Background Prostate cancer (PC) is the most commonly diagnosed male malignancy and an important cause of mortality. Androgen deprivation therapy is the first line treatment but, unfortunately, a large part of patients evolves to a castration-resistant stage, for which no effective cure is currently available. The DNA/RNA helicase DHX9 is emerging as an important regulator of cellular processes that are often deregulated in cancer. Methods To investigate whether DHX9 modulates PC cell transcriptome we performed RNA-sequencing analyses upon DHX9 silencing in the androgen-responsive cell line LNCaP. Bioinformatics and functional analyses were carried out to elucidate the mechanism of gene expression regulation by DHX9. Data from The Cancer Genome Atlas were mined to evaluate the potential role of DHX9 in PC. Results We found that up-regulation of DHX9 correlates with advanced stage and is associated with poor prognosis of PC patients. High-throughput RNA - sequencing analysis revealed that depletion of DHX9 in androgen-sensitive LNCaP cells affects expression of hundreds of genes, which significantly overlap with known targets of the Androgen Receptor (AR). Notably, AR binds to the DHX9 promoter and induces its expression, while Enzalutamide-mediated inhibition of AR activity represses DHX9 expression. Moreover, DHX9 interacts with AR in LNCaP cells and its depletion significantly reduced the recruitment of AR to the promoter region of target genes and the ability of AR to promote their expression in response to 5α-dihydrotestosterone. Consistently, silencing of DXH9 negatively affected androgen-induced PC cell proliferation and migration. Conclusions Collectively, our data uncover a new role of DHX9 in the control of the AR transcriptional program and establish the existence of an oncogenic DHX9/AR axis, which may represent a new druggable target to counteract PC progression.
Background Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance—IR or diabetes mellitus—T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. Methods Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. Results Compared with EU and IR, T2D was associated with increased filling pressures (E/e′ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p < 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p < 0.05). Likewise, impairment in peak oxygen consumption (peak VO 2 ) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p < 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO 2 in the T2D group (+ 13% increase in RV dimension, − 21% decline in TAPSE/PAPS ratio and − 20% decrease in peak VO 2 ). Conclusion The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis. Trial registration ClinicalTrials.gov identifier: NCT023358017
Batteries are complex systems that need to be properly managed to guarantee safe and optimal operations. Model predictive control (MPC) is an advanced control strategy that, thanks to its characteristics, can be embedded into battery management systems (BMS) to derive optimal charging strategies. However, deterministic MPC, which relies on a nominal model only, is not adequate in a realistic scenario in which cells parameters are not known exactly. In this paper, stochastic MPC is proposed for the optimal charging of a Li-ion battery pack to account for the presence of parameter uncertainties. The adopted scheme relies on the polynomial chaos expansion paradigm for the propagation of uncertainties through the model equations and allows to satisfy safety constraints with a guaranteed probability. The results highlight the advantages of stochastic MPC over different scenarios when compared to a deterministic MPC approach.
Introduction/purpose Postmortem computed tomography (PMCT) is a valuable tool for analyzing the death of patients with SARS-CoV-2 infection. The purpose of this study was to investigate the correlation between PMCT lung findings in autopsy cadavers positive for SARS-CoV-2 infection and the severity of COVID-19 lung disease by histopathological analysis. Materials and methods We reviewed chest PMCT findings, paying particular attention to the lung parenchyma, in 8 autopsy cases positive for SARS-CoV-2. Correlations between chest PMCT and histopathological findings were assessed. Clinical conditions and comorbidities were also recorded and discussed. The primary cause of death was finally considered. Results In 6/8 cases, pulmonary PMCT findings were massive consolidation (4/8) and bilateral diffuse mixed densities with a crazy-paving pattern (2/8). These cases showed severe pulmonary signs of COVID-19 at histopathological analysis. In the remaining 2/8 cases, pulmonary PMCT findings were scant antideclive ground-glass opacities in prevalent gradient densities attributed to hypostasis. In 4/8 cases with massive consolidations, important comorbidities were noted. In 6/8 cases with severe pulmonary histopathological signs of lung COVID-19, autopsy found that the cause of death was cardiorespiratory failure. In the remaining 2/8 cases, histopathological analysis revealed lung alterations due to edema and some signs of SARS-CoV-2 infection; the cause of death was not attributed to SARS-CoV-2 infection (Table 1). Discussion and conclusion Chest PMCT findings correlate with the severity of COVID-19 lung disease at histopathology examination. According to our results, there may also be a relationship between cause of death and PMCT findings in COVID-19, which must be critically analyzed considering clinical antemortem data.
