Search

Antiandrogens have been used for the treatment of prostate cancer as a single agent or in combination with hormone deprivation therapy. New generation antiandrogens act like androgen receptor inhibitors (ARIs). Their binding complex blocks the pathways of cellular proliferation and differentiation of the prostate. Enzalutamide, apalutamide and darolutamide are the new ARIs that demonstrated acceptable tolerability and toxicity, both active in hormone-sensitive and castration-resistant prostate cancer (CRPC). There is no evidence of superiority of one drug over the other, therefore the therapeutic choice depends on the safety profile in relation to the individual patient, their comorbidities and clinical condition. ARIs have also shown promising results in association with new drugs that are active on patients with metastatic CRPC carrying the mutated breast cancer gene (BRCA). Before undergoing new antiandrogenic therapies, patients should be evaluated for cardiological and metabolic risk and possible drug interactions.

Background: Invasive fungal infections (IFIs) represent a major cause of morbidity among allogeneic hematopoietic stem cell transplantation (allo-HSCT). Isavuconazole (ISA) is a broad-spectrum triazole with favorable safety profile. Objectives and design: Herein, we evaluate the real life coadministration of ISA and sirolimus in allo-HSCT recipients in a single-center retrospective analysis, describing clinical efficacy, safety, and therapeutic drug monitoring (TDM) of both drugs. Methods: All consecutive allo-HSCT recipients who received the coadministration of ISA and sirolimus for at least 2 weeks between July 2017 and December 2022 were included in this retrospective analysis. TDM was longitudinally performed during treatment. IFIs were classified according to the revised European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus criteria. Results: A total of 51 recipients were included in the analysis. A total of 17 patients received ISA as continuous antifungal treatment for IFI diagnosed before transplant: one patient experienced a probable invasive pulmonary aspergillosis, and one patient switched from ISA to liposomal amphotericin B for a possible IFI. A total of 34 patients started ISA as antifungal therapy for IFI diagnosed after transplant. Sixteen of 34 were treated for a proven/probable breakthrough IFI during mold-active prophylaxis: 6/16 patients died for IFI after a median of 51 days of ISA. Eighteen of 34 started ISA as empirical therapy for a possible IFI: 15/18 patients were alive with resolution of infection after 6 weeks, 1 died for disease progression, and 2 had empirically changed antifungal therapy due to pneumonia progression. Clinical and radiological response rate was 68% after 90 days from IFI diagnosis. No toxicities related to drug–drug interaction have been registered in patients reaching concomitant therapeutic levels of ISA and sirolimus. Conclusion: The coadministration of ISA and sirolimus was safe and feasible in this cohort, confirming favorable clinical efficacy in patients with multiple-drug coadministration.

BackgroundA sex-based evaluation of prognosis in heart failure (HF) is lacking.Methods and resultsWe analyzed the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score registry, which includes HF with reduced ejection fraction (HFrEF) patients. A cross-validation procedure was performed to estimate weights separately for men and women of all MECKI score parameters: left ventricular ejection fraction (LVEF), hemoglobin, kidney function assessed by Modification of Diet in Renal Disease, blood sodium level, ventilation vs. carbon dioxide production slope, and peak oxygen consumption (peakVO2). The primary outcomes were the composite of all-cause mortality, urgent heart transplant, and implant of a left ventricle assist device. The difference in predictive ability between the native and sex recalibrated MECKI (S-MECKI) was calculated using a receiver operating characteristic (ROC) curve at 2 years and a calibration plot. We retrospectively analyzed 7,900 HFrEF patients included in the MECKI score registry (mean age 61 ± 13 years, 6,456 men/1,444 women, mean LVEF 33% ± 10%, mean peakVO2 56.2% ± 17.6% of predicted) with a median follow-up of 4.05 years (range 1.72–7.47). Our results revealed an unadjusted risk of events that was doubled in men compared to women (9.7 vs. 4.1) and a significant difference in weight between the sexes of most of the parameters included in the MECKI score. S-MECKI showed improved risk classification and accuracy (area under the ROC curve: 0.7893 vs. 0.7799, p = 0.02) due to prognostication improvement in the high-risk settings in both sexes (MECKI score >10 in men and >5 in women).ConclusionsS-MECKI, i.e., the recalibrated MECKI according to sex-specific differences, constitutes a further step in the prognostic assessment of patients with severe HFrEF.

