Neoadjuvant chemotherapy with dose-dense MVAC in muscle-invasive bladder cancer: a tertiary center experience.

PURPOSE: Neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) patients has proven beneficial in overall survival. However, the optimal regimen is still a matter of debate. MATERIALS AND METHODS: In this retrospective analysis, we evaluate the results obtained in 42 patients treated in our center with 4 cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) followed by radical cystectomy from August 2015 to October 2020. All patients had cT2 or higher non-metastatic MIBC. Clinical and pathological outcomes are reported. RESULTS: Of the 42 patients, 90.5% were men (n = 38) and the mean age was 65 years. All of them had ECOG 0-1 at diagnosis and most tumors had an initial clinical stage T2N0 (76%). Thirty-six patients (85.7%) completed 4 cycles of neoadjuvant treatment, and 21.4% required a dose reduction. The most frequent adverse event (AE) was grade 1-2 asthenia (81%), while neutropenia was the most frequent grade 3 or higher AE (38%). Complete pathological response (ypT0, ypN0) was achieved in 50% of patients (n = 21), and down-staging was observed in 57.1% (n = 24). Only one patient presented radiological progressive disease during neoadjuvant treatment (2.4%), and after a mean follow-up time of 31.5 months, 33.3% of patients experienced disease recurrence. CONCLUSIONS: Neoadjuvant chemotherapy with 4 cycles of dd-MVAC is an effective regimen with high rates of pathological complete responses and down-staging along with an acceptable toxicity profile. DD-MVAC should be considered as an alternative to cisplatin and gemcitabine in patients with good clinical performance status.

The Dark Side of Multimedia Devices: Negative Consequences for Socioemotional Development in Early Childhood.

There is growing concern about the relationship between screen use by young children and negative effects on their development, as children with developmental and socioemotional impairments tend to have difficulties in their relationships and increased academic problems. The aim of our study was to analyse the relationship between the use of multimedia devices and paediatric symptoms in children below 5 years old. Data from 534 Portuguese parents of children aged from 18 to 57 months were collected via a self-report questionnaire. Children's daily exposure to multimedia devices was nearly 2 h per day. Paediatric symptoms were positively associated with watching television and screen time and negatively associated with parents' working hours. Touchscreen use was more frequent among girls and older children. Parents' working hours comprised the most significant predictor of paediatric symptoms. Our findings reinforce past findings on the adverse links between the use of multimedia devices and paediatric symptoms and also highlight the influence of other variables like the child's age and gender, as well as parental factors. The need to both create a more comprehensive framework regarding the long-term effects of multimedia device use and delineate effective strategies for prevention and intervention with parents and children is discussed.

ß-Glucosidase activity and antimicrobial properties of potentially probiotic autochthonous lactic cultures.

Background: The demand for lactic acid bacteria products, especially probiotics, has increased. Bacteria that increase polyphenol bioavailability and act as bio preservatives are sought after. This study aims to identify autochthonous lactic acid cultures from EMBRAPA that demonstrate ß-glucosidase activity and inhibitory effect on microbial sanitary indicators. Methods: Cell-free extracts were obtained by sonicating every 5 s for 40 min. The extracts were mixed with cellobiose and incubated at 50 °C. The reaction was stopped by immersing the tubes in boiling water. The GOD-POD reagent was added for spectrophotometer readings. Antimicrobial activity was tested against reference strains using the agar well diffusion method. Lactic cultures in MRS broth were added to 0.9 cm wells and incubated. The diameter of the inhibition zones was measured to determine the extension of inhibition. Results: Only L. rhamnosus EM1107 displayed extracellular ß-glucosidase activity, while all autochthonous strains except L. plantarum CNPC020 demonstrated intracellular activity for this enzyme. L. plantarum CNPC003 had the highest values. On the other hand, L. plantarum CNPC020, similarly to L. mucosae CNPC007, exhibited notable inhibition against sanitary indicators. These two strains significantly differed from the other five autochthonous cultures regarding S. enterica serovar Typhimurium ATCC 14028 inhibition (P < 0.05). However, they did not differ from at least one positive control in terms of inhibition against S. aureus ATCC 25923 and E. coli ATCC 25922 (P > 0.05). Therefore, it is advisable to consider these cultures separately for different technological purposes, such as phenolics metabolism or bio preservative activity. This will facilitate appropriate selection based on each specific property required for the intended product development.

