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Objectives We implemented narrative medicine in clinical practice using the Digital Narrative Medicine (DNM) platform. Methods We conducted a preliminary, open, uncontrolled, real-life study in the oncology and radiotherapy departments of Istituto di Ricovero e Cura a Carattere Scientifico National Cancer Institute Regina Elena, Rome, Italy. We recruited adult Italian-speaking patients who then completed the DNM diary from the start of treatment. The primary endpoint was DNM feasibility; secondary endpoints were health care professionals’ opinions about communication, therapeutic alliance, and information collection and patients’ opinions about therapeutic alliance, awareness, and coping ability. We used open- and closed-ended questions (scores 1 to 5) and a structured interview. Results Thirty-one patients (67%) used the diary (84% women). Health care professionals’ mean scores for feasibility and utility were ≥4.0. Patients’ utility scores were related to health care professionals’ feedback regarding the narratives. The main advantages for health care professionals were the opportunity to obtain relevant patient data and to strengthen communication and patient relationships (mean scores 4.4–5.0). Both groups strongly encouraged introduction of the diary in clinical practice. Conclusion Use of the DNM in oncology patients assisted clinicians with understanding their patients experience.

A game-theoretic approach based on the framework of transferable-utility cooperative games is developed to assess the reliability of transfer nodes in public transportation networks in the case of stochastic transfer times. A cooperative game is defined, whose model takes into account the public transportation system, the travel times, the transfers and the associated stochastic transfer times, and the users’ demand. The transfer stops are modeled as the players of such a game, and the Shapley value – a solution concept in cooperative game theory – is used to identify their centrality and relative importance. Theoretical properties of the model are analyzed. A two-level Monte Carlo approximation of the vector of Shapley values associated with the nodes is introduced, which is efficient and able to take into account the stochastic features of the transportation network. The performance of the algorithm is investigated, together with that of its distributed computing variation. The usefulness of the proposed approach for planners and policy makers is shown with a simple example and on a case study from the public transportation network of Auckland, New Zealand.

Background Passive immunotherapy has been evaluated as a therapeutic alternative for patients with COVID-19 disease. Equine polyclonal immunotherapy for COVID-19 (EPIC) showed adequate safety and potential efficacy in a clinical trial setting and obtained emergency use authorization in Argentina. We studied its utility in a real world setting with a larger population. Methods We conducted a retrospective cohort study at “Hospital de Campaña Escuela-Hogar" (HCEH) in Corrientes, Argentina, to assess safety and effectiveness of EPIC in hospitalized adults with severe COVID-19 pneumonia. Primary endpoints were 28-days all-cause mortality and safety. Mortality and improvement in modified WHO clinical scale at 14 and 21 days were secondary endpoints. Potential confounder adjustment was made by logistic regression weighted by the inverse of the probability of receiving the treatment (IPTW) and doubly robust approach. Findings Subsequent clinical records of 446 non-exposed (Controls) and 395 exposed (EPIC) patients admitted between November 2020 and April 2021 were analyzed. Median age was 58 years and 56.8% were males. Mortality at 28 days was 15.7% (EPIC) vs. 21.5% (Control). After IPTW adjustment the OR was 0.66 (95% CI: 0.46–0.96) P = 0.03. The effect was more evident in the subgroup who received two EPIC doses (complete treatment, n = 379), OR 0.58 (95% CI 0.39 to 0.85) P = 0.005. Overall and serious adverse events were not significantly different between groups. Conclusions In this retrospective cohort study, EPIC showed adequate safety and effectiveness in the treatment of hospitalized patients with severe SARS-CoV-2 disease.

In the quest for high-energy neutrino sources, the Astrophysical Multimessenger Observatory Network has implemented a new search by combining data from the High Altitude Water Cherenkov (HAWC) Observatory and the Astronomy with a Neutrino Telescope and Abyss environmental RESearch (ANTARES) neutrino telescope. Using the same analysis strategy as in a previous detector combination of HAWC and IceCube data, we perform a search for coincidences in HAWC and ANTARES events that are below the threshold for sending public alerts in each individual detector. Data were collected between 2015 July and 2020 February with a live time of 4.39 yr. Over this time period, three coincident events with an estimated false-alarm rate of

The Crusade song Ara sai eu presents two different versions, one trasmitted by DcFIKd, and the other by M. The M version is curiously preceded by two stanzas addressed to the jongleur Fuilheta (Fuilheta, vos mi preiatz qe ieu chan, BdT 80.17), while the part dedicated to the Crusade includes three stanzas and a tornada, of which the first two resemble the corresponding stanzas in DcFIKd, while the third and the tornada are isolated. The two stanzas, exclusive to M 232r, are in fact a fragment of a sirventes joglaresc, which has been transmitted as a single text along with the three stanzas that represent an alternative, previous and ‘short’ version of the Crusade song. Therefore, it is likely that the rest of the sirventes had been lost and that the M scribe, influenced by the perfect identity of the metric scheme and rhymes, replaced the missing strophes with those of Bertran's crusade song (which would constitute the metric model). Another problem is the relationship between the two versions, because of the high number of variants, beginning with the incipit, which in M is Ara parra de prez qals a plus gran. By analyzing the divergent lessons, a sort of sequence of the different versions may be traced and it is possible that the DcFIKd version has been rearranged by the author, with the changing of the historical events. In order to clarify the spacetime coordinates and the historical background of these two versions, we follow the careful analysis already carried out by Gérard Gouiran, trying to examine his conclusions in depth and, in some cases, to reach a slightly divergent view.

