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Joana Gameiro,1 José Agapito Fonseca,1 Joana Monteiro Dias,1 Maria João Melo,1 Sofia Jorge,1 José Velosa,2 José António Lopes1 1Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, Lisboa, Portugal; 2Department of Gastroenterology and Hepatology, Centro Hospitalar Lisboa Norte, Lisboa, Portugal Introduction: Acute kidney injury (AKI) is common in hospitalized patients with cirrhosis and is associated with poor prognosis. A risk prediction score combining values easily measured at admission could be valuable to stratify patients for prevention, monitoring and early intervention, ultimately improving patient care and outcomes. The aim of this study was to develop a risk score for AKI in a cohort of cirrhotic patients. Patients and methods: We cross-examined the data from a retrospective analysis of 186 patients with cirrhosis admitted to the Gastroenterology and Hepatology Service of Centro Hospitalar Lisboa Norte from January 2003 to December 2005. AKI was defined as an increase in serum creatinine (SCr)≥0.3 mg/dL within 48 hours or a percentage increase in SCr≥50% from baseline. Neutrophil-to-lymphocyte ratio (NLR) was used as a marker for inflammation. A receiver operating characteristic (ROC) curve was produced to assess the discriminative ability of the variables. Cutoff values were defined as those with highest validity. The final AKI risk score model was assessed using the ROC curve. Results: A total of 52 patients (28%) developed AKI. Higher baseline SCr (p

Acute kidney injury (AKI) is characterized by a rapid decline of renal function associated with worse outcomes. The purpose of the authors is to perform a critical review of the incidence, risk factors, pathogenesis and outcome of AKI in HIV‐infected patients. Human immunodeficiency virus (HIV)‐infected patients have an increased risk of developing AKI, to which contribute both HIV‐dependent and HIV‐independent factors as well as the nephrotoxicity of drugs used. The increased risk of AKI in HIV‐infected patients and its negative impact on prognosis highlights the need for identification of patients at risk, creation of prevention strategies and management. HIV‐infected patients have an increased risk of developing AKI, to which both HIV‐dependent and HIV‐independent factors contribute, as well as the nephrotoxicity of drugs used. The increased risk of AKI in HIV‐infected patients and its negative impact on prognosis highlight the need for identification of patients at risk, creation of prevention strategies and management. [ABSTRACT FROM AUTHOR]

Fábio Marcon Alfieri,1 Marcelo Riberto,2 Lucila Silveira Gatz,3 Carla Paschoal Corsi Ribeiro,4 José Augusto Fernandes Lopes,4 Linamara Rizzo Battistella41São Paulo Adventist University Center, São Paulo, 2Faculty of Medicine in Ribeirão Preto, University of São Paulo, 3Physical Educator, São Paulo, 4School of Medicine, Institute of Physical Medicine and Rehabilitation, Clinics Hospital of University of São Paulo, São Paulo, BrazilObjective: The objective of this study was to analyze the efficacy of multisensory versus muscle strengthening to improve postural control in healthy community-dwelling elderly.Participants: We performed a single-blinded study with 46 community-dwelling elderly allocated to strength (GS, n = 23; 70.18 ± 4.8 years 22 women and 1 man) and multisensory exercises groups (GM, n = 23; 68.8 ± 5.9 years; 22 women and 1 man) for 12 weeks.Methods: We performed isokinetic evaluations of muscle groups in the ankle and foot including dorsiflexors, plantar flexors, inversion, and eversion. The oscillation of the center of pressure was assessed with a force platform.Results: The GM group presented a reduction in the oscillation (66.8 ± 273.4 cm2 to 11.1 ± 11.6 cm2; P = 0.02), which was not observed in the GS group. The GM group showed better results for the peak torque and work than the GS group, but without statistical significance.Conclusion: Although the GM group presented better results, it is not possible to state that one exercise regimen proved more efficacious than the other in improving balance control.Keywords: postural control, aging, exercise, multisensory, strengthening