Severe form of lymphocutaneous sporotrichosis: a case report.

Sporotrichosis is the most frequent subcutaneous mycosis in Latin America. It is caused by species of the genus Sporothrix. Infection in humans occurs through the entry of the fungus into the skin. Zoonotic outbreaks involving cats in the transmission of the disease have been frequently reported. The lymphocutaneous form is the most commonly observed and the upper limbs are the most affected sites. We report a case of a 64-year-old healthy female patient with a lymphocutaneous form with rapid progression of lesions, which was refractory to initial treatment with itraconazole. Treatment with liposomal amphotericin B was performed with a satisfactory resolution, but aesthetic and functional sequelae in the left upper limb were installed.

IgA antibody dynamics in healthcare workers after CoronaVac® vaccination and heterologous Comirnaty® booster dose.

BACKGROUND: This study is aimed at calculating the IgA antibody dynamic range in healthcare workers (HCWs) after immunization with CoronaVac® and Comirnaty® booster dose. METHODS: A total of 118 HCW serum samples from Southern Brazil were collected the day before the first vaccine dose (day 0) and + 20, + 40, + 110, + 200 days following the vaccine's first dose, and + 15 days after a Comirnaty® booster dose. Immunoglobulin A (IgA) was quantified using immunoassays for anti-S1 (spike) protein antibodies (Euroimmun, Lübeck, Germany). RESULTS: Seroconversion for the S1 protein occurred in 75 (63.56%) and 115 (97.47%) HCWs by day + 40 and day + 15 after the booster dose, respectively. There was an absence of IgA antibodies after the booster dose in two (1.69%) HCWs undergoing biannual rituximab administration and one (0.85%) HCW for no apparent reason. CONCLUSION: Complete vaccination showed a significant IgA antibody production response, and the booster dose considerably increased this response.

A low-threshold sleep intervention for improving sleep quality and well-being.

Background: Approximately one-third of the healthy population suffer from sleep problems, but only a small proportion of those affected receive professional help. Therefore, there is an urgent need for easily accessible, affordable, and efficacious sleep interventions. Objective: A randomized controlled study was conducted to investigate the efficacy of a low-threshold sleep intervention consisting of either (i) sleep data feedback plus sleep education or (ii) sleep data feedback alone in comparison with (iii) no intervention. Material and methods: A total of 100 employees of the University of Salzburg (age: 39.51 ± 11.43 years, range: 22-62 years) were randomly assigned to one of the three groups. During the 2-week study period, objective sleep parameters were assessed via actigraphy. In addition, an online questionnaire and a daily digital diary were used to record subjective sleep parameters, work-related factors, as well as mood and well-being. After 1 week, a personal appointment was conducted with participants of both experimental group 1 (EG1) and experimental group 2 (EG2). While the EG2 only received feedback about their sleep data from week 1, the EG1 additionally received a 45-min sleep education intervention containing sleep hygiene rules and recommendations regarding stimulus control. A waiting-list control group (CG) did not receive any feedback until the end of the study. Results: Results indicate positive effects on sleep and well-being following sleep monitoring over the course of 2 weeks and minimal intervention with a single in-person appointment including sleep data feedback. Improvements are seen in sleep quality, mood, vitality, and actigraphy-measured sleep efficiency (SE; EG1), as well as in well-being and sleep onset latency (SOL) in EG2. The inactive CG did not improve in any parameter. Conclusion: Results suggest small and beneficial effects on sleep and well-being in people being continuously monitored and receiving (actigraphy-based) sleep feedback when paired with a single-time personal intervention.

Thymic alterations resulting from experimental visceral leishmaniasis in a Syrian hamster (Mesocricetus auratus).