Background Cerebral vasospasm is one of the frequent complications that can occur following subarachnoid hemorrhage (SAH). With new protocols in the management of SAH, the combined risk of death and long-term disability has been reduced by about 10% compared with the past. Objective This work aims to report the latest updates on the vasospasm developing after the SAH in patients in the ICU department. In this short review, we reviewed the latest scientific findings on the mechanisms of vasospasm, and, in addition, we considered it necessary to review the literature to report the tools for early diagnosis of vasospasm and the best treatment strategies to prevent the negative outcome in patients admitted to ICU. Scope The aim of this narrative review is to report the main characteristics of vasospasm, new diagnostic methods and, especially, more effective treatment of vasospasm. Materials and methods The peer-reviewed articles analyzed were selected from PubMed, google scholar, Embase, Scopus databases in the previous 20 years and using the keywords words "vasospam", "vasospasm diagnosis", "vasospasm and SAH", "vasospasm treatment", non-traumatic brain injury. Among the 78 papers identified, 43 articles were selected; after title - abstract examination and removing the duplicates, only 31 articles were examined. Results Vasospasm can be classified according to clinical (asymptomatic vs symptomatic) and diagnostic (angiographic vs ultrasound) methods. Various procedures such as TCD and CT perfusion are used for early diagnosis and close monitoring of this condition. The treatment of vasospasm consists of both prevention (nimodipine, statitis, magnesium sulphate) and active treatment (mainly endovascular). Conclusion As the review shows, vasospasm is a complication of SAH, a complication that is difficult to recognise early and treat with the best outcome. However, with the equipment we have, it has been possible to improve the outcome, even if it is still not ideal, of patients who develop vasospasm. Several studies are in the final stages to improve the outcome of this unfortunately frequent condition.
Luxury firms, including high‐end watch manufacturers, use crowdfunding as an alternative source of entrepreneurial finance. Respondents indicated that intention to crowdfund luxury brand start‐ups have both external and internal antecedents with the slight majority focusing on the extrinsic factors. The “luxury” proposition exhibits integrated motivation, which is conceptualized and personalized to the tastes of each investor.
Precision medicine is a medical model that proposes the customization of medical treatments to the individual patient, as opposed to a one-drug-fits-all model. Such a “personalized medicine” approach has been widely adopted in several medical fields, such as cancer medicine, but the implementation of precision medicine in cardiovascular medicine has not been similarly straightforward. Because pharmacogenomics plays an important role in the safety and efficacy of cardiovascular drug therapy, there has been a great interest in the use of tools aiming at personalizing antiplatelet therapy. Moreover, antiplatelet therapy is essential for the treatment of cardiovascular patients to reduce the risk of thrombotic complications, particularly those undergoing percutaneous coronary intervention, but it is inevitably associated with increased bleeding risk. In this review, the authors discuss the rationale, summarize the evidence and discuss the current and future directions for the personalization of antiplatelet treatment regimens in patients undergoing percutaneous coronary intervention.