This study proposes a simulation-based methodology for estimating the energy saving achievable through the implementation of a just-in-time morning ramp-up procedure in a warehouse (equipped with a heat pump). In this methodology, the operation of the heating supply unit each day is initiated at a different time, aiming at achieving the desired setpoint upon (and not before) the expected arrival of the occupants. It requires the estimation of the ramp-up duration (the time it takes the heating system to bring the indoor temperature to the desired setpoint), which can be provided by machine learning-based models. To justify the corresponding required deployment investment, an accurate estimation of the resulting achievable energy saving is needed. Accordingly, physics-based energy behavior simulations are first performed. Next, various ML algorithms are employed to estimate the ramp-up duration using the simulated time-series data of indoor temperature, setpoints, and weather conditions. It is shown that the proposed pipelines can estimate the ramp-up duration with a mean absolute error of about 3 min in all indoor spaces. To assess the resulting potential energy saving, a re-simulation is conducted using ML-based ramp-up estimations for each day, resulting in an energy savings of approximately 10%.

Objectives: The present study evaluated a new smartphone-based program to help 12 participants with intellectual disability plus visual and motor impairments to self-regulate their stimulation input (thus avoiding their dependence on staff) through simple non-verbal responses. Method: Nonconcurrent multiple baseline designs across participants were used to assess the effects of the program. The technology used for the program involved a Samsung J4 Plus smartphone with Android 9.0 operating system, two voice recording devices, smart-plugs, and a mini speaker. The smartphone was provided with a Google account and Internet connection, which allowed the participants to access Google Assistant and Google Play Music. The participants could make requests for two different types of stimulation (e.g. songs and familiar voices or noises) by activating via hand pressure the two voice recording devices. The verbal request messages emitted by the devices were recognized by the Google Assistant, which led the smartphone to deliver the related stimulation. Results: During the baseline sessions (without the support of the voice recording devices), the participants failed to access any stimulation. During the intervention and post-intervention phases (with the support of the voice recording devices), all participants managed to access the types of stimulation available independently. The mean frequency of responses (i.e. activations of both voice recording devices) per session ranged between about 8 and 14. Conclusion: The new smartphone-based program can be viewed as a useful resource to enable individuals like the participants of this study to access preferred stimulation independently.

Abstract Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem disorder; cardiac involvement may include eosinophilic myocarditis. A 67‐year‐old woman presented with 1‐week history of dyspnoea and orthopnoea. She had a history of adult‐onset asthma and peripheral eosinophilia. The investigations showed T‐wave inversion on lateral leads, peripheral eosinophilia, elevated troponin and BNP values, and severe biventricular systolic dysfunction with diffuse hypokinesia and apical akinesia. Computed tomography excluded coronary disease and showed bilateral basal ground‐glass opacities, air‐space consolidation, and bilateral reticular‐nodular pattern. Cardiac magnetic resonance findings were compatible with active myocardial inflammation. An endomyocardial biopsy (EMB) confirmed the diagnosis of eosinophilic myocarditis, and a therapy with oral corticosteroids and heart failure medications was started.

A case study represented by an assisted living facility in Norway is modeled utilizing physics-based data-driven digital twin (DT) of the indoor thermal spaces with indoor temperature. Autoregressive Distributed Lag (ARDL), Machine Learning (ML), and Non-linear Autoregressive (NARX) models with timeseries and sliding-window cross-validation are compared. Results show that NARX models have the highest accuracy, with a MAPE score of 0.03%. In addition, the sliding-window enhanced the models’ accuracy and reduced the cyclical pattern for the autocorrelated values. The HVAC systems in this study case are representative of those found in Norwegian buildings, making the digital twin calibration applicable to other facilities.

