Influence of build direction, post-polymerization time, and aging on the fracture resistance and marginal and internal discrepancies of three-dimensional printed provisional crowns.

To evaluate the effect of build direction, post-polymerization time, and aging on the fracture resistance, failure mode, margin quality and Marginal (MD) and Internal Discrepancies (ID), and degree of conversion of tridimensional (3D) printed provisional crowns using the liquid crystal display technique (LCD). A left mandibular first molar was prepared and scanned. After, a full crown was designed (ExoCad) and exported to the LCD-printer software. One hundred and eighty crowns were printed at two build directions (30°, 90°) and post-polymerized for different periods (15, 30, 45 min). Half of the samples were aged (ST) in distilled water (37 °C/90 days). The marginal quality of the crowns was evaluated by the Schriwer method under a stereomicroscope (40x). The replica technique was used to measure the MD and ID and measured under a stereomicroscope (10x), through 20 reference points defined in 5 regions: Occlusal (O), Cusp (CP), Axial (AX), Chamfer (CH), and Finish Line (F). After, the crowns were cemented onto the respective dies using temporary cement and submitted to compression test (ISO150, 1 mm/min, 100 kgf).The failure mode was classified by Burke's fracture mode. The degree of conversion was evaluated through Fourier Transform Infrared Spectroscopy. The data (µm) of MD and ID and fracture resistance (N) were subjected to ANOVA (3 factors) and Tukey's test (5%); Weibull analysis was also performed for fracture resistance data (N). For MD, ID and fracture resistance ANOVA revealed that all factors (P < .001) were significant. For aged groups, the crowns printed at 30° showed lower MD (Tukey). The O_90_30 min (172.13A µm) and O_90_15 min (170.20A µm) groups showed the highest ID values. Higher resistance values were observed for the 30_45 min (844.30A N), 30_30 min (835.35A N), and 90_30 min (820.62A N) groups (Tukey). In the margin analysis, 98.6% of the crowns printed at 30° showed smooth margins without defects. The most prevalent fracture mode (41.7%) was Burke type 5. The degree of conversion (DC) increased with increasing post-polymerization time and aging. Printing provisional crowns at 30° provided lower crown MD and ID, as well as higher fracture resistance. A post-polymerization time of 30 min resulted in higher crown fracture resistance, while aging reduced the resistance of the crowns.

Effect of different surface treatments and adhesive cementation on the surface topography and flexural strength of translucent and ultra-translucent monolithic zirconia.

PURPOSE: To evaluate the effect of different surface treatments and adhesive cementation on the miniflexural strength (MFS) of monolithic zirconia. MATERIALS AND METHODS: Two-hundred and forty (240) sintered bars of translucent zirconia (ZT) and ultra-translucent zirconia (ZUT) were obtained (8 mm ×2 mm ×1 mm). The bars were divided into 16 groups (n = 15) according to the factors "Zirconia" (ZT and ZUT), "Cementation" (Cem) and "surface treatment" (Ctrl:Control, Al:Aluminum oxide/Al2O3 50 µm, Si:Silica/SiO2 coated alumina particles oxide 30 µm, Gl:Glazing+hydrofluoric acid). Half of the bars received an adhesive layer application, followed by application of resin cement and light curing. The surface roughness was measured in non-cemented groups. All the bars were subjected to the MFS test (1.0 mm/min; 100 kgf). Scanning electron microscopy was used for qualitative analyses. MFS data (MPa) and roughness (µm) were statistically evaluated by three-way and two-way ANOVA respectively and Tukey's test (5%). RESULTS: The surface treatment and the interaction were significant for roughness. Glazing promoted less roughness compared to silicatization. Regarding MFS, only the zirconia and surface treatment factors were significant. For ZT, the sandblasted groups had an increase in MFS and glazing reduced it. There was no difference between the groups without cementation for the ZUT; however, ZUT.Si/Cem, and ZUT.Al/Cem obtained superior MFS among the cemented groups. CONCLUSIONS: Sandblasting increases the flexural strength for ZT, while glaze application tends to reduce it. Applying resin cement increases the flexural strength of ZUT when associated with sandblasting. Sandblasting protocols promote greater surface roughness.

In Vivo Activity of Intestinal P-Glycoprotein and Hepatic Organic Anion Transporters Polypeptide in Pregnancy and Postpartum.

