Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report.

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

Private school canteens: an analysis of the economic and financial aspects of the traditional and the healthy models.

BACKGROUND: One of the reasons for the more prominent resistance of canteen managers to implementing healthy canteens is based on the belief in the economic infeasibility of these models. The research aimed to verify the economic and financial viability of traditional and healthy models of school canteens in a Brazilian metropolis. METHODS: The case study was carried out with 36 companies in the school canteen sector in a Brazilian metropolis. The classification of items sold in canteens considered the extent and purpose of food processing according to the NOVA Classification. The characterization and definition of traditional canteens and healthy canteens were proposed considering the amount of in natura or minimally processed foods and culinary preparations without the presence of ultra-processed foods; the percentage of ultra-processed foods or processed foods or culinary preparations with the presence of ultra-processed foods; and the existence of prohibited foods. The economic and financial analysis was carried out mainly through the evaluation of profitability. Data were collected through an electronic self-administered questionnaire sent to canteen managers. The Mann-Whitney test was used to compare medians and the Chi-Square/Fisher's Exact Test to compare proportions. RESULTS: The study included six companies, responsible for 36 canteen units in private schools, 30 classified in the traditional model (83.3%), and six in the healthy model (16.7%). The median percentage of natural, minimally processed foods and commercialized culinary preparations was higher among the healthy model canteens (87.9% vs. 60.0%, p < 0.001). While the median percentage of ultra-processed, processed, or preparations with the presence of ultra-processed (40.0% vs. 12.1%, p < 0.001) and prohibited foods (10.0% vs. 0%, p < 0.001) sold was higher in the traditional model canteens. The results indicated that the profitability in the healthy canteens was higher (p < 0.001) than in the traditional ones. CONCLUSIONS: Healthy school canteens showed better financial and economic results compared to traditional canteens with emphasis on greater profitability and a shorter recovery time of the initial investment.

Integration of artificial neural network and physiologically based biopharmaceutic models in the development of sustained-release formulations.

Model-informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained-release matrix tablet of metformin HCl 500 mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage® XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage® XR release. The optimized formulation was evaluated and compared to Glucophage® XR using PBBM modeling and vBE. The optimized formulation consisted of 228 mg of hydroxypropyl methylcellulose (HPMC) and 151 mg of PVP, and exhibited an observed release rate of 42% at 1 h, 47% at 2 h, 55% at 4 h, and 58% at 8 h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model-informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments.

Complications of central venous catheterization at a vascular surgery service in a teaching hospital: a prospective cohort study.

Background: Central venous catheters are essential for management of hospitalized patients, but their insertion is subject to complications that can make them unusable and/or cause patient morbidity. There are few data on the incidence of these complications and the variables associated with these outcomes in Brazil. Objectives: To determine the incidence of mechanical complications and failures of short stay central venous catheters fitted by the vascular surgery service at a teaching hospital and identify variables associated with their occurrence. Methods: This was a prospective cohort of 73 attempts to fit patients with a central venous catheter performed by the vascular surgery service at a teaching hospital from July to October of 2022. Results: Mechanical complications occurred in 12 cannulation attempts (16.44%) and there were 10 failures (13.70%). The factors associated with mechanical complications were less experienced operators (p < 0.001), less specialized operators (p = 0.014), a failed attempt prior to requesting help from the vascular surgery service (p = 0.008), and presence of at least two criteria for difficulty (p = 0.007). Conclusions: The local incidence of mechanical complications and central venous cannulation failures was similar to rates described in the international literature, but higher than rates in other Brazilian studies. The results suggest that the degree of experience of the person fitting the catheter, history of a failed prior attempt, and presence of at least two criteria for difficulty identified before the procedure were associated with worse outcomes.

Survival and analysis of predictors of mortality in patients undergoing replacement renal therapy: a 20-year cohort.