BackgroundImpaired iron transport (IIT) is a form of iron deficiency (ID) defined as transferrin saturation (TSAT)

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate that UBQLN2 regulates the domesticated gag-pol retrotransposon ‘paternally expressed gene 10 (PEG10)’ in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated ‘nucleocapsid’ fragment, which uniquely localizes to the nucleus and changes the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through the regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.

People with severe/profound and multiple disabilities may receive insufficient stimulation and correspondingly show low levels of happiness (satisfaction). Various stimulation strategies have been proposed to address this situation. This study aimed to extend the assessment of two of those strategies (i.e., self-regulated and staff-regulated stimulation strategies) with 12 participants who were exposed to each strategy. During intervention sessions with self-regulated stimulation, the participants sat at a desk and received stimulation if they pushed a panel in front of them thus activating a smartphone's proximity sensor. During intervention sessions with staff-regulated stimulation, they sat at a desk and received stimulation independent of any response. All participants showed increases in indices of satisfaction with self-regulated stimulation. Nine of them also showed such increases with staff-regulated stimulation. The participants' level of satisfaction during self-regulated stimulation sessions was frequently higher than that observed during staff-regulated stimulation sessions. Staff personnel interviewed about the two strategies provided higher scores for self-regulated stimulation. The self-regulated stimulation strategy may be considered preferable to the staff-regulated stimulation strategy because of its impact on participants' satisfaction and active responding.

Abstract Background Despite experiencing high rates of trauma and trauma-related conditions, people with psychosis are seldomly asked about possible traumatic events. While there are some barriers to discussing trauma in clinical services, research has shown that disclosure is not only possible but also beneficial to both psychotic and traumatic symptoms. The current study is the first to evaluate service users’ perception of the influence of trauma on the development and maintenance of their psychotic symptoms, as well as their views on how their life and mental health have been affected by traumatic events and their disclosure (or lack of). Methods Eleven participants with experiences of psychosis and trauma took part in semi-structured interviews. Results Consistently with previous literature, our participants reported high rates of interpersonal trauma, but had rarely had the opportunity to discuss any of these events. Using thematic analysis, we identified three major themes that have important implications for healthcare: factors that facilitate or hinder talking about trauma; consequences of talking or not; and relationship between trauma and psychosis. Participants generally benefited from talking about trauma and concerningly often associated the prolonged lack of opportunities to discuss traumatic events with negative feelings towards the self and with a deterioration of their mental health. Participants also recognised direct links between past traumas and the content and characteristics of their psychotic experiences. Conclusions Our findings highlight the importance, as perceived by service users, of discussing trauma and looking at psychosis through a “trauma lens”. These results stress the need to systematically assess trauma history and traumatic symptoms in psychosis and might potentially help to overcome clinicians’ worries about discussing trauma with service users. Our findings underscore the need to change current practice and implement trauma-informed approaches to understand clients’ difficulties and provide support.

This study proposes a simulation-based methodology for estimating the energy saving achievable through the implementation of a just-in-time morning ramp-up procedure in a warehouse (equipped with a heat pump). In this methodology, the operation of the heating supply unit each day is initiated at a different time, aiming at achieving the desired setpoint upon (and not before) the expected arrival of the occupants. It requires the estimation of the ramp-up duration (the time it takes the heating system to bring the indoor temperature to the desired setpoint), which can be provided by machine learning-based models. To justify the corresponding required deployment investment, an accurate estimation of the resulting achievable energy saving is needed. Accordingly, physics-based energy behavior simulations are first performed. Next, various ML algorithms are employed to estimate the ramp-up duration using the simulated time-series data of indoor temperature, setpoints, and weather conditions. It is shown that the proposed pipelines can estimate the ramp-up duration with a mean absolute error of about 3 min in all indoor spaces. To assess the resulting potential energy saving, a re-simulation is conducted using ML-based ramp-up estimations for each day, resulting in an energy savings of approximately 10%. [ABSTRACT FROM AUTHOR]

