radiation may help reduce a biofilm-associated infection at the implant site as well as in the surrounding bone. These findings encourage further investigation into the use of targeted and non-targeted radiation, potentially combined with antibiotics, to develop effective strategies for eradicating biofilm-associated implant infections. Full article

Background: Dietary acid load (DAL) influences acid–base balance and has been implicated in chronic metabolic disorders. However, its association with excess weight (EW; overweight/obesity) remains insufficiently studied, particularly in Chinese populations with unique dietary patterns. Clarifying this relationship is crucial for guiding targeted nutritional strategies aimed at reducing obesity and associated metabolic risks in China. Methods: This cross-sectional study analyzed data from 7758 adults in the China Health and Nutrition Survey (CHNS), a multistage, stratified cluster survey. Dietary intake was evaluated using three consecutive 24 h recalls, and DAL was calculated using potential renal acid load (PRAL) and net endogenous acid production (NEAP). The relationship between DAL and EW was analyzed using multivariable logistic regression, with additional insights gained from subgroup analyses and restricted cubic spline (RCS) methods. Results: The final analysis encompassed 7758 individuals, among whom 3072 (39.6%) were diagnosed with EW. After adjusting for all relevant factors, a higher DAL was found to be significantly associated with an increased risk of EW. Individuals in the highest tertile experienced a 27% increased risk associated with PRAL (OR = 1.27, 95% CI: 1.09–1.48, p = 0.002) and a 14% increased risk associated with NEAP (OR = 1.14, 95% CI: 1.01–1.29, p = 0.029), demonstrating a consistent linear trend (p < 0.001). Subgroup analyses showed that the positive association between DAL and EW was particularly evident in men (PRAL: OR = 1.40, 95% CI: 1.12–1.76; NEAP: OR = 1.46, 95%: 1.14–1.85) and in participants younger than 60 years (PRAL: OR = 1.32, 95%CI: 1.11–1.58). Importantly, the association remained significant among individuals without diabetes, hypertension, or heart disease (PRAL: OR = 1.26, 95% CI: 1.08–1.47). RCS analysis further confirmed a linear dose–response relationship between DAL and EW risk. Conclusions: This study establishes a significant dose–response relationship between higher DAL and increased risk of EW in Chinese adults. These findings underscore the potential of diets with lower acid load, particularly those rich in fruits and vegetables, as a strategic approach to mitigating the obesity epidemic. Full article

Background/Objectives: Lipid nanoparticles (LNPs) have demonstrated notable clinical success as advanced drug delivery systems. However, the development of novel covalently bonded ionizable lipids faces substantial technical challenges, as their modification is difficult and they have a high molecular weight. To address this issue, we report the use of host–guest complexes in supramolecular chemistry as functional lipid motifs for constructing LNPs. Methods: Ionizable amine β-cyclodextrin (amine β-CD)-derived host–guest amphiphilic lipid molecules (HGLs) were designed for the construction of multi-stage assembly supramolecular LNPs (MSLNPs). The structure–function relationships and stability of MSLNPs were explored by screening eight types of amine β-CDs and varying the ratio of HGL to yolk phosphatidylcholine. Stability screening and molecular dynamics simulations were performed to clarify the self-assembly mechanisms and optimal formulations, followed by a systematic evaluation of delivery performance. Results: MSLNPs showed a high drug-loading efficiency (> 30%), a rapid-response release in acidic environments, and multi-pathway cellular uptake. In vivo delivery experiments using ethylenediamine β-CD-based MSLNPs in mice revealed no significant immunogenicity, no significant abnormalities in organs/tissues or their functions, a unique biodistribution pattern, and pronounced renal targeting. The successful development of MSLNPs with acidic pH-responsive control, a high delivery efficiency, and renal-targeting properties simplifies LNP preparation. Conclusions: This study offers novel insights into the design of simplified LNPs and the optimization of targeted delivery, with potential applications in renal disease therapy. Full article

Background: Albania is undergoing rapid nutrition transition, yet cardiometabolic (CM) risk in young adults is poorly characterized. We report baseline, cross-sectional findings from a WHO-aligned sentinel study examining diet, physical activity and early CM phenotypes, with fat quality examined as a modifiable exposure. Methods: Young adults recruited on campus (n = 262; median age, 21 years; 172 women, 90 men) underwent standardized anthropometry, seated blood pressure (BP) and fasting glucose (FG). Diet was assessed by two interviewer-administered 24 h recalls and activity outlined by the IPAQ-short form. We derived potential renal acid load (PRAL) and a MASLD-oriented nutrient score, computed a composite CM risk score (cCMRS: sex-standardized mean of WHtR, mean arterial pressure, FG) and fitted prespecified energy-partition models for isocaloric +5% of energy substitutions (SFA → PUFA; SFA → MUFA) with Benjamini–Hochberg false discovery rate (FDR) control. Results: Despite normal average BMI (23.4), risk clustering was common: elevated BP in 63% of men and 30% of women, impaired FG (100–125 mg/dL) in almost one third and central adiposity (WHtR ≥ 0.5) in 51% of men and 24% of women. Diets were SFA-rich (~17–19%E), sodium-dense and low in fiber and several micronutrients (e.g., vitamin D, folate, potassium). In isocaloric models, SFA → PUFA was associated with more favorable nutrient signatures: MASLD-oriented score −28% (p < 0.001; FDR-significant) and PRAL −33% (p = 0.007; FDR-borderline/suggestive). Conclusions: A waist-centric CM subphenotype—central adiposity co-occurring with upward BP shifts and intermittent dysglycemia—was detectable in young adults despite normal average BMI, against a background of poor diet quality and low activity. These baseline surveillance signals are not causal effects. Integration into routine with WHO-aligned NCD surveillance is feasible. Prospective follow-up (biomarker calibration, device-based activity, repeated waves) will refine inferences and inform scalable proactive prevention. Full article