This study investigates the influence of pregnancy on the in vivo activity of the intestinal P-glycoprotein (P-gp) and hepatic organic anion transporters polypeptide (OATP/BCRP) using, respectively, fexofenadine and rosuvastatin as probe drugs. Eleven healthy participants were investigated during the third trimester of pregnancy (Phase 1, 28 to 38 weeks of gestation) and in the postpartum period (Phase 2, 8 to 12 weeks postpartum). In both phases, after administration of a single oral dose of fexofenadine (60 mg) and rosuvastatin (5 mg), serial blood samples were collected for up to 24 h. Rosuvastatin and fexofenadine in plasma were analyzed by LC-MS/MS using previously validated methods. The pharmacokinetic parameters of fexofenadine and rosuvastatin (Phoenix WinNonLin software) with normal distribution (Shapiro-Wilk test) are presented as geometric mean and 90% confidence interval. Phases 1 and 2 were compared using the t test (P < .05). Fexofexadine AUC0-24 values do not differ (P-value: .0715) between Phase 1 (641.9 ng h/mL [500.6-823.1]) and Phase 2 (823.8 ng h/mL [641.5-1057.6]) showing that pregnancy (third trimester) does not alter intestinal P-gp activity. However, rosuvastatin AUC0-24 values are higher (P-value: .00005) in Phase 1 (18.7 ng h/mL [13.3-26.4]) when compared to Phase 2 (9.5 ng h/mL [6.7-13.4]), suggesting inhibition of OATP1B1/OATP1B3 transporters. In conclusion, pregnancy assessed during the third trimester does not alter the intestinal P-gp activity but reduces the activity of hepatic OATP1B1/OATP1B3 transporters. Therefore, adjustments in dosage regimens may be necessary for drugs with low therapeutic index, substrates of the OATP1B1/OATP1B3 transporters, administered during the third trimester of pregnancy.

Accuracy, adaptation and margin quality of monolithic zirconia crowns fabricated by 3D printing versus subtractive manufacturing technique: A systematic review and meta-analysis of in vitro studies.

OBJECTIVE: The purpose of this systematic review and meta-analysis was to evaluate the accuracy (trueness and precision), marginal and internal adaptation, and margin quality of zirconia crowns made by additive manufacturing compared to subtractive manufacturing technology. METHODS: The investigation adhered to the PRISMA-ScR guidelines for systematic reviews and was registered at the Prospero database (n°CRD42023452927). Four electronic databases, including PubMed, Scopus, Embase, and Web of Science and manual search was conducted to find relevant studies published until September 2023. In vitro studies that assessed the trueness and precision, marginal and internal adaptation, and margin quality of printed crowns compared to milled ones were included. Studies on crowns over implants, pontics, temporary restorations, laminates, or exclusively experimental materials were excluded. RESULTS: A total of 9 studies were included in the descriptive reporting and 7 for meta-analysis. The global meta-analysis of the trueness (P<0.74,I2=90 %) and the margin quality (P<0.61,I2=0 %) indicated no significant difference between the root mean square of printed and milled zirconia crowns. The subgroup analysis for the printing system showed a significant effect (P<0.01). The meta-analysis of the crown areas indicated no significant difference in most of the areas, except for the marginal (favoring milled crowns) and axial (favoring printed crowns) areas. For precision and adaptation, both methods showed a clinically acceptable level. CONCLUSIONS: Additive manufacturing technology produces crowns with trueness and margin quality comparable to subtractive manufacturing. Both techniques have demonstrated the ability to produce crowns with precision levels, internal discrepancy, and marginal fit within clinically acceptable limits. CLINICAL SIGNIFICANCE: 3D printing emerges as a promising and potentially applicable alternative method for manufacturing zirconia crowns, as it shows trueness and margin quality comparable to restorations produced by the subtractive method.

The role of metabolic syndrome as a mediator in the relationship between CCL11 levels and the presence of a mood episode with mixed features in young adults with bipolar disorder.

Mixed features presentation in bipolar disorder (BD) represents the most severe form of the disease. BD may lead to cognitive and functional deterioration, a process known as neuroprogression, which appears to be exacerbated by increased serum levels of CCL11, a neuroprogression-related cytokine. Metabolic syndrome (MetS) is highly prevalent in BD, and it is known that the presence of MetS may increase inflammation, which may contribute to increased CCL11 levels, and consequently impact on the severity of the disorder. What is not known is whether the MetS mediates the association between CCL11 levels and the presence of mood episodes with mixed features in BD. Therefore, the aim of this study was to investigate the mediating effect of MetS on the relationship between CCL11 levels and the presence of mood episodes with mixed features in BD, in a population-based study. This is a cross-sectional study that included 184 young adults, 92 with BD and 92 populational controls, matched by sex and age. BD diagnosis was assessed using the Mini International Neuropsychiatric Interview - PLUS. Mood episodes with mixed features was defined according to DSM-IV and DSM-5 criteria. MetS was defined according to the National Cholesterol Education Program (NCEP/ATP III). Substance use was assessed through the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). CCL11 serum levels were analyzed using the multiplex analysis method Luminex 200™ system. The mediation model was tested using the MedMod module of the JAMOVI 2.4.8 software. Mediation analysis indicated a trend towards significance of MetS mediating the association between CCL11 and the presence of a mood episode with mixed features in BD (p = 0.065). Individuals with BD presenting with a mood episode with mixed features and MetS may have accelerated neuroprogression due to the influence of MetS on CCL11 levels, therefore, assessing for MetS occurrence in this population and implementing early interventions to prevent its development may be effective ways of delaying cognitive impairments related to this cytokine.

Exploring protective factors in a high-risk subsample: the pivotal role of paternal support in preventing depression in a cohort of young adults.

BACKGROUND: Major depressive disorder (MDD) is a global concern due to its widespread prevalence and morbidity. Identifying protective factors in high-risk individuals, including those with a familial predisposition, maltreatment history, and socio-economic vulnerabilities, is crucial. METHODS: We assessed a high-risk subsample within a young adult population cohort (n = 791; mean age = 31.94 [SD = 2.18]) across three waves. Using multiple regression models to analyse higher education, feeling supported, spirituality, psychotherapy access, higher socioeconomic status, involvement in activities, cohabitation, and family unity in Waves 1 and 2, and their association with MDD resilience at Wave 3. RESULTS: In the high-risk group, MDD incidence was 13.7% (n=24). Paternal support had a protective effect on MDD incidence (OR = 0.366; 95% CI [0.137 to 0.955], p = 0.040) and suicidal attempt risk (OR = 0.380; 95% CI [0.150 to 0.956], p = 0.038). Higher resilience scores were also protective (OR = 0.975; 95% CI [0.953 to 0.997], p = 0.030), correlating with reduced BDI (r = 0.0484; B = -0.2202; 95% CI [-0.3572 to -0.0738]; p = 0.003) and MADRS scores (r = 0.0485; B = -0.2204; 95% CI [-0.3574 to -0.0741]; p = 0.003). CONCLUSIONS: Our paper emphasizes reorienting the MDD approach, focusing on positive prevention strategies. It highlights fathers' crucial role in family-based interventions and promoting resilience in high-risk populations.

Effect of ZrO2 paste, surface treatments, and storage on Weibull characteristics and resin bond strength to zirconia.

The objective is to evaluate the effect of different surface treatments and storage on the shear strength of ultratranslucent zirconia. 36 blocks of ultra-translucent zirconia were fabricated (7x7x2mm) and sintered. Then, divided into 12 groups according to the "surface treatment" (C -Primer; Al -Sandblasting with Al2O3 + Primer; Si -Silicate + Primer; Gl -Glaze + HF + Primer; Z -Zirlink; Zp -Zirlink + Primer) and "storage" factors (ST-with 150 days/37º and without). After surface treatment, five cylinders (Ø=2mm; h=2.0mm) of resin cement (n=15) were constructed in each ceramic block; at the end, the shear strength test was performed (1mm/min, 50Kgf), and analysis of surface failures. 60 additional samples (2x2x2mm) were made for extras analysis (surface roughness, MEV, and EDS). Bond strength and surface roughness data were statistically evaluated by ANOVA (2 factors/1 factor), Tukey test (5%), and Weibull analysis, respectively. ANOVA (2-way) revealed that all factors were statistically significant for bond strength. The silicatization groups (SiST: 30.47AMPa; Si: 29.21AMPa) showed the highest bond strength values, regardless of storage (Tukey's test). While the groups treated with Zirlink (ZST: 2.76FMPa; Z: 5.27EFMPa) showed the lowest values, just similar to the GlST group (5.14EFMPa). The Weibull modulus (m) showed a statistical difference between groups (p=0.000). ANOVA (1 factor) revealed that the "surface treatment" factor (p=0.0000) was statistically significant for surface roughness. Therefore, the application of Zirlink and Glaze on pre-sintered zirconia did not promote efficient adhesion of the ultratranslucent zirconia to the resin cement, even when associated with a primer containing MDP.

Factors associated with suicide risk in young women with premenstrual dysphoric disorder: A population-based study.

PURPOSE: Women with premenstrual dysphoric disorder (PMDD) are more likely to report suicide ideation and behavior when compared to women without PMDD. However, there is a lack of studies investigating the risk factors for suicide risk in women with PMDD. Thus, the aim of this study is to assess the factors associated with suicide risk in young women with PMDD. METHODS: This is a cross-sectional study including 128 young women with PMDD who were recruited from the community. PMDD and suicide risk were assessed by trained psychologists using the Mini International Neuropsychiatric Interview (MINI-PLUS). Suicide risk evaluation includes six questions that assess suicidal intention, planning and previous attempts. Subjects who answer yes to any of the six questions are classified as having current suicide risk. RESULTS: The prevalence of current suicide risk in women with PMDD was 28.1%. The factors associated with suicide risk in this population were: presenting current panic disorder (OR: 18.71 [95% CI: 1.02 - 343.27], p=0.048), a non-white skin color (OR: 4.18 [CI 95%: 1.28 - 13.61], p=0.018), greater severity of depressive symptoms (OR: 1.22 [95% CI: 1.12 - 1.32], < 0.001), and history of childhood trauma (OR: 1.04 [95% CI: 1.01 - 1.08], 0.010). CONCLUSION: Our findings indicate that there are key sociodemographic and clinical factors associated with suicide risk in young women with PMDD, enabling clinicians to identify at-risk individuals who could benefit from further screening and interventions.

Spatial-temporal pattern of colorectal cancer mortality in a Northeastern Brazilian State.

Colorectal cancer (CRC) is one of the most common cancer types worldwide. Its increasing mortality trends, especially in emerging countries, are a concern. The aim of this study was to analyse mortality trends and spatial patterns of CRC in the state of Sergipe, Brazil, from 1990 to 2019. Trends were calculated using data from the Online Mortality Atlas and Joinpoint Regression Program 4.8.0.1. Spatial analyses were performed using the empirical Bayesian model and Moran indices calculated by TerraView 4.2.2 between 1990 to 1999, 2000 to 2009 and 2010 to 2019. A total of 1585 deaths were recorded during the study period, with 58.42% among females. Trends were increasing and constant for both sexes and all age groups studied. The highest mean annual percent change was 6.2 {95% Confidence interval (CI) 3.4;9.0} for males aged +65 years and 4.5 (95% CI 3.2;5.8) for females aged 50-64 years. There was positive spatial autocorrelation for both sexes in all periods studied when using the Moran index for Bayesian rates. In summary, a consistent trend of increasing colorectal cancer (CRC) mortality has been observed overall. Nevertheless, an altered spatial distribution among males has emerged over the studied period.

Mechanistic Framework to Predict Maternal-Placental-Fetal Pharmacokinetics of Nifedipine Employing Physiologically Based Pharmacokinetic Modeling Approach.

Nifedipine is used for treating mild to severe hypertension and preventing preterm labor in pregnant women. Nevertheless, concerns about nifedipine fetal exposure and safety are always raised. The aim of this study was to develop and validate a maternal-placental-fetal nifedipine physiologically based pharmacokinetic (PBPK) model and apply the model to predict maternal, placental, and fetal exposure to nifedipine at different pregnancy stages. A nifedipine PBPK model was verified with nonpregnant data and extended to the pregnant population after the inclusion of the fetoplacental multicompartment model that accounts for the placental tissue and different fetal organs within the Simcyp Simulator version 22. Model parametrization involved scaling nifedipine transplacental clearance based on Caco-2 permeability, and fetal hepatic clearance was obtained from in vitro to in vivo extrapolation encompassing cytochrome P450 3A7 and 3A4 activities. Predicted concentration profiles were compared with in vivo observations and the transplacental transfer results were evaluated using 2-fold criteria. The PBPK model predicted a mean cord-to-maternal plasma ratio of 0.98 (range, 0.86-1.06) at term, which agrees with experimental observations of 0.78 (range, 0.59-0.93). Predicted nifedipine exposure was 1.4-, 2.0-, and 3.0-fold lower at 15, 27, and 39 weeks of gestation when compared with nonpregnant exposure, respectively. This innovative PBPK model can be applied to support maternal and fetal safety assessment for nifedipine at various stages of pregnancy.