This study investigated whether chronic undernutrition alters the mitochondrial structure and function in renal proximal tubule cells, thus impairing fluid transport and homeostasis. We previously showed that chronic undernutrition downregulates the renal proximal tubules (Na + +K + )ATPase, the main molecular machine responsible for fluid transport and ATP consumption. Male rats received a multifactorial deficient diet, the so-called Regional Basic Diet (RBD), mimicking those used in impoverished regions worldwide, from weaning to a juvenile age (3 months). The diet has a low content (8 %) of poor-quality proteins, low lipids, and no vitamins compared to control (CTR). We investigated citrate synthase activity, mitochondrial respiration (oxygraphy) in phosphorylating and non-phosphorylating conditions with different substrates/inhibitors, potential across the internal membrane (Δψ), and anion superoxide/H 2 O 2 formation. The data were correlated with ultrastructural alterations evaluated using transmission electron microscopy (TEM) and focused ion beam scanning electron microscopy (FIB-SEM). Citrate synthase activity decreased (∼50 %) in RBD rats, accompanied by a similar reduction in respiration in non-phosphorylating conditions, maximum respiratory capacity, and ATP synthesis. The Δψ generation and its dissipation after carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone remained unmodified in the survival mitochondria. H 2 O 2 production increased (∼100 %) after Complex II energization. TEM demonstrated intense matrix vacuolization and disruption of cristae junctions in a subpopulation of RBD mitochondria, which was also demonstrated in the 3D analysis of FIB-SEM tomography. In conclusion, chronic undernutrition impairs mitochondrial functions in renal proximal tubules, with profound alterations in the matrix and internal membrane ultrastructure that culminate with the compromise of ATP supply for transport processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study proposes a novel non-linear modelling approach to predict the dissolution profiles of extended-release tablets, by combining a full-factorial design, curve fitting to the dissolution profiles, and artificial neural networks (ANN), with linear regression methods, partial least squares (PLS) and multiple linear regression (MLR) as benchmarks. Hydroxypropylmethylcellulose (HPMC) and carboxymethylcellulose (CMC) grades, active pharmaceutical ingredient (API) lubrication, and compression force were chosen as DoE factors. The resulting batches were tested to obtain their corresponding dissolution profile, and a first-order dissolution equation was fitted to each profile. ANN, PLS and MLR were used to model and predict the tablet-specific constant k which then served to simulate dissolution profiles. This study demonstrates how non-linear methods, specifically ANN, outperform traditional linear models in predicting the complex interactions affecting drug release from extended-release formulations., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hyperkalemia is a potentially life-threatening condition frequently encountered in clinical practice, particularly among patients with chronic kidney disease, heart failure, diabetes, and hypertension and those undergoing treatment with renin-angiotensin-aldosterone system inhibitors (RAASi). The management of chronic and acute hyperkalemia is complex and requires timely intervention to prevent severe complications such as cardiac arrhythmias and sudden death. Traditional therapeutic approaches to chronic hyperkalemia, including dietary potassium restriction, use of diuretics, and administration of cation-exchange resins like sodium polystyrene sulfonate, often suffer from limitations like gastrointestinal side effects, variable efficacy, delayed onset of action, and RAASi treatment discontinuation. In recent years, the development of new potassium binders, specifically patiromer and sodium zirconium cyclosilicate (SZC), has revolutionized the management of hyperkalemia. Patiromer, a non-absorbed polymer, binds potassium in the gastrointestinal tract in exchange for calcium, thus facilitating its excretion. SZC operates by exchanging sodium and hydrogen ions for potassium, leading to efficient potassium removal. Both agents have demonstrated rapid and sustained reductions in serum potassium levels, coupled with favorable safety and tolerability profiles, in multiple clinical trials. This review article, authored by a multidisciplinary group of Portuguese experts in hyperkalemia management, provides an in-depth analysis of the efficacy and safety of current therapeutic strategies and highlights the clinical potential of new potassium binders. The introduction of patiromer and SZC offers significant advantages over traditional therapies, providing effective and better-tolerated options for patients. The review highlights the role of these novel agents in contemporary hyperkalemia management and calls for ongoing research to further refine treatment protocols and improve patient outcomes., Competing Interests: Declarations. Ethics approval: Not applicable. Consent for publication: All the authors have read and approved the final version of the manuscript and gave their consent for publication. Competing interests: C.F received consultancy fees, lectures, or sponsorship of scientific meetings from AstraZeneca, Bayer, Bial, Boehringer Ingelheim, Novartis, Novo Nordisk, Pfizer, Roche Diagnosis, Servier, CSL Vifor, companies that research and commercialize drugs for the treatment of heart failure patients. G.C. received speaking fees from Servier, Novartis, CSL Vifor, and Boehringer. C.G. is employed by Fresenius Medical Care as Head of the Nutrition Department. G.S. received speaking fees from CSL Vifor, AstraZeneca, Alnylam and Baxter. I.M. received speaking fees from AstraZeneca, Bayer, Bial, CSL Vifor, Daiichi-Sankyo, Novartis, Pfizer, Roche Diagnostics, and Servier. I.M. served on advisory boards for AstraZeneca, Bayer, Bial, CSL Vifor, Novartis, Novo Nordisk, and Servier. A.F. received Advisory Board and consultancy fees, lectures, or sponsorship of scientific meetings from AstraZeneca, Astellas, CSL Vifor, Fresenius Medical Care, MSD-Merck Sharp & Dohme companies., (© 2024. The Author(s).)

The continuous feeding-mixing system ensures the composition uniformity down to the tableting continuous manufacturing line so that a quality end-product is consistently delivered. Near-infrared spectroscopy (NIRS) enables in-line assessment of the blend's critical quality attributes in real-time. In this study, the effect of total feed rate and impeller speed on the continuous blending process monitored in-line by NIRS was examined by principal component analysis (PCA), ANOVA simultaneous component analysis (ASCA) and partial least squares (PLS) regression. Process data were generated by a factorial experimental design with process parameters and a constant formulation comprised of: 30 % (wt/wt) ibuprofen, 67.5 % (wt/wt) microcrystalline cellulose, 2 % (wt/wt) of sodium starch glycolate and 0.5 % (wt/wt) of magnesium stearate. The PCA hinted at the prevalence of impeller speed effect on ibuprofen concentration due to path length variation of the NIR light caused by the fluidized behaviour in the powder blend as a result of high speed ranges (>300 rpm). The ASCA model indicated that while both impeller speed and total feed rate effects were statistically significant (p-value=0.004), the impeller speed was the factor that contributed the most to the spectral variance (55.5 %). The PLS regression model for the ibuprofen content resulted in a RMSECV of 1.3 % (wt/wt) and showed that impeller speed was yet again the factor that exerted the major influence on spectral variance, owing to its wavelength-dependent effect that prevents common pre-processing techniques from eliminating it across the entire NIR range. The best sample presentation to the NIR probe was achieved at low impeller speed ranges (<600 rpm) and low total feed rates (<15 kg/h), such that it enhanced the PLS model ability to predict the ibuprofen concentration in the blend., (Copyright © 2024. Published by Elsevier B.V.)