Background/Objectives: Increasing evidence indicates that a vegetarian diet may provide renal protection and improve metabolic health in patients with chronic kidney disease (CKD). However, transitioning from an omnivorous to a vegetarian diet can be challenging. A more practical alternative could be to increase the consumption of plant protein. In this cross-sectional study, we investigated the association between increased plant protein intake and adherence to a low-protein diet (LPD) and the effect on biochemical parameters, body composition, and muscle strength in patients with non-dialysis CKD stages 3–5. Methods: The daily dietary intake of 377 patients, aged 68.5 ± 12.1 years, was evaluated using a quantitative food frequency questionnaire. Plant protein intake percentage was calculated as (daily plant protein intake/total protein intake) × 100%, and the potential renal acid load (PRAL) was estimated. A LPD was defined as a diet with a daily protein intake of <0.8 g/kg of body weight. Anthropometric measurements, body composition, and handgrip strength were assessed in a subgroup comprising 260 patients. The lean tissue index (LTI) and fat tissue index (FTI) were calculated by dividing lean mass and fat mass (kg) by the height in m², respectively. Results: Of the included 377 patients, 69.5% adhered to the LPD. Further, a 10% increase in plant protein intake was associated with a 20% increase in the likelihood of LPD adherence (OR, 1.20, 95% CI, 1.06 to 1.37), lower PRAL (β = −1.10 per 10% increase, 95% CI, −1.63 to −0.57), and higher serum bicarbonate levels (β = 0.24, 95% CI, 0.02 to 0.45). Analysis of the 260-patient subgroup revealed that a 10% increase in plant protein intake was associated with lower body mass index (β = −0.82, 95% CI, −1.05 to −0.59), FTI (β = −0.71, 95% CI, −1.01 to −0.40), waist circumference (β = −2.11, 95% CI, −2.80 to −1.41), hip circumference (β = −1.25, 95% CI, −1.75 to −0.75), waist-to-hip ratio (β = −0.91, 95% CI, −1.44 to −0.38), and waist-to-height ratio (β = −1.25, 95% CI, −1.71 to −0.80). There was no significant association between increased plant protein intake and LTI and handgrip strength. Conclusions: Increased intake of plant protein can reduce dietary acid load, alleviate metabolic acidosis, and potentially improve adiposity parameters without compromising lean mass and handgrip strength. Full article

Background/Objectives: Aging is a natural, gradual, and irreversible process associated with disruptions in homeostasis, causing several unfavorable changes, including changes in body composition. Some studies show that higher water intake can be related to a healthier body composition, but studies in older adults are rare. The aim of this study is to assess the relationship between water intake, dietary acid load, and body composition, and also to assess the interrelationship of these two factors with body composition in older women. Methods: This cross-sectional study involved 195 independently living women aged 65–84. Body composition was assessed using fan-beamed dual-energy X-ray absorptiometry (DXA). Potential renal acid load (PRAL) and water intake were evaluated using the 3-day food record method. Results: Higher water intake was associated with significantly lower android (p = 0.004), gynoid (p < 0.001), and total body fat mass (p = 0.005), as well as higher lean body mass (p = 0.021). Among the assessed anthropometric indicators, only for the appendicular lean mass (ALM) was there a significant difference between the “low-PRAL diet” compared to the “high-PRAL diet” (6.2 ± 0.8 vs. 6.0 ± 0.9 kg/m²; p = 0.045). A “low-PRAL diet” was characterized by a significantly lower energy value, lower protein intake, and a higher plant-to-animal protein ratio than a “high-PRAL diet”. Conclusions: A more acidifying diet pattern appeared to have an adverse effect on lean body mass in older women. The ratio of plant to animal protein may be crucial in this relationship. Full article