BACKGROUND: The thymus is a lymphoid organ responsible for the development and maturation of T cells, which are part of the Th1, Th2, Th17, and Treg immune responses triggered by visceral leishmaniasis. The maturation and immunological development of T lymphocytes require a bidirectional interaction between the thymic microenvironment of epithelial cells, dendritic cells, and macrophages and the extracellular matrix with differentiating lymphocytes. OBJECTIVES: We evaluated the morphological characteristics and tissue distribution of hematopoietic and stromal cells in the thymuses of hamsters experimentally infected with Leishmania infantum, aiming to gain an insight into the pathophysiology of the disease. METHODS: Fifteen hamsters were subjected to intraperitoneal experimental infection with 107L. infantum promastigotes (MHOM/BR/1972/BH46). The animals were divided into three groups, each comprising five infected hamsters, and were then euthanized 15, 60, and 120 days postinfection. The control groups consisted of three groups of five healthy hamsters euthanized simultaneously with the infected ones. Thymic morphology was evaluated through histopathology and the cell composition through immunohistochemistry. We used antibodies to mark mesenchymal cells (anti-vimentin), epithelial cells (anti-cytokeratin), macrophages (anti-MAC387), B lymphocytes (anti-CD79a), and T lymphocytes (anti-CD3). Immunohistochemistry was also used to mark the parasite in the thymus. RESULTS: Infected and control hamsters showed no difference in thymic morphology and degree of atrophy. After 15 days of infection, CD3 + T lymphocytes in the thymus showed an increase that stabilized over time. At 120 days of infection, we detected a significant decrease in CD79a+ B lymphocytes. The parasite was present in the medullary and corticomedullary regions of 9 out of 15 hamsters. These findings confirm that the presence of a parasite can cause changes in a thymus cell population. However, further studies are needed to evaluate these changes' effects on the immune response of infected animals.

Cyclodextrin-based dermatological formulations: Dermopharmaceutical and cosmetic applications.

The progress in new delivery systems for active ingredients has boosted the dermopharmaceutical and cosmetic fields by allowing formulations to display enhanced skin permeation capabilities. Cyclodextrins (CDs) are cyclic oligosaccharides able to form host-guest inclusion complexes with guest active molecules, resulting in improved physicochemical properties of such molecules. The incorporation of CDs in dermopharmaceutical and cosmetics formulations has received much attention since the late 1970 s by enhancing modulation of the passage through the skin and vectorization into the target site while simultaneously offering a biocompatible delivery system. This paper features the advantages of CDs in dermopharmaceutical and cosmetic applications, such as the improvement of the apparent solubility and the stability of the active ingredients, the possibility of masking unpleasant odors, among others that are be described, emphasizing that these versatile skin active ingredient carriers are strongly promising both in the treatment of skin diseases and in the improvement of cosmetic formulations.

Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor.

Cytogenetic abnormalities (CAs) are known to be the preponderant prognostic factor in multiple myeloma. Our team has recently developed a prognostic score based on 6 CAs, with which del(1p32) appears to be the second worst abnormality after del(17p). This study aimed to confirm the adverse effect of 1p32 deletion in patients with newly diagnosed multiple myeloma (NDMM). Among 2551 patients with newly diagnosed multiple myeloma, 11% were harboring del(1p32). Their overall survival (OS) was significantly inferior compared with patients without del(1p32) (median OS: 49 months vs 124 months). Likewise, progression-free survival was significantly shorter. More importantly, biallelic del(1p32) conferred a dramatically poorer prognosis than a monoallelic del(1p32) (median OS: 25 months vs 60 months). As expected, the OS of patients with del(1p32) significantly decreased when this abnormality was associated with other high-risk CAs [del(17p), t(4;14), or gain(1q)]. In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse effect of del(1p32) in multiple myeloma and the relevance of its assessment at diagnosis.

Severe form of lymphocutaneous sporotrichosis: a case report

ABSTRACT Sporotrichosis is the most frequent subcutaneous mycosis in Latin America. It is caused by species of the genus Sporothrix. Infection in humans occurs through the entry of the fungus into the skin. Zoonotic outbreaks involving cats in the transmission of the disease have been frequently reported. The lymphocutaneous form is the most commonly observed and the upper limbs are the most affected sites. We report a case of a 64-year-old healthy female patient with a lymphocutaneous form with rapid progression of lesions, which was refractory to initial treatment with itraconazole. Treatment with liposomal amphotericin B was performed with a satisfactory resolution, but aesthetic and functional sequelae in the left upper limb were installed.

