Esketamine for Unipolar Major Depression With Psychotic Features: A Retrospective Chart Review and Comparison With Nonpsychotic Depression.

PURPOSES/BACKGROUND: The aims of the study were to assess subanesthetic esketamine as an antidepressant for major depressive disorder with psychotic features (PMDD) and to compare posttreatment symptoms among those with PMDD to a sample of nonpsychotic depression (major depressive disorder [MDD]). METHODS/PROCEDURES: This study is a retrospective chart review of patients with major depression and current psychotic symptoms, treated with a single parenteral 0.5-mg/kg dose of esketamine. Depression symptoms were assessed at baseline and 24-hour posttreatment with the Montgomery-Åsberg Depression Rating Scale. Individuals with PMDD were matched in a 1:2 ratio to nonpsychotic MDD patients from a randomized, noninferiority clinical trial of esketamine. FINDINGS/RESULTS: A total of 15 individuals with PMDD were included, which had higher baseline depression scores (PMDD = 40.9, MDD = 33.6, P = 0.004). A statistically significant change in depressive symptoms was found for the PMDD sample (ß = -16.20 [95% confidence interval, -23.30 to -9.10], P < 0.001), and no difference between PMDD and MDD groups was observed in the matched-sample analysis (ß = -2.2 [95% confidence interval, -9.32 to 4.58], P = 0.537). Treatment-induced dissociative symptoms were present for both groups, self-contained to within 2 hours after treatment, and no exacerbation of psychotic symptoms was found in clinical assessments. IMPLICATIONS/CONCLUSIONS: Results suggest a single 0.5-mg/kg dose of esketamine may benefit individuals with PMDD, and the symptom reduction may be comparable with esketamine's effects for MDD. Furthermore, esketamine may induce an antidepressant response in those with PMDD without complication of psychotic symptoms. Future research with controlled designs is warranted.

Clinical predictors of depressive symptom remission and response after racemic ketamine and esketamine infusion in treatment-resistant depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide and most people do not achieve symptom remission. Treatment-resistant depression (TRD) is characterized by the failure of at least one adequate trial of a major class of antidepressant, with adequate time and dosage. We aimed to identify clinical predictors of depressive symptom remission and response 24 h and 7 days after racemic ketamine and esketamine infusions. METHODS: A randomized, double-blind, active-controlled, non-inferiority trial using ketamine and esketamine in TRD. Individuals diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders version IV and fulfilling TRD criteria were recruited from March 2017 to June 2018. Participants received a single subanesthetic dose of ketamine (0.5 mg/kg) or esketamine (0.25 mg/kg) for 40 min. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and symptom remission was defined as a MADRS score ≤7 and response defined as ≥50% reduction in depressive symptom severity, 24 h and 7 days after the infusion. Clinical variables were selected based on previous clinical trials. Stepwise backward logistic regression was used, considering a confidence level of 95%. RESULTS: 61 subjects were included: 39 (63.9%) were females with a mean age of 47.2 ± 14.9. Higher number of therapeutic failures (Odds Ratio (OR) = 0.677; 95% confidence interval (CI): 0.47-0.97) and higher severity of illness (OR = 0.912; 95% CI: 0.83-0.99) were associated with fewer remissions of depressive symptoms 7 days after intervention, and with fewer response in 24 h (OR = 0.583; 95% CI: 0,40; 0,84 and OR = 0.909; 95% CI: 0,83; 0,99, respectively). CONCLUSION: Number of treatment failures and severity of illness were predictors of fewer remissions and responses of depressive symptoms in this TRD population. Study of predictors of remission may contribute to better selection patients that may benefit from receiving ketamine.

Neovaginoplasty with tilapia fish skin: a series of eleven cases.

INTRODUCTION AND HYPOTHESIS: Mayer-Rokitansky-Küster-Hauser syndrome affects about 1 in 5000 live female births and is associated with gonadal dysgenesis and primary amenorrhea. Neovaginoplasty has been established as an appropriate treatment option for patients who have failed or denied dilation therapy. In search of accessible, economical material with low risk of complications, the team proposed the use of Nile tilapia fish skin (NTFS) as an innovative biomaterial in the neovaginoplasty procedure for vaginal agenesis management. NTFS has noninfectious microbiota, morphologic structure comparable to human skin and high in vivo bioresorption. METHODS: In this descriptive study, the method offered an anatomical and functional neovagina to 11 patients efficiently, quickly and safely. Correct post-surgical dilation is still extremely important to keep the neovagina's size > 6 cm. RESULTS: Histological and immunohistochemical analysis demonstrated the formation of a stratified squamous epithelium with strong marking for cytokeratins, FGF and EGFR, similar to healthy adult vaginal tissue. CONCLUSIONS: Since NTFS is a low cost and easily accessible biomaterial, this technique proves to be an inexpensive therapeutic possibility for the health system with excellent advantages for patients.