Fecal microbiota transplantation (FMT) consists of infusion of feces from a donor to a recipient patient in order to restore the resident microbial population. FMT has shown to be a valid clinical option for Clostridioides difficile infections (CDI). However, this approach shows several criticalities, such as the recruiting and screening of voluntary donors. Our aim was to evaluate the therapeutic efficacy of a synthetic bacterial suspension defined “Bacterial Consortium” (BC) infused in the colon of CDI patients. The suspension was composed by 13 microbial species isolated by culturomics protocols from healthy donors’ feces. The efficacy of the treatment was assessed both clinically and by metagenomics typing. Fecal samples of the recipient patients were collected before and after infusion. DNA samples obtained from feces at different time points (preinfusion, 7, 15, 30, and 90 days after infusion) were analyzed by next-generation sequencing. Before infusion, patient 1 showed an intestinal microbiota dominated by the phylum Bacteroidetes. Seven days after the infusion, Bacteroidetes decreased, followed by an implementation of Firmicutes and Verrucomicrobia. Patient 2, before infusion, showed a strong abundance of Proteobacteria and a significant deficiency of Bacteroidetes and Verrucomicrobia. Seven days after infusion, Proteobacteria strongly decreased, while Bacteroidetes and Verrucomicrobia increased. Metagenomics data revealed an “awakening” by microbial species absent or low concentrated at time T0 and present after the infusion. In conclusion, the infusion of selected bacteria would act as a trigger factor for “bacterial repopulation” representing an innovative treatment in patients with Clostridioides difficile infections.
Rehabilitation of an edentulous posterior maxilla with dental implants is challenging, and sinus floor augmentation could be considered as an important surgical procedure for bone augmentation in this region before implant placement. Platelet-rich fibrin (PRF) is a new-generation platelet concentrate with simplified processing: its application in sinus floor augmentation has been widely investigated in literature. However, the biological properties and actual efficacy of this product remain controversial. This study assessed the effect of sinus floor augmentation with PRF versus freeze-dried bone allograft (FDBA) on stability of one-stage dental implants. This split-mouth randomized clinical trial evaluated 10 patients who required bilateral sinus floor augmentation. PRF and L-PRF membrane were used in one quadrant while FDBA and collagen membrane were used in the other quadrant. Implant stability was assessed by resonance frequency analysis (RFA) immediately, and 2, 4, and 6 months after implant placement. The implant stability quotient (ISQ) was compared over time and between the two groups using repeated measures ANOVA and independent sample t-test. The mean ISQ significantly increased over time in both groups (p < 0.001). The increase was greater in the PRF group (p < 0.05). Within the limitations of this study, PRF yielded superior results compared with FDBA regarding the stability of one-stage dental implants.
Background Uganda accounts for 5% of all malaria cases and deaths reported globally and, in endemic countries, pregnancy is a risk factor for both acquisition of P. falciparum infection and development of severe malaria. In recent years, malaria control has been threatened by COVID-19 pandemic and by the emergence, in Northern Uganda, of both resistance to artemisinin derivatives and to sulfadoxine-pyrimethamine. Methods In this facility-based, prospective, observational study, pregnant women will be recruited at antenatal-care visits and followed-up until delivery. Collected data will explore the incidence of asymptomatic parasitemia and malaria-related outcomes, as well as the attitudes towards malaria prevention, administration of intermittent preventive treatment, healthcare seeking behavior and use of insecticide-treated nets. A subpopulation of women diagnosed with malaria will be recruited and their blood samples will be analyzed for detection of genetic markers of resistance to artemisinin derivatives and sulfadoxine-pyrimethamine. Also, to investigate the impact of COVID-19 on malaria care among pregnant women, a retrospective, interrupted-time series will be conducted on at the study sites for the period January 2018 to December 2021. Discussion The present study will explore the impact of COVID-19 pandemic on incidence of malaria and malaria-related adverse outcomes, along with the prevalence of resistance to artemisinin derivatives and to sulfadoxine-pyrimethamine. To our knowledge, this is the first study aiming to explore the combined effect of these factors on a cohort of pregnant women. Trial registration : This study has been registered on the ClinicalTrials.gov public website on 26th April, 2022. ClinicalTrials.gov Identifier: NCT05348746.