Cyclodextrins as an encapsulation molecular strategy for volatile organic compounds- Pharmaceutical applications.

The use of essential oils has gained importance due to their wide range of biological properties. Essential oils comprise a complex mixture of volatile organic compounds (VOCs), so the study of VOCs as active pharmaceutical ingredients is often more precise and fruitful. VOCs are natural origin molecules that constitute a sustainable alternative to synthetic drugs due to their important therapeutic value. However, VOCs possess poor solubility in aqueous solutions, high volatility, and, consequently, low stability and bioavailability, limiting VOC handling in industry and their potential use in therapeutics, despite their promising biological properties. Thereby, cyclodextrins (CDs) have emerged as suitable carriers of VOCs, giving rise to so-called VOC/CD inclusion complexes. CDs constitute an inexpensive viable solution for encapsulating VOCs to improve their properties, namely their apparent solubility and stability toward pH, light, and temperature. This review provides a conceptual framework of several VOC/CD inclusion complexes developed. In addition, the most exploited preparation techniques and their influence on the values of encapsulation efficiency and formation constant (Kf) are highlighted. The most recent in vitro or in vivo biological experiments regarding VOC/CD inclusion complexes in the development of pharmaceutical products are also presented. Finally, the toxicological, and regulatory aspects are discussed.

Cyclodextrin-based delivery systems in parenteral formulations: A critical update review.

Parenteral formulations are indispensable in clinical practice and often are the only option to administer drugs that cannot be administrated through other routes, such as proteins and certain anticancer drugs - which are indispensable to treat some of the most prevailing chronic diseases worldwide (like diabetes and cancer). Additionally, parenteral formulations play a relevant role in emergency care since they are the only ones that provide an immediate action of the drug after its administration. However, the development of parenteral formulations is a complex task owing to the specific quality and safety requirements set for these preparations and the intrinsic properties of the drugs. Amongst all the strategies that can be useful in the development of parenteral formulations, the formation of water-soluble host-guest inclusion complexes with cyclodextrins (CDs) has proven to be one of the most advantageous. CDs are multifunctional pharmaceutical excipients able to form water-soluble host-guest inclusion complexes with a wide variety of molecules, particularly drugs, and thus improve their apparent water-solubility, chemical stability, and bioavailability, to make them suitable for parenteral administration. Besides, CDs can be employed as building blocks of more complex injectable drug delivery systems with enhanced characteristics, such as nanoparticles and supramolecular hydrogels, that has been found particularly beneficial for the delivery of anticancer drugs. However, only a few CDs are considered safe when parenterally administered, and some of these types are already approved to be used in parenteral dosage forms. Therefore, the application of CDs in the development of parenteral formulations has been a more common practice in the last few years, due to their significant worldwide acceptance by the health authorities, promoting the development of safer and more efficient injectable drug delivery systems.

HIV, syphilis, hepatitis B and C in key populations: results of a 10-year cross-sectional study, Southern Brazil.

OBJECTIVE: Although the development of prevention and treatment strategies for sexually transmitted infections in key groups has improved over the years, they still remain a challenge for health systems worldwide. In this context, the objective of this study is to assess the seroprevalence in the tested population, with an emphasis on key populations, aiming at identifying the participants' profile and consequently the development of testing strategies. METHODS: The present study analyzed the seroprevalence of HIV, syphilis, and hepatitis B and C, and the epidemiological profiles of key and general populations tested at a reference public health facility for sexually transmitted infections testing and counseling in the city of Curitiba, Southern Brazil. A cross-sectional study was conducted to report data from 2010 to 2019. RESULTS: A total of 67,448 samples were analyzed, 9,086 of these tested positive, 3,633 (56%) for HIV, 4,978 (77%) for syphilis, 340 (5%) for hepatitis C virus (HCV), and 135 (2%) for hepatitis B virus (HBV). Overall, most of the participants were men (79 to 87%), and predominantly white. For HIV and syphilis, the predominant age groups were 21-30 years old (48 and 50%), HBV 21-40 years old (31%), and HCV 41-60 years old (25%). A high seroprevalence of HIV and syphilis was observed in the investigated key populations with a higher frequency in sex workers, men who have sex with men, and transgender. CONCLUSION: The progressive increase in syphilis cases emphasizes the need for effective interventions to enhance adherence to the use of condoms, and to expand diagnosis and treatment for these key populations.

