Bos indicus Carcasses Suspended by the Pelvic Bone Require a Shorter Aging Time to Meet Consumer Expectations Regarding Meat Quality.

This study evaluated the effects of hanging the carcass by the Achilles tendon (AS) versus pelvic suspension (PS) on meat quality traits. Bos indicus carcasses of two distinct biological types/sex categories comprised 10 young Brangus heifers and 10 Nellore bulls which were finished in a feedlot. Half-carcasses of each biological type/sex category were randomly hung using Achilles suspension (n = 20, AS) or pelvic suspension (n = 20, PS) for 48 h. At boning, longissimus samples were collected for evaluation by untrained consumers for tenderness, liking of flavor, juiciness and overall acceptability, after aging for 5 or 15 days. Objective samples were also tested for shear force (SF), Minolta meat colour, ultimate pH, cooking loss (CL) and purge loss (PL). There was a positive effect (p < 0.01) of PS on the sensory tenderness of Nellore bulls and Brangus heifers aged for 5 days compared to the AS method. At 15 days of aging, difference in sensory tenderness was observed (p < 0.05) in either group. Additionally, an interaction occurred between the suspension method and the aging of Nellore beef (p < 0.05) on liking of flavor, juiciness and overall acceptance, while the same effects were not observed for Brangus beef (p > 0.05). Nellore carcasses submitted to PS tended (p = 0.06) to produce more tender meat than those submitted to AS (SF = 44.62 ± 6.96 vs. 50.41 ± 8.04 N), and lower CL (p < 0.05) were found (27.7 vs. 30.9%). Carcass-suspension methods did not influence meat color, pH or PL in either group (p > 0.05). The PS contributes to improve the quality of Bos indicus bulls loins; in addition, this method allows a reduction in the aging time from 15 to 5 days, and it can be used to supply meat consumer markets which accept a certain level of eating quality.

Effect of Crude Glycerin in the Feed of Lactating Goats on Concentrations of Essential and Toxic Metals in Serum, Urine, Milk, and Artisanal "Coalho" Cheese.

Goat farming is concentrated in semi-arid and tropical regions in Brazil. From 2006 to 2017, the number of goats sold in the country increased by 65.7%. The dairy products from these animals present higher digestibility, high vitamin A and B content, hypoallergenicity, and less lactose compared to dairy products from cows, in addition to having a higher sales value. Since corn and soybean meal generate an expense for feed management, crude glycerin, originating from the manufacture of biodiesel, has been studied as an energy substitute. However, this product contains heavy metals, posing risks to animal and human health. Few data are available on trace elements in biological samples and products derived from goats' milk with the dietary introduction of glycerin. The objective was to quantify aluminum (Al), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb), and zinc (Zn) in the serum, urine, milk, and artisanal "coalho" cheese of dairy goats fed different levels of crude glycerin in feed management. In total, 16 Saanen goats were selected, lactating females, that were distributed in four Latin squares and randomly treated with different levels of crude glycerin (0, 5, 10, and 15%). After the end of each experiment cycle, serum, urine, milk, and artisanal "coalho" cheese samples were collected at the four moments. The samples were submitted to digestion assisted by microwave radiation. The multi-element analysis was carried out using inductively coupled plasma optical emission spectrometry (ICP OES). There was no influence of crude glycerin levels replacing corn in serum, milk, urine, and artisanal "coalho" cheese. The serum concentration of the metals Cu, Fe, Zn, and Mn; urine concentrations of Cu, Zn, Mn, Mo, and Cr; and milk and artisanal "coalho" cheese concentrations of Cu, Zn, and Mn remained within the standards found in the literature. The inclusion of 5 to 15% of crude glycerin, derived from cotton oil, in the diets of dairy goats in partial replacement of corn, does not alter the concentration of essential and toxic metals in serum, urine, milk, and artisanal "coalho" cheese and does not, therefore, present a risk factor for intoxication.

