Diagnostic Yield of Endoscopic Ultrasound in Common Bile Duct Dilation: A Real Breakthrough.

BACKGROUND: Endoscopic ultrasound (EUS) is important for the evaluation of patients with common bile duct (CBD) dilation. AIMS: The purpose of this study was to evaluate the diagnostic performance of EUS for CBD dilation in patients with negative initial studies. METHODS: This was a retrospective cohort study that included patients who underwent EUS for CBD dilation (≥ 7 mm if intact anatomy or ≥ 10 mm if prior cholecystectomy) in the absence of pathology on previous ultrasonography (US), computed tomography (CT), and/or magnetic resonance cholangiopancreatography (MRCP). RESULTS: A total of 109 patients were included, among whom 41 had a positive EUS: 33 choledocholithiasis (30.3%), 6 chronic pancreatitis (5.5%), and 2 ampullary cancer (1.8%). If the EUS was negative, no pathology was found during 1-year follow-up. Older age was associated with positive EUS (79 versus 71 years, p = 0.030). Patients with jaundice, cholelithiasis, and altered liver biochemistry were 16.2 (p = 0.002), 3.1 (p = 0.024), and 2.9 (p = 0.009) times more likely to have positive EUS, respectively. A total of 53 patients had a negative MRCP (48.6%); those with biliary abdominal pain and jaundice were 15.5 (p < 0.001) and 20.0 (p = 0.007) times more likely to have positive EUS, respectively. Considering asymptomatic patients with normal liver tests, CBD diameter ≥ 10 mm in US and ≥ 11 mm in CT can predict a positive EUS (AUC 0.754, p = 0.047 and AUC 0.734, p = 0.048). CONCLUSIONS: EUS is a useful diagnostic method for patients with unexplained CBD dilation, even if negative MRCP, and especially in patients with older age, abdominal pain, jaundice, cholelithiasis, and/or altered liver biochemistry. CBD diameter in US and CT had a moderate discriminative ability in predicting positive EUS in asymptomatic patients without altered liver biochemistry.

Chemotherapy-induced oral mucositis: hierarchical analysis of recurrence factors.

PURPOSE: This study aimed to analyze, through a hierarchical model, the risk factors associated with the recurrence of chemo-induced oral mucositis (OM) in children and adolescents. METHODS: A retrospective cohort with 31 individuals of both sexes, aged 1-18 years, who were undergoing chemotherapy, and presented OM lesions was conducted. Data collection included analysis of medical records, interviews, and intraoral examination. Information regarding patients' socioeconomic and demographic profile, underlying disease, antineoplastic regimen, hematological condition, and oral health status were collected. To assess the association of independent variables with the outcome, the Chi-square, Fisher's Exact, and Mann-Whitney tests were used, in addition to a binary logistic regression model, with a maximum error of 5% and a 95% confidence interval. RESULTS: Significant associations were observed between the history of OM and the diagnosis of the child/adolescent, neutrophil count, previous cancer treatments and the chemotherapy scheme in use (p < 0.05). Binary logistic regression revealed a 13.69 higher risk of developing OM recurrence in individuals who received high-dose methotrexate (MTX) therapy. CONCLUSION: Socioeconomic and demographic factors did not influence OM recurrence. However, clinical variables, such as neutropenia, diagnosis of leukemia, and high-dose MTX protocols increase the chance of OM new cases.

Músculos Isquiotibiales. Análisis de su Uso y Propuesta de Inclusión en Terminologia Anatomica / Hamstring Muscles. Analysis of its Use and Proposal for Inclusion in Terminologia Anatomica