Literature on the impact of the SARS-CoV-2 pandemic on the mental health of Health Care Workers (HCWs) is mostly based on cross-sectional surveys. We designed a longitudinal study to assess work-related stress and mental health before and after the pandemic onset in a university-hospital in Lombardia region, Italy. We report on sample representativeness and structural validity of questionnaires assessing work stress (HSE Indicator Tool, HSE-IT) and work satisfaction (WS), which were not validated in the HCWs population. n = 1287 HCWs from 67 hospital wards/offices were invited to an online survey in summer 2019 (pre-COVID-19 wave) and again during winter 2020 (COVID-19 wave). Selected hospital wards/offices did not differ from the remaining wards for turn-over and down-sizing rates, overload, sick leaves, and night shifts (Wilcoxon rank tests p-values > 0.05). Participation rates were 70% (n = 805) and 60% (n = 431) in the pre-COVID-19 and COVID-19 waves, respectively. Socio-demographic and work-related characteristics did not impact data completeness nor participation to the COVID-19 wave. While confirming a 7-component structure for HSE-IT, we identified a new factor related to participation in work organization. A one-factor model for WS had satisfactory fit. Our longitudinal study based on a representative sample and adopting validated questionnaires is well-suited to elucidate the role of work conditions on the development of mental health disorders in HCWs.
It is unclear if the factor structure of the questionnaires that were employed by studies addressing the impact of COVID-19 on the mental health of Healthcare Workers (HCW) did not change due to the pandemic. The aim of this study is to assess the factor structure and longitudinal measurement invariance of the Maslach Burnout Inventory (MBI) and the factor structure of the General Health Questionnare-12 (GHQ-12), PTSD Checklist for DSM-5-Short Form (PCL-5-SF), Connor-Davidson Resilience Scale-10 (CD-RISC-10) and Post-Traumatic Growth Inventory-Short Form (PTGI-SF). Out of n = 805 HCWs from a University hospital who responded to a pre-COVID-19 survey, n = 431 were re-assessed after the COVID-19 outbreak. A Confirmatory Factor Analysis (CFA) on the MBI showed adequate fit and good internal consistency only after removal of items 2, 6, 12 and 16. The assumptions of configural and metric longitudinal invariance were met, whereas scalar longitudinal invariance did not hold. CFAs and exploratory bifactor analyses performed using data from the second wave confirmed that the GHQ-12, the PCL-5-SF, the PTGI-SF and the CD-RISC-10 were unidimensional. In conclusion, we found support for a refined version of the MBI. The comparison of mean MBI values in HCWs before and after the pandemic should be interpreted with caution.
Few data are available on the prevalence of right ventricle (RV) systolic dysfunction, assessed including RV strain, and RV to pulmonary artery (PA) coupling in patients with aortic stenosis (AS) submitted to TAVI and the early effect of the procedure. We performed standard and speckle tracking echocardiography in 80 patients with severe AS the day before TAVI and within 48 h after TAVI. In all patients we measured TAPSE/PASP (cut-off for RV-PA uncoupling 0.31) and in 60/80 we were able to analyze RV global longitudinal strain (RV-GLS) and RV free wall strain (RV-FWS). RVFAC and TAPSE were impaired in 8.3% while RV-GLS and RV-FWS in 45% and 33.3% respectively before TAVI. TAPSE/PASP < 0.31 was documented in 7/80 patients (8.7%) before TAVI. These subjects differed from patients with TAPSE/PASP ≥ 0.31 for: enlarged left ventricular (LV) end-diastolic and end-systolic volumes (p < 0.001), worst LV ejection fraction (p < 0.001) and RVFAC (p < 0.001), worst RV-GLS and RV-FWS (p = 0.01 and p = 0.03) and bigger right atrium (RA) area (p < 0.001). After TAVI, RV systolic function did not improve while PASP significantly decreased (p = 0.005) driving the improvement of TAPSE/PASP (p = 0.01). Patients with TAPSE/PASP improvement (51%) differed from the others for worst pre-TAVI diastolic function (E/eʹ p = 0.045), RVFAC (p = 0.042), RV-GLS (p = 0.049) and RA area (p = 0.02). RV-GLS unveils RV systolic dysfunction in as much as 45% of patients with AS vs only 8.3% revealed by conventional echocardiography. RV systolic function does not significantly improve early after TAVI while RV-PA coupling does. Patients with lower TAPSE/PASP at baseline have worst LV and RV systolic function as well as larger RA. Patients who improve TAPSE/PASP after TAVI are those with worst diastolic function, RV systolic function and larger RA at baseline.