Treating Affect Phobias: Therapeutic Alliance as a Moderator of the Emotional Experience Effect on Outcomes

Psychodynamic-oriented psychotherapies have demonstrated their efficacy in emotional disorders’treatment. However, it remains unclear what are the specific mechanisms accounting for change. Inpsychodynamic psychotherapeutic models as the Affect Phobia Therapy (APT), emphasis is placedon therapeutic relationship and the ability of clients to regain adaptive contact with their emotions.Specifically, it is argued that there must be a high therapeutic alliance for the emotions’ exposure tolead to positive outcomes. This exploratory study aimed to examine whether the level of therapeuticalliance (high vs. low) moderates the contribution of emotional experience to outcomes. Twenty-sixclients (65% females; Mage= 25; SD= 7.26) with depressive and/or anxiety symptoms undergoing apsychodynamic psychotherapy on a university counselling centre were included. After each weeklysession, clients answered measures of therapeutic alliance, emotional experience, and outcomes(Psychological Well-Being and Subjective Discomfort). Data were analysed using Hierarchical LinearModels for longitudinal data. Results indicated that effect of emotional experience on outcomesdepends on levels of therapeutic alliance. In clients with low therapeutic alliance, higher levelsof emotional experience contributed to a decrease in Psychological Well-Being and an increasein Subjective Discomfort across sessions. In clients with higher levels of alliance, both outcomesdecreased significantly between sessions, regardless of the emotional experience effect. Our findingshighlight that it is important to consider that exposure to adaptive emotions may have adverse effectswhen a strong alliance is not established (AU)

Primary plasma cell leukemias displaying t(11;14) have specific genomic, transcriptional, and clinical features.

Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that has not benefited from recent therapeutic advances in the field. Because it is very rare and heterogeneous, it remains poorly understood at the molecular level. To address this issue, we performed DNA and RNA sequencing of sorted plasma cells from a large cohort of 90 newly diagnosed pPCL and compared with MM. We observed that pPCL presents a specific genomic landscape with a high prevalence of t(11;14) (about half) and high-risk genomic features such as del(17p), gain 1q, and del(1p32). In addition, pPCL displays a specific transcriptome when compared with MM. We then wanted to characterize specifically pPCL with t(11;14). We observed that this subentity displayed significantly fewer adverse cytogenetic abnormalities. This translated into better overall survival when compared with pPCL without t(11;14) (39.2 months vs 17.9 months, P = .002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far.

The association of breastfeeding and other factors on respiratory virus positivity and severity in hospitalized children.

Acute respiratory infections (ARIs) are the most prevalent diseases in children under 5 years old, and viruses are the leading cause. ARIs arise due to numerous factors, including age, contact with siblings or other children in daycare centers, and environmental pollution. Breastfeeding reportedly confers protection against ARIs through bioactive components related to mucous epithelial immunity. This study aimed to evaluate the frequency and severity of viral ARIs in hospitalized children, together with the status and duration of exclusive breastfeeding (EBF) and other associated factors. It comprised an epidemiological surveillance study to investigate respiratory viruses in hospitalized children, in which demographic and clinical data were collected. Overall, 279 patients were included, 190 (68%) had positive viral results, and 132 (47%) were exclusively breastfed. In an adjusted analysis, it was observed that older children, the parents' educational level, and the presence of chronic disease were significantly related to EBF for more than 6 months. No significant differences were observed in viral positivity and disease severity concerning EBF. Whereas the EBF status was associated with a positive rate of virus detection, the significance did not remain after adjustment, and it was not considered a protective factor against ARIs. On the other hand, young age and exposure to tobacco were confirmed as risk factors of frequency and severity, respectively. Such confounding factors can impact the analysis and should be considered in future studies.

Toll-like receptor 4 selective inhibition in medullar microenvironment alters multiple myeloma cell growth.