Effect of ZrO2 paste, surface treatments, and storage on Weibull characteristics and resin bond strength to zirconia

Abstract The objective is to evaluate the effect of different surface treatments and storage on the shear strength of ultratranslucent zirconia. 36 blocks of ultra-translucent zirconia were fabricated (7x7x2mm) and sintered. Then, divided into 12 groups according to the "surface treatment" (C -Primer; Al -Sandblasting with Al2O3 + Primer; Si -Silicate + Primer; Gl -Glaze + HF + Primer; Z -Zirlink; Zp -Zirlink + Primer) and "storage" factors (ST-with 150 days/37º and without). After surface treatment, five cylinders (Ø=2mm; h=2.0mm) of resin cement (n=15) were constructed in each ceramic block; at the end, the shear strength test was performed (1mm/min, 50Kgf), and analysis of surface failures. 60 additional samples (2x2x2mm) were made for extras analysis (surface roughness, MEV, and EDS). Bond strength and surface roughness data were statistically evaluated by ANOVA (2 factors/1 factor), Tukey test (5%), and Weibull analysis, respectively. ANOVA (2-way) revealed that all factors were statistically significant for bond strength. The silicatization groups (SiST: 30.47AMPa; Si: 29.21AMPa) showed the highest bond strength values, regardless of storage (Tukey's test). While the groups treated with Zirlink (ZST: 2.76FMPa; Z: 5.27EFMPa) showed the lowest values, just similar to the GlST group (5.14EFMPa). The Weibull modulus (m) showed a statistical difference between groups (p=0.000). ANOVA (1 factor) revealed that the "surface treatment" factor (p=0.0000) was statistically significant for surface roughness. Therefore, the application of Zirlink and Glaze on pre-sintered zirconia did not promote efficient adhesion of the ultratranslucent zirconia to the resin cement, even when associated with a primer containing MDP.

Resumo O objetivo é avaliar o efeito de diferentes tratamentos superficiais e do envelhecimento na resistência ao cisalhamento da zircônia ultratranslúcida. Foram confeccionados 36 blocos de zircônia ultratranslúcida (7x7x2mm) e sinterizados. Em seguida, divididos em 12 grupos de acordo com o "tratamento de superfície" (C-Primer; Al-Jateamento com Al2O3+Primer; Si-Silicato+Primer; Gl -Glaze+HF+Primer; Z-Zirlink; Zp-Zirlink+Primer) e fatores de "armazenamento" (ST-com, 150 dias/37º e sem). Após o tratamento superficial, foram construídos cinco cilindros (Ø=2mm; h=2,0mm) de cimento resinoso (n=15) em cada bloco cerâmico; ao final foi realizado o ensaio de resistência ao cisalhamento (1mm/min, 50Kgf) e análise de falhas superficiais. Foram confeccionadas 60 amostras adicionais (2x2x2mm) para análises extras (rugosidade superficial, MEV e EDS). Os dados de resistência de união e rugosidade superficial foram avaliados estatisticamente por ANOVA (2 fatores/1fator), teste de Tukey (5%) e análise de Weibull, respectivamente. ANOVA (2 fatores) revelou que todos os fatores foram estatisticamente significativos para a resistência de união. Os grupos de silicatização (SiST: 30,47AMPa; Si: 29,21AMPa) apresentaram os maiores valores de resistência de união, independente do armazenamento (Tukey). Enquanto os grupos tratados com Zirlink (ZST: 2,76FMPa; Z: 5,27EFMPa) apresentaram os valores mais baixos, apenas semelhantes ao grupo GlST (5,14EFMPa). O módulo de Weibull (m) apresentou diferença estatística entre os grupos (p=0,000). A ANOVA (1 fator) revelou que o fator "tratamento superficial" (p=0,0000) foi estatisticamente significativo para rugosidade superficial. Portanto, a aplicação de Zirlink e do Glaze na zircônia pré-sinterizada não promoveu adesão eficiente da zircônia ultratranslúcida ao cimento resinoso, mesmo quando associada a primer contendo MDP.

Influence of the postpolymerization type and time on the flexural strength and dimensional stability of 3D printed interim resins.

STATEMENT OF PROBLEM: The mechanical strength of 3-dimensionally (3D) printed interim resins is unclear but influenced by printing parameters. Evidence regarding standardization of the postpolymerization type and time for 3D printed interim resins is sparse. PURPOSE: The purpose of this in vitro study was to evaluate the influence of postpolymerization type and time on flexural strength and dimensional stability of 3D printed resins for interim restorations. MATERIAL AND METHODS: A total of 288 bars were 3D printed (Form 2; Formlabs, stereolithography-SLA, 50 µm, 30 degrees), (25×2×2 mm; International Organization for Standardization-ISO 4049:2019) abraded and randomly divided into 9 groups (n=30) according to postpolymerization (Ultraviolet device-UV; Microwave with water-MWA; Microwave without water-MW) and time (15, 20, and 30 minutes for UV; and 5, 8, and 10 minutes for MW and MWA). Each bar was then measured with digital calipers at 11 points for length, thickness, and width before and after postpolymerization to analyze dimensional stability. The flexural strength was then measured (σ; 980.6 N, 1 mm/minute) and the fractured surfaces were analyzed with scanning electron microscopy. The σ (MPa) data were evaluated by using a 2-way analysis of variance (ANOVA) and the Tukey honestly significant difference (HSD) pairwise comparisons test (α=.05). Dimensional stability data (mm) were analyzed by using the Kruskal-Wallis test and Dwass-Steel-Critchlow-Fligner multiple comparisons. The Weibull analysis was performed with σ data. RESULTS: The 2-way ANOVA revealed that all factors and their interaction were significant for σ (P<.001). The UV groups presented the highest σ values, being statistically higher than all MW and MWA groups. The Weibull analysis revealed that postpolymerization UV groups found the highest values regarding the characteristic strength, although the MW 8-minute group (13.71) found the highest value for the Weibull modulus. Furthermore, the Kruskal-Wallis test revealed that only the postpolymerization factor was significant for dimensional stability (P<.001). The postpolymerization microwave groups found greater expansion variations at all times, with the MW 8-minute group (0.78 ±0.54) presenting the greatest variation in dimensional stability. CONCLUSIONS: UV was determined to be the most suitable type of postpolymerization for interim printed resin among the postpolymerization methods, regardless of the application time. The postpolymerization MW groups found greater variations in dimensional stability.

Total, Unbound, Renal, and Hepatic Clearances of Raltegravir and the Formation and Elimination Clearances of Raltegravir Glucuronide in Pregnant Women.

This work aimed to evaluate the total, unbound, renal, and hepatic clearances of raltegravir (RAL) and the formation and elimination clearances of raltegravir glucuronide (RAL GLU) in pregnant women living with HIV. The participants received RAL 400 mg twice daily during the third trimester (n = 15) of gestation, delivery (n = 15), and the postpartum period (n = 8). Pharmacokinetic parameter values were calculated on the basis of plasma and urine data using noncompartmental methods. RAL clearances for the third trimester of gestation were as follows: total clearance: geometric mean, 63.63 L/h (95% CI, 47.5-85.25); renal clearance: geometric mean, 2.56 L/h (95% CI, 1.96-3.34); hepatic clearance: geometric mean, 60.52 L/h (95% CI, 44.65-82.04); and unbound clearance: geometric mean, 281.14 L/h (95% CI, 203.68-388.05). RAL GLU formation and elimination clearances for the third trimester of gestation were 7.57 L/h (95% CI, 4.94-11.6) and 8.71 L/h (95% CI, 6.71-11.32), respectively. No differences were observed in RAL GLU pharmacokinetic parameters between the third trimester of gestation and the postpartum period, except for higher formation (7.57 vs 4.03 L/h) and elimination (8.71 vs 4.92 L/h) clearances during the third trimester. The findings based on plasma and urine data are consistent with an increase in the hepatic uridine 5' diphospho-glucuronosyltransferase isoenzymes activities involved in RAL metabolism during pregnancy, and the formation of RAL GLU is a minor route of RAL elimination. Compared to the postpartum period, in the third trimester of gestation, the similar RAL plasma exposure in pregnant women reinforces the maintenance of an RAL regimen including a 400-mg oral dose twice daily during pregnancy.