Intravenous arketamine for treatment-resistant depression: open-label pilot study.

We aimed to analyze the efficacy and safety of arketamine, the R(-)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points [CI 95% 13.6-27.0; p < 0.001]; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.

Comparative study of impulsiveness and risk behaviors among infected individuals with hepatitis C virus and human T-cell lymphotropic virus type 1.

INTRODUCTION AND OBJECTIVES: Hepatitis C virus (HCV) and human T-cell lymphotropic virus type 1 (HTLV-1) infections have chronic courses. HCV is primarily transmitted via the hematogenous route, whereas HTLV-1 is primarily transmitted sexually, although it can also be transmitted by blood. Individuals chronically infected with either HTLV-1 or HCV can differ in terms of behavioral characteristics and personality traits. This study compared the occurrence of risk behaviors and impulsivity aspects between HCV and HTLV-1 carriers. MATERIALS AND METHODS: Observational, comparative and cross-sectional study that involved a sample of outpatients who had HCV or HLTV-1, by way of a sociodemographic and behavioral questionnaire and the Barratt Impulsiveness Scale - BIS-11. 143 individuals with HCV and 113 individuals with HTLV-1 were evaluated. RESULTS: There was a difference with regards to gender among patients, with mostly males affected in the HCV group. Risk behaviors commonly mediated by impulsiveness were significantly more frequent in the HCV group. Similarly, overall impulsiveness and domain nonplanning were higher in the HCV group. Multivariate analysis showed that increased age, male gender, higher nonplanning scores and HCV infection were independent factors for the occurrence of risk behaviors. Both groups presented high rates of other sexually transmitted diseases and a low rate of condom use in sexual relations. CONCLUSIONS: This study confirms the higher rate of risk behaviors and the levels of impulsiveness commonly observed in patients with HCV, along with comparisons to patients with HTLV-1.

Low Serum Trough Concentrations and High Vancomycin Minimum Inhibitory Concentration in Methicillin-Sensitive Staphylococcus aureus From Hemodialysis Patients in Brazil.

BACKGROUND: The empiric antimicrobial therapy for bacteremia of long-term hemodialysis (HD) outpatients is currently based on the combination of vancomycin and gentamicin because of the high frequency of isolated Staphylococcus species. The vancomycin trough level range from 15 to 20 mcg/mL is expected for therapeutic success against methicillin-resistant Staphylococcus aureus with vancomycin minimum inhibitory concentration (MIC) ≥1.0 mcg/mL. Despite the availability of clinical practice guidelines for vancomycin therapeutic drug monitoring, these target serum concentrations are not reached in many patients. METHODS: In this study, the authors investigated the vancomycin trough levels in 20 HD patients with S. aureus bacteremia and the antimicrobial susceptibility pattern of 45 S. aureus strains isolated from 45 HD patients. The vancomycin serum concentration was determined by chemiluminescent assay. The MIC was determined by broth microdilution method. RESULTS: None of the HD patients included in this study had vancomycin trough concentrations within the therapeutic range. Also, the vancomycin MIC for most methicillin-sensitive S. aureus isolated from bacteremia was ≥1.0 mcg/mL. CONCLUSIONS: The therapeutic range of vancomycin was not achieved, and vancomycin MIC was surprisingly high in methicillin-sensitive S. aureus.

The Portuguese Version of the Immunosuppressant Therapy Adherence Scale (ITAS) among Liver Transplant Recipient Patients: Translation and Psychometric Properties.