Terminologia Anatomica Internacional publicada el año 2019 en inglés y el 2001 en español contiene los nombres oficiales de las estructuras anatómicas. Sin embargo, existen términos que no están incluidos en esta terminología, y son ampliamente utilizados, es el caso del término músculos isquiotibiales. El objetivo de este trabajo fue analizar la utilización del término músculos isquiotibiales, músculos del compartimento femoral posterior y músculos del compartimento femoral flexor. Se realizó una revisión narrativa que incluyó 37 libros de anatomía, 3 diccionarios de terminología médica y biológica, 10 bases de datos y 15 recursos digitales. En los libros publicados después del año 2001 el 55,6 % utilizaba el término músculos isquiotibiales y el 18,5 % utilizó músculos del compartimento femoral posterior. En ningún diccionario se encontró el uso de los términos músculos isquiotibiales, músculos del compartimento femoral posterior ni músculos del compartimento femoral flexor. En las bases de datos se encontraron 12.104 artículos con el término músculos isquiotibiales, cinco con el término músculos del compartimento femoral posterior y uno con el término músculos del compartimento femoral flexor. En los recursos digitales de anatomía el 50 % utilizaba el término músculos isquiotibiales, el 37,5 % el término músculos del compartimento femoral posterior y el 12,5 % músculos del compartimento femoral flexor. En conclusión, el uso del término músculos isquiotibiales supera ampliamente al uso de los términos indicados por Terminologia Anatomica Internacional. Adicionalmente, este término es anatómicamente descriptivo y unívoco. Al respecto, parece apropiado valorar la incorporación del término músculos isquiotibiales en Terminologia Anatomica Internacional.

SUMMARY: The Terminologia Anatomica published in 2019 in English and 2001 in Spanish conTAIns the official names of anatomical structures. However, there are terms that are not included in this terminology, and are widely used, such as the term "hamstring muscles. The objective of this work was to analyze the use of the terms hamstring muscles, muscles of the posterior compartment of thigh and muscles of the flexor compartment of thigh. A narrative review was carried out that included 37 anatomy books, 3 dictionaries of medical and biological terminology, 10 databases and 15 digital resources. Results: In the books published after 2001, 55.6 % used the term hamstring muscles, 18.5 % muscles of the posterior compartment of thigh and 0 % muscles of the flexor compartment of thigh; In no dictionary was the use of the terms hamstring muscles, muscles of the posterior compartment of thigh or muscles of the flexor compartment of thigh found; In the databases, 12,104 articles were found with the term hamstring muscles, 5 with the term muscles of the posterior compartment of thigh and 1 with the term muscles of the flexor compartment of thigh; In the digital anatomy resources, 50 % used the term hamstring muscles, 37.5 % the term muscles of the posterior compartment of thigh and 12.5 % muscles of the flexor compartment of thigh. In conclusion, the use of the term hamstring muscles far exceeds the use of the terms indicated by the International Anatomical Terminology. Additionally, this term is anatomically descriptive and univocal. In this regard, it seems appropriate to assess the incorporation of the term hamstring muscles in Terminologia Anatomica.

Ocimum gratissimum essential oil in the transport water of Brycon hilarii: implications at water quality, blood parameters and residues in tissue and plasma.

Transporting live fish is a common practice in fish farming, and is certainly one of the main problems that affect fish homeostasis. In this scenario, the use of natural additives has shown promise in improving fish resistance to adverse situations. This study aimed to assess the impact of Ocimum gratissimum L. essential oil (OGEO) on water quality, hematological parameters, and residue levels in the plasma, fillet, and liver of juvenile piraputanga (Brycon hilarii) during a two-hour transportation period. The fish were divided into plastic bags (4 L) and exposed to three different OGEO concentrations (10, 20, and 30 mg L-1), while a control group received no OGEO (three repetitions each). After the two-hour transportation, blood samples were collected, as well as portions of the fillet and liver for quantifying essential oil compounds, which were also measured in the plasma. Oxygen levels remained high throughout the transportation period, in all groups, while the pH decreased. Hemoglobin, MCHC, and MCH increased in fish exposed to OGEO concentrations of 20 and 30 mg L-1, compared to the control group. However, lymphocyte counts and the concentrations of essential oil compounds in plasma, fillet, and liver increased with higher OGEO concentrations. The use of 10 mg L-1 OGEO in the two-hour transport water is promising to ensure the survival and well-being of Brycon hilarii juveniles (weighing 16 g), showing to be safe and effective. The residual concentration of eugenol the major compound of OGEO in the fillet remains below the maximum limit of the recommended daily intake.