Circulating small extracellular vesicles (sEVs) contribute to inflammation, coagulation and vascular injury, and have great potential as diagnostic markers of disease. The ability of sEVs to reflect myocardial damage assessed by Cardiac Magnetic Resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) is unknown. To fill this gap, plasma sEVs were isolated from 42 STEMI patients treated by primary percutaneous coronary intervention (pPCI) and evaluated by CMR between days 3 and 6. Nanoparticle tracking analysis showed that sEVs were greater in patients with anterior STEMI (p = 0.0001), with the culprit lesion located in LAD (p = 0.045), and in those who underwent late revascularization (p = 0.038). A smaller sEV size was observed in patients with a low myocardial salvage index (MSI, p = 0.014). Patients with microvascular obstruction (MVO) had smaller sEVs (p < 0.002) and lower expression of the platelet marker CD41–CD61 (p = 0.039). sEV size and CD41–CD61 expression were independent predictors of MVO/MSI (OR [95% CI]: 0.93 [0.87–0.98] and 0.04 [0–0.61], respectively). In conclusion, we provide evidence that the CD41–CD61 expression in sEVs reflects the CMR-assessed ischemic damage after STEMI. This finding paves the way for the development of a new strategy for the timely identification of high-risk patients and their treatment optimization.

We implemented a unique strategy to construct a recombinant attenuated Edwardsiella vaccine (RAEV) with a biological containment phenotype that causes regulated bacterial cell wall lysis. This process ensures that the vaccine strain is not able to persist in the environment. The murA gene is responsible for the catalysis of one of the first steps in the biosynthesis of muramic acid, which is a crucial component of the bacterial cell wall. The regulated lysis phenotype was achieved by inserting the tightly regulated araC ParaBAD cassette in place of the chromosomal murA promoter. Strains with this mutation require growth media supplemented with arabinose in order to survive. Without arabinose, they are unable to synthesize the peptidoglycan cell wall. Following the colonization of fish lymphoid tissues, the murA protein is no longer synthesized due to the lack of arabinose. Lysis is subsequently achieved in vivo, thus preventing the generation of disease symptoms and the spread of the strain into the environment. Vaccine strain χ16016 with the genotype ΔPmurA180::TT araC ParaBAD murA is attenuated and shows a higher LD50 value than that of the wild-type strain. Studies have demonstrated that χ16016 induced TLR4, TLR5, TLR8, TLR9, NOD1 and NOD2-mediated NF-κB pathways and upregulated the gene expression of various cytokines, such as il-8, il-1β, tnf-a, il-6 and ifn-γ in catfish. We observed significant upregulation of the expression profiles of cd4, cd8 and mhc-II genes in different organs of vaccinated catfish. Vaccine strain χ16016 induced systemic and mucosal IgM titers and conferred significant protection to catfish against E. piscicida wild-type challenge. Our lysis RAEV is the first live attenuated vaccine candidate designed to be used in the aquaculture industry that displays this biological containment property.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) constitutes a heterogeneous subset of ALL with a uniformly unfavorable prognosis. The identification of mutations amenable to treatment with tyrosine kinase-inhibitors (TKIs) represents a promising field of investigation. We report the case of a young patient affected by relapsed/refractory Ph-like ALL treated with chimeric antigen receptor T (CAR-T) cells after successful bridging with compassionate-use ponatinib and low-dose prednisone. We restarted low-dose ponatinib maintenance three months later. Twenty months later, measurable residual disease negativity and B-cell aplasia persist. To the best of our knowledge, this is the first case reporting the use of ponatinib in Ph-like ALL as a bridge to and maintenance after CAR-T cell therapy.