Bone marrow (BM) mesenchymal stromal cells (MSCs) are abnormal in multiple myeloma (MM) and play a critical role by promoting growth, survival, and drug resistance of MM cells. We observed higher Toll-like receptor 4 (TLR4) gene expression in MM MSCs than in MSCs from healthy donors. At the clinical level, we highlighted that TLR4 expression in MM MSCs evolves in parallel with the disease stage. Thus, we reasoned that the TLR4 axis is pivotal in MM by increasing the protumor activity of MSCs. Challenging primary MSCs with TLR4 agonists increased the expression of CD54 and interleukin-6 (IL-6), 2 factors directly implicated in MM MSC-MM cell crosstalk. Then, we evaluated the therapeutic efficacy of a TLR4 antagonist combined or not with conventional treatment in vitro with MSC-MM cell coculture and in vivo with the Vk*MYC mouse model. Selective inhibition of TLR4 specifically reduced the MM MSC ability to support the growth of MM cells in an IL-6-dependent manner and delayed the development of MM in the Vk*MYC mouse model by altering the early disease phase in vivo. For the first time, we demonstrate that specific targeting of the pathological BM microenvironment via TLR4 signaling could be an innovative approach to alter MM pathology development.

Parenting Sense of Competence: Psychometrics and Invariance among a Community and an At-Risk Samples of Portuguese Parents.

Parenting sense of competence refers to parents' perception about their ability to perform the parenting role, one of the key dimensions in family dynamics. This construct is even more important in families at psychosocial risk, where the exercise of parenting can be more challenging. The Parenting Sense of Competence scale (PSOC) is a self-report measure that aims to assesses one's perceived efficacy and satisfaction with parenting. In this cross-sectional and instrumental study, we aimed to examine the psychometric properties of the PSOC among a Portuguese sample of community (n = 205) and at-psychological-risk (n = 273) parents. Participants completed the PSOC, the Enrich Marital Satisfaction Scale, the Parenting Stress Index, and the Parenting Alliance Inventory. Results from confirmatory factor analysis showed that a two-factor revised model obtained the best fit, with some items being removed. Our data confirmed that the PSOC has good psychometric properties, with acceptable reliability and validity and measurement invariance across the community and the at-risk samples. Findings of this psychometric exploration provided evidence that the PSOC is a reliable measure of easy application and interpretation for assessing the perceived competence of Portuguese parents.

As Escalas de Bem-Estar Infantil (EBI): Características Psicométricas da Versão Portuguesa / Child Well-Being Scales (CWBS): Psychometric Properties of the Portuguese Version

Resumo Em Portugal, existe escassez de instrumentos aferidos para avaliar os programas de proteção da infância. Este estudo analisou as características psicométricas das Escalas de Bem-Estar Infantil (EBI), destinadas à avaliação multidimensional de potenciais situações de maltrato e negligência, em 276 famílias em risco psicossocial. Foram também recolhidas medidas de eficácia, satisfação e sintomatologia parental. A análise fatorial exploratória sugere uma estrutura com três fatores, similar à versão original, com boa consistência interna (α entre 0,82 e 0,86) e bons indicadores de ajustamento (GFI = 0,97, RMSR = 0,06). Relativamente à validade de construto, foram encontradas correlações significativas que correspondiam à expectativa teórica. Os resultados sustentam a aplicabilidade das EBI para a avaliação e tomada de decisão nas medidas de proteção da criança.

Abstract There is a lack of validated instruments to evaluate child protection programs in Portugal. The present study analyzed the psychometric characteristics of the Child Well-Being Scales (CWBS), a multidimensional measure of potential situations of abuse and neglect, in 276 families at psychosocial risk. Measures of parental efficiency, satisfaction and parental symptomatology were also collected. Through exploratory factor analysis, a 3-factor solution, similar to the original version was identified, with high levels of internal consistency (α between 0.82-0.86) and good model fit (GFI = 0.97, RMSR = 0.06). Regarding construct validity, significant correlations were found that were in line with theoretical expectation. Our results support the utility of EBI as a guide to the assessment and decision-making regarding child protection measures.