Issue 3-The occupational burden of respiratory diseases, an update.

INTRODUCTION AND AIMS: Workplace exposures are widely known to cause specific occupational diseases such as silicosis and asbestosis, but they also can contribute substantially to causation of common respiratory diseases. In 2019, the American Thoracic Society (ATS) and the European Respiratory Society (ERS) published a joint statement on the occupational burden of respiratory diseases. Our aim on this narrative review is to summarise the most recent evidence published after the ATS/ERS statement as well as to provide information on traditional occupational lung diseases that can be useful for clinicians and researchers. RESULTS: Newer publications confirm the findings of the ATS/ERS statement on the role of workplace exposure in contributing to the aetiology of the respiratory diseases considered in this review (asthma, COPD, chronic bronchitis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, infectious pneumonia). Except for COPD, chronic bronchitis and infectious pneumonia, the number of publications in the last 5 years for the other diseases is limited. For traditional occupational lung diseases such as silicosis and asbestosis, there are old as well as novel sources of exposure and their burden continues to be relevant, especially in developing countries. CONCLUSIONS: Occupational exposure remains an important risk factor for airways and interstitial lung diseases, causing occupational lung diseases and contributing substantially in the aetiology of common respiratory diseases. This information is critical for public health professionals formulating effective preventive strategies but also for clinicians in patient care. Effective action requires shared knowledge among clinicians, researchers, public health professionals, and policy makers.

Characterisation of Portuguese radiotherapy departments: Organisation, occupational exposure values and diagnostic reference levels for breast and prostate computed tomography planning.

INTRODUCTION: Portugal currently hosts 24 active radiotherapy departments, 8 public and 16 privates, presenting potential radiation exposure risks to multidisciplinary teams. Patients in these treatments also face ionising radiation during treatment planning and verification. METHODS: Authorisation and ethical approval were secured for a national online survey, disseminated to radiotherapy departments across Portugal. The survey encompassed three sections: equipment, staff, and radiographer role characterisation; occupational exposure values for one month; and exposure parameters, including computed tomography (CT) dose values [CT dose index (CTDIvol) and dose length product (DLP)] for breast and prostate cancer CT planning. Local Diagnostic Reference Levels (DRLs) derived were based on the 75th percentile of median dose values. RESULTS: The study garnered a 50% response rate from public institutions, 12,5% from private and 25% from all active radiotherapy institutions in Portugal. All departments employ Three-Dimensional Conformal Radiation Therapy (3D-CRT) and incorporate Intensity Modulated Radiation Therapy (IMRT) and/or Volumetric Modulated Arc Therapy (VMAT) irradiation techniques. Additionally, half of the departments also perform Brachytherapy (BT). Radiographers demonstrated an occupational dose of zero mSv. CT planning dose values were 13 mGy and 512 mGy cm for breast CT and 16 mGy and 689 mGy cm for prostate CT, pertaining to CTDIvol and DLP, respectively. CONCLUSION: Most aspects of national radiotherapy characterisation align with the established literature. Occupational exposure values exhibited consistency across radiotherapy modalities. An approach to national DRLs was formulated for breast and prostate CT planning, yielding values congruent with recent European studies. IMPLICATIONS FOR PRACTICE: This study offers vital insights for analysing occupational contexts and risk prevention, serving as the initial characterisation of the national radiotherapy landscape. It also pioneers the calculation of DRLs for CT planning in radiotherapy to optimise procedures.

Long-term follow-up of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease: An analysis of survival and disability milestones.