INTRODUCTION AND AIM: Transplant recipients are chronically ill patients who rely on medical treatment throughout life to achieve positive results. Despite that, medication nonadherence after liver transplantation is extremely common. The self-report, one of several methods for measuring adherence, is easy to apply and low cost. Thus, this study aims to translate and validate the Immunosuppressant Therapy Adherence Instrument (ITAS) in Brazilian Portuguese for liver transplant recipients. MATERIAL AND METHODS: A total of 139 liver transplant recipients were selected from a general hospital, who were assessed by using the Portuguese version of ITAS. The scale was translated based on the model proposed by Wild, et al. and its psychometric properties were assessed. RESULTS: The average Cronbach's α coefficient was 0.830. ITAS and Basel Assessment of Adherence with Immunosuppressive Medications Scale (BAASIS) presented significant correlation, with a Spearman's ρ coefficient = 0.300 (S = 309,580; p < 0.001). The area under the receiver operating characteristics (ROC) curve was 0.638 (95% CI: 0.557 - 0.715). Factor analysis results indicated that the carelessness factor model was the optimal model, and the factor "feeling worse" was the lowest. CONCLUSION: The Portuguese version of ITAS has adequate psychometric properties to measure adherence to immunosuppressant therapy.

Heterogeneous production of proteases from Brazilian clinical isolates of Pseudomonas aeruginosa.

BACKGROUND: Pseudomonas aeruginosa is an important human pathogen that causes severe infections in a wide range of immunosuppressed patients. Herein, we evaluated the proteolytic profiles of 96 Brazilian clinical isolates of P. aeruginosa recovered from diverse anatomical sites. METHODS: Cell-associated and extracellular proteases were evidenced by gelatin-SDS-PAGE and by the cleavage of soluble gelatin. Elastase was measured by using the peptide substrate N-succinyl-Ala-Ala-Ala-p-nitroanilide. The prevalence of elastase genes (lasA and lasB) was evaluated by PCR. RESULTS: Bacterial extracts were initially applied on gelatin-SDS-PAGE and the results revealed four distinct zymographic profiles as follows: profile I (composed by bands of 145, 118 and 50kDa), profile II (118 and 50kDa), profile III (145kDa) and profile IV (118kDa). All the proteolytic enzymes were inhibited by EDTA, identifying them as metalloproteases. The profile I was the most detected in both cellular (79.2%) and extracellular (84.4%) extracts. Overall, gelatinase and elastase activities measured in the spent culture media were significantly higher (around 2-fold) compared to the cellular extracts and the production level varied according to the site of bacterial isolation. For instance, tracheal secretion isolates produced elevated amount of gelatinase and elastase measured in both cellular and extracellular extracts. The prevalence of elastase genes revealed that 100% isolates were lasB-positive and 85.42% lasA-positive. Some positive/negative correlations were showed concerning the production of gelatinase, elastase, isolation site and antimicrobial susceptibility. CONCLUSION: The protease production was highly heterogeneous in Brazilian clinical isolates of P. aeruginosa, which corroborates the genomic/metabolic versatility of this pathogen.

Anti-Pseudomonas aeruginosa activity of 1,10-phenanthroline-based drugs against both planktonic- and biofilm-growing cells.

OBJECTIVES: The beneficial antimicrobial properties of 1,10-phenanthroline (phen)-based drugs, together with the imperative need to develop new chemotherapeutic options for prevention/treatment of infections caused by MDR Gram-negative bacteria, led us to evaluate the effects of phen, 1,10-phenanthroline-5,6-dione (phendione), [Ag(phendione)2]ClO4 and [Cu(phendione)3](ClO4)2·4H2O on planktonic- and biofilm-growing Pseudomonas aeruginosa. METHODS: Thirty-two non-duplicated Brazilian clinical isolates of P. aeruginosa with distinct genetic backgrounds were used in all experiments. The effect of test compounds on planktonic bacterial proliferation was determined as recommended by CLSI protocol. The effect on biofilm formation was evaluated by crystal violet incorporation (biomass determination) and XTT (viability assay). Mature biofilm disorganization was evidenced by staining with crystal violet. RESULTS: Phen-based compounds presented anti-P. aeruginosa activity, but with different potencies concerning the geometric mean MIC: [Cu(phendione)3](2+) (7.76 µM) > [Ag(phendione)2](+) (14.05 µM) > phendione (31.15 µM) > phen (579.28 µM). MICs of each compound were similar irrespective of whether the P. aeruginosa isolates were susceptible or resistant to classical antimicrobials (ceftazidime, meropenem and imipenem). The pretreatment of bacteria with phen, phendione and phendione's metal derivatives at 0.5 × MIC value inhibited biofilm formation, particularly the use of [Cu(phendione)3](2+) and [Ag(phendione)2](+), which significantly reduced both biomass (48% and 44%, respectively) and viability (78% and 77%, respectively). The compounds studied also disrupted mature biofilm in a dose-dependent manner, especially [Ag(phendione)2](+) and [Cu(phendione)3](2+) (IC50, 9.39 and 10.16 µM, respectively). CONCLUSIONS: Coordination of phendione to Ag(+) and Cu(2+) represents a new promising group of anti-infective agents, which revealed a potent anti-P. aeruginosa action against both planktonic- and biofilm-growing cells.