BACKGROUND: optimal management of end-stage renal disease (ESRD) in hemodialysis (HD) patients should be more studied because it is a serious risk factor for mortality, being considered an unquestionable global priority. METHODS: we performed a retrospective cohort study from the Nephrology Service in Brazil evaluating the survival of patients with ESRD in HD during 20 years. Kaplan-Meier method with the Log-Rank and Cox's proportional hazards model explored the association between survival time and demographic factors, quality of treatment and laboratory values. RESULTS: Data from 422 patients were included. The mean survival time was 6.79 ± 0.37. The overall survival rates at first year was 82,3%. The survival time correlated significantly with clinical prognostic factors. Prognostic analyses with the Cox proportional hazards regression model and Kaplan-Meier survival curves further identified that leukocyte count (HR = 2.665, 95% CI: 1.39-5.12), serum iron (HR = 8.396, 95% CI: 2.02-34.96), serum calcium (HR = 4.102, 95% CI: 1.35-12.46) and serum protein (HR = 4.630, 95% CI: 2.07-10.34) as an independent risk factor for the prognosis of survival time, while patients with chronic obstructive pyelonephritis (HR = 0.085, 95% CI: 0.01-0.74), high ferritin values (HR = 0.392, 95% CI: 0.19-0.80), serum phosphorus (HR = 0.290, 95% CI: 0.19-0.61) and serum albumin (HR = 0.230, 95% CI: 0.10-0.54) were less risk to die. CONCLUSION: survival remains low in the early years of ESRD treatment. The present study identified that elevated values of ferritin, serum calcium, phosphorus, albumin, leukocyte, serum protein and serum iron values as a useful prognostic factor for the survival time.

Weight variation in users of depot-medroxyprogesterone acetate, the levonorgestrel-releasing intrauterine system and a copper intrauterine device for up to ten years of use.

BACKGROUND AND OBJECTIVE: Data on record regarding weight variation in depot-medroxyprogesterone acetate (DMPA) and levonorgestrel-releasing intrauterine system (LNG-IUS) users are controversial. To date, no studies have yet evaluated weight variation in DMPA and LNG-IUS users in up to ten years of use compared to non-hormonal contraceptive users. MATERIALS AND METHODS: A retrospective study analysed weight variations in 2138 women using uninterruptedly DMPA (150 mg intramuscularly, three-monthly; n = 714), the LNG-IUS (n = 701) or a copper-intrauterine device (Cu-IUD; n = 723). RESULTS: At the end of the first year of use, there was a mean weight increase of 1.3 kg, 0.7 kg and 0.2 kg among the DMPA-, LNG-IUS- and Cu-IUD users, respectively, compared to weight at baseline (p < 0.0001). After ten years of use, the mean weight had risen by 6.6 kg, 4.0 and 4.9 kg among the DMPA-, LNG-IUS- and Cu-IUD users, respectively. DMPA-users had gained more weight than LNG-IUS- (p = 0.0197) and than Cu-IUD users (p = 0.0294), with the latter two groups not differing significantly from each other in this respect (p = 0.5532). CONCLUSION: Users of hormonal and non-hormonal contraceptive methods gained a significant amount of weight over the years. DMPA users gained more weight over the treatment period of up to ten years than women fitted with either a LNG-IUS or a Cu-IUD.

Treatment of lower limb telangiectasias with Nd: Yag 1064 nm laser with and without tumescent anesthesia - TTL technique.

INTRODUCTION: Transdermal laser is an option for varicous veins treatment, yet it may be painful. In this study, we will present a technique for performing tumescent anesthesia associated to transdermal laser (TTL) to reduce pain during treatment. OBJECTIVE: The study compares pain during treatment of telangiectasias in lower limb with and without tumescent anesthesia to offer a less painful procedure. METHODS: 50 CEAP C1 patients with bilateral telangiectasias on thighs underwent transdermal laser treatment, using tumescent anesthesia on one side and standard technique on the other. Pain was assessed via the Visual Analogue Scale. The outcomes were compared with Student's t-test. Significance was set at p < .05. RESULTS: Laser treatment without tumescent anesthesia resulted in a VAS pain score of 7.9, versus 0.0 with anesthesia, showing a significant statistical difference. CONCLUSION: Tumescent anesthesia and transdermal laser (TTL) is capable of reducing pain in laser treatment of telangiectasias and reticular veins.

Model-Informed drug development of gastroretentive release systems for sildenafil citrate.