Terapia adjunta com agentes biológicos na periodontite experimental / Adjunctive therapy with biological agents in experimental periodontitis

A presente dissertação foi dividida em dois estudos. O primeiro estudo teve como objetivo desenvolver uma revisão de literatura de trabalhos pré-clínicos que resumisse o papel de diversos fármacos usados para prevenção e tratamento da doença periodontal experimental e destaca a ação direcionada de todos os fármacos com propriedades antirreabsortivas. Além disso, esta revisão fornece uma avaliação oportuna e crítica para o uso científico racional dos medicamentos antirreabsortivos e imunomoduladores em estudos pré-clínicos, o que ajuda a entender a base para sua aplicação clínica. Pode-se concluir a partir dos achados descritos, que fitoterápicos, suplementação com ômega 3 e probióticos tem ganhado cada vez mais atenção devido às suas atividades moduladoras e antirreabsortivas e a ausência de efeitos colaterais, sendo considerados alternativas promissoras como adjuvantes da raspagem subgengival e alisamento radicular em pacientes suscetíveis. O segundo estudo, objetivou-se realizar uma revisão sistemática sobre os potenciais benefícios de agentes biológicos como adjuvantes no tratamento da periodontite experimental em modelos animais, respondendo a seguinte questão: qual é o potencial protetor dos agentes biológicos contra a reabsorção óssea alveolar durante a progressão da periodontite experimental? Os critérios de elegibilidade dos estudos foram baseados na estratégia PI/ECOS, ou seja, P = periodontite; I/E agentes biológicos; C mesma exposição/intervenção; I = exceto sobre o uso de agentes biológicos; e S = resultados secundários (inflamação). Como resultado, 5236 estudos foram selecionados inicialmente por meio de buscas manuais nas bases de dados incluídas . Após a leitura dos resumos e dos textos e de acordo com os critérios de inclusão, 39 estudos que atenderam aos critérios de inclusão foram incluídos neste estudo. Vinte e três agentes biológicos foram avaliados nos estudos incluídos. A maioria dos estudos utilizou o modelo de ligadura de periodontite experimental (PE) para testar o uso de produtos biológicos como estratégias preventivas ou terapêuticas. As dosagens dos produtos biológicos e os períodos de indução da doença variaram com base no modelo de periodontite utilizado. Como principal resultado de todos os estudos, a perda óssea alveolar pôde ser significativamente inibida com a aplicação de produtos biológicos e a redução de mediadores pró-inflamatórios quando comparados aos controles tratados. Em conclusão, essa revisão sistemática demonstrou que os agentes biológicos possuem efeitos benéficos na redução da perda óssea e na diminuição da inflamação durante a progressão da periodontite em modelos animais. (AU)

This MSc dissertation was divided into two studies. The first study aimed to develop a literature review including preclinical studies summarizing the role of various compounds used for the prevention and treatment of periodontitis and highlights the targeted action of all drugs with antiresorptive properties. In addition, this review provided a timely and critical assessment for the rational scientific use of antiresorptive and immunomodulatory drugs in preclinical studies, which helps to understand the basis for their clinical application. It can be concluded from the findings described, that phytotherapeutics, omega-3 supplementation, and probiotics have gained increasing attention due to their modulating and antiresorptive activities and the absence of side effects, and are considered promising alternatives as adjuvants to subgingival scaling and root planing in susceptible patients. In the second study, the aim was to perform a systematic review on the benefits of biological agents as adjuvants in the treatment of experimental periodontitis in animal models, answering the following question: What is the protective potential of biological agents against alveolar bone resorption during the course of experimental periodontitis progression? The criteria for eligibility of the studies were based in PI/ECOs strategy, as such (P) animal models with periodontitis; (I/E) biological agents with protective potential against bone resorption in periodontitis (prevention) or additional benefit as an adjunctive in the treatment of periodontitis; (C) same intervention/exposition as the intervention group (I), except for the use biological agents; (O) alveolar bone resorption (primary outcomes). Secondary outcomes: periodontal parameters, effectiveness of periodontitis-treatment, and adverse effects; (s) no restriction for study design on primary studies (exclusion criteria: randomized clinical trials, clinical studies, and different types of review studies). Study quality was assessed using Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) Risk of Bias tool. As a result, 5236 initial results from datasets, registries, and manual searches resulted in 39 suitable studies that met the inclusion criteria. Twenty-three biological agents were evaluated in the included studies. Most studies used the ligation model of experimental periodontitis (EP) to test the use of biologics as preventive or therapeutic strategies. The dosages of the biologics and periods of disease induction varied based on the PE model used. As the main outcome of all studies, alveolar bone loss could be significantly inhibited with the application of biologics and the reduction of pro-inflammatory mediators when compared to treated controls. Taken together, this systematic review demonstrated that biologics have beneficial effects in reducing bone loss and decreasing inflammation during the progression of periodontitis in animal models. (AU)

Pharmacokinetics and Pharmacodynamics of TAK-164 Antibody Drug Conjugate Coadministered with Unconjugated Antibody.