Candida parapsilosis (sensu lato) isolated from hospitals located in the Southeast of Brazil: Species distribution, antifungal susceptibility and virulence attributes.

Candida parapsilosis (sensu lato), which represents a fungal complex composed of three genetically related species - Candida parapsilosis sensu stricto, Candida orthopsilosis and Candida metapsilosis, has emerged as an important yeast causing fungemia worldwide. The goal of the present work was to assess the prevalence, antifungal susceptibility and production of virulence traits in 53 clinical isolates previously identified as C. parapsilosis (sensu lato) obtained from hospitals located in the Southeast of Brazil. Species forming this fungal complex are physiologically/morphologically indistinguishable; however, polymerase chain reaction followed by restriction fragment length polymorphism of FKS1 gene has solved the identification inaccuracy, revealing that 43 (81.1%) isolates were identified as C. parapsilosis sensu stricto and 10 (18.9%) as C. orthopsilosis. No C. metapsilosis was found. The geographic distribution of these Candida species was uniform among the studied Brazilian States (São Paulo, Rio de Janeiro and Espírito Santo). All C. orthopsilosis and almost all C. parapsilosis sensu stricto (95.3%) isolates were susceptible to amphotericin B, fluconazole, itraconazole, voriconazole and caspofungin. Nevertheless, one C. parapsilosis sensu stricto isolate was resistant to fluconazole and another one was resistant to caspofungin. C. parapsilosis sensu stricto isolates exhibited higher MIC mean values to amphotericin B, fluconazole and caspofungin than those of C. orthopsilosis, while C. orthopsilosis isolates displayed higher MIC mean to itraconazole compared to C. parapsilosis sensu stricto. Identical MIC mean values to voriconazole were measured for these Candida species. All the isolates of both species were able to form biofilm on polystyrene surface. Impressively, biofilm-growing cells of C. parapsilosis sensu stricto and C. orthopsilosis exhibited a considerable resistance to all antifungal agents tested. Pseudohyphae were observed in 67.4% and 80% of C. parapsilosis sensu stricto and C. orthopsilosis isolates, respectively. The secretion of phytase (93% versus 100%), aspartic protease (88.4% versus 90%), esterase (20.9% versus 50%) and hemolytic factors (25.6% versus 40%) was detected in C. parapsilosis sensu stricto and C. orthopsilosis isolates, respectively; however, no phospholipase activity was identified. An interesting fact was observed concerning the caseinolytic activity, for which all the producers (53.5%) belonged to C. parapsilosis sensu stricto. Collectively, our results add new data on the epidemiology, antifungal susceptibility and production of potential virulence attributes in clinical isolates of C. parapsilosis complex.

Virulence attributes in Brazilian clinical isolates of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic human pathogen responsible for causing a huge variety of acute and chronic infections with significant levels of morbidity and mortality. Its success as a pathogen comes from its genetic/metabolic plasticity, intrinsic/acquired antimicrobial resistance, capacity to form biofilm and expression of numerous virulence factors. Herein, we have analyzed the genetic variability, antimicrobial susceptibility as well as the production of metallo-ß-lactamases (MBLs) and virulence attributes (elastase, pyocyanin and biofilm) in 96 strains of P. aeruginosa isolated from different anatomical sites of patients attended at Brazilian hospitals. Our results revealed a great genetic variability, in which 86 distinct RAPD types (89.6% of polymorphisms) were detected. Regarding the susceptibility profile, 48 strains (50%) were resistant to the antimicrobials, as follows: 22.92% to the three tested antibiotics, 12.5% to both imipenem and meropenem, 11.46% to ceftazidime only, 2.08% to imipenem only and 1.04% to both ceftazidime and meropenem. Out of the 34 clinical strains of P. aeruginosa resistant to both imipenem and meropenem, 25 (73.53%) were MBL producers by phenotypic method while 12 (35.29%) were PCR positive for the MBL gene SPM-1. All P. aeruginosa strains produced pyocyanin, elastase and biofilm, although in different levels. Some associations were demonstrated among the susceptibility and/or production of these virulence traits with the anatomical site of strain isolation. For instance, almost all strains isolated from urine (85.71%) were resistant to the three antibiotics, while the vast majority of strains isolated from rectum (95%) and mouth (66.67%) were susceptible to all tested antibiotics. Urine isolates produced the highest pyocyanin concentration (20.15±5.65 µg/ml), while strains isolated from pleural secretion and mouth produced elevated elastase activity (1441.43±303.08 FAU) and biofilm formation (OD590 0.676±0.32), respectively. Also, MBL-positive strains produced robust biofilm compared to MBL-negative strains. Collectively, the production of site-dependent virulence factors can be highlighted as potential therapeutic targets for the treatment of infections caused by heterogeneous and resistant strains of P. aeruginosa.