Gastroretentive drug delivery systems (GRDDS) are modified-release dosage forms designed to prolong their residence time in the upper gastrointestinal tract, where some drugs are preferentially absorbed, and increase the drug bioavailability. This work aimed the development of a novel GRDDS containing 60 mg of sildenafil citrate, and the evaluation of the feasibility of the proposed formulation for use in the treatment of pulmonary arterial hypertension (PAH), for once a day administration, by using in silico pharmacokinetic (PK) modeling and simulations using GastroPlusTM. The Model-Informed Drug Development (MIDD) approach was used in formulation design and pharmacokinetic exposure prospecting. A 22 factorial design with a central point was used for optimization of the formulation, which was produced by direct compression and characterized by some tests, including buoyancy test, assay, impurities, and in vitro dissolution. A compartmental PK model was built using the GatroPlusTM software for virtual bioequivalence of the proposed formulations in comparison with the defined target release profile provided by an immediate release (IR) tablet formulation containing 20 mg of sildenafil administered three times a day (TID). The results of the factorial design showed a direct correlation between the dissolution rate and the amount of hydroxypropyl methyl cellulose (HPMC) in the formulations. By comparing the PK parameters predicted by the virtual bioequivalence, the formulations F1, F2, F3 and F5 failed on bioequivalence. The F4 showed bioequivalence to the reference and was considered the viable formulation to substitute the IR. Thus, GRDDS could be a promising alternative for controlling the release of drugs with a pH-dependent solubility and narrow absorption window, specifically in the gastric environment, and an interesting way to reduce dose frequency and increase the drug bioavailability. The MIDD approach increases the level of information about the pharmaceutical product and guide the drug development for more assertive ways.

Bacteria, yeasts, and fungi associated with larval food of Brazilian native stingless bees.

Stingless bees are a diverse group with a relevant role in pollinating native species. Its diet is rich in carbohydrates and proteins, by collecting pollen and nectar supplies the development of its offspring. Fermentation of these products is associated with microorganisms in the colony. However, the composition of microorganisms that comprise this microbiome and its fundamental role in colony development is still unclear. To characterize the colonizing microorganisms of larval food in the brood cells of stingless bees Frieseomelitta varia, Melipona quadrifasciata, Melipona scutellaris, and Tetragonisca angustula, we have utilized molecular and culture-based techniques. Bacteria of the phyla Firmicutes, Proteobacteria, Actinobacteria, and fungi of the phyla Ascomycota, Basidiomycota, Mucoromycota, and Mortierellomycota were found. Diversity analysis showed that F. varia had a greater diversity of bacteria in its microbiota, and T. angustula had a greater diversity of fungi. The isolation technique allowed the identification of 189 bacteria and 75 fungi. In summary, this research showed bacteria and fungi associated with the species F. varia, M. quadrifasciata, M. scutellaris, and T. angustula, which may play an essential role in the survival of these organisms. Besides that, a biobank with bacteria and fungus isolates from LF of Brazilian stingless bees was created, which can be used for different studies and the prospection of biotechnology compounds.

Differential gene expression by RNA-seq during Alzheimer's disease-like progression in the Drosophila melanogaster model.

Alzheimer's disease (AD) is characterized by progressive, irreversible loss of memory and cognitive function. Drosophila melanogaster and other animal models are used to study several diseases, in order to elucidate unknown mechanisms and develop potential therapies. Molecular studies require biological samples and, for neuropathologies such as AD biopsy of the human brain, are invasive and potentially damaging. The solution is to use animal models, such as D. melanogaster, which is a model organism that can replace mammalian organisms in such studies. In this study, we evaluated the climbing ability and differential gene expression during AD progression due to the amylodoigenic pathway using RNA-seq, and we performed an in silico analysis of a fruit fly AD-like GFP (Green Fluorescent Protein) model with GFP expression in the pan-neural elav driver. A total of 1388 genes were differentially expressed in all analyzed groups. The main pathways related to those Differentially Expressed Genes (DEGs) during aging and AD progression were evaluated using the fly genes and human orthologs, in order to link genomic information to higher-order functional information with gene pathway mapping. We identified pathways present in all analyzed groups, such as metabolic pathways, ribosomal pathways, proteasome pathways and immune system pathways. Some of the genes were validated by qPCR. Knockdown of CG17754 gene by RNAi promoted degeneration in the fly eye, validating these findings in vivo. The identification of similarities in molecular pathways between the transgenic fly AD-like GFP model and mammals related to AD provides new insights into the use of this fly in screening novel anti-AD drugs.

10-hydroxy-2E-decenoic acid (10HDA) does not promote caste differentiation in Melipona scutellaris stingless bees.

In bees from genus Melipona, differential feeding is not enough to fully explain female polyphenism. In these bees, there is a hypothesis that in addition to the environmental component (food), a genetic component is also involved in caste differentiation. This mechanism has not yet been fully elucidated and may involve epigenetic and metabolic regulation. Here, we verified that the genes encoding histone deacetylases HDAC1 and HDAC4 and histone acetyltransferase KAT2A were expressed at all stages of Melipona scutellaris, with fluctuations between developmental stages and castes. In larvae, the HDAC genes showed the same profile of Juvenile Hormone titers-previous reported-whereas the HAT gene exhibited the opposite profile. We also investigated the larvae and larval food metabolomes, but we did not identify the putative queen-fate inducing compounds, geraniol and 10-hydroxy-2E-decenoic acid (10HDA). Finally, we demonstrated that the histone deacetylase inhibitor 10HDA-the major lipid component of royal jelly and hence a putative regulator of honeybee caste differentiation-was unable to promote differentiation in queens in Melipona scutellaris. Our results suggest that epigenetic and hormonal regulations may act synergistically to drive caste differentiation in Melipona and that 10HDA is not a caste-differentiation factor in Melipona scutellaris.

Kefir metabolites in a fly model for Alzheimer's disease.

Alzheimer's Disease (AD) is the most common cause of dementia among elderly individuals worldwide, leading to a strong motor-cognitive decline and consequent emotional distress and codependence. It is traditionally characterized by amyloidogenic pathway formation of senile plaques, and recent studies indicate that dysbiosis is also an important factor in AD's pathology. To overcome dysbiosis, probiotics-as kefir-have shown to be a great therapeutic alternative for Alzheimer's disease. In this present work, we explored kefir as a probiotic and a metabolite source as a modulator of microbiome and amyloidogenic pathway, using a Drosophila melanogaster model for AD (AD-like flies). Kefir microbiota composition was determined through 16S rRNA sequencing, and the metabolome of each fraction (hexane, dichloromethane, ethyl acetate, and n-butanol) was investigated. After treatment, flies had their survival, climbing ability, and vacuolar lesions accessed. Kefir and fraction treated flies improved their climbing ability survival rate and neurodegeneration index. In conclusion, we show that kefir in natura, as well as its fractions may be promising therapeutic source against AD, modulating amyloidogenic related pathways.

Low-grade albuminuria in adult and elderly individuals with diabetes mellitus and arterial hypertension accompanied by Primary Health Care.

Diabetes mellitus (DM) and arterial hypertension (AH) are the two main clinical conditions related to Chronic Kidney Disease (CKD); disease also identify by the levels of low-grade albuminuria (LGA). Few studies have simultaneously investigated the associations of glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) with LGA. Our study aimed to investigate and compare the association of HbA1c and FPG with the probability of LGA in adult and elderly individuals with DM and AH, within the scope of Primary Health Care (PHC). Cross-sectional study involving 737 Brazilians individuals previously diagnosed with hypertension and/or diabetes. Tests for HbA1c, FPG and LGA were performed. LGA was defined as the highest quartile of albumin urinary (≥ 13 mg/g) among individuals with urinary LGA < 30 mg / g. A significant increase in the prevalence of LGA was found with increasing levels of HbA1c (p < 0.001). There was a significant association of HbA1c with LGA (p < 0.001) and increased probability of LGA for participants with HbA1c ≥ 6.5% compared to those with Hba1c < 5.7% (OR [95% CI]: 2.43 [1.32-4.46], p < 0.05), after adjusting for confounding factors, except when adjusted for FPG (p = 0.379 and p = 0.359, respectively). HbA1c and FPG were significantly associated in a collinear manner with an increased probability of LGA in adult and elderly individuals with DM and AH.

Hypertriglyceridemic waist phenotype and associated factors in individuals with arterial hypertension and/or diabetes mellitus.

Cardiovascular diseases are among the main causes of death in Brazil and worldwide. The literature indicates the hypertriglyceridemic waist phenotype (HTWP) as an accessible alternative for the identification of cardiovascular and metabolic risk. The present study aimed to identify the prevalence and factors associated with HTWP in individuals diagnosed with arterial hypertension (AH) and/or diabetes mellitus type 2 (DM2). A cross-sectional study was conducted with individuals diagnosed with AH and/or DM2. The study data were collected through semi-structured interviews containing socio-demographic information, lifestyle, health care, in addition to anthropometric assessment, blood pressure measurement and biochemical blood tests. The prevalence of HTWP was estimated and bivariate and multivariate logistic regression was used to assess the factors associated with HTWP. Of the 788 individuals analysed, 21⋅5 % had the HTWP. In the adjusted model, the following variables remained associated with a greater chance of presenting HTWP: sex, age, body mass index (BMI) and very-low-density lipoprotein (VLDL). Being female increased the chance of HTWP by 7⋅7 times (OR 7⋅7; 95 % CI 3⋅9, 15⋅2). The one-year increase in age increased the chance of HTWP by 4 % (OR 1⋅04; 95 % CI 1⋅02, 1⋅06). The addition of 1 mg/dl of VLDL-c increased the chance of HTWP by 15 % (odds ratio (OR) 1⋅15; 95 % confidence interval (CI) 1⋅12, 1⋅18), as well as the increase of 1 kg/m2 in the BMI increased the chance of this condition by 20 % (OR 1⋅20; 95 % CI 1⋅15, 1⋅27). The prevalence of HTWP was associated with females, older age, higher BMI, higher VLDL-c and risk waist/height ratio.

Management Strategies for Lamb Production on Pasture-Based Systems in Subtropical Regions: A Review.

Sheep production on pasture plays an important role in subtropical climates around the world, with great economic and environmental relevance to those regions. However, this production is much lower than its true potential in subtropical regions, largely due to lack of knowledge of how to feed grazing lambs, and mitigate gastrointestinal parasite infections. Due to weather instability and the high growth rate of tropical grasses, it is difficult to adjust the quality and quantity of feed consumed by lambs. In addition, due to warm, wet weather during spring, summer, and autumn, gastrointestinal parasite infection can be intense on subtropical pastures. Thus, the objective of this paper is to summarize 17 years of research in southern regions of Brazil testing alternative management for sheep farmers under these challenging conditions. Our review indicates that ewes play important roles raising their lambs. Besides protecting and providing milk, they leave a better pasture structure for lamb nutrition. The use of creep feeding and creep grazing are additional alternatives to improve lamb growth. However, feeding supplementation with concentrate can deteriorate pasture quality at the end of the summer-autumn season. Gastrointestinal parasitic infections can be reduced with improved lamb nutrition, although L3 larvae of Haemonchus contortus can be present at various pasture heights. This indicates that it is difficult to control L3 ingestion solely by manipulating grazing heights. We summarize important technologies for raising lambs on pasture-based systems to make the best of high herbage growth and minimize intense parasitic infections common in subtropical regions. We discuss research results in light of the latest studies from other ecoregions and climates, although there is a lack of similar research in subtropical regions of the world.

Dietary intake, anthropometric measurements, biochemistry profile and their associations with chronic kidney disease and diabetes mellitus.

The chronic kidney disease (CKD) and diabetes mellitus (DM) are considered a serious public health problem. The objective was investigating the association of DM with the anthropometric measures, biochemical profile and dietary intake in patients with CKD. Is a cross-sectional study done in 2017, with 51 patients previously diagnosed with CKD. We collect socio-demographic, lifestyle variables, anthropometric measurements, biochemical profile and dietary intake. We using the Kolmogorov-Smirnov test, followed by Pearson's χ2 test and Student's t test. Data were analysed using several multivariable logistic regression models, including the socio-demographic, anthropometric, dietary intake and biochemical variable. Variables with P ≤ 0⋅20 in the univariate analyses were selected and kept in the block in the simple and multiple logistic regression analysis, to determine the differences between the categories and the factors associated with the presence of DM or not, remaining in the model final, only the significant variables (P ≤ 0⋅05). Each variable was adjusted for all other variables included in the univariate analysis. The strength of the association was assessed by the odds ratio and 95% confidence intervals (CI). The multivariate logistic regression analysis evidenced that the increase of 1 cm in waist circumference and 1 mg/dl in VLDL-c values increases the chance of DM, respectively, by 8⋅4% (OR 1⋅076; P 0⋅05) and 8⋅8% (OR 1⋅102; P 0⋅01). In contrast, an increase of 1 mg/dl in total cholesterol decreases the chance of developing DM by 3⋅1% (OR 0⋅965; P 0⋅01), that is, it becomes a protective factor. The present study identified the associations between overweight, dietary intake and biochemical tests.

Individual and Combined Components of Metabolic Syndrome with Chronic Kidney Disease in Individuals with Hypertension and/or Diabetes Mellitus Accompanied by Primary Health Care.