Background: Planning for vascular access (VA) creation is essential in pre-dialysis patients although optimal timing for VA referral and placement is debatable. Guidelines suggest referral when eGFR is 15-20 mL/min/1.73 m 2 . This study aimed to validate the use of kidney failure risk equation (KFRE) in VA planning., Methods: Retrospective analysis of all adult patients with CKD who were referred for first VA placement, namely AVF or AVG, at a tertiary center, between January 2018 and December 2019. The four-variable KFRE was calculated. Start of KRT, mortality, and VA placement were assessed in a 2-year follow-up. We used Cox regression to predict KRT start and calculated the ROC curve., Results: 256 patients were included and 64.5% were male, mean age was 70.4 ± 12.9 years and mean eGFR was 16.09 ± 10.43 mL/min/1.73 m 2 . One hundred fifty-nine patients required KRT (62.1%) and 72 (28.1%) died in the 2-year follow-up. The KFRE accurately predicted KRT start within 2-years (38.3 ± 23.8% vs 17.6 ± 20.9%, p  < 0.001; HR 1.05 95% CI (1.06-1.12), p  < 0.001), with an auROC of 0.788 ( p  < 0.001, 95% CI (0.733-0.837)). The optimal KFRE cut-off was >20%, with a HR of 9.2 (95% CI (5.06-16.60), p  < 0.001). Patients with KFRE ⩾ 20% had a significant lower mean time from VA consult to KRT initiation (10.8 ± 9.4 vs 15.6 ± 10.3 months, p  < 0.001). On a sub-analysis of patients with an eGFR < 20 mL/min/1.73 m 2 , a KFRE ⩾ 20% was also a significant predictor of 2-year start of KRT, with an HR of 6.61 (95% CI (3.49-12.52), p  < 0.001)., Conclusion: KFRE accurately predicted 2-year KRT start in this cohort of patients. A KFRE ⩾ 20% can help to establish higher priority patients for VA placement. The authors suggest referral for VA creation when eGFR < 20 mL/min/1.73 m 2 and KFRE ⩾ 20%., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Reliable vascular access (VA) is required for patients receiving chronic hemodialysis (HD) treatment. Vascular mapping using duplex doppler ultrasonography (DUS) can aid in planning VA construction. Greater handgrip strength (HGS) was found to be associated with more developed distal vessels both in chronic kidney disease (CKD) patients and healthy individuals, and patients with lower HGS had worse morphologic vessel characteristics and were, therefore, less likely to construct distal VA., Objectives: This study aims to describe and analyze clinical, anthropometric, and laboratory characteristics of patients who underwent vascular mapping prior to VA creation., Research Design: Prospective analysis., Subjects: Adult patients with CKD referred for vascular mapping, at a tertiary center, between March 2021 and August 2021., Measures: Preoperative DUS by a single experienced nephrologist was carried out. HGS was measured using a hand dynamometer, and PAD was defined as ABI < 0.9. Sub-groups were analyzed according to distal vasculature size (<2 mm)., Results: A total of 80 patients were included, with a mean age of 65.7 ± 14.7 years; 67.5% were male, and 51.3% were on renal replacement therapy (RRT). Twelve (15%) participants had PAD. HGS was higher in the dominant arm (20.5 ± 12.0 vs 18.8 ± 11.2 kg). Fifty-eight (72.5%) patients had vessels smaller than 2 mm in diameter. There were no significant differences between groups concerning demographics or comorbidities (diabetes, HTN, PAD). HGS was significantly higher in patients with distal vasculature greater than or equal to 2 mm in diameter (dominant arm: 26.1 ± 15.5 vs 18.4 ± 9.7 kg, p  = 0.010; non-dominant arm: 24.1 ± 15.3 vs 16.8 ± 8.6, p  = 0.008)., Conclusions: Higher HGS was associated with more developed distal cephalic vein and radial artery. Low HGS might be an indirect sign of suboptimal vascular characteristics, which might help predict the outcomes of VA creation and maturation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Rituximab (RTX) has been reported as an effective treatment alternative in primary forms of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) associated with steroid dependence and frequent relapses. However, the optimal RTX regimen and the outcomes of further doses of RTX remain unclear. This study aimed to evaluate the use of induction and maintenance RTX therapy for adults with primary podocytopathies., Methods: We performed a retrospective case series on adult patients with steroid-dependent podocytopathies who received an induction RTX therapy. Maintenance therapy was performed at physician's discretion. Remission and relapse rates, concomitant corticosteroids and immunosuppressants use, B-cell depletion and adverse events were analyzed., Results: Fourteen patients (mean age at start of RTX 29.1 ± 21.9 years) with MCD ( n = 7) or FSGS ( n = 7) were treated with 2 doses of 1,000 mg 2 weeks apart ( n = 13) or four doses of 375 mg/m 2 ( n = 1) of RTX. At last follow-up (mean 47.3 ± 101.7 months), 10 patients were in complete remission and two remained in partial remission. A reduction in the number of relapses, number of patients under corticosteroids and immunosuppressants, and dose of prednisolone was observed when compared to baseline (14 [100%] vs. 5 [35.7%]; 8/14 [57.1%] vs. 4/12 [33.3%]; 13/14 [92.9%] vs. 7/12 [58.3%]; 20 mg/day vs. 5.25 mg/day, respectively). Maintenance RTX therapy was used in 6 patients, with sustained complete remission. Infusion reactions were observed in 4 patients (one required treatment withdrawal)., Conclusions: Our findings support the use of RTX for a steroid-free remission in podocytopathies and suggest that maintenance RTX is well-tolerated and associated with prolonged remission. Further studies are needed to confirm its efficacy and safety and establish the optimal induction and maintenance RTX regimen in steroid-dependent podocytopathies., Competing Interests: There is no conflict of interest. The results presented in this paper have not been published previously in whole or part., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Pseudomonas aeruginosa poses a significant threat to immunocompromised individuals and those with cystic fibrosis. Treatment relies on antibiotics, but persistent infections occur due to intrinsic and acquired resistance of P. aeruginosa towards multiple classes of antibiotics. To date, there are no licensed vaccines for this pathogen, prompting the urgent need for novel treatment approaches to combat P. aeruginosa infection and persistence. Here we validated AAV vectored immunoprophylaxis as a strategy to generate long-term plasma and mucosal expression of highly protective monoclonal antibodies (mAbs) targeting the exopolysaccharide Psl (Cam-003) and the PcrV (V2L2MD) component of the type-III secretion system injectosome either as single mAbs or together as a bispecific mAb (MEDI3902) in a mouse model. When administered intramuscularly, AAV-αPcrV, AAV-αPsl, and AAV-MEDI3902 significantly protected mice challenged intranasally with a lethal dose of P. aeruginosa strains PAO1 and PA14 and reduced bacterial burden and dissemination to other organs. While all AAV-mAbs provided protection, AAV-αPcrV and AAV-MEDI3902 provided 100% and 87.5% protection from a lethal challenge with 4.47 × 10 7 CFU PAO1 and 87.5% and 75% protection from a lethal challenge with 3 × 10 7 CFU PA14, respectively. Serum concentrations of MEDI3902 were ~10× lower than that of αPcrV, but mice treated with this vector showed a greater reduction in bacterial dissemination to the liver, lung, spleen, and blood compared to other AAV-mAbs. These results support further investigation into the use of AAV vectored immunoprophylaxis to prevent and treat P. aeruginosa infections and other bacterial pathogens of public health concern for which current treatment strategies are limited., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To evaluate the effects of Lower Extremity - Constraint Induced Movement Therapy on gait function and balance in chronic hemiparetic patients., Methods: Randomized, controlled, single-blinded study. We recruited chronic post stroke patients and allocated them to Lower Extremity - Constraint Induced Movement Tharapy (LE-CIMT) or Control Group. The LE-CIMT group received this protocol 2.5 hour/day for 15 followed days, including: 1) intensive supervised training, 2) use of shaping as a strategy for motor training, and 3) application of a transfer package. The control group received conventional physiotherapy for 2.5 hours/day for 15 followed days. Outcomes were assessed at baseline, after the interventions, and after 6 months, through 6-minute walk test and Mini-Balance Evaluation Systems Test; 10-meter walk test, Timed Up and Go, 3-D gait analysis, and Lower Extremity - Motor Activity Log., Results: LE-CIMT was superior on the Assistance and confidence subscale of Lower Extremity - Motor Activity Log, Mini-BESTest and 6-minute walk test. The effect size for all outcomes was small when comparing both groups. LE-CIMT showed clinically significant differences in daily activities, balance, and gait capacity, with no clinically significant difference for spatiotemporal parameters., Conclusion: The LE-CIMT protocol had positive outcomes on balance, performance, and confidence perception.

Sepsis-associated kidney injury is common in critically ill patients and significantly increases morbidity and mortality rates. Several complex pathophysiological factors contribute to its presentation and perpetuation, including macrocirculatory and microcirculatory changes, mitochondrial dysfunction, and metabolic reprogramming. Recovery from acute kidney injury (AKI) relies on the evolution towards adaptive mechanisms such as endothelial repair and tubular cell regeneration, while maladaptive repair increases the risk of progression to chronic kidney disease. Fundamental management strategies include early sepsis recognition and prompt treatment, through the administration of adequate antimicrobial agents, fluid resuscitation, and vasoactive agents as needed. In septic patients, organ-specific support is often required, particularly renal replacement therapy (RRT) in the setting of severe AKI, although ongoing debates persist regarding the ideal timing of initiation and dosing of RRT. A comprehensive approach integrating early recognition, targeted interventions, and close monitoring is essential to mitigate the burden of SA-AKI and improve patient outcomes in critical care settings.

The parasite Leishmania (Viannia) braziliensis is widely distributed in Brazil and is one of the main species associated with human cases of different forms of tegumentary leishmaniasis (TL) such as cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML). The mechanisms underlying the pathogenesis of TL are still not fully understood, but it is known that factors related to the host and the parasite act in a synergistic and relevant way to direct the response to the infection. In the host, macrophages have a central connection with the parasite and play a fundamental role in the defense of the organism due to their ability to destroy intracellular parasites and present antigens. In the parasite, some intrinsic factors related to the species or even the strain analyzed are fundamental for the outcome of the disease. One of them is the presence of Leishmania RNA Virus 1 (LRV1), an endosymbiont virus that parasitizes some species of Leishmania that triggers a cascade of signals leading to a more severe TL phenotype, such as ML. One of the strategies for understanding factors associated with the immune response generated after Leishmania/host interaction is through the analysis of molecular patterns after infection. Thus, the gene expression profile in human monocyte-derived macrophages obtained from healthy donors infected in vitro with L. braziliensis positive (LbLRV1+) and negative (LbLRV1-) for LRV1 was evaluated. For this, the microarray assay was used and 162 differentially expressed genes were identified in the comparison LbLRV1+ vs. LbLRV1-, 126 upregulated genes for the type I and II interferons (IFN) signaling pathway, oligoadenylate synthase OAS/RNAse L, non-genomic actions of vitamin D3 and RIG-I type receptors, and 36 down-regulated. The top 10 downregulated genes along with the top 10 upregulated genes were considered for analysis. Type I interferon (IFNI)- and OAS-related pathways results were validated by RT-qPCR and Th1/Th2/Th17 cytokines were analyzed by Cytometric Bead Array (CBA) and enzyme-linked immunosorbent assay (ELISA). The microarray results validated by RT-qPCR showed differential expression of genes related to IFNI-mediated pathways with overexpression of different genes in cells infected with LbLRV1+ compared to LbLRV1- and to the control. No significant differences were found in cytokine levels between LbLRV1+ vs. LbLRV1- and control. The data suggest the activation of gene signaling pathways associated with the presence of LRV1 has not yet been reported so far. This study demonstrates, for the first time, the activation of the OAS/RNase L signaling pathway and the non-genomic actions of vitamin D3 when comparing infections with LbLRV1+ versus LbLRV1- and the control. This finding emphasizes the role of LRV1 in directing the host's immune response after infection, underlining the importance of identifying LRV1 in patients with TL to assess disease progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Felipin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The advancement of AAV vectors into clinical testing has accelerated rapidly over the past two decades. While many of the AAV vectors being utilized in clinical trials are derived from natural serotypes, engineered serotypes are progressing toward clinical translation due to their enhanced tissue tropism and immune evasive properties. However, novel AAV vectors require formulation and stability testing to determine optimal storage conditions prior to their use in a clinical setting., Results: Here, we evaluated the thermal stability of AAV6.2FF, a rationally engineered capsid with strong tropism for lung and muscle, in two different buffer formulations; phosphate buffered saline (PBS), or PBS supplemented with 0.001% non-ionic surfactant Pluronic F68 (PF-68). Aliquots of AAV6.2FF vector encoding the firefly luciferase reporter gene (AAV6.2FF-ffLuc) were incubated at temperatures ranging from -20°C to 55°C for varying periods of time and the impact on infectivity and particle integrity evaluated. Additionally, the impact of several rounds of freeze-thaw treatments on the infectivity of AAV6.2FF was investigated. Vector infectivity was measured by quantifying firefly luciferase expression in HEK 293 cells and AAV particle integrity was measured by qPCR quantification of encapsidated viral DNA., Conclusions: Our data demonstrate that formulating AAV6.2FF in PBS containing 0.001% PF-68 leads to increased stability and particle integrity at temperatures between -20℃ to 21℃ and protection against the destructive effects of freeze-thaw. Finally, AAV6.2FF-GFP formulated in PBS supplemented with 0.001% PF-68 displayed higher transduction efficiency in vivo in murine lung epithelial cells following intranasal administration than vector buffered in PBS alone further demonstrating the beneficial properties of PF-68., (© 2024. The Author(s).)