The development of new antibody-drug conjugates (ADCs) has led to the approval of 7 ADCs by the FDA in 4 years. Given the impact of intratumoral distribution on efficacy of these therapeutics, coadministration of unconjugated antibody with ADC has been shown to improve distribution and efficacy of several ADCs in high and moderately expressed tumor target systems by increasing tissue penetration. However, the benefit of coadministration in low expression systems is less clear. TAK-164, an ADC composed of an anti-GCC antibody (5F9) conjugated to a DGN549 payload, has demonstrated heterogeneous distribution and bystander killing. Here, we evaluated the impact of 5F9 coadministration on distribution and efficacy of TAK-164 in a primary human tumor xenograft mouse model. Coadministration was found to improve the distribution of TAK-164 within the tumor, but it had no significant impact (increase or decrease) on efficacy. Experimental and computational evidence indicates that this was not a result of tumor saturation, increased binding to perivascular cells, or compensatory bystander effects. Rather, the cellular potency of DGN549 was matched with the single-cell uptake of TAK-164 making its IC50 close to its equilibrium binding affinity (KD), and as such, coadministration dilutes total DGN549 in cells below the maximum cytotoxic concentration, thereby offsetting an increased number of targeted cells with decreased ability to kill each cell. These results provide new insights on matching payload potency to ADC delivery to help identify when increasing tumor penetration is beneficial for improving ADC efficacy and demonstrate how mechanistic simulations can be leveraged to design clinically effective ADCs.

The effect of socioeconomic aspects and dental history on pediatric patients' dental anxiety.

This study aimed to characterize the profile of dental anxiety in pediatric patients, identifying the effect exerted by socioeconomic factors using dental data. A cross-sectional study design with a sample of 120 children aged 7-12 years old was used. Data relating to anxiety levels prior to dental care, socioeconomic aspects (family income, education level, child's school type), and child's dental history (previous dental appointments, previous treatment, caries experience) were collected. Additionally, participants completed the Brazilian version of the Children's Fear Survey Schedule- Dental Subscale (B-CFSS-DS) to assess dental anxiety. Descriptive analyses, chi-squared (X 2 ) tests, and Mann-Whitney U tests were performed, with a significance level of 5%. A total of 51 boys (42.5%) and 69 girls (57.5%) were included. There was no significant difference in dental anxiety between them. However, younger children had higher mean B-CFSS-DS scores (p = 0.036, Mann-Whitney). A higher prevalence of dental anxiety was found in participants from low-income families (p = 0.012, X 2 ) and in patients who did not receive endodontic treatment (p=0.034, X 2 ). Higher mean B-CFSS-DS scores were also observed in participants who did not receive endodontic treatment (p=0.001, Mann-Whitney) compared with those that did receive endodontic treatment. No relationship was found between education level, patient school type, first dental appointment, caries experience, and dental anxiety data. Younger children presented a profile of greater dental anxiety. Socioeconomic factors and dental data exerted some effect on dental anxiety, where children from low-income families and those not subjected to endodontic treatment displayed higher rates of dental anxiety.

Pharmacological Therapies for the Management of Inflammatory Bone Resorption in Periodontal Disease: A Review of Preclinical Studies.