TIME UNTIL THE START OF ANTIBIOTIC PROPHYLAXIS AND THE RISK OF OPEN FRACTURE INFECTION: A SYSTEMATIC REVIEW.

Open fractures are highly incident injuries closely related to the modern life, in which accidents caused by motor vehicles or other machines impart high energy to bone tissue. Individual morbidity is represented by the functional impairment resultant of infection, nonunion, or vicious healing. In terms of public health, there are huge costs involved with the treatment of these fractures, particularly with their complications. One of the critical issues in managing open fractures is the use of antibiotics (ATB), including decisions about which specific agents to administer, duration of use, and ideal timing of the first prophylactic dose. Although recent guidelines have recommended starting antibiotic prophylaxis as soon as possible, such a recommendation appears to stem from insufficient evidence. In light of this, we conducted a systematic review, including studies that addressed the impact of the time to first antibiotic and the risk of infectious outcomes. Fourteen studies were selected, of which only four found that the early initiation of treatment with antibiotics is able to prevent infection. All studies had important risks of bias. The results indicate that this question remains open, and further prospective and methodologically sound studies are necessary in order to guide practices and health policies related to this matter. Level of Evidence II; Therapeutic Studies Investigating the Results Level of Treatment.

As fraturas expostas são lesões altamente incidentes, intimamente relacionadas à vida moderna, na qual os acidentes causados por veículos automotores ou outros aparatos transmitem alta energia ao tecido ósseo. A morbidade individual é representada pelo comprometimento funcional resultante de infecção, não-união ou cicatrização viciosa. Há enormes custos envolvidos no tratamento dessas fraturas em termos de saúde pública, principalmente quanto as complicações. Uma das questões críticas no tratamento de fraturas expostas é o uso de antibióticos, incluindo as decisões sobre quais agentes específicos devem ser administrados, a duração e o momento ideal para a primeira dose profilática. Embora as diretrizes recentes tenham recomendado o início da profilaxia antibiótica o mais rápido possível, essa recomendação parece se basear em evidências insuficientes. Em vista disso, realizamos uma revisão sistemática, incluindo estudos que abordaram o impacto do tempo até o primeiro antibiótico e o risco de resultados infecciosos. Foram selecionados 14 estudos, dos quais apenas quatro concluíram que o início precoce do tratamento com antibióticos é capaz de prevenir infecções. Todos os estudos tinham riscos importantes de viés. Os resultados indicam que essa questão permanece em aberto, sendo necessários mais estudos prospectivos e metodologicamente sólidos para orientar as práticas e políticas de saúde relacionadas a esse assunto. Nível de Evidência II; Estudos Terapêuticos que Investigam o Nível de Resultados do Tratamento.

Trend in the Prevalence of Overweight and Obese Adults in São Paulo, Brazil: Analysis between the Years 2006 and 2019.