Wine aroma is one of the most frequently used and explored quality indicators. Typically, its assessment involves estimating the volatile composition of wine or highly trained assessors conducting sensory analysis. However, current methodologies rely on slow, expensive and complicated analytical procedures. Additionally, sensory evaluation is inherently subjective in nature. Therefore, the aim of this work is to verify the feasibility of using FTIR spectroscopy as a fast and easy methodology for the early detection of some of the most common off-odors in wines. FTIR spectroscopy was combined with partial least squares (PLS) regression for the simultaneous measurement of isoamyl alcohol, isobutanol, 1-hexanol, butyric acid, isobutyric acid, decanoic acid, ethyl acetate, furfural and acetoin. The precision and accuracy of developed calibration models (R 2 P > 0.90, range error ratio > 12.1 and RPD > 3.1) proved the ability of the proposed methodology to quantify the aforementioned compounds.

Background: Autologous hematopoietic stem cell transplant plays an important role in multiple myeloma (MM) treatment. Increasing incidence of MM and growing awareness of acute kidney injury (AKI) as a complication of hematopoietic stem cell transplant results in the need to better understand AKI in these patients. We aimed to evaluate incidence, risk factors and 5-year prognostic impact of AKI in MM patients undergoing autologous hematopoietic stem cell transplant., Methods: Retrospective cohort study. AKI was defined by the KDIGO classification using creatinine and urinary output criteria. We used survival analysis methods considering competing events for risk factors and disease-free survival, Cox proportional regression for overall survival and stepwise regression methods for multivariable models., Results: We analyzed data regarding 143 patients. The cumulative incidence of AKI and moderate-to-severe AKI was 49.7% and 14.1%, respectively. Factors with independent impact on AKI were obesity (HR: 1.83, 95% CI 1.07-3.11; p = 0.026), Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥ 2 (HR: 1.85, 95% CI 1.08-3.17), chronic kidney disease (CKD) (HR: 2.06, 95% CI 1.05-4.04), amyloidosis (HR: 2.25, 95% CI 1.25-4.06), mucositis grade 3-4 (HR: 2.19, 95% CI 1.25-3.86) and exposure to nephrotoxic drugs (HR: 2.0856, 95% CI 1.04-4.19). Moderate-to-severe AKI had an impact (HR: 1.62, 95% CI 1.15-2.31) on 5-year overall survival., Conclusion: Acute kidney injury affects almost half of MM patients undergoing autologous hematopoietic stem cell transplantation, and reduction in urinary output allows early diagnosis in almost a quarter of the patients. Obesity, HCT-CI ≥ 2, CKD, amyloidosis, mucositis grade 3-4 and exposure to nephrotoxic drugs are significant risk factors. Moderate-to-severe AKI is associated with lower 5-year overall survival., (© 2023. The Author(s).)

Introduction: Despite the efficacy of the COVID-19, the search for improvements in the management of severe/critical cases continues to be important. The aim is to demonstrate the kinetics of 4 serological markers in patients with COVID-19 who evolved in hypoxemia., Methods: From June to December 2020, the Health Secretariat of Rondônia State, Brazil, established a home medical care service team (HMCS) that provided clinical follow-up for health professionals and military personnel with COVID-19. The clinical and laboratory monitoring was individualized at home by a nursing and medical team. In addition to laboratory parameters, C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, and D-dimer levels were periodically taken to monitor the evolution of treatment., Results: Of 218 patients telemonitored, 48 patients needed special care by the HMCS team due to shortness of breath. Chest tomography showed multiple ground-glass shadows and lung parenchymal condensations that was compatible with secondary bacterial infection associated with leukocytosis, for which antibiotics were prescribed. The symptoms were accompanied by increases of CRP and IL-6 levels followed by fibrinogen after a few days, for which an anticoagulant therapy was included. Thirty-three patients evolved to improvements in clinical signs and laboratory results. Between the sixth and eighth day of illness, 15 patients presented signs of hypoxemia with low O 2 saturation accompanied with an increase in the respiratory rate, with some of them requiring oxygen therapy. As they did not present signs of clinical severity, but their laboratory markers showed an abrupt IL-6 peak that was higher than the increase in CRP and a new alteration in fibrinogen levels, they received a supplemental dose of anticoagulant and a high dose of corticosteroids, which resulted in clinical improvement., Conclusion: Our study demonstrates that monitoring of IL-6 and CRP may identify precocious hypoxemia in COVID-19 patients and prevented the progressive deterioration of the lung injury., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The Health Secretariat of Rondônia State provided the funding for the multidisciplinary home care service, supplies and medicines. The latter were provided by the Management and Pharmaceutical Assistance Coordination (CGAF). The State Laboratory of Pathologies and Clinical Analysis of Rondônia State (LEPAC) provided the laboratory markers for monitoring patients during subsequent daily follow-up. All the authors declare that there are no competing interests., (© The Author(s) 2024.)

Background: The first few months of hemodialysis (HD) are associated with a higher risk of mortality. Protein-energy malnutrition is a demonstrated major risk factor for mortality in this population. The C-Reactive Protein to Albumin ratio (CAR) has also been associated with increased mortality risk. The aim of this study was to determine the predictive value of CAR for six-month mortality in incident HD patients., Methods: Retrospective analysis of incident HD patients between January 2014 and December 2019. CAR was calculated at the start of HD. We analyzed six-month mortality. A Cox regression was performed to predict six-month mortality and the discriminatory ability of CAR was determined using the receiver operating characteristic (ROC) curve., Results: A total of 787 patients were analyzed (mean age 68.34 ± 15.5 years and 60.6% male). The 6-month mortality was 13.8% ( n  = 109). Patients who died were significantly older ( p  < 0.001), had more cardiovascular disease ( p  = 0.010), had central venous catheter at the start of HD ( p  < 0.001), lower parathyroid hormone (PTH) level ( p  = 0.014) and higher CAR ( p  = 0.015). The AUC for mortality prediction was 0.706 (95% CI (0.65-0.76), p  < 0.001). The optimal CAR cutoff was ≥ 0.5, HR 5.36 (95% CI 3.21-8.96, p  < 0.001)., Conclusion: We demonstrated that higher CAR was significantly associated with a higher mortality risk in the first six months of HD, highlighting the prognostic importance of malnutrition and inflammation in patients starting chronic HD.

Eligibility and indication for autologous hematopoietic stem cell transplantation (HSCT) in patients with lymphoma are increasing. Acute kidney injury (AKI) is a known complication of HSCT with studies including a miscellaneous of hematological diagnoses and using different definitions of AKI. We aimed to evaluate incidence, risk factors and prognostic impact of AKI post-HSCT in patients with lymphoma submitted to autologous HSCT using the KDIGO classification with both serum creatinine and urinary output criteria. We performed a single-center retrospective cohort study including patients with lymphoma admitted for autologous HSCT. We used survival analysis with competing risks to evaluate cumulative incidence of AKI, AKI risk factors and AKI impact on disease-free survival. We used Cox regression for impact of AKI on overall survival. We used backward stepwise regression to create multivariable models. A total of 115 patients were included. Cumulative incidence of AKI: 63.7% 100 d post-HSCT. First diagnosis criteria: creatinine in 54.8%, urinary output in 41.1% and both in 4.1%. AKI highest stage: 1 in 57.5%, 2 in 17.8% and 3 in 24.7%. Variables independently associated with higher incidence of AKI were: use of nephrotoxic drugs (HR: 2.87, 95% CI: 1.07-7.65; p  = 0.035), mucositis (HR: 1.95, 95% CI: 1.16-3.29; p  = 0.012) and shock (HR: 2.63, 95% CI: 1.19-5.85; p  = 0.017). Moderate to severe AKI was independently associated with lower overall survival (HR: 2.04, 95% CI: 1.06-3.94; p  = 0.033). No association with relapse nor progression to chronic kidney disease (CKD) was found. AKI affects almost two thirds of patients with lymphomas submitted to autologous HSCT. Nephrotoxic drugs, mucositis and shock are important independent AKI risk factors. More than one third of AKI episodes are moderate to severe and these are associated with lower overall survival.

Soil properties influence greatly the status of vine plants which consequently influences the quality of wine. Therefore, in the context of viticulture management, it is extremely important to assess the physical and chemical parameters of vineyards soils. In this study, the soils of two vineyards were analysed by near-infrared (NIR) spectroscopy and established analytical reference procedures. The main objective of this study was to verify if NIR spectroscopy is a potential tool to discriminate the soils of both vineyards as well as to quantify differences of soil's parameters. For that, a total of eight sampling spots were selected at each vineyard taking into consideration the soil type and sampled at different depths. The data analysis was performed using analysis of variance (ANOVA), principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) and partial least squares (PLS) regression. The ANOVA results revealed that 12 out of the 18 parameters analysed through the reference procedures can be considered statistically different (p < 0.05). Regarding PCA, the obtained results revealed a clear separation between the scores of both vineyards either considering NIR spectra or the chemical parameters. The PLS-DA model was able to obtain 100 % of correct predictions for the discrimination of both vineyards. PLS regression analysis using NIR spectra revealed R 2 P and RER values higher than 0.85 and 10, respectively, for 8 (pH (H 2 O), N, Ca 2+ , Mg 2+ , SB, CEC, ECEC and GSB) of the 18 chemical parameters evaluated. Concluding, these results demonstrate that it is possible to discriminate the soils of the different vineyards through NIR spectroscopy as well as to quantify several chemical parameters through soils NIR spectra in a rapid, accurate, cost-effective, simple and environmentally friendly way when compared to the reference procedures., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Although there are no approved countermeasures available to prevent or treat disease caused by Marburg virus (MARV), potently neutralizing monoclonal antibodies (mAbs) derived from B cells of human survivors have been identified. One such mAb, MR191, has been shown to provide complete protection against MARV in nonhuman primates. We previously demonstrated that prophylactic administration of an adeno-associated virus (AAV) expressing MR191 protected mice from MARV. Here, we modified the AAV-MR191 coding sequence to enhance efficacy and reevaluated protection in a guinea pig model. Remarkably, 4 different variants of AAV-MR191 provided complete protection against MARV, despite administration 90 days prior to challenge. Based on superior expression kinetics, AAV-MR191-io2, was selected for evaluation in a dose-reduction experiment. The highest dose provided 100% protection, while a lower dose provided ∼88% protection. These data confirm the efficacy of AAV-mediated expression of MR191 and support the further development of this promising MARV countermeasure., Competing Interests: Potential conflicts of interest. S. K. W. is an inventor on issued patents in Canada and United States for the AAV6.2FF capsid, which are owned by the University of Guelph, and licensed to Avamab Pharma, Inc. S. K. W. and B. T. are scientific founders of Avamab Pharma, Inc., a preclinical, prerevenue stage company dedicated to research and development of AAV gene therapies for the treatment and prevention of infectious diseases. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© 2023, The authors and His Majesty the King in Right of Canada, as represented by the Minister of Health, have joint ownership of copyright in this article.)

L-Amino acid oxidase (LAAO) is an enzyme found in snake venom that has multifaceted effects, including the generation of hydrogen peroxide (H 2 O 2 ) during oxidative reactions, leading to various biological and pharmacological outcomes such as apoptosis, cytotoxicity, modulation of platelet aggregation, hemorrhage, and neutrophil activation. Human neutrophils respond to LAAO by enhancing chemotaxis, and phagocytosis, and releasing reactive oxygen species (ROS) and pro-inflammatory mediators. Exosomes cellular nanovesicles play vital roles in intercellular communication, including immune responses. This study investigates the impact of Calloselasma rhodostoma snake venom-derived LAAO (Cr-LAAO) on human neutrophil exosome release, including activation patterns, exosome formation, and content. Neutrophils isolated from healthy donors were stimulated with Cr-LAAO (100 μg/mL) for 3 h, followed by exosome isolation and analysis. Results show that Cr-LAAO induces the release of exosomes with distinct protein content compared to the negative control. Proteomic analysis reveals proteins related to the regulation of immune responses and blood coagulation. This study uncovers Cr-LAAO's ability to activate human neutrophils, leading to exosome release and facilitating intercellular communication, offering insights into potential therapeutic approaches for inflammatory and immunological disorders.

This study was designed to characterize mice bone marrow (BM) and bone marrow-derived dendritic cells (BMDC) and to compare the surface markers expression and inflammatory cytokine liberation in response to LPS and Bothrops jararacussu venom (BjV) stimulation. Typical morphology was observed in BM and BMDCs from the 4th up to the 8th day of culture using recombinant mouse GM-CSF and IL-4. A high basal level of MHC-II, CD1d, CD83, CD11c, CD80, and low CD86 was expressed by BM cells. After stimulation with GM-CSF/IL-4 for BMDCs differentiation, the BM cells differentiated into BMDCs presented MHC-II, CD1d, CD83, CD11c, CD86, and CD80 expression on the 4th - 8th day accompanied with high levels of TNF-α liberated. The difference between the surface markers' expression was observed in this time course in which CD1d, CD11c, and CD80 remained in high levels of expression, while MHC-II and CD83 showed moderate expression during the differentiation period. Also, cytokines liberation was monitored over the period of the BMDCs culture, and on the 6th day, low levels of IL-6 and IL-1β were found, while high levels of TNF-α on the 4th and 8th days, both of which contributed to the maturity of the BMDCs. Maturation of DCs with LPS showed significant upregulation of surface markers (MHC-II, CD1d, CD83, CD86, CD80) and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) liberation. On the other hand, BjV induced a decrease in CD1d, CD11c, CD83, and CD86 expression in mature BMDCs which was not observed when LPS was used to stimulate BMDCs which probably induces impairment in T-cell activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Hematopoietic stem cell transplant (HSCT) is an important treatment option for hematologic malignancies. Acute kidney injury (AKI) is a common complication in HSCTs and is related to worse outcomes. We aimed to create a predictive risk score for AKI in HSCT considering variables available at the time of the transplant. We performed a retrospective cohort study. AKI was defined by the KDIGO classification using creatinine and urinary output criteria. We used survival analysis with competing events. Continuous variables were dichotomized according to the Liu index. A multivariable analysis was performed with a backward stepwise regression. Harrel's C-Statistic was used to evaluate the performance of the model. Points were attributed considering the nearest integer of two times each covariate's hazard ratio. The Liu index was used to establish the optimal cut-off. We included 422 patients undergoing autologous (61.1%) or allogeneic (38.9%) HSCTs for multiple myeloma (33.9%), lymphoma (27.3%), and leukemia (38.8%). AKI cumulative incidence was 59.1%. Variables eligible for the final score were: hematopoietic cell transplant comorbidity index ≥2 (HR: 1.47, 95% CI: 1.08-2.006; p = 0.013), chronic kidney disease (HR: 2.10, 95% CI: 1.31-3.36; p = 0.002), lymphoma or leukemia (HR: 1.69, 95% CI: 1.26-2.25; p < 0.001) and platelet-to-lymphocyte ratio > 171.9 (HR: 1.43, 95% CI: 1.10-1.86; p = 0.008). This is the first predictive risk score for AKI in patients undergoing HSCTs and the first study where the platelet-to-lymphocyte ratio is independently associated with AKI.