BACKGROUND: Data on the long-term survival and incidence of disability milestones after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) is limited. OBJECTIVES: To estimate mortality and assess the frequency/time-to-development of disability milestones (falls, freezing, hallucinations, dementia, and institutionalization) among PD patients post STN-DBS. METHODS: A longitudinal retrospective study of patients undergoing STN-DBS. For mortality, Cox proportional hazards regression analysis was performed. For disease milestones, competing risk analyses were performed and cumulative incidence functions reported. The strength of association between baselines features and event occurrence was calculated based on adjusted hazard ratios. RESULTS: The overall mortality for the 109 patients was 16 % (62.1 ± 21.3 months after surgery). Falls (73 %) and freezing (47 %) were both the earliest (40.4 ± 25.4 and 39.6 ± 28.4 months, respectively) and most frequent milestones. Dementia (34 %) and hallucinations (32 %) soon followed (56.2 ± 21.2 and mean 60.0 ± 20.7 months after surgery, respectively). Higher ADL scores in the OFF state and higher age at surgery were associated with falls, freezing, dementia and institutionalization. CONCLUSIONS: Long-term mortality rate is low after STN-DBS. Disease milestones occur later during the disease course, with motor milestones appearing first and at a higher frequency than cognitive ones.

Nitrogen metabolism in maize plants submitted to drought, brassinosteroids and azospirillum.

The water deficit in particular, reduces the productivity of vegetable crops. To minimize these harmful effects on agriculture, several agronomic and physiological practices are being studied, such as the use of bacteria and water stress attenuators, such as brassinosteroids. Considering the socioeconomic relevance of corn culture and its sensitivity when exposed to water deficit, the objective of the present study was to evaluate the action of brassinosteroids and azospirillum on nitrogen metabolism in corn plants subjected to water stress conditions. The experiment was carried out in a greenhouse, in a period of 47 days, with corn plants, using the hybrid K9606 VIP3. The design was completely randomized, in a 2x2x3 factorial scheme, with six replications. The first factor corresponds to two water regimes (presence and absence of water deficit). The second corresponds to inoculation via seed of Azospirillum brasiliense and absence of inoculation. And the third corresponds to the application of three concentrations of brassinosteroids (0, 0.3 and 0.6 µM). Were determined Nitrate; nitrate reductase; free ammonium; total soluble aminoacids; soluble proteins; proline; glycine betaine and glutamine synthetase. The lack of water in plants provided a reduction in the protein and nitrate reductase contents, in leaves and roots. For ammonium, plants with water deficit inoculated at a concentration of 0.3 µM, obtained an increase of 7.16 (70.26%) and 13.89 (77.04%) mmol NH4 + .Kg-1. DM (Dry mass) on the leaf and root respectively. The water deficit in the soil provided significant increases in the concentrations of glycine betaine, nitrate, proline and aminoacids, both in the leaves and in the roots of the corn plants. On the other hand, the contents of glutamine synthetase had a reduction in both leaves and roots.

Definition of protocols for cryopreservation and three-dimensional in vitro culture of prepubertal goat testicular tissue after histomorphological, ultrastructural, and functional analysis.

This study aims to define the best method (slow freezing or vitrification) and fragment size (1, 5, or 9 mm³) for prepubertal goat testis cryopreservation, as well as to evaluate testicular morphological integrity after cryopreservation and in vitro culture (IVC). Initially (experiment I), 1, 5, or 9 mm³ testis fragments were cryopreserved by slow freezing using a Mr. Frosty container with 20% Dimethylsulfoxide (DMSO) or vitrified using the Ovarian Tissue Cryosystem (OTC) device, (Equilibration solution - ES: 10% DMSO and 10% ethylene glycol - EG; Vitrification solution - VS: 20% DMSO and 20% EG) and then subjected to morphological analysis, type I and III collagen quantification and gene expression (Oct4, C-kit, Bax, and Bcl-2). Subsequently, (experiment II), fresh or cryopreserved by slow freezing testis fragments were cultured in vitro and submitted to morphological analysis by scanning electron microscopy. The data from the experiment I revealed fewer morphological alterations in 1 and 5 mm³ fragments after vitrification and slow freezing, respectively. The percentage of type I collagen fibers in 5 and 9 mm³ frozen was higher than in fresh or vitrified fragments. For type III collagen, fresh or frozen fragments of 1 and 5 mm3 showed a higher percentage than fragments of 9 mm3. Gene expression for Oct4 and C-kit after slow freezing or vitrification in the 5 mm3 fragments was lower than that observed in the fresh fragments. The Bax:Bcl-2 ratio in the 1 and 9 mm³ fragments was lower than in the 5 mm³ fragments for fresh fragments or after freezing. In experiment II, fragments cultured in vitro, previously frozen or not, showed more morphological alterations than fresh or frozen fragments. We concluded that slow freezing of 5 mm³ fragments was the best protocol for cryopreserving prepubertal goat testis and although the results of IVC are encouraging, it still needs improvement to restore testicular function after cryopreservation.