The aim of this study was to investigate the trend in the prevalence of overweight and obese adults in São Paulo, Brazil, between 2006 and 2019 across chronic diseases and the domains of physical activity. A descriptive retrospective study was carried out on the trend in the prevalence of 26.612 overweight and obese adults (10.150 men and 16.462 women). All data analyzed were based on information from the national system for monitoring risk factors called Protective and Risk Factors for Chronic Diseases by Telephone Survey-VIGITEL. The variables obese and overweight were analyzed in general and stratified by sex, age group, education level, each type of physical activity domain (yes or no), presence of hypertension and diabetes (yes or no), and smoking (yes or no). The prevalence of obesity significantly increased from 11.1% in 2006 to 19.8% in 2019, regardless of age, sex, physical activity practice, and presence of diabetes or hypertension, except for people aged 55-64 y, working people, and smokers. The total prevalence of overweight adults significantly increased overall (from 30.5% in 2006 to 33.4% in 2019) but it significantly increased only in females, in people aged 18-24 y, those who are non-white, those with an education level of 9-11 y, those who are not working, those who are non-smokers, those who did not have diabetes or hypertension, and those who were not physically active during leisure time but physically active at work and at home. There was a significant increase in the prevalence of overweight adults and especially of obese adults living in the city of São Paulo (Brazil) between 2006 and 2019, the latter being observed in nearly every analyzed sub-category, regardless of age, sex, physical activity practice, and presence of diabetes or hypertension.

Racial iniquity in mortality from cervical cancer in Brazil: a time trend study from 2002 to 2021. / Iniquidade racial na mortalidade por câncer de colo de útero no Brasil: estudo de séries temporais de 2002 a 2021.

This ecological study examined time series, from 2002 to 20121, of age-adjusted coefficients of cervical cancer mortality, in Brazil, in women aged 20 years or more, by race. The information sources were Brazil's mortality information system (Sistema de Informação sobre Mortalidade - SIM) and the official bureau of statistics (Instituto Brasileiro de Geografia e Estatística - IBGE). Annual changes in age-adjusted mortality rates were calculated using the Prais-Winsten linear regression method. Black women die more and the rate is decreasing less. Racial inequality has increased over the years. In 2002, there were 0.08 more deaths per 100,000 women in the black population than among white women; in 2021, the number was one death. Health policymaking should consider racial differences in the implementation of strategies and goals.

O objetivo desse artigo é analisar séries temporais da mortalidade por câncer de colo do útero segundo raça/cor no Brasil de 2002 a 2021. Estudo ecológico de séries temporais com dados do Sistema de Informação sobre Mortalidade e informações populacionais do IBGE. Variações anuais das taxas de mortalidade ajustadas por idade de mulheres de 20 anos ou mais foram estimadas pelo modelo de regressão linear simples com correção de Prais-Winsten. Foram registrados 133.429 óbitos por câncer de colo de útero, destes, 51,2% foram de mulheres negras. As mulheres negras morrem mais e têm menor queda do coeficiente. Houve aumento da desigualdade racial ao longo dos anos. Em 2002, ocorriam 0,08 óbitos/100 mil mulheres a mais na população negra comparada com a população branca; em 2021 esse número é de aproximadamente 1 óbito. Para a elaboração de políticas de saúde da mulher devem ser consideradas as diferenças raciais na implementação de estratégias e metas.

Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study.

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Urease inhibitors technologies as strategy to mitigate agricultural ammonia emissions and enhance the use efficiency of urea-based fertilizers.

Experiments were conducted to evaluate the stability and degradation of NBPT under storage conditions and to quantify urease activity, ammonia losses by volatilization, and agronomic efficiency of urea treated with different urease inhibitors, measured in the field. Experiments included urea treated with 530 mg NBPT kg-1 (UNBPT) in contact with six P-sources (monoammonium phosphate-MAP; single superphosphate; triple superphosphate; P-Agrocote; P-Phusion; P-Policote), with two P-concentrations (30; 70%); the monitoring four N-technologies (SoILC; Limus; Nitrain; Anvol); and the application of conventional urea (UGRAN) or urea treated with urease inhibitors as topdressing in three maize fields, at three N rates. It is concluded that: the mixture of UNBPT and P-fertilizers is incompatible. When MAP granules were coated to control P-release (P-Agrocote), the degradation of NBPT was moderate (approximately 400 mg kg-1 at the end of the storage test). SoILC and Limus solvent technologies extended the NBPT half-life by up to 3.7 and 4.7 months, respectively. Under field, each inhibition technology reduced urease activity, and lowered the intensity of ammonia emission compared to UGRAN by 50-62%. Our results show that the concentration of NBPT is reduced by up to 53.7% for mixing with phosphates. In addition, even with coatings, the storage of mixtures of urea with NBPT and phosphates should be for a time that does not reduce the efficiency of the inhibitor after application, and this time under laboratory conditions was 168 h. The reduction of NBPT concentration in urea is reduced even in isolated storage, our results showed that the half-life time is variable according to the formulation used, being 4.7, 3.7, 2.8 and 2.7 days for Limus, SoILC, Nitrain and Anvol, respectively. The results of these NBPT formulations in the field showed that the average losses by volatilization in the three areas were: 15%, 16%, 17%, 19% and 39% of the N applied, for SoILC, Anvol, Nitrain, Limus and urea, respectively. The rate of nitrogen application affected all agronomic variables, with varied effects in Ingaí. Even without N, yields were higher than 9200 kg ha-1 of grains. The increase in nitrogen rates resulted in linear increases in production and N removal in Luminárias and Ingaí, but in Lavras, production decreased above 95.6 kg ha-1 of N. The highest production in Lavras (13,772 kg ha-1 of grains) occurred with 100 kg ha-1 of N. The application of Anvol reduced the removal of N in Ingaí.