Se catalogan las 87 especies de Fulgoroidea registradas para Chile pertenecientes a 12 familias. Se recopilan antecedentes nomenclaturales, distribucionales, de plantas hospedantes, y se observa como dudosa la presencia de cuatro especies. Se proporcionan claves para el reconocimiento de las familias, géneros y, en algunos casos, especies. Se reporta un alto endemismo de esta superfamilia para el país, especialmente en el Archipiélago de Juan Fernández y en la zona central, aunque aún falta explorar más las zonas extremas. Se encontraron siete especies en Chile que han sido reportadas como plagas en otras regiones del mundo, pero sin confirmación de daño económico ni de transmisión de agentes infecciosos en nuestro país. Se considera que el conocimiento del rol fitosanitario de los Fulgoroidea aún es bastante escaso, pero el presente aporte contribuirá para comenzar a avanzar en esta materia. Se proponen los siguientes cambios taxonómicos: Catonia maculata (Blanchard, 1852) comb. nov. y como sinónimo senior de Cixius valdiviensis Blanchard, 1852 syn. nov. y Cixius irroratus Blanchard, 1852 syn. nov.; Calbodus correntosoensis (Muir, 1929) comb. nov. y restituido de su sinonimia con C. pallidulus Blanchard, 1852; se sinonimiza Delphacodes latus Remes Lenicov y Tesón, 1979 bajo Calbodus patquianus Fennah, 1965 (syn. nov.) y Delphacodes argentina Remes Lenicov y Tesón, 1979 bajo Nothodelphax atlanticus nigrescens Fennah, 1965 (syn. nov.); Myrophenges Fennah, 1965 se reclasifica desde Achilidae a Derbidae insertae sedis.

Objective The aim of the study was to describe the epidemiology and outcome of patients hospitalised during the COVID-19 pandemic in intensive cardiac care units (ICCs).Design Non-interventional, retrospective and prospective, nationwide study.Setting 109 private or public ICCs in Italy.Participants 6054 consecutive patients admitted to Italian ICCs during COVID-19 pandemic.Primary and secondary outcome measures To obtain accurate and up-to-date information on epidemiology and outcome of patients admitted to ICCs during the COVID-19 pandemic, the impact that the COVID-19 infection may have determined on the organisational pathways and in-hospital management of the various clinical conditions being admitted to ICCs.Results Acute coronary syndromes were the most frequent ICC discharge diagnoses followed by heart failure and hypokinetic arrhythmias. The prevalence of COVID-19 positivity was approximately 3%. Most patients with a COVID-19 diagnosis at discharge (52%) arrived to ICC from other wards, in particular 22% from non-cardiology ICCs. The overall mortality was 4.2% during ICC and 5.8% during hospital stay. The cause of in-hospital death was cardiac in 74.4% of the cases, non-cardiovascular in 13.5%, vascular in 5.8% and related to COVID-19 in 6.3% of the patients.Conclusions This study provides a unique nationwide picture of current ICC care during COVID-19 pandemic.Trial registration number NCT04744415.

After allogeneic hematopoietic stem cell transplantation (HSCT), the emergence of circulating cytomegalovirus (CMV)- specific T cells correlates with protection from CMV reactivation, an important risk factor for non-relapse mortality. However, functional assays measuring CMV-specific cells are time-consuming and often inaccurate at early time-points. We report the results of a prospective single-center, non-interventional study that identified the enumeration of Dextramerpositive CMV-specific lymphocytes as a reliable and early predictor of viral reactivation. We longitudinally monitored 75 consecutive patients for 1 year after allogeneic HSCT (n=630 samples). The presence of ≥0.5 CMV-specific CD8+ cells/mL at day +45 was an independent protective factor from subsequent clinically relevant reactivation in univariate (P