Periodontitis, a highly prevalent multicausal chronic inflammatory and destructive disease, develops as a result of complex host-parasite interactions. Dysbiotic bacterial biofilm in contact with the gingival tissues initiates a cascade of inflammatory events, mediated and modulated by the host's immune response, which is characterized by increased expression of several inflammatory mediators such as cytokines and chemokines in the connective tissue. If periodontal disease (PD) is left untreated, it results in the destruction of the supporting tissues around the teeth, including periodontal ligament, cementum, and alveolar bone, which lead to a wide range of disabilities and poor quality of life, thus imposing significant burdens. This process depends on the differentiation and activity of osteoclasts, the cells responsible for reabsorbing the bone tissue. Therefore, the inhibition of differentiation or activity of these cells is a promising strategy for controlling bone resorption. Several pharmacological drugs that target osteoclasts and inflammatory cells with immunomodulatory and anti-inflammatory effects, such as bisphosphonates, anti-RANK-L antibody, strontium ranelate, cathepsin inhibitors, curcumin, flavonoids, specialized proresolving mediators, and probiotics, were already described to manage inflammatory bone resorption during experimental PD progression in preclinical studies. Meantime, a growing number of studies have described the beneficial effects of herbal products in inhibiting bone resorption in experimental PD. Therefore, this review summarizes the role of several pharmacological drugs used for PD prevention and treatment and highlights the targeted action of all those drugs with antiresorptive properties. In addition, our review provides a timely and critical appraisal for the scientific rationale use of the antiresorptive and immunomodulatory medications in preclinical studies, which will help to understand the basis for its clinical application.

Simulating the Selection of Resistant Cells with Bystander Killing and Antibody Coadministration in Heterogeneous Human Epidermal Growth Factor Receptor 2-Positive Tumors.

Intratumoral heterogeneity is a leading cause of treatment failure resulting in tumor recurrence. For the antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1), two major types of resistance include changes in human epidermal growth factor receptor 2 (HER2) expression and reduced payload sensitivity, which is often exacerbated by heterogenous HER2 expression and ADC distribution during treatment. ADCs with bystander payloads, such as trastuzumab-monomethyl auristatin E (T-MMAE), can reach and kill adjacent cells with lower receptor expression that cannot be targeted directly with the ADC. Additionally, coadministration of T-DM1 with its unconjugated antibody, trastuzumab, can improve distribution and minimize heterogeneous delivery. However, the effectiveness of trastuzumab coadministration and ADC bystander killing in heterogenous tumors in reducing the selection of resistant cells is not well understood. Here, we use an agent-based model to predict outcomes with these different regimens. The simulations demonstrate that both T-DM1 and T-MMAE benefit from trastuzumab coadministration for tumors with high average receptor expression (up to 70% and 40% decrease in average tumor volume, respectively), with greater benefit for nonbystander payloads. However, the benefit decreases as receptor expression is reduced, reversing at low concentrations (up to 360% and 430% increase in average tumor volume for T-DM1 and T-MMAE, respectively) for this mechanism that impacts both ADC distribution and efficacy. For tumors with intrinsic payload resistance, coadministration uniformly exhibits better efficacy than ADC monotherapy (50%-70% and 19%-36% decrease in average tumor volume for T-DM1 and T-MMAE, respectively). Finally, we demonstrate that several regimens select for resistant cells at clinical tolerable doses, which highlights the need to pursue other mechanisms of action for durable treatment responses. SIGNIFICANCE STATEMENT: Experimental evidence demonstrates heterogeneity in the distribution of both the antibody-drug conjugate and the target receptor in the tumor microenvironment, which can promote the selection of resistant cells and lead to recurrence. This study quantifies the impact of increasing the antibody dose and utilizing bystander payloads in heterogeneous tumors. Alternative cell-killing mechanisms are needed to avoid enriching resistant cell populations.

The effect of socioeconomic aspects and dental history on pediatric patients' dental anxiety

Abstract This study aimed to characterize the profile of dental anxiety in pediatric patients, identifying the effect exerted by socioeconomic factors using dental data. A cross-sectional study design with a sample of 120 children aged 7-12 years old was used. Data relating to anxiety levels prior to dental care, socioeconomic aspects (family income, education level, child's school type), and child's dental history (previous dental appointments, previous treatment, caries experience) were collected. Additionally, participants completed the Brazilian version of the Children's Fear Survey Schedule- Dental Subscale (B-CFSS-DS) to assess dental anxiety. Descriptive analyses, chi-squared (X 2 ) tests, and Mann-Whitney U tests were performed, with a significance level of 5%. A total of 51 boys (42.5%) and 69 girls (57.5%) were included. There was no significant difference in dental anxiety between them. However, younger children had higher mean B-CFSS-DS scores (p = 0.036, Mann-Whitney). A higher prevalence of dental anxiety was found in participants from low-income families (p = 0.012, X 2 ) and in patients who did not receive endodontic treatment (p=0.034, X 2 ). Higher mean B-CFSS-DS scores were also observed in participants who did not receive endodontic treatment (p=0.001, Mann-Whitney) compared with those that did receive endodontic treatment. No relationship was found between education level, patient school type, first dental appointment, caries experience, and dental anxiety data. Younger children presented a profile of greater dental anxiety. Socioeconomic factors and dental data exerted some effect on dental anxiety, where children from low-income families and those not subjected to endodontic treatment displayed higher rates of dental anxiety.

Key metrics to expanding the pipeline of successful antibody-drug conjugates.

Although the recent FDA approval of six new antibody-drug conjugates (ADCs) is promising, attrition of ADCs during clinical development remains high. The inherent complexity of ADCs is a double-edged sword that provides opportunities for perfecting therapeutic action while also increasing confounding factors in therapeutic failures. ADC design drives their pharmacokinetics and pharmacodynamics, and requires deeper analysis than the commonly used Cmax and area under the curve (AUC) metrics to scale dosing to the clinic. Common features of current FDA-approved ADCs targeting solid tumors include humanized IgG1 antibody domains, highly expressed tumor receptors, and large antibody doses. The potential consequences of these shared features for clinical pharmacokinetics and mechanism of action are discussed, and key design aspects for successful solid tumor ADCs are highlighted.

PK/PD modeling of daptomycin against MRSA and MRSE and Monte Carlo simulation for bacteremia treatment.

OBJECTIVES: The aim of this study was to investigate the effect of daptomycin against methicillin-resistant staphylococci (MRSA and MRSE) bacteremia using computer modeling. METHODS: A pharmacokinetic/pharmacodynamic (PK/PD) modeling strategy to explain the data from an in vitro dynamic model employing time-kill curves for MRSA and MRSE was proposed. Bacterial killing was followed over time by determining viable counts and the resulting time-kill data was analyzed. Monte Carlo simulations were performed using pharmacokinetic parameters and pharmacodynamic data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. Simulations were conducted to assess the reduction in the number of colony-forming units (CFU)/mL for 18 days of treatment with daptomycin at doses of 6, 8, and 10 mg/kg/24 h or 48 h with variations in creatinine clearance (CLCR): 15-29 mL/min/1.73 m2, 30-49 mL/min/1.73 m2, 50-100 mL/min/1.73 m2, as well as for defining the probability of reaching the target fAUC/MIC = 80 in the same dose and clearance range. A PK/PD model with saturation in the number of bacteria in vitro, growth delay, and bacterial death, as well as Hill's factor, was used to describe the data for both MRSA and MRSE. RESULTS: Monte Carlo simulations showed that for MRSA there was a reduction > 2 log CFU/mL with doses ≥ 6 mg/kg/day in 75th percentile of the simulated population after 18 days of treatment with daptomycin, whereas for MRSE this reduction was observed in 95th percentile of the population. CONCLUSIONS: The presented in vitro PK/PD model and associated modeling approach were able to characterize the time-kill kinetics of MRSA and MRSE. Our study based on PTAs suggests that doses ≥ 6 mg/kg/day of daptomycin should be used to treat bacteremia caused by MRSA and MRSE in patients with CLCR of 15-29 mL/min/1.73 m2. For patients with CLCR ≥ 50 mL/min/1.73 m2, it would be necessary to employ a dose of 10 mg/kg/day to treat complicated bacteremias.

Perception Regarding Pediatric Dentist's Appearance and Factors Influencing the Child's Responses.

OBJECTIVE: To develop, validate, and apply an instrument for assessing the children's perception regarding pediatric dentist's appearance, based upon the influence of age, gender, previous dental experience, and anxiety. STUDY DESIGN: Images and a nine-item questionnaire were developed. The acceptability, convergent-construct validity, and reliability based on reproducibility and internal consistency were evaluated. The validated instrument was applied in a cross-sectional study, with children (n=120) aged 7-12 years asked to evaluate images of pediatric dentists wearing different dental attire (A:all-white (control); B:printed coat and cap, colorful face mask; C:printed coat, cap and face mask; and D:white coat and cap, printed face mask). Children's age, gender, and previous dental experiences were collected with the guardians. The Children's Fear Survey Schedule-Dental Subscale assessed children's anxiety. Descriptive and inferential statistics were carried out (p<0.05). RESULTS: The instrument showed excellent acceptability, construct validity with moderate and strong correlations (>0.40), satisfactory reproducibility (ICC >0.70), and internal consistency (Cronbach's alpha coefficient >0.70). Considering only the attire, the children's perceptions were more positive with the use of attire C and D (p<0.05). Intergroup analysis of all the variables did not identify a statistically significant difference (p>0.05). In the intragroup analysis, compared to attire A: younger children have higher perception scores to attire D; girls, children with previous experience and without anxiety favored attire C and D; and children without previous experience showed no difference in comparison to A but did between B and C (p<0.05). CONCLUSION: The C and D attires promoted a more positive perception of the appearance of a pediatric dentist when compared to A; however, age, gender, previous dental experience, and anxiety did not influence the perception scores.

Biomass of unconventional plants from Brazilian semiarid as substrate for hydrolytic enzymes production by Aspergillus niger under solid and submerged fermentation

Aspergillus niger KIJH was grown in solid and submerged fermentation using leaves and roots (with and without bark) of plants typically from Brazilian semiarid as substrate to produce a multienzymatic extract, which was characterised for its potential biotechnological applications. Solid-state fermentation (SSF) was applied to select the most promising plants biomass as induction substrates for the production of hydrolytic enzymes by fungus. The best biomasses were used as substrate in submerged fermentation (SmF) assays at two scales. Samples of up scale fermented culture were partially purified by ultrafiltration and activity and pH and temperature stability of CMCase and xylanase were evaluated. A. niger KIJH produced hydrolytic enzymes under SSF containing unconventional plants biomass from Brazilian semiarid. In SmF conditions, maximum CMCase (0.264 U mL-1) and xylanase (1.163 U mL-1) activities were induced by Jacaratia corumbensis. Scaling up the SmF to 500 mL of medium was able to maintain constant the production of CMCase (0.346 U mL-1) and xylanase (1.273 U mL-1) on the fermented culture. Ultrafiltered and concentrated extract presented CMCase activities practically constant in all temperature ranges (30-80°C) and pH (3.0-9.0), while xylanase optimum activity temperature was 50°C and pH in the range of 3.0 to 5.0. CMCase activity remained stable for 24 hours at 50°C

Biomass of unconventional plants from Brazilian semiarid as substrate for hydrolytic enzymes production by Aspergillus niger under solid and submerged fermentation

Aspergillus niger KIJH was grown in solid and submerged fermentation using leaves and roots (with and without bark) of plants typically from Brazilian semiarid as substrate to produce a multienzymatic extract, which was characterised for its potential biotechnological applications. Solid-state fermentation (SSF) was applied to select the most promising plants biomass as induction substrates for the production of hydrolytic enzymes by fungus. The best biomasses were used as substrate in submerged fermentation (SmF) assays at two scales. Samples of up scale fermented culture were partially purified by ultrafiltration and activity and pH and temperature stability of CMCase and xylanase were evaluated. A. niger KIJH produced hydrolytic enzymes under SSF containing unconventional plants biomass from Brazilian semiarid. In SmF conditions, maximum CMCase (0.264 U mL-1) and xylanase (1.163 U mL-1) activities were induced by Jacaratia corumbensis. Scaling up the SmF to 500 mL of medium was able to maintain constant the production of CMCase (0.346 U mL-1) and xylanase (1.273 U mL-1) on the fermented culture. Ultrafiltered and concentrated extract presented CMCase activities practically constant in all temperature ranges (30-80°C) and pH (3.0-9.0), while xylanase optimum activity temperature was 50°C and pH in the range of 3.0 to 5.0. CMCase activity remained stable for 24 hours at 50°C a

Pigment production by Fusarium solani BRM054066 and determination of antioxidant and anti-inflammatory properties.

The fungal kingdom has been widely studied as a source of bioactive compounds of interest to the pharmaceutical and food industry. This paper studies the production of natural red pigments by Fusarium solani BRM054066 in the submerged fermentation system, using Doehlert experimental design to determine optimal cultivation conditions. The chemical composition of the red pigment was determined by Nuclear Magnetic Resonance spectroscopy (NMR) and Ultra-Performance Liquid Chromatography coupled to Mass Spectrometry (UPLC-MS). Antioxidant activity was assessed by the ability to sequester of free radical DPPH. In the analysis of anti-inflammatory activity, murine peritoneal macrophages activated by LPS were used, and the gene expression of TNF-α, IL-1ß, IL-6, IL-10 and IL-17 was determined using qPCR. As a result, it was found that agitation at 200 rpm and glucose concentration ≥ 20 g/L promote the best results in the production of red pigment. The chemical compounds identified were two naphthoquinones, fusarubin and dihydrofusarubin, and an anthraquinone, a bostrycoidin, being fusarubin the majority compound. The red pigment showed antioxidant activity by scavenge 50% of the DPPH radical, in a concentration of 24 µg/mL. The pigment also showed an effective anti-inflammatory capacity by reducing the overexpression of the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 and promoting the production of anti-inflammatory IL-10 and IL-17, in murine macrophages activated by LPS (p < 0.05). According to the results, the fungus F. solani BRM054066, under optimized conditions of cultivation, proved to be a promising source of biologically active natural pigments with wide industrial applicability.

An Agent-Based Systems Pharmacology Model of the Antibody-Drug Conjugate Kadcyla to Predict Efficacy of Different Dosing Regimens.

The pharmaceutical industry has invested significantly in antibody-drug conjugates (ADCs) with five FDA-approved therapies and several more showing promise in late-stage clinical trials. The FDA-approved therapeutic Kadcyla (ado-trastuzumab emtansine or T-DM1) can extend the survival of patients with tumors overexpressing HER2. However, tumor histology shows that most T-DM1 localizes perivascularly, but coadministration with its unconjugated form (trastuzumab) improves penetration of the ADC into the tumor and subsequent treatment efficacy. ADC dosing schedule, e.g., dose fractionation, has also been shown to improve tolerability. However, it is still not clear how coadministration with carrier doses impacts efficacy in terms of receptor expression, dosing regimens, and payload potency. Here, we develop a hybrid agent-based model (ABM) to capture ADC and/or antibody delivery and to predict tumor killing and growth kinetics. The results indicate that a carrier dose improves efficacy when the increased number of cells targeted by the ADC outweighs the reduced fractional killing of the targeted cells. The threshold number of payloads per cell required for killing plays a pivotal role in defining this cutoff. Likewise, fractionated dosing lowers ADC efficacy due to lower tissue penetration from a reduced maximum plasma concentration. It is only beneficial when an increase in tolerability from fractionation allows a higher ADC/payload dose that more than compensates for the loss in efficacy from fractionation. Overall, the multiscale model enables detailed depictions of heterogeneous ADC delivery, cancer cell death, and tumor growth to show how carrier dosing impacts efficacy to design the most efficacious regimen.

Economic impact of the clinical pharmacist interventions in the pediatric intensive care unit

Clinical pharmacists in intensive care units are involved in patient safety, technical guidance and cost saving with rational use of medicines. This study aimed to estimate the cost saving of clinical pharmacist interventions in pediatric intensive care units (PICU). This was a retrospective, observational study. Savings were measured for three months based on (1) Clinical pharmacist interventions from prescription analysis, (2) Individualized doses of four antibiotics, (3) Comparison of drugs dispensing systems before and after the decentralization of pharmacy services. The main outcome is costs saving with strategic planning of medication use based on local reality. A number of 73 clinical pharmacist interventions were made, from which 13 allowed the calculation of economic impact, saving US$ 633.38/year. Cost saving from individualized doses of four antibiotics was US$ 8,754.46/year. The decentralization of pharmacy services saved US$ 28,770.52/year. The evaluated interventions were successful. Clinical pharmacist interventions, individualized antimicrobials doses and decentralization of pharmacy services reduce costs in the hospital.

Repeatability estimates and minimum number of evaluations for selection of elephant-grass genotypes for herbage production / Estimativas de repetibilidade e número mínimo de avaliações para seleção de genótipos de capim-elefante para produção de forragem

In forage-plants breeding, the selection of superior genotypes has been undertaken through successive harvests in previously established intervals. However, this process involves many steps, the evaluation of many traits, and a great spending with costs and labor. Thus the estimate of the repeatability is essential in improvement of perennials, it allows predicting genotypic value of the individual, the minimum number of evaluations in the selection of genotypes and minimizes resources and time in the selection of promising individuals. The objective of this study was to estimate the repeatability coefficient for morphological traits in elephant grass and determine the number of evaluations needed for phenotypic selection more efficient. The experimental randomized block design with 53 genotypes and two replications. The repeatability coefficients were estimated for variables plant height, number of tillers, stem diameter and dry matter yield, using the methods of Anova, Principal Components and Structural Analysis. We observed significant differences between genotypes (P <0.01) for all variables. The main components provide larger estimates of repeatability when compared to other methods. Estimates of the repeatability coefficients are of high magnitude average for the variables plant height (0.44) number of tillers (0.44) and stem diameter (0.63) and low magnitude for dry matter production (0.27). The Principal Components method requires five, five, two and eleven measurements for plant height, number of tillers, stem diameter and dry matter yield, respectively, with 80% reliability.

No melhoramento de plantas forrageiras, a seleção de genótipos superiores tem sido realizada mediante a realização de cortes sucessivos em intervalos previamente estabelecidos. Entretanto este processo envolve muitas etapas, avaliação de muitos caracteres e um grande dispêndio de custos e mão-de-obra. Assim, a estimativa da repetibilidade é essencial no melhoramento de plantas perenes, pois permite predizer o valor genotípico do indivíduo, o número mínimo de avaliações na seleção de genótipos e minimiza recursos e tempo na seleção de indivíduos promissores. O objetivo deste trabalho foi obter estimativas do coeficiente de repetibilidade para caracteres morfoagronômicos em capim-elefante e determinar o número de avaliações necessárias para seleção fenotípica com maior eficiência. Utilizou-se delineamento experimental de blocos casualizados com 53 genótipos e duas repetições. Foram estimados os coeficientes de repetibilidade para as variáveis altura de plantas (ALT), número de perfilhos (NP), diâmetro de colmo (DC) e produtividade de matéria seca (PMS), utilizando-se os métodos da Anova, Componentes principais e Análise estrutural. Observaram-se diferenças significativas entre os genótipos (p<0,01) para todas as variáveis avaliadas. Os componentes principais proporcionam maiores estimativas de repetibilidade em relação aos demais métodos. As estimativas dos coeficientes de repetibilidade são de média a alta magnitude, para as variáveis ALT, NP e DC e de baixa magnitude para PMS. Com base no método dos Componentes Principais são necessárias cinco, cinco, duas e onze medidas para altura da planta, número de perfilhos, diâmetro do caule e rendimento de matéria seca, respectivamente, com 80% de confiabilidade.

Time-kill curves of daptomycin and Monte Carlo simulation for the treatment of bacteraemia caused by Enterococcus faecium.

OBJECTIVES: The aim of this study was to investigate the effect of daptomycin against vancomycin-resistant Enterococcus faecium bacteraemia using computer modelling. METHODS: Data obtained in vitro from time-kill curves were evaluated by PK/PD modelling and Monte Carlo simulations to determine the logarithmic reduction in the number of colony-forming units (CFU)/mL over 18 days of daptomycin treatment at 6, 8, and 10 mg/kg doses every 24 or 48 h and with variations in creatinine clearance (CLCR) of 15-29, 30-49, and 50-100 mL/min/1.73 m2. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) for an area under the unbound drug concentration-time curve/minimum inhibitory concentration (fAUC/MIC) > 36 at the same doses and CLCR. RESULTS: Static time-kill model was employed to investigate the antibacterial efficacy of constant daptomycin concentrations. The time-kill curve analysis was performed using mathematical modelling based on a Hill coefficient factor. There was an expressive reduction (> 2 Log CFU/mL) over 18 days of daptomycin treatment in 75th percentile of individuals with CLCR of 15-100 mL/min/1.73 m2) with daptomycin 6-10 mg/kg/day, except for daptomycin every 48 h. Using fAUC/MIC > 36, PTA was > 90% at MICs ≤ 2 µg/mL. CONCLUSIONS: Higher daptomycin doses were associated with higher mortality in time-kill curves. The simulations indicated that independent of the CLCR the therapeutic responses of VRE occur with doses of daptomycin ≥ 6 mg/kg/day and daptomycin every 48 h is insufficient to treat enterococcal bacteraemia.