Sulfate supply decreases barium availability, uptake, and toxicity in lettuce plants grown in a tropical Ba-contaminated soil.

Barium (Ba) is a non-essential element that can cause toxicity in living organisms and environmental contamination. Plants absorb barium predominantly in its divalent cationic form Ba2+. Sulfur (S) can decrease the availability of Ba2+ in the soil by causing its precipitation as barium sulfate, a compound known for its very low solubility. The objective of this study was to evaluate the effect of soil sulfate supply in soil Ba fractions, as well as on plant growth, and Ba and S uptake by lettuce plants grown in artificially Ba-contaminated soil under greenhouse conditions. The treatments consisted of five Ba doses (0, 150, 300, 450, and 600 mg kg-1 Ba, as barium chloride) combined with three S doses (0, 40, and 80 mg kg-1 S, as potassium sulfate). The treatments were applied to soil samples (2.5 kg) and placed in plastic pots for plant cultivation. The Ba fractions analyzed were extractable-Ba, organic matter-Ba, oxides associated-Ba, and residual-Ba. The results indicate that the extractable-Ba fraction was the main one responsible for Ba bioavailability and phytotoxicity, probably corresponding to the exchangeable Ba in the soil. The dose of 80 mg kg-1 of S reduced extractable-Ba by 30% at higher Ba doses while it increased the other fractions. Furthermore, S supply attenuated the growth inhibition in plants under Ba exposure. Thus, S supply protected the lettuce plants from Ba toxicity by reduction of Ba availability in soil and plant growth enhancement. The results suggest that sulfate supply is a suitable strategy for managing Ba-contaminated areas.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.

OBJECTIVES: Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). METHODS: Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. RESULTS: There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. CONCLUSION: There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion.

Does the intensity of dissociation predict antidepressant effects 24 hours after infusion of racemic ketamine and esketamine in treatment-resistant depression? A secondary analysis from a randomized controlled trial.

BACKGROUND: Ketamine and esketamine have both shown significant antidepressant effects in treatment-resistant depression (TRD), and conflicting evidence suggests that induced dissociation by these drugs can be a clinical predictor of esketamine/ketamine's efficacy. METHODS: This study is a secondary analysis from a bi-center, randomized, controlled trial. Participants were randomly assigned 1:1 to receive an IV infusion of esketamine (.25 mg/kg) or racemic ketamine (.50 mg/kg) over 40 minutes. Dissociative symptoms were assessed using the Clinician-Administered Dissociative State Scale (CADSS) 40 minutes following the beginning of the infusion. The variation in depression scores was measured with the Montgomery-Asberg Depression Rating Scale (MADRS), which was administered before the intervention as a baseline measure and 24 hrs, 72 hrs, and 7 days following infusion. RESULTS: Sixty-one patients were included in the analysis. Examining CADSS scores of 15 or below, for every 1-point increment in the CADSS score, there was a mean change of -0.5 (SD = 0.25; p-value 0.04) of predicted MADRS score from baseline to 24 hrs. The results for 72 hrs and 7 days following infusion were not significant. Limitations: This study was not designed to assess the relationship between ketamine or esketamine-induced dissociation and antidepressant effects as the main outcome, therefore confounding variables for this relationship were not controlled. CONCLUSION: We suggest a positive relationship between dissociation intensity, measured by CADSS, and antidepressant effect 24 hours after ketamine and esketamine infusion for a CADSS score of up to 15 points.

Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study.

BACKGROUND: Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo. METHODS: This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model. RESULTS: Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal. LIMITATIONS: This was a pilot study with a small sample and underpowered. CONCLUSIONS: Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations.