Multitarget Compounds for Neglected Diseases: A Review.

Neglected diseases are a group of infectious diseases, many of them parasitic, that mainly affect the poorest populations with limited access to health services, especially those living in remote rural areas and slums. According to the World Health Organization (WHO), neglected diseases put the lives of more than 200 million people at risk, and treatment is made difficult by the occurrence of resistance to existing medications, as well as the high level of toxicity. In this way, the potential of multitarget compounds is highlighted, defined as compounds designed to modulate multiple targets of relevance to disease, with the overall goal of enhancing efficacy and/or improving safety. Thus, the objective of our study is to evaluate existing multi-target compound approaches for neglected diseases, with an emphasis on Leishmaniasis, Chagas Disease, and Arboviruses. A literature review was performed by searching the database "Web of Sciences". In relation to the diseases covered in this work, Leishmaniasis, individually, was the one that presented the largest number of articles (11) that dealt with the topic, which can be justi-fied by the high prevalence of this disease in the world, the second most common disease was Dengue, followed by Chagas disease, Chikungunya virus, and Zika virus. Furthermore, the multi-target potential of phenolic compounds was observed in all diseases under study, with the mecha-nisms related to the nucleus and transcription being the most reported mechanisms. From this per-spective, it is worth highlighting the effectiveness of approaches related to multitarget drugs in discovering new therapeutic agents for neglected diseases.

Inhibition of the morphological transition of Candida spp. by riparins I-IV.

Candida spp. is an opportunistic pathogen capable of causing superficial to invasive infections. Morphological transition is one of the main virulence factors of this genus and, therefore, is an important variable to be considered in pharmacological interventions. Riparins I, II, III, and IV are alkamide-type alkaloids extracted from the unripe fruit of Aniba riparia, whose remarkable pharmacological properties were previously demonstrated. This work aimed to evaluate in silico and in vitro the inhibitory effects of Riparins on the morphological transition of Candida albicans, Candida tropicalis, and Candida krusei. Molecular docking was applied to analyze the inhibitory effects of riparins against proteins such as N-acetylglucosamine, CYP-51, and protein kinase A (PKA) using the Ramachandran plot. The ligands were prepared by MarvinSketch and Spartan software version 14.0, and MolDock Score and Rerank Score were used to analyze the affinity of the compounds. In vitro analyses were performed by culturing the strains in humid chambers in the presence of riparins or fluconazole (FCZ). The morphology was observed through optical microscopy, and the size of the hyphae was determined using the ToupView software. In silico analysis demonstrated that all riparins are likely to interact with the molecular targets: GlcNAc (>50%), PKA (>60%), and CYP-51 (>70%). Accordingly, in vitro analysis showed that these compounds significantly inhibited the morphological transition of all Candida strains. In conclusion, this study demonstrated that riparins inhibit Candida morphological transition and, therefore, can be used to overcome the pathogenicity of this genus.

Rare Presentation and Diagnostic Challenge of a Germ Cell Tumor of the Yolk Sac Type.

Opsoclonus-ataxia paraneoplastic syndrome (OAPS) is a rare neurological disorder often associated with malignancies. This case report highlights an unusual instance of OAPS linked to a yolk sac (germ cell) tumor, a correlation underrepresented in the medical literature. The patient presented with distinct neurological symptoms alongside mediastinal lymphadenopathies. The subsequent diagnostic journey revealed a yolk sac germ cell tumor. Following incisional biopsies and treatment, the patient experienced fluctuations in mental status, leading to challenges in initiating chemotherapy. Despite these complications, a multidisciplinary approach involving neurologists, oncologists, and hematologists was pivotal. The case emphasizes the complexities of managing OAPS in tandem with a germ cell tumor, underscoring the need for further research and highlighting the significance of specialized neurological evaluation in similar cases.

Riparin II-type benzamides as novel antibiofilm agents against dermatophytes: chemical synthesis, in vitro, ex vivo and in silico evaluation.

BACKGROUND: The ability of dermatophytes to develop biofilms in host tissues confers physical and biochemical resistance to antifungal drugs. Therefore, research to find new compounds against dermatophyte biofilm is crucial. OBJECTIVES: To evaluate the antifungal activity of riparin II (RIP2), nor-riparin II (NOR2) and dinor-riparin II (DINOR2) against Trichophyton rubrum, Microsporum canis and Nannizzia gypsea strains. METHODS: Initially, we determined the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of benzamides. We evaluated the inhibitory effects on the development of dermatophyte biofilms using in vitro and ex vivo models. Finally, we built three-dimensional models of the sulphite pump Ssu1 to investigate the interactions with the benzamides by molecular docking. RESULTS: RIP2 showed a broad spectrum of activity against T. rubrum, M. canis and N. gypsea, whereas NOR2 and DINOR2 were more selective. Furthermore, the shortening of the carbon chain from RIP2 benzamide to NOR2 and DINOR2 homologs caused a decrease in the MIC values. The benzamides reduced biofilm production and viability in vitro (P < 0.05) at MIC. This result was similar ex vivo in human nail fragments tests, but NOR2 and DINOR2 showed significant results at 2xMIC (P < 0.05). We constructed a model of the Ssu1 protein for each dermatophyte with high similarity. Molecular docking showed that the benzamides obtained higher binding energy values than ciclopirox. CONCLUSIONS: Our study shows the antibiofilm potential for riparin II-type benzamides as new drugs targeting dermatophytes by inhibiting the Ssu1 protein.

Myocardial Injury Progression after Radiofrequency Ablation in School-Age Children. / Progressão da Lesão Miocárdica após Ablação por Radiofrequência em Crianças em Idade Escolar.

BACKGROUND: The past decades have seen the rapid development of the invasive treatment of arrhythmias by catheter ablation procedures. Despite its safety and efficacy being well-established in adults, to date there has been little data in pediatric scenarios. One of the main concerns is the possible expansion of the ablation procedure scar in this population and its consequences over the years. OBJECTIVES: This study aimed to analyze the risk of myocardial injury progression after radiofrequency catheter ablation in pediatric patients. METHODS: This is a retrospective study of 20 pediatric patients with previous ablation for treatment of supraventricular arrhythmia that underwent cardiac magnetic resonance and coronary angiography for evaluation of myocardial fibrosis and the integrity of the coronary arteries during follow-up. RESULTS: The median age at ablation procedure was 15.1 years (Q1 12.9, Q3 16.6) and 21 years (Q1 20, Q3 23) when the cardiac magnetic resonance was performed. Fourteen of them were women. Nodal reentry tachycardia and Wolf-Parkinson-White Syndrome were the main diagnosis (19 patients), with one patient with atrial tachycardia. Three patients had ventricular myocardial fibrosis, but with a volume < 0.6 cm 3 . None of them developed ventricular dysfunction and no patient had coronary lesions on angiography. CONCLUSION: Radiofrequency catheter ablation did not show to increase the risk of myocardial injury progression or coronary artery lesions.

FUNDAMENTO: As últimas décadas têm assistido ao rápido desenvolvimento do tratamento invasivo de arritmias por procedimentos de ablação por cateter. Apesar da sua segurança e eficácia bem estabelecida em adultos, até o momento, há poucos dados nos cenários pediátricos. Uma das principais preocupações é a possível expansão da cicatriz do procedimento de ablação nessa população e suas consequências ao longo dos anos. OBJETIVOS: Este estudo teve como objetivo analisar o risco da progressão da lesão miocárdica após ablação por cateter de radiofrequência em pacientes pediátricos. MÉTODOS: Este é um estudo retrospectivo de 20 pacientes pediátricos com tratamento prévio de arritmia supraventricular com ablação, submetidos à ressonância magnética cardíaca e angiografia coronária para avaliação de fibrose miocárdica e da integridade das artérias coronárias durante o acompanhamento. RESULTADOS: A idade mediana no procedimento de ablação foi 15,1 anos (Q1 12,9, Q3 16,6) e 21 anos (Q1 20, Q3 23) quando a ressonância magnética cardíaca foi realizada. Quatorze dos pacientes eram mulheres. Taquicardia por reentrada nodal e síndrome de Wolf-Parkinson-White foram os principais diagnósticos (19 pacientes), com um paciente com taquicardia atrial. Três pacientes apresentaram fibrose miocárdica ventricular, mas com um volume inferior a 0,6 cm 3 . Nenhum deles desenvolveu disfunção ventricular e nenhum paciente apresentou lesões coronarianos na angiografia. CONCLUSÃO: A ablação por cateter de radiofrequência não mostrou aumentar o risco de progressão de lesão miocárdica ou de lesões na artéria coronária.

Progressão da Lesão Miocárdica após Ablação por Radiofrequência em Crianças em Idade Escolar / Myocardial Injury Progression after Radiofrequency Ablation in School-Age Children

Resumo Fundamento As últimas décadas têm assistido ao rápido desenvolvimento do tratamento invasivo de arritmias por procedimentos de ablação por cateter. Apesar da sua segurança e eficácia bem estabelecida em adultos, até o momento, há poucos dados nos cenários pediátricos. Uma das principais preocupações é a possível expansão da cicatriz do procedimento de ablação nessa população e suas consequências ao longo dos anos. Objetivos Este estudo teve como objetivo analisar o risco da progressão da lesão miocárdica após ablação por cateter de radiofrequência em pacientes pediátricos. Métodos Este é um estudo retrospectivo de 20 pacientes pediátricos com tratamento prévio de arritmia supraventricular com ablação, submetidos à ressonância magnética cardíaca e angiografia coronária para avaliação de fibrose miocárdica e da integridade das artérias coronárias durante o acompanhamento. Resultados A idade mediana no procedimento de ablação foi 15,1 anos (Q1 12,9, Q3 16,6) e 21 anos (Q1 20, Q3 23) quando a ressonância magnética cardíaca foi realizada. Quatorze dos pacientes eram mulheres. Taquicardia por reentrada nodal e síndrome de Wolf-Parkinson-White foram os principais diagnósticos (19 pacientes), com um paciente com taquicardia atrial. Três pacientes apresentaram fibrose miocárdica ventricular, mas com um volume inferior a 0,6 cm 3 . Nenhum deles desenvolveu disfunção ventricular e nenhum paciente apresentou lesões coronarianos na angiografia. Conclusão A ablação por cateter de radiofrequência não mostrou aumentar o risco de progressão de lesão miocárdica ou de lesões na artéria coronária.

Abstract Background The past decades have seen the rapid development of the invasive treatment of arrhythmias by catheter ablation procedures. Despite its safety and efficacy being well-established in adults, to date there has been little data in pediatric scenarios. One of the main concerns is the possible expansion of the ablation procedure scar in this population and its consequences over the years. Objectives This study aimed to analyze the risk of myocardial injury progression after radiofrequency catheter ablation in pediatric patients. Methods This is a retrospective study of 20 pediatric patients with previous ablation for treatment of supraventricular arrhythmia that underwent cardiac magnetic resonance and coronary angiography for evaluation of myocardial fibrosis and the integrity of the coronary arteries during follow-up. Results The median age at ablation procedure was 15.1 years (Q1 12.9, Q3 16.6) and 21 years (Q1 20, Q3 23) when the cardiac magnetic resonance was performed. Fourteen of them were women. Nodal reentry tachycardia and Wolf-Parkinson-White Syndrome were the main diagnosis (19 patients), with one patient with atrial tachycardia. Three patients had ventricular myocardial fibrosis, but with a volume < 0.6 cm 3 . None of them developed ventricular dysfunction and no patient had coronary lesions on angiography. Conclusion Radiofrequency catheter ablation did not show to increase the risk of myocardial injury progression or coronary artery lesions.

Comparison of pre- and postoperative functional dependence in older adults submitted to hip arthroplasty / Comparação do nível de dependência funcional pré e pós-operatório de idosos submetidos à artroplastia de quadril

Abstract Introduction Femur fractures and hip osteoarthritis affect the functional independence of older adults. Hip arthroplasty (HA) is a surgery to treat these conditions and physiotherapy can reduce functional dependence levels. Objective Compare pre- and postoperative functional dependence in older adults submitted to HA, assess the association between functional dependence and independence, and whether age is associated with greater functional dependence in these patients. Methods A quantitative cross-sectional descriptive comparative study with older adult volunteers submitted to HA evaluated before and after surgery using the Katz index and Functional Independence Measure (FIM). Comparative analysis was performed via Wilcoxon's matched pairs test and Spearman's correlation. Linear regression was applied to assess the influence of functional dependence on postoperative independence (p < 0.05). Results Forty-eight patients were evaluated in the pre- and postoperative stages using the Katz index, which demonstrated reduced functional dependence after HA. The FIM assessment indicated greater post-operative functional dependence, demonstrating the surgical procedure combined with early physiotherapy while patients were hospitalized promoted functional independence in older adults. Additionally, there was a directly proportional relationship between dependence level and age. Conclusion Functional dependence declined after HA, which improved independence in older adults. Functional dependence affected postoperative independence and age influenced functional dependence.

Resumo Introdução Fraturas de colo do fêmur e osteoartrose no quadril afetam a independência funcional de idosos. A artroplastia de quadril (AQ) é uma cirurgia para tratar essas condições e a fisioterapia pode reduzir o nível de dependência funcional. Objetivo Comparar o nível de dependência funcional pré e pós-operatório de idosos submetidos à AQ, avaliar a associação entre dependência funcional e independência funcional e verificar se a idade está associada à pior dependência funcional destes pacientes. Métodos Estudo transversal, descritivo, quantitativo e de associação, onde voluntários idosos submetidos à AQ foram avaliados no pré e pós-operatório usando o índice de Katz e a Medida de Independência Funcional (MIF). A análise comparativa foi realizada com os testes estatísticos Wilcoxon pareado e correlação de Spearman. Uma regressão linear examinou a influência da dependência funcional na independência pós-operatória (p < 0,05). Resultados Quarenta e oito pacientes foram avaliados tanto no pré quanto no pós-operatório por meio do índice Katz, observando-se uma redução da dependência funcional após o procedimento de AQ. A avaliação da MIF demonstrou que houve aumento da independência funcional no pós-operatório, demonstrando que o procedimento cirúrgico associado à fisioterapia precoce, enquanto o paciente ainda está hospitalizado, promoveu a independência funcional. Além disto, houve uma relação diretamente proporcional entre nível de dependência e idade. Conclusão A dependência funcional reduziu após a cirurgia de AQ e aumentou a independência em idosos. A dependência funcional impactou a independência após a cirurgia e a idade influenciou a dependência funcional.

EXPLORATORY ANALYSIS OF DIETARY PATTERNS OF PATIENTS WITH GASTRIC ADENOCARCINOMA: A CASE-CONTROL STUDY IN CENTRAL BRAZIL.

BACKGROUND: Diet is one of the most important modifiable risk factors for the incidence of gastric cancer. OBJECTIVE: To carry out an exploratory analysis on the dietary patterns of individuals with gastric adenocarcinoma (AdG) in the Central Brazil region. METHODS: This is a case-control study carried out from April 2019 to July 2022, in three reference centers for cancer treatment in Goiânia-GO. The cases were patients diagnosed with AdG, the control 1 dyspeptic patients submitted to upper digestive endoscopy and the control 2 patients without gastric complaints. In the three groups, patients aged 18 to 75 years and of both sexes were recruited. To assess food consumption, a Food Frequency Questionnaire validated for the Brazilian population was used. Dietary patterns were identified by Exploratory Factor Analysis (EFA), using principal component analysis as the extraction method, followed by Varimax rotation. RESULTS: The commonality values in the EFA for the foods/food groups consumed by the cases and controls were above 0.30 for all variables. The variance explained by the model was 66.7% for cases, 60.3% for control 1 and 59.7% for control 2. Three eating patterns were identified in cases, control 1 and control 2 that explained 34, 87%, 35.41% and 33.25% respectively of the total variance. The first pattern ("healthy") was characterized by the consumption of vegetables, fruits, meat and cheese; the second ("unhealthy") for sausages, pizzas, snacks, ketchup, sweet drinks and instant noodles and the third ("prudent") rice, beans, meat and fried fish and pasta. CONCLUSION: This study identified three dietary patterns among patients with AdG and controls in the Central Brazil region. According to the identified patterns, it will be possible to establish a relationship between diet and other epidemiological measures aimed at the prevention of gastric cancer.

Análise exploratória dos padrões alimentares de pacientes com adenocarcinoma gástrico: um estudo de caso-controle na Região Brasil Central / Exploratory analysis of dietary patterns of patients with gastric adenocarcinoma: a case-control study in central brazil

ABSTRACT Background: Diet is one of the most important modifiable risk factors for the incidence of gastric cancer. Objective: To carry out an exploratory analysis on the dietary patterns of individuals with gastric adenocarcinoma (AdG) in the Central Brazil region. Methods: This is a case-control study carried out from April 2019 to July 2022, in three reference centers for cancer treatment in Goiânia-GO. The cases were patients diagnosed with AdG, the control 1 dyspeptic patients submitted to upper digestive endoscopy and the control 2 patients without gastric complaints. In the three groups, patients aged 18 to 75 years and of both sexes were recruited. To assess food consumption, a Food Frequency Questionnaire validated for the Brazilian population was used. Dietary patterns were identified by Exploratory Factor Analysis (EFA), using principal component analysis as the extraction method, followed by Varimax rotation. Results: The commonality values in the EFA for the foods/food groups consumed by the cases and controls were above 0.30 for all variables. The variance explained by the model was 66.7% for cases, 60.3% for control 1 and 59.7% for control 2. Three eating patterns were identified in cases, control 1 and control 2 that explained 34, 87%, 35.41% and 33.25% respectively of the total variance. The first pattern ("healthy") was characterized by the consumption of vegetables, fruits, meat and cheese; the second ("unhealthy") for sausages, pizzas, snacks, ketchup, sweet drinks and instant noodles and the third ("prudent") rice, beans, meat and fried fish and pasta. Conclusion: This study identified three dietary patterns among patients with AdG and controls in the Central Brazil region. According to the identified patterns, it will be possible to establish a relationship between diet and other epidemiological measures aimed at the prevention of gastric cancer.

RESUMO Contexto: A dieta é um dos fatores de risco modificáveis mais importante para a incidência de câncer gástrico. Objetivo: Realizar uma análise exploratória sobre os padrões alimentares de indivíduos com adenocarcinoma gástrico (AdG) na região Brasil central. Métodos: Este é um estudo de caso-controle realizado no período de abril de 2019 a julho de 2022, em três centros de referência para o tratamento para câncer em Goiânia-GO. Os casos foram pacientes diagnosticados com AdG, o controle 1 pacientes dispépticos submetidos a endoscopia digestiva alta e o controle 2 pacientes sem queixas gástricas. Nos três grupos foram recrutados pacientes de 18 a 75 anos e de ambos os sexos. Para avaliar o consumo alimentar foi utilizado um Questionário de Frequência Alimentar validado para a população brasileira. Os padrões alimentares foram identificados por Análise Fatorial Exploratória (AFE), utilizando a análise de componentes principais como método de extração, seguida pela rotação Varimax. Resultados: Os valores de comunalidade na AFE para os alimentos/grupos alimentares consumidos pelos casos e controles ficaram acima de 0,30 para todas as variáveis. A variância explicada pelo modelo foi de 66,7%, para casos, 60,3% para o controle 1 e 59,7% para o controle 2. Foram identificados três padrões alimentares nos casos, controle 1 e controle 2 que explicaram 34,87%, 35,41% e 33,25% respectivamente da variância total. O primeiro padrão ("saudável") foi caracterizado pelo consumo de vegetais, frutas, carne e queijos; o segundo ("não saudável") por embutidos, pizzas, snacks, ketchup, bebidas doces e macarrão instantâneo e o terceiro ("prudente") arroz, feijão, carnes e peixes fritos e massas. Conclusão: Esse estudo identificou três padrões alimentares entre os pacientes com AdG e os controles na região Brasil central. De acordo com os padrões identificados, será possível estabelecer uma relação entre a dieta e outras medidas epidemiológicas destinadas à prevenção do câncer gástrico.

Three-year remission of metastatic breast cancer with treatment with ado-trastuzumab emtansine.

Globally, breast cancer is the most frequently diagnosed malignancy and the leading cause of oncological death in women. Metastatic disease at diagnosis (de novo stage IV breast cancer) will be identified in about 5% of patients. Treatment options vary based on several factors, namely whether the tumour is hormone receptor positive and whether human epidermal growth factor receptor 2 (HER2) is overexpressed. Here, we report a case of HER2 positive metastatic breast cancer on a woman in her late 30s, with remission for over 3 years under second-line treatment with ado-trastuzumab emtansine, with no significant toxicity and good tolerability. The timing to stop treatment under these circumstances presents a challenge and more data are needed to substantiate the decision to stop or maintain treatment in this small population.

Evaluation of the antibacterial and inhibitory activity of the MepA efflux pump of Staphylococcus aureus by riparins I, II, III, and IV.

The efflux pump mechanism contributes to the antibiotic resistance of widely distributed strains of Staphylococcus aureus. Therefore, in the present work, the ability of the riparins N-(4-methoxyphenethyl)benzamide (I), 2-hydroxy-N-[2-(4-methoxyphenyl)ethyl]benzamide (II), 2, 6-dihydroxy-N-[ 2-(4-methoxyphenyl)ethyl]benzamide (III), and 3,4,5-trimethoxy-N-[2-(4-methoxyphenethyl)benzamide (IV) as potential inhibitors of the MepA efflux pump in S. aureus K2068 (fluoroquinolone-resistant). In addition, we performed checkerboard assays to obtain more information about the activity of riparins as potential inhibitors of MepA efflux and also analyzed the ability of riparins to act on the permeability of the bacterial membrane of S. aureus by the fluorescence method with SYTOX Green. A molecular coupling assay was performed to characterize the interaction between riparins and MepA, and ADMET (absorption, distribution, metabolism, and excretion) properties were analyzed. We observed that I-IV riparins did not show direct antibacterial activity against S. aureus. However, combination assays with substrates of MepA, ciprofloxacin, and ethidium bromide (EtBr) revealed a potentiation of the efficacy of these substrates by reducing the minimum inhibitory concentration (MIC). Furthermore, increased EtBr fluorescence emission was observed for all riparins. The checkerboard assay showed synergism between riparins I, II, and III, ciprofloxacin, and EtBr. Furthermore, riparins III and IV exhibited permeability in the S. aureus membrane at a concentration of 200 µg/mL. Molecular docking showed that riparins I, II, and III bound in a different region from the binding site of chlorpromazine (standard pump inhibitor), indicating a possible synergistic effect with the reference inhibitor. In contrast, riparin IV binds in the same region as the chlorpromazine binding site. From the in silico ADMET prediction based on MPO, it could be concluded that the molecules of riparin I-IV present their physicochemical properties within the ideal pharmacological spectrum allowing their preparation as an oral drug. Furthermore, the prediction of cytotoxicity in liver cell lines showed a low cytotoxic effect for riparins I-IV.

Adjuvant Hyperthermic Intravesical Chemotherapy in Intermediate- and High-Risk Non-muscle Invasive Bladder Cancer.

INTRODUCTION: Non-muscle invasive bladder cancer (NMIBC) is a frequently diagnosed neoplasm, which is typically managed with transurethral resection of bladder tumor (TURBT) eventually followed by intravesical therapies. Bacillus Calmette-Guérin (BCG) is used as first-line adjuvant treatment in high- (HR) and intermediate-risk (IR) NMIBC, although, in the latter, mitomycin C (MMC) may also be used. Multiple limitations to the use of BCG encouraged the search for therapeutic alternatives. In this context, hyperthermic intravesical chemotherapy with MMC (HIVEC-MMC) emerged as a promising therapy in the adjuvant setting for NMIBC. The aim of our study was to evaluate the tolerability, compliance, and survival outcomes of HIVEC-MMC in patients with IR- and HR-NMIBC. MATERIAL AND METHODS: This was a single-center retrospective analysis of IR- and HR- NMIBC patients who received HIVEC-MMC after TURBT between August 2018 and August 2022. Levels of risk stratification were defined using the European Association of Urology (EAU) criteria. The protocol consisted of four weekly HIVEC-MMC instillations (induction) followed by six monthly instillations (maintenance). The primary outcomes were to evaluate the tolerability and compliance with the HIVEC-MMC protocol and secondary outcomes were disease-free survival (DFS) and overall survival (OS). For the purpose of statistical analysis, methods of descriptive statistics, survival analysis (Kaplan-Meier estimation), and multivariate analysis (Cox regression, and binary logistic regression) were used. RESULTS: Fifty-seven patients were enrolled with a median age of 67.9 (34.4-83.5) years old. In this cohort, 40 patients (70.2%) had primary tumors. At the time of referral for HIVEC-MMC, the majority of the patients had IR-NMIBC (n= 33, 57.9%). A total of 41 patients (71.9%) completed the HIVEC-MMC protocol. Disease recurrence and adverse events (AEs) were the most common reasons to stop the protocol. After a median follow-up of 31 months (95% CI, 5.0-54.0), 32 patients (61.4%) were disease-free, 22 (38.6%) experienced recurrent disease and six patients (10.5%) died, although only one death was directly attributable to bladder cancer. The median DFS was 42 months (95% CI, 28.0-56.0). Completion of the HIVEC-MMC maintenance phase protocol stood as a predictive factor for DFS (44 months, 95% CI 29.1-58.9 vs. 14 months, 95% CI 0.0-29.6, p < 0.001; HR 4.48, 95% CI 1.65-12.15). The median OS was not reached; the 24- and 48-month OS were 92.6% and 82.7%, respectively. EAU risk group, ECOG-PS, and completion of HIVEC protocol were found to be significant predictive factors of OS but lost their significance on multivariate analysis. However, if we exclude those who experienced recurrence during the maintenance phase protocol, treatment completion had a significant positive impact on OS (HR: 42.8, 95% CI 1.75-1045.072, p= 0.021). CONCLUSIONS: Our study suggests that HIVEC is a secure and well-tolerated treatment with promising efficacy data, making this therapeutic approach a feasible option in IR- and HR-NMIBC patients, mainly in those who cannot tolerate or have contraindications to BCG therapy, but also as an alternative during BCG shortages.

HER2 Status in RAS and BRAF Wild-Type Metastatic Colorectal Cancer: A Portuguese Study.

INTRODUCTION: Colorectal cancer (CRC) is the second-most deadly cancer worldwide. However, there remains a scarcity of precision treatments available for this type of cancer. Amplification or overexpression of human epidermal growth factor receptor 2 (HER2+) is a well-established therapeutic target in gastric and breast cancer. HER2 is positive in approximately 5% of CRC cases and has been implicated in resistance to therapy with anti-epidermal growth factor receptor antibodies. The aim of this study was to evaluate HER2 status in RAS and BRAF wild-type metastatic CRC (mCRC) and its correlation with survival outcomes. MATERIALS AND METHODS: A single-center retrospective analysis of RAS and BRAF wild-type mCRC patients undergoing systemic treatment was conducted from July 2014 to September 2020. Tissue HER2 status was determined by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) and/or chromogenic in situ hybridization (CISH). HER2+ was defined as IHC3 (+) or IHC2 (+) through FISH or CISH (+). RESULTS: Fifty-nine patients were included. The median age of all the included patients was 64 years (33-82). Four patients had HER2+ tumors (7%). Four patients had HER2+ tumors (7%). The majority of HER2+ mCRC cases were males (n=3) and left-sided CRC (n=3). All patients received FOLFIRI plus cetuximab as first-line treatment. At the median follow-up of 24.0 months, patients with HER2-negative mCRC presented with a median overall survival (mOS) of 39.4 months (95% confidence interval (CI) 32.7-46.0) and the four patients with HER2+ mCRC had a mOS of 20.4 months (95% CI; 9.5-31.3; p=0.07). In HER2-negative patients, the median PFS (mPFS) was 11.3 months (95% CI; 9.2-13.4) vsHER2-positive patients with a mPFS of 10.9 months (95% CI; 1.3-20.4; p=0.47). CONCLUSIONS: To our knowledge, this is the first study reporting HER2+ in mCRC patients in a Portuguese population and the HER2+ rate was consistent with previous studies. Our study suggests that HER2+ may potentially be a marker that is able to predict poor prognosis in RAS and BRAF wild-type mCRC.

Hypoglycaemia management with a hypercaloric supplementation in neonatal puppies delivered by caesarean section.

There is a high perinatal mortality rate in dogs, estimated at 20%, and one of the leading causes of this rate is hypoglycaemia. Therefore, we aimed to evaluate the efficacy of a hypercaloric supplement containing vitamins and amino acids in newborn puppies presenting hypoglycaemia at birth. Ninety-nine pups were divided into four groups: normoglycaemic caesarean section (NORMOCS), hypoglycaemic caesarean section supplemented with the hypercaloric (SUPLCS), hypoglycaemic caesarean section supplemented with glucose (GLICCS) and eutocic delivery (EUT). We evaluated the following parameters glycaemia, Apgar score, neurological reflexes and rectal temperature of neonates at the following moments 5 min (M5), 30 min (M30) and 60 min (M60) after birth. Brachycephalic dogs were 73.3% (22/30) of caesarean sections (c-sections). The puppy's average glycaemia represented about 90% of the maternal glycaemia, while 15.1% (14/99) of the neonates had hypoglycaemia (<90 mg/dL) at M0 and 46.5% (44/99) at M60. Only four neonates had glycaemia below 40 mg/dL at M30 but without showing any clinical signs. The puppy's fasting while waiting for the intraoperative period and the dam's anaesthetic recovery was considered risk factors for hypoglycaemia. There was no difference in mean blood glucose levels or vitality parameters among puppies from the SUPLCS and GLICCS. In conclusion, the hypercaloric supplement can be used as a replacement for glucose in hypoglycaemic puppies and it can also bring nutritional benefits for the puppy. The prepartum glycaemia of the dam is an important parameter to be measured, and the appropriate management of it reduces the chances of the puppies being born with hypoglycaemia.

B-Cell Lymphoma Intramedullary Tumor: Case Report and Systematic Review.

Intramedullary tumors represent the major cause of spinal cord injuries, and its symptoms include pain and weakness. Progressive weakness may concomitantly occur in the upper and lower limbs, along with lack of balance, spine tenderness, sensory loss, trophic changes of extremity, hyperreflexia, and clonus. The study protocol was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search of the MEDLINE electronic database was performed to identify the studies reporting the clinical features of children and adults who presented with an intramedullary lymphoma. Twenty-one studies were included, reporting 25 cases. Manuscripts were excluded if the full-text article was not available, original data were not reported (e.g., review articles), or if the main disease was not intramedullary lymphoma. A structured data extraction form was employed to standardize the identification and retrieval of data from manuscripts. To enlighten the discussion, a case is also presented. An 82-year-old woman with Fitzpatrick skin type II, diagnosed and treated for non-Hodgkin's lymphoma 7 years ago, was admitted with mental confusion and memory loss for the past 2 months-evolving with recurring falls from her own height. One day before admission, she displayed Brown-Séquard syndrome. An expansive lesion from C2 to C4 in the cervical spinal cord was found and a hypersignal spinal cord adjacent was described at the bulb medullary transition to the C6-C7 level. A primary spinal cord tumor was considered, as well as a melanoma metastasis, due to the lesion's flame pattern. The patient presented a partial recovery of symptoms and a reduction of the spinal cord edema after being empirically treated with corticosteroids, but the lesion maintained its extent. Subsequently, a large diffuse B-cell lymphoma with nongerminal center was found in open body biopsy, infiltrating neural tissue. The main objective of the present study is to report a surgical case treated for a large diffuse B-cell lymphoma, in addition to presenting the results of a systematic review of primary intramedullary spinal cord lymphoma.

Immune Response to SARS-CoV-2 Vaccination in Cancer Patients: A Prospective Study.

Introduction Cancer patients on active treatment are at increased risk of developing coronavirus disease 2019 (COVID-19), making effective immunization of the utmost importance. However, the effectiveness of vaccination in this population is still unclear. This study aims to evaluate the response against COVID-19 in a cohort of patients with active cancer under immunosuppressive therapy. Methods This was a prospective, cross-sectional, single-center study that included patients with cancer under immunosuppressive therapy vaccinated against COVID-19 between April and September 2021. Exclusion criteria were: previous known severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, single-dose vaccine or incomplete vaccination scheme. Immunoglobulin G (IgG) anti-SARS-CoV-2 antibody levels were assessed using 35.2 binding antibody units (BAU)/mL as the positive cut-off. Assessments were performed 14-31 days after the first and second dose and three months after the second dose. Results A total of 103 patients were included. The median age was 60 years. Most patients were being treated for gastrointestinal cancer (n=38, 36.9%), breast cancer (n=33, 32%) or head and neck cancer (n=18, 17.5%). At evaluation, 72 patients (69.9%) were being treated with palliative intent. The majority were being treated with chemotherapy (CT) alone (57.3%). At the first assessment, levels of circulating SARS-CoV-2 IgG consistent with seroconversion were present in 49 patients (47.6%). At the time of the second assessment, 91% (n=100) achieved seroconversion. Three months after the second dose, 83% (n=70) maintained levels of circulating SARS-CoV-2 IgG consistent with seroconversion. In this study, no SARS-CoV-2 infection was reported in the study population. Conclusions Our findings suggest that this group of patients had a satisfactory COVID-19 immunization response. Although promising, this study should be replicated on a wider scale in order to validate these findings.

In vitro and ex vivo antibiofilm activity of riparin 1, and its nor and dinor homologs, against dermatophytes.

Dermatophytosis is one of the most frequent superficial mycoses in the world. They are mainly caused by the dermatophytes Trichophyton rubrum and Microsporum canis. Biofilm production is an essential factor in the pathogenesis of dermatophytes; it confers drug resistance and significantly impairs antifungal effectiveness. Therefore, we evaluated the antibiofilm activity of an alkamide-type alkaloid called riparin 1 (RIP1) against clinically relevant dermatophytes. We also produced synthetic nor (NOR1) and dinor (DINOR1) homologs for pharmacological evaluation, with a 61-70% yield. We used in vitro (96-well polystyrene plates) and ex vivo (hair fragments) models to verify the effects of these compounds on the formation and viability of biofilms. RIP1 and NOR1 showed antifungal activity against strains of T. rubrum and M. canis, but DINOR1 showed no significant antifungal activity against the dermatophytes. Furthermore, RIP1 and NOR1 significantly reduced the viability of biofilms in vitro and ex vivo (P < 0.05). RIP1 was more potent than NOR1, possibly due to the distance between the p-methoxyphenyl and the phenylamide moieties in these compounds. Due to the significant antifungal and antibiofilm activities observed for RIP1 and NOR1, we suggest that they could be useful in the treatment of dermatophytosis.

Antifungal and Antibiofilm Activity of Riparin III against Dermatophytes.

The ability of dermatophytes to develop biofilms is possibly involved in therapeutic failure because biofilms impair drug effectiveness in the infected tissues. Research to find new drugs with antibiofilm activity against dermatophytes is crucial. In this way, riparins, a class of alkaloids that contain an amide group, are promising antifungal compounds. In this study, we evaluated the antifungal and antibiofilm activity of riparin III (RIP3) against Trichophyton rubrum, Microsporum canis, and Nannizzia gypsea strains. We used ciclopirox (CPX) as a positive control. The effects of RIP3 on fungal growth were evaluated by the microdilution technique. The quantification of the biofilm biomass in vitro was assessed by crystal violet, and the biofilm viability was assessed by quantifying the CFU number. The ex vivo model was performed on human nail fragments, which were evaluated by visualization under light microscopy and by quantifying the CFU number (viability). Finally, we evaluated whether RIP3 inhibits sulfite production in T. rubrum. RIP3 inhibited the growth of T. rubrum and M. canis from 128 mg/L and N. gypsea from 256 mg/L. The results showed that RIP3 is a fungicide. Regarding antibiofilm activity, RIP3 inhibited biofilm formation and viability in vitro and ex vivo. Moreover, RIP3 inhibited the secretion of sulfite significantly and was more potent than CPX. In conclusion, the results indicate that RIP3 is a promising antifungal agent against biofilms of dermatophytes and might inhibit sulfite secretion, one relevant virulence factor.

Predictors of cognitive dysfunction one-year post COVID-19.

OBJECTIVES: (a) To characterize the frequency of objective cognitive deficits and self-perceived cognitive difficulties and (b) to explore demographic and clinical predictors of cognitive dysfunction and cognitive complaints. METHOD: One hundred and ten adults diagnosed with COVID-19 between March and November 2020, aged ≤ 74 years underwent a brief neuropsychological evaluation 12 months after infection, which included: Brief Visuospatial Memory Test-Revised, California Verbal Learning Test, and Symbol Digit Modalities Test. T scores < 38 were considered abnormal performance; cognitive dysfunction was defined as ≥ 2 abnormal tests. Participants also completed Broadbent's Cognitive Failure Questionnaires (CFQ), Hospital Anxiety and Depression Scale, Modified Fatigue Impact Scale, and Short-Form Health Survey. CFQ ≥ 43 was considered indicative of cognitive complaints. RESULTS: Twenty participants (18.2%) had cognitive dysfunction and 36 (33.3%) had cognitive complaints. Cognitive dysfunction was related to lower education, preinfection history of headache/migraine, and acute COVID-19 symptoms of headache and sleep disturbance. Cognitive complaints were more likely to occur in women, those with fewer years of education, and acute COVID-19 symptoms of headache and sleep disturbance. Cognitive complaints were also significantly related to symptoms of anxiety, depression, and fatigue. Sex and psychopathology were not significant predictors of cognitive dysfunction. Modest associations were found between CFQ total score and cognitive test performance. DISCUSSION: A subset of individuals develops cognitive difficulties in the context of post-COVID syndrome. Results may support the protective effect of education, a known proxy of cognitive reserve. COVID-19 infection symptoms of headache and sleep disturbance appear to be risk factors for long-term cognitive difficulties. (PsycInfo Database Record (c) 2023 APA, all rights reserved).