Background: Leafy vegetables represent an excellent dietary source of trace elements such as Fe and Zn. Nevertheless, Fe and Zn bioaccessibility can lessen due to a high concentration of anti-nutritional compounds. The encapsulation of Fe and Zn salts as granules could be used to fortify these leafy vegetables., Method: Three leafy vegetables, spinach, Swiss chard and Ethiopian mustard were fortified with iron sulfate and zinc sulfate as granules and free salts in order to test the improvements in the bioaccessibility and fulfillments of DRIs. Fe and Zn granules were prepared in a fluidized bed granulator. A probabilistic analysis was performed, using experimental data, to assess bioaccessible intake and fulfillments of DRIs in European populations., Results: Fe contents ranged between 4.8 mg/100 g of Ethiopian mustard to 157.4 mg/100 g of spinach. Fe and Zn bioaccessibility percentages were low for Swiss chard and spinach without fortification. Fortification with granules improved Fe bioaccessibility of these latter vegetables (196 and 223 mg/100 g). Zn contents in samples without fortification ranged between 2.3 mg/100 g for Ethiopian mustard and 7.4 mg/100 g for spinach. Zn fortification as granules improved Zn bioaccessibility for the three vegetables studied. Thus, Zn bioccessible concentrations ranged between 17.4 and 108 mg/100 g for the solubility assay and between 5.9 and 31.1 mg/100 g for the dialyzability assay. Besides, the probability analysis showed that fortification had a better performance in meeting DRIs for those populations with higher consumption levels of leafy vegetables., Conclusions: The probability analysis demonstrated that fortification can be a suitable strategy to meet DRIs for both trace elements, which was especially remarkable for Fe. Fortification with granule was more effective in most the cases, although for Ethiopian mustard, free salt of Fe showed a better performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Aphasia is a language disorder that occurs after brain injury and directly affects an individual's communication. The incidence of stroke increases with age, and one-third of people who have had a stroke develop aphasia. The severity of aphasia changes over time and some aspects of language may improve, while others remain compromised. Battery task training strategies are used in the rehabilitation of aphasics. The idea of this research is to use electroencephalography (EEG) as a non-invasive method, of electrophysiological monitoring, with a group of aphasic patients in rehabilitation process in a prevention and rehabilitation unit of the person with disabilities of the Unified Health System (SUS), of reference in the state of Bahia-Brazil. In this study, the goal is to analyze brain activation and wave frequencies of aphasic individuals during a sentence completion task, to possibly assist health professionals with the analysis of the aphasic subject's rehabilitation and task redefinition. We adopted the functional magnetic resonance imaging (fMRI) paradigm, proposed by the American Society for Functional Neuroradiology as a reference paradigm. We applied the paradigm in the group of aphasics with preserved comprehension, right hemiparesis, and left hemisphere injured or affected by stroke. We analyzed four electrodes (F3/F4 and F7/F8) corresponding to the left/right frontal cortex. Preliminary results of this study indicate a more robust activation in the right hemisphere (average of aphasics), with a difference of approximately 14% higher in Theta and Alpha frequencies, with 8% higher in low Beta (BetaL) and with approximately 1% higher in high Beta frequency (BetaH), Gamma frequency was higher by approximately 3% in the left hemisphere of the brain. The difference in electrical activation may be revealing to us a migration of language to the non-language dominant hemisphere. We point to possible evidence suggesting that EEG may be a promising tool for monitoring the rehabilitation of the aphasic subject., Competing Interests: The authors declare that they have no competing interests., (© 2023 Lima et al.)

In this study, an integrated flowsheet model of the continuous feeder-mixer system was calibrated, simulated and compared against experimental data. The feeding process was first investigated using two major components (ibuprofen and microcrystalline cellulose (MCC)), in a formulation comprised of: 30 wt% of ibuprofen, 67.5 wt% MCC, 2 wt% of sodium starch glycolate and 0.5 wt% of magnesium stearate. The impact of a refill on feeder performance was experimentally evaluated for different operating conditions. Results showed that it had no influence on feeder performance. While simulations with the feeder model fairly reproduced the material behaviour observed in the feeder, unintended disturbances were underpredicted due to the model's low complexity. Experimentally, mixer's efficiency was assessed based on ibuprofen residence time distribution. Mean residence time pointed to a higher mixer's efficiency at lower flow rates. Blend homogeneity results showed that for the entire set of experiments, ibuprofen RSD < 5%, irrespective of process variables. A feeder-mixer flowsheet model was calibrated, after regressing the axial model coefficients. The regression curves exhibited a R 2 above 0.96, whereas the RMSE varied from 1.58x10 -4 to 1.06x10 -3 s -1 across all fitted curves. Simulations confirmed that flowsheet model captured the powder dynamics inside the mixer and qualitatively predicted the mixer's filtering ability against feeding composition fluctuations, as well as ibuprofen RSD in blend, in line with real experiments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Bothrops venom contains a high amount of secreted phospholipase A 2 (sPLA 2 s) enzymes responsible for the inflammatory reaction and activation of leukocytes in cases of envenoming. PLA 2 s are proteins that have enzymatic activity and can hydrolyze phospholipids at the sn-2 position, thereby releasing fatty acids and lysophospholipids precursors of eicosanoids, which are significant mediators of inflammatory conditions. Whether these enzymes have a role in the activation and function of peripheral blood mononuclear cells (PBMCs) is not known. Here we show for the first time how two secreted PLA 2 s (BthTX-I and BthTX-II) isolated from the venom of Bothrops jararacussu affect the function and polarization of PBMCs. Neither BthTX-I nor BthTX-II exhibited significant cytotoxicity to isolated PBMCs compared with the control at any of the time points studied. RT-qPCR and enzyme-linked immunosorbent assays were used to determine changes in gene expression and the release of pro-inflammatory (TNF-α, IL-6, and IL-12) and anti-inflammatory (TGF-β and IL-10) cytokines, respectively, during the cell differentiation process. Lipid droplets formation and phagocytosis were also investigated. Monocytes/macrophages were labeled with anti-CD14, -CD163, and -CD206 antibodies to assay cell polarization. Both toxins caused a heterogeneous morphology (M1 and M2) on days 1 and 7 based on immunofluorescence analysis, revealing the considerable flexibility of these cells even in the presence of typical polarization stimuli. Thus, these findings indicate that the two sPLA 2 s trigger both immune response profiles in PBMCs indicating a significant degree of cell plasticity, which may be crucial for understanding the consequences of snake envenoming., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Se in the form of sodium selenite was microencapsulated by spray - drying and added to a food matrix (yogurt) to study the potential improvement of its bioaccessibility. Yogurt samples were also supplemented with Se in free salt form. Se-loaded microparticles were successfully prepared by spray-drying with production yields above 70%. The supplementation of yogurt with Se in the form of free sodium selenite had a low effect on improving the bioaccessibility of this micronutrient (1%). In turn, Se microencapsulation with mannitol or mannitol/gastro-resistant polymer (Eudragit®) had a strong impact on bioaccessibility results. After the gastric phase, Se bioaccessibility reached values of 21 and 40% for the microencapsulated formulations, respectively. This percentage rose to 55% at the end of intestinal phase, showing no differences between both formulations. Our results show the relevance of microencapsulation as an effective tool to improve the bioaccessibility of micronutrients when they are used in food supplementation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)