Chronic kidney disease (CKD) is a major global health challenge, significantly contributing to morbidity and mortality due to its strong association with cardiovascular complications, metabolic imbalances, and reduced quality of life. Among the various interventions for CKD management, nutrition therapy plays a critical role in slowing disease progression and improving patient outcomes. The Plant-Dominant Low-Protein Diet (PLADO) has emerged as a promising dietary strategy that prioritizes plant-based protein sources while restricting overall protein intake, offering potential renal, cardiovascular, and metabolic benefits. This review evaluates current evidence on the efficacy of PLADO in CKD management, analyzing its impact on renal function, cardiovascular health, and systemic inflammation. Key findings suggest that PLADO can delay CKD progression, reduce dialysis dependence, and mitigate cardiovascular risks through lower dietary acid load, increased fiber intake, and anti-inflammatory properties. Additionally, PLADO has been shown to support gut microbiota diversity and reduce uremic toxin production, offering metabolic advantages beyond kidney health. While PLADO appears nutritionally adequate, concerns remain regarding protein sufficiency, potassium management, and long-term adherence. Its successful implementation requires tailored meal planning, patient education, and regular clinical monitoring to optimize outcomes and mitigate potential risks. This review highlights the importance of integrating PLADO into CKD management as a holistic, patient-centered dietary approach, particularly in regions like Cyprus, where no studies have evaluated its applicability. By synthesizing existing research, this review provides insights for clinicians, dietitians, and researchers to further explore long-term outcomes, adherence strategies, and feasibility across diverse healthcare settings. Future studies should focus on large-scale randomized controlled trials (RCTs) to establish PLADO’s role in CKD dietary guidelines and clinical practice. Full article

Chronic kidney disease (CKD) is a global health crisis affecting over 10% of the population, with mortality rates increasing significantly. Current management strategies, including expensive medications and renal replacement therapies, highlight the need for cost-effective, conservative approaches. This review examines the evidence for plant-dominant low-protein diets (PLADO) in managing non-dialysis-dependent CKD. Existing guidelines for protein restriction in CKD vary considerably, with inconsistencies and a lack of personalization noted in the KDOQI and KDIGO recommendations. While traditional low-protein diet trials show limited success due to poor adherence and marginal benefits, PLADO offers a potentially more sustainable alternative. PLADO’s advantages include improved nutrient density, reduced dietary acid load, anti-inflammatory effects, and beneficial modulation of the gut microbiome, potentially reducing uremic toxins and improving cardiovascular health. However, challenges remain, including adherence issues, potential nutrient deficiencies, and potassium management. Although observational studies show promise, further large-scale randomized controlled trials are necessary to validate PLADO’s efficacy and establish optimal dietary composition. A personalized, multidisciplinary approach is essential for successful implementation and monitoring to maximize PLADO’s benefits in improving outcomes for individuals with NDD-CKD. Full article

Background: Dietary composition is one of the factors influencing the acid–base balance of the body by providing acid or base precursors. One of the methods for assessing the acid-forming potential of a diet is to calculate its potential renal acid load (PRAL). The aim of this study was to identify the sociodemographic, lifestyle, and health factors related to the PRAL. Methods: Dietary intake was assessed among 133 individuals aged 70+ years using the three-day record method. Results: The average PRAL value was 15.7 mEq/day (range from −42.4 to +101.7). The diets of a majority of the participants (71.4%) had acid-forming potential (PRAL > 0). From a univariate analysis, the acid-forming potential of the diets was linked mainly to women (65.3% in PRAL > 0 group vs. 10.5% in PRAL < 0 group), people using dietary supplements, those who consumed alcohol, those who assessed their health as being at least good, people with osteoporosis, those hospitalized during the previous year, and those with rather lower physical activity. Conclusions: From a multivariate analysis, gender was the strongest predictor of an acid-forming diet, but the following also contributed: an average self-rated health status (compared to good), a good health status (compared to poor), alcohol drinking, hospitalization, lack of nutritional knowledge, and, to a lesser extent, non-frail status (compared to pre-frail). Therefore, more extensive nutritional education in the identified groups is required. Full article

Background: Dietary acid load (DAL) is closely related to several chronic diseases. However, the link between DAL and chronic kidney disease (CKD) remains scarce and without data from the Chinese populations whose diet is quite different from people in Western countries. Methods: This study evaluated DAL by potential renal acid load (PRAL) and net endogenous acid production (NEAP). We clarified the relationship between DAL and CKD by logistic regression analysis based on data from the China Health and Nutrition Survey (CHNS). Results: The final analysis included 7699 individuals, of whom 811 (11.44%) were CKD patients. Although there was no notable link between PRAL and CKD, higher NEAP levels were independently correlated with CKD. As NEAP values rise, so does CKD prevalence. This trend remains highly significant even after adjustments. In subgroup analyses, the relationship between NEAP and CKD was more consistent in the elderly and subjects with a waistline of less than 82 cm and those without diabetes and heart disease. RCS analysis further confirmed the clear linear relationship between the OR of CKD and NEAP score. Conclusions: This study highlighted that higher NEAP was positively correlated with the risk of CKD. Full article