Failure to predict amikacin elimination in critically ill patients with cancer based on the estimated glomerular filtration rate: applying PBPK approach in a therapeutic drug monitoring study.

PURPOSE: The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer. METHODS: In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range. RESULTS: During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5 mg/kg dose); 3.8 vs 4.5 L/h (1500 mg dose) and 2.2 vs 3.1 L/h (25 mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400 mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function). CONCLUSION: This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients.

Potential Role of Novel Cardiovascular Biomarkers in Pediatric Patients with Chronic Kidney Disease.

BACKGROUND: Cardiovascular Disease is the leading cause of death in adult and pediatric patients with Chronic Kidney Disease (CKD) and its pathogenesis involves the interaction of multiple pathways. As Inflammatory mechanisms play a critical role in the vascular disease of CKD pediatric patients, there are several biomarkers related to inflammation strongly associated with this comorbidity. OBJECTIVE: This review provides available evidence on the link between several biomarkers and the pathophysiology of heart disease in patients with CKD. METHODS: The data were obtained independently by the authors, who carried out a comprehensive and non-systematic search in PubMed, Cochrane, Scopus, and SciELO databases. The search terms were "Chronic Kidney Disease", "Cardiovascular Disease", "Pediatrics", "Pathophysiology", "Mineral and Bone Disorder (MBD)", "Renin Angiotensin System (RAS)", "Biomarkers", "BNP", "NTproBNP", "CK-MB", "CXCL6", "CXCL16", "Endocan-1 (ESM-1)", "FABP3", "FABP4", h-FABP", "Oncostatin-M (OSM)", "Placental Growth Factor (PlGF)" and "Troponin I". RESULTS: The pathogenesis of CKD-mediated cardiovascular disease is linked to inflammatory biomarkers, which play a critical role in the initiation, maintenance, and progression of cardiovascular disease. There are several biomarkers associated with cardiovascular disease in pediatric patients, including BNP, NTproBNP, CK-MB, CXCL6, CXCL16, Endocan-1 (ESM-1), FABP3, FABP4, Oncostatin-M (OSM), Placental Growth Factor (PlGF), and Troponin I. CONCLUSION: The pathogenesis of CKD-mediated cardiovascular disease is not completely understood, but it is linked to inflammatory biomarkers. Further studies are required to elucidate the pathophysiological and potential role of these novel biomarkers.

Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy.

Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker.

Childhood trauma, inflammatory biomarkers and the presence of a current depressive episode: Is there a relationship in subjects from a population study?

This study aims to compare the serum cytokine levels between controls, individuals with a current depressive episode (CDE) with childhood trauma and individuals with CDE without childhood trauma. This is a cross-sectional with paired sample nested in a population-based study. For the purposes of the current study, subjects who had psychotic symptoms, generalized anxiety disorder, and who refused to perform blood collection were excluded. Subsequently, only individuals who had a current depressive episode were selected (n = 76). Another 76 subjects were randomly paired by sex and age, constituting a population control group. The measurements of serum cytokine levels were performed using the multiplex analysis method. In the group with a CDE, when compared to the population control group, the following cytokines were high: IL-1ß, IL-2, IL-4, IL-6, IL-17A, IFN-γ and TNF-α (p < 0.05). On the other hand, there was a decrease in the levels of cytokines IL-10 (p = 0.027) and IL12p70 (p = 0.001). Bonferroni test demonstrates that there is no statistically significant difference in serum cytokine levels between subjects with a CDE, with and without trauma (p > 0.05). In a multivariable logistic regression, adjusting for socioeconomic status, tobacco, alcohol and illicit drugs abuse/dependence, and use of psychiatric medication, we found that cytokines serum levels remained associated with CDE even when adjusted for these potential confounders. Our findings demonstrate that monitoring cytokine levels and immune function may be beneficial in preventing the development of a CDE. However, future research is necessary to investigate the impact of trauma on the relationship between inflammation and CDE.