PURPOSE: To identify the associations between MetS and its components and chronic kidney disease (CKD) in a population with arterial hypertension (AH), or diabetes mellitus (DM) accompanied by the Primary Health Care (PHC). PATIENTS AND METHODS: A cross-sectional study with 788 individuals diagnosed with AH and/or DM followed by PHC of Viçosa, Brazil. Anthropometric, biochemical and clinical measures were performed for the diagnosis of MetS and CKD. MetS was identified using the NCEP-ATPIII criteria. CKD was identified by estimating the glomerular filtration rate using the CKD-EPI equation. Logistic regression models were used to estimate the chances of CKD associated with MetS and its components and specific combinations of components. RESULTS: The prevalence of MetS reported in the population was 65.4%, that of hidden CKD was 15.4%. The prevalence of CKD among participants with MetS was 75.2%. The most prevalent component of MetS in the population was AH (96.7%). Elevated fasting blood glucose, central obesity, and reduced HDL-c were significantly associated with an increased chance of CKD (OR = 2.80, 95% CI 1.76-4.45, OR = 1.68, 95% CI, 05-2.71, OR = 1.61, CI 95% 1.03-2.50, respectively). For the multivariate adjustment, the participants with MetS were 2 times more likely to have CKD than those without MetS (OR = 2.07; 95% CI, 1.25-3.44). The combination of three components of MetS high blood pressure, abdominal obesity and elevated fasting blood glucose and the combination of four components of MetS high blood pressure, reduced HDL-c, high fasting blood glucose and abdominal obesity were associated with increased odds of CKD (OR = 2.67, CI 95% 1.70-4.20, OR = 2.50, CI 95% 1.55-4.02, respectively). CONCLUSION: MetS, as well as its individual or combined components were independently associated with CKD in the population with AH and/or DM accompanied by PHC.

Prevalence of chronic kidney disease in Brazilians with arterial hypertension and/or diabetes mellitus.

The present study aimed to evaluate the prevalence of chronic kidney disease (CKD) in individuals with arterial hypertension (AH) and/or diabetes mellitus (DM) accompanied by Primary Health Care (PHC) in Brazil. The estimated glomerular filtration rate (eGFR) based on creatinine, and urinary albumin-to-creatinine ratio (ACR) were measured in 841 subjects with AH and/or DM, followed by PHC in the city of Viçosa. The CKD was diagnosed according to KDIGO criteria. Sociodemographic, clinical, and anthropometric factors related to the prevalence of CKD were investigated through multiple logistic regression. The prevalence of hidden CKD was 15.4%. Of these, 7.5% were identified by albuminuria (ACR ≥30 mg/g) with slightly decreased eGFR. Age, baseline disease, waist circumference (WC), and systolic blood pressure remained associated with CKD after multivariate analysis. The two major risk factors for hidden CKD were the presence of AH in association with DM and an increase in age. Hidden CKD was more common within people with AH and DM, and with high WC, glycosylated hemoglobin, and serum phosphorus as well as male gender and decreased serum albumin. This knowledge of risk associations can help avoid progression to CKD.

Brain-enriched MicroRNA-184 is downregulated in older adults with major depressive disorder: A translational study.

Changes in microRNAs (miRNAs) expression have been described in major depressive disorder in young and middle-aged adults. However, no study has evaluated miRNA expression in older adults with major depression (or late-life depression [LLD]). Our primary aim was to evaluate the expression of miRNAs in subjects with LLD. We first evaluated the miRNA expression using next-generation sequencing (NGS) and then we validated the miRNAs found in NGS in an independent sample of LLD patients, using RT-qPCR. Drosophila melanogaster model was used to evaluate the impact of changes in miRNA expression on behavior. NGS analysis showed that hsa-miR-184 (log2foldchange = -4.21, p = 1.2 × 10-03) and hsa-miR-1-3p (log2foldchange = -3.45, p = 1.3 × 10-02) were significantly downregulated in LLD compared to the control group. RT-qPCR validated the downregulation of hsa-miR-184 (p < 0.001), but not for the hsa-miR-1-3p. The knockout flies of the ortholog of hsa-miR-184 showed significantly reduced locomotor activity at 21-24 d.p.e (p = 0.04) and worse memory retention at 21-24 d.p.e (24h post-stimulus, p = 0.02) compared to control flies. Our results demonstrated that subjects with LLD have significant downregulation of hsa-miR-184. Moreover, the knockout of hsa-miR-184 in flies lead to depressive-like behaviors, being more pronounce in older flies.