Bothrops jararacussu snake venom decreases CD1d, CD83, and CD86 expression on bone marrow-derived dendritic cells.

This study was designed to characterize mice bone marrow (BM) and bone marrow-derived dendritic cells (BMDC) and to compare the surface markers expression and inflammatory cytokine liberation in response to LPS and Bothrops jararacussu venom (BjV) stimulation. Typical morphology was observed in BM and BMDCs from the 4th up to the 8th day of culture using recombinant mouse GM-CSF and IL-4. A high basal level of MHC-II, CD1d, CD83, CD11c, CD80, and low CD86 was expressed by BM cells. After stimulation with GM-CSF/IL-4 for BMDCs differentiation, the BM cells differentiated into BMDCs presented MHC-II, CD1d, CD83, CD11c, CD86, and CD80 expression on the 4th - 8th day accompanied with high levels of TNF-α liberated. The difference between the surface markers' expression was observed in this time course in which CD1d, CD11c, and CD80 remained in high levels of expression, while MHC-II and CD83 showed moderate expression during the differentiation period. Also, cytokines liberation was monitored over the period of the BMDCs culture, and on the 6th day, low levels of IL-6 and IL-1ß were found, while high levels of TNF-α on the 4th and 8th days, both of which contributed to the maturity of the BMDCs. Maturation of DCs with LPS showed significant upregulation of surface markers (MHC-II, CD1d, CD83, CD86, CD80) and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α) liberation. On the other hand, BjV induced a decrease in CD1d, CD11c, CD83, and CD86 expression in mature BMDCs which was not observed when LPS was used to stimulate BMDCs which probably induces impairment in T-cell activation.

The spatial distribution of microplastics in topsoils of an urban environment - Coimbra city case-study.

Due to their seemingly ubiquitous nature and links to environmental and human health problems, microplastics are quickly becoming a major concern worldwide. Artificial environments, such as those found in urban environments, represent some of the main sources of microplastic. However, very few studies have focused on the occurrence of microplastics in urban soils. The aim of the current research was to evaluate the microplastic contamination in urban soils from artificial and natural land uses throughout Coimbra city, Portugal. Sixty-seven spaces and ten land use areas were evaluated. The artificial land use areas were dumps, landfills, parking lots, industries and construction areas, and the natural land use areas were forests, urban parks, moors (wetlands), pastures and urban agricultural areas. Microplastic extraction was done by density separation. Quantification and size measurements of microplastics was carried out using a microscope. Polymer types were identified by µ-FTIR for 25% of the samples. The microplastic content ranged from 5 × 103 to 571 × 103 particles·kg-1, with a mean of 106 × 103 particle·kg-1. The green park was the land use with the highest concentration of microplastics (158 × 103 particle·kg-1) and the forest was the one with the lowest concentration (55 × 103 particle·kg-1). The landfill (150 × 103 particle·kg-1), industry (127 × 103 particle·kg-1) and dump (126 × 103 particle·kg-1) were the artificial spaces with the highest levels of microplastics. The main polymers detected were polypropylene and polyethylene, followed by polyvinyl chloride and rubber, and the main sizes measured between 50 and 250 µm. Our results indicate that natural spaces can contain higher amounts of microplastics as compared to artificial spaces in the urban environment. This suggests that microplastics are easily transported through the urban landscape and that urban green spaces can retain microplastics in their soils. Land use planning may present an opportunity to better control the levels of microplastics in urban environments.

ESMO Expert Consensus Statements on Cancer Survivorship: promoting high-quality survivorship care and research in Europe.

BACKGROUND: The increased number of cancer survivors and the recognition of physical and psychosocial challenges, present from cancer diagnosis through active treatment and beyond, led to the discipline of cancer survivorship. DESIGN AND METHODS: Herein, we reflected on the different components of survivorship care, existing models and priorities, in order to facilitate the promotion of high-quality European survivorship care and research. RESULTS: We identified five main components of survivorship care: (i) physical effects of cancer and chronic medical conditions; (ii) psychological effects of cancer; (iii) social, work and financial effects of cancer; (iv) surveillance for recurrences and second cancers; and (v) cancer prevention and overall health and well-being promotion. Survivorship care can be delivered by structured care models including but not limited to shared models integrating primary care and oncology services. The choice of the care model to be implemented has to be adapted to local realities. High-quality care should be expedited by the generation of: (i) focused and shared European recommendations, (ii) creation of tools to facilitate implementation of coordinated care and (iii) survivorship educational programs for health care teams and patients. The research agenda should be defined with the participation of health care providers, researchers, policy makers, patients and caregivers. The following patient-centered survivorship research areas were highlighted: (i) generation of a big data platform to collect long-term real-world data in survivors and healthy controls to (a) understand the resources, needs and preferences of patients with cancer, and (b) understand biological determinants of survivorship issues, and (ii) develop innovative effective interventions focused on the main components of survivorship care. CONCLUSIONS: The European Society for Medical Oncology (ESMO) can actively contribute in the efforts of the oncology community toward (a) promoting the development of high-quality survivorship care programs, (b) providing educational material and (c) aiding groundbreaking research by reflecting on priorities and by supporting research networking.

In vitro- and in vivo-derived early antral follicles have comparable in vitro follicular growth and oocyte maturation rates in goats.

Recent in vitro follicle culture (IVFC) studies in caprine have yielded lower maturation rates using late preantral follicles compared to early antral follicles. Thus, research focusing on developing stage-specific customized culture systems able to improve the efficiency of IVFC for late preantral follicles are warranted. This study aimed to compare the morphometric features, estradiol production, and gene expression between early antral caprine follicles produced in vitro and in vivo. In vitro-derived early antral follicles were produced after a 6-day in vitro culture of late preantral follicles, while in vivo-derived early antral follicles were yielded immediately after isolation from the ovaries; antral follicles were, thereafter, cultured for 18 days. In vitro-derived antral follicles were cultured either in a medium developed for preantral follicles (PF medium) or in a medium developed for antral follicles (AF medium). In vivo-derived early antral follicles, on the other hand, were cultured in AF medium (Control treatment). Results demonstrated that in vitro-derived antral follicles cultured in PF medium produced higher estradiol concentration, and m-RNA expression for matrix metalloproteinase-9 (MMP-9), and insulin receptor when compared to both in vitro- and in vivo-derived antral follicles cultured in AF medium. Remarkably, in vitro-derived antral follicles cultured in PF medium had similar MII and oocytes ≥110 µm rates compared with in vivo-derived antral follicles (Control treatment). In conclusion, when cultured in a single and appropriate medium (i.e., PF medium), in vitro-derived early antral follicles had comparable oocyte maturation rates to the in vivo-derived early antral follicles.

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra.

High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100-300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.

Androgen-deprivation therapy and cognitive decline in the NEON-PC prospective study during the COVID-19 pandemic.

BACKGROUND: Androgen-deprivation therapy (ADT) has been associated with cognitive decline, but results are conflicting. This study describes changes in cognitive performance in patients with prostate cancer, according to ADT, during the first year after prostate cancer diagnosis. PATIENTS AND METHODS: Patients with prostate cancer treated at the Portuguese Institute of Oncology of Porto (n = 366) were evaluated with the Montreal Cognitive Assessment (MoCA), before treatment and after 1 year. All baseline evaluations were performed before the coronavirus disease 2019 (COVID-19) pandemic and 69.7% of the 1-year assessments were completed after the first lockdown. Cognitive decline was defined as the decrease in MoCA from baseline to the 1-year evaluation below 1.5 standard deviations of the distribution of changes in the whole cohort. Participants scoring below age- and education-specific normative reference values in the MoCA were considered to have cognitive impairment. Age- and education-adjusted odds ratios (aORs) were computed for the association between ADT and cognitive outcomes. RESULTS: Mean MoCA scores increased from baseline to the 1-year evaluation (22.3 versus 22.8, P < 0.001). Cognitive decline was more frequent in the ADT group, and even more after the onset of the COVID-19 pandemic (aOR 6.81 versus 1.93, P for interaction = 0.233). The 1-year cumulative incidence of cognitive impairment was 6.9% (9.1% before and 3.7% after the pandemic onset), which was higher among patients receiving ADT, but only after the pandemic (aOR 5.53 versus 0.49, P for interaction = 0.044). CONCLUSIONS: ADT was associated with worse cognitive performance of patients with prostate cancer, mostly among those evaluated after the first COVID-19 lockdown.

In vitro cytotoxic effects of 5-Fluorouracil on isolated murine ovarian preantral follicles.

5 fluorouracil (5FU), an antineoplastic drug, is often utilized in the therapeutic regimen for several types of cancer, including the hepatoblastoma in children. The effects of 5FU on the population of ovarian preantral follicles, which is the largest oocyte reservoir, is still poorly understood. The integrity of the ovarian preantral follicle pool is important for lifelong fertility. The better understanding of such effects may favor intervention strategies to protect fertility in 5FU-treated children and women coping with cancer. To analyze the effects of 5FU on isolated murine secondary follicles in vitro, ovaries were collected from young mice (28-30 days old), and secondary follicles were isolated and cultured for 12 days in basic culture medium, with or without 5FU at concentrations of 0.3 mM, 1 mM, 3 mM, 10 mM, and 30 mM. In the in vitro study, we analyzed the percentage of morphologically normal follicles, antrum formation, follicular diameter, and hormone production. On day 12, oocytes were recovered for in vitro maturation. 5FU treatment did not alter the percentage of morphologically normal follicles. On day 12, only 1, 10, and 30 mM 5FU significantly reduced the percentage of antrum. From day 4 onwards, 5FU treatments significantly reduced follicle diameter. The meiosis resumption rate was significantly lower in all 5FU treatments. 5FU concentrations ≥3 mM reduced estradiol levels. In conclusion, 5FU does not affect follicular morphology. However, 5FU deleteriously affects follicular growth, estradiol production, and oocyte maturation in isolated ovarian follicles.

Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer.

BACKGROUND: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants. PATIENTS AND METHODS: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy. RESULTS: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group. CONCLUSION: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing.

Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy.

Gastrointestinal mucositis is a complication of anticancer treatment, with few validated in vitro systems suitable to study the complex mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX). Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. The protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005-50 µg/mL) folinic acid. The impact of microbial-derived short-chain fatty acids was evaluated by supplementation with butyrate in the organoid model. MTX caused a dose-dependent reduction in cell metabolic activity and citrulline production that was salvaged by folinic acid treatment. Overall, MTX causes significant organoid damage, which can be reversed upon removal of MTX. The protective effect of folinic acid suggest that the organoids respond in a clinical relevant manner. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever.

PURPOSE: Conditioning therapy with high-dose melphalan (HDM) is associated with a high risk of gut toxicity, fever and infections in haematopoietic stem cell transplant (HSCT) recipients. However, validated preclinical models that adequately reflect clinical features of melphalan-induced toxicity are not available. We therefore aimed to develop a novel preclinical model of melphalan-induced toxicity that reflected well-defined clinical dynamics, as well as to identify targetable mechanisms that drive intestinal injury. METHODS: Male Wistar rats were treated with 4-8 mg/kg melphalan intravenously. The primary endpoint was plasma citrulline. Secondary endpoints included survival, weight loss, diarrhea, food/water intake, histopathology, body temperature, microbiota composition (16S sequencing) and bacterial translocation. RESULTS: Melphalan 5 mg/kg caused self-limiting intestinal injury, severe neutropenia and fever while impairing the microbial metabolome, prompting expansion of enteric pathogens. Intestinal inflammation was characterized by infiltration of polymorphic nuclear cells in the acute phases of mucosal injury, driving derangement of intestinal architecture. Ileal atrophy prevented bile acid reabsorption, exacerbating colonic injury via microbiota-dependent mechanisms. CONCLUSION: We developed a novel translational model of melphalan-induced toxicity, which has excellent homology with the well-known clinical features of HDM transplantation. Application of this model will accelerate fundamental and translational study of melphalan-induced toxicity, with the clinical parallels of this model ensuring a greater likelihood of clinical success.

Behavioral aspects of waterbirds / Aspectos comportamentais de aves aquáticas

Abstract Estuaries are used by waterbirds as foraging, resting and nesting sites, serving also as shelter for migratory birds. The dynamics of this avifauna in an aquatic environment may be associated with the differences of time of day, tide height, temperature, wind speed and use of the site by different species. This study had the objective of evaluating behavioral aspects of aquatic birds, relating the influence of environmental variables with their activities. Bird counts were performed at the mouth of two important rivers of the state of Santa Catarina, Brazil, during two-hour intervals throughout the day in monthly samplings between June (2015) and May (2016). A total of 44 species were recorded, ten of which were migratory. The most recorded behaviors were foraging and resting. The Kruskal-Wallis analysis indicated no significant difference in behavior between the sampling intervals. The Bray-Curtis similarity test resulted in three groups: 1) - species that foraged most of the time; 2) - species that rested most of the time; and 3) - same time in both activities. The Indicator Species Analysis showed that 17 species were associated with only one microhabitat and 15 species with more than one. The Canonical Correlation Analysis indicated that only tide height, temperature and rainfall variables were correlated with the behaviors performed and only the resting activity was positively correlated with all variables. This may be associated with thermoregulation and the ability of some species to stay in midlitoral at high tide. The results demonstrate that different waterbird species used the studied areas in different ways. Thus, the heterogeneity of microhabitats in an aquatic environment of extreme importance for the coexistence and maintenance of the diversity of waterbirds.

Resumo Estuários são utilizados por aves aquáticas como locais de forrageio, descanso e nidificação, servindo, também, como pontos de parada para aves migratórias. A dinâmica dessa avifauna em um ambiente pode estar associada a diferenças entre horários do dia, altura da maré, temperatura, velocidade do vento e uso do local. Esse trabalho teve o objetivo de avaliar aspectos comportamentais de aves aquáticas, relacionando a influência de variáveis ambientais com suas atividades. Amostragens mensais foram realizadas na foz de dois importantes rios do Estado de Santa Catarina, Brasil, entre junho de 2015 e maio de 2016, em intervalos de duas horas no decorrer do dia. Um total de 44 espécies foram registradas, dez das quais foram migratórias. Os comportamentos mais observados foram forrageio e descanso. A análise de Kruskall-Wallis não indicou diferenças significativas no comportamento entre os horários de amostragem. O teste de similaridade Bray-Curtis resultou em três agrupamentos: 1) - espécies que forragearam na maior parte do tempo; 2) - espécies que descansaram na maior parte do tempo; e 3) - mesma quantidade de tempo em ambas atividades. A Análise de Espécies Indicadoras mostrou que 17 espécies estiveram associadas com apenas um microhabitat e 15 espécies com mais de um. A Análise de Correlação Canônica indicou que apenas as variáveis maré, temperatura e precipitação foram significativamente correlacionadas com os comportamentos demonstrados e apenas a atividade de descanso foi positivamente correlacionada com as todas as variáveis. Isso pode estar associado com a termorregulação e com a habilidade de algumas espécies de permanecer no mediolitoral durante a maré cheia. Os resultados demonstram que diferentes espécies de aves aquáticas utilizaram as áreas estudadas de diferentes maneiras. Assim, a heterogeneidade de microhabitats em um ambiente aquático é de extrema importância para a coexistência e a manutenção da diversidade de aves.