Immune checkpoint inhibitors (ICIs) have completely reshaped the treatment of many malignancies, with remarkable improvements in survival outcomes. In ovarian cancer (OC), however, this emerging class of drugs has not yet found a favorable use due to results from phase I and II studies, which have not suggested a substantial antitumoral activity of these agents when administered as monotherapy. Robust preclinical data seem to suggest that the combination ICIs with poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) may result in a synergistic activity; furthermore, data from phase II clinical studies, evaluating this combination, have shown encouraging outcomes especially for those OC patients not suitable for platinum retreatment. While waiting for ongoing phase III clinical trial results, which will clarify the role of ICIs in combination with PARPis in the newly diagnosed OC, this review aims to summarize the preclinical data and clinical evidence available to date.
The present study aimed to investigate the association between learning skills and creative thinking and to assess their relations with self-efficacy. In doing so, we used an approach that aimed to go beyond the dichotomous comparison between students with Specific Learning Disability (SLD) vs. students without SLD, which could potentially reduce complexity. Given that learning skills are distributed across a continuum, we considered them as continuous measures to study their association with creativity. Standardized reading, text comprehension, math tests, and creativity (TTCT) and creative problem-solving tasks, together with Raven’s Standard Progressive Matrices and the General Self-Efficacy scale, were administered to 180 high school students, aged 14 to 17 years, attending a vocational school. Regression analyses showed that reading speed, comprehension, and multiplications skills were negative predictors of fluency and flexibility and positive predictors of elaboration in divergent thinking, whereas reading accuracy positively predicted fluency and flexibility and negatively elaboration. Creative problem-solving skills were positively predicted by reading speed and comprehension and negatively by reading accuracy. A negative correlation was found between fluency and self-efficacy, which resulted to be positively correlated with reading accuracy. These findings emphasize the possibility to compensate for learning difficulties by using creative potential as a protective factor contrasting the risk of abandoning school prematurely, thus supporting poor-achieving students in the decrease of self-efficacy and satisfaction in their school career.
Objective: Imposter syndrome (IS) occurs when high-achieving individuals have a pervasive sense of self-doubt combined with fear of being exposed as a fraud, despite objective measures of success. This is one of the main causes of burnout among professionals, threatening their mental health and general well-being. The prevalence and severity of IS among neurosurgery residents and young neurosurgeons has not been yet studied. The primary outcomes of this study were the prevalence and severity of IS. Methods: An anonymous cross-sectional survey including both a demographic questionnaire (Clance Imposter Phenomenon Survey) and compensatory mechanisms was distributed to young neurosurgeons and residents in neurosurgery in Italy. Results: A total of 103 responses were collected. The prevalence rate was 81.6%. Among the respondents with IS, 42.7% showed moderate signs, 27.2% frequent, and only 11.7% had an intense symptomatology. Level of education, female sex, and academic achievements were all identified as predictive factors of IS. Conclusions: A total of 81.6% of respondents reported potentially significant levels. The implications of IS on both the outcomes in patients and the well-being of neurosurgeons should be evaluated in future studies.
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