Background: Epidemiological characteristics and prognostic profiles of patients with newly diagnosed coronary artery disease (CAD) are heterogeneous. Therefore, providing individualized cardiovascular (CV) risk stratification and tailored prevention is crucial.Objective: Phenotypic unsupervised clustering integrating clinical, coronary computed tomography angiography (CCTA), and cardiac magnetic resonance (CMR) data were used to unveil pathophysiological differences between subgroups of patients with newly diagnosed CAD.Materials and Methods: Between 2008 and 2020, consecutive patients with newly diagnosed obstructive CAD on CCTA and further referred for vasodilator stress CMR were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular death or non-fatal myocardial infarction. For this exploratory work, a cluster analysis was performed on clinical, CCTA, and CMR variables, and associations between phenogroups and outcomes were assessed.Results: Among 2,210 patients who underwent both CCTA and CMR, 2,015 (46% men, mean 70 ± 12 years) completed follow-up [median 6.8 (IQR 5.9–9.2) years], in which 277 experienced a MACE (13.7%). Three mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: (PG1) CAD in elderly patients with few traditional risk factors; (PG2) women with metabolic syndrome, calcified plaques on CCTA, and preserved left ventricular ejection fraction (LVEF); (PG3) younger men smokers with proximal non-calcified plaques on CCTA, myocardial scar, and reduced LVEF. Using survival analysis, the occurrence of MACE, cardiovascular mortality, and all-cause mortality (all p < 0.001) differed among the three PG, in which PG3 had the worse prognosis. In each PG, inducible ischemia was associated with MACE [PG1, Hazards Ratio (HR) = 3.09, 95% CI, 1.70–5.62; PG2, HR = 3.62, 95% CI, 2.31–5.7; PG3, HR = 3.55, 95% CI, 2.3–5.49; all p < 0.001]. The study presented some key limitations that may impact generalizability.Conclusions: Cluster analysis of clinical, CCTA, and CMR variables identified three phenogroups of patients with newly diagnosed CAD that were associated with distinct clinical and prognostic profiles. Inducible ischemia assessed by stress CMR remained associated with the occurrence of MACE within each phenogroup. Whether automated unsupervised phenogrouping of CAD patients may improve clinical decision-making should be further explored in prospective studies.

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era . No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

New evidence on the impact of dysregulation of the CDK4/6 pathway on breast cancer (BC) cell proliferation has led to the development of selective CDK4/6 inhibitors, which have radically changed the management of advanced BC. Despite the improved outcomes obtained by CDK4/6 inhibitors, approximately 10% of tumors show primary resistance, whereas acquired resistance appears to be an almost ubiquitous occurrence, leading to treatment failure. The identification of differentially expressed genes or genomic mutational signatures able to predict sensitivity or resistance to CDK4/6 inhibitors is critical for medical decision making and for avoiding or counteracting primary or acquired resistance against CDK4/6 inhibitors. In this review, we summarize the main mechanisms of resistance to CDK4/6 inhibitors, focusing on those associated with potentially relevant biomarkers that could predict patients’ response/resistance to treatment. Recent advances in biomarker identification are discussed, including the potential use of liquid biopsy for BC management and the role of multiple microRNAs as molecular predictors of cancer cell sensitivity and resistance to CDK4/6 inhibitors.

BackgroundDurum wheat (Triticum durum Desf.) is a tetraploid cereal grown in the medium to low-precipitation areas of the Mediterranean Basin, North America and South-West Asia. Genomics applications in durum wheat have the potential to boost exploitation of genetic resources and to advance understanding of the genetics of important complex traits (e.g. resilience to environmental and biotic stresses). A dense and accurate consensus map specific for T. durum will greatly facilitate genetic mapping, functional genomics and marker-assisted improvement.ResultsHigh quality genotypic data from six core recombinant inbred line populations were used to obtain a consensus framework map of 598 simple sequence repeats (SSR) and Diversity Array Technology® (DArT) anchor markers (common across populations). Interpolation of unique markers from 14 maps allowed us to position a total of 2,575 markers in a consensus map of 2,463 cM. The T. durum A and B genomes were covered in their near totality based on the reference SSR hexaploid wheat map. The consensus locus order compared to those of the single component maps showed good correspondence, (average Spearman's rank correlation rho ρ value of 0.96). Differences in marker order and local recombination rate were observed between the durum and hexaploid wheat consensus maps. The consensus map was used to carry out a whole-genome search for genetic differentiation signatures and association to heading date in a panel of 183 accessions adapted to the Mediterranean areas. Linkage disequilibrium was found to decay below the r2 threshold=0.3 within 2.20 cM, on average. Strong molecular differentiations among sub-populations were mapped to 87 chromosome regions. A genome-wide association scan for heading date from 27 field trials in the Mediterranean Basin and in Mexico yielded 50 chromosome regions with evidences of association in multiple environments.ConclusionsThe consensus map presented here was used as a reference for genetic diversity and mapping analyses in T. durum, providing nearly complete genome coverage and even marker density. Markers previously mapped in hexaploid wheat constitute a strong link between the two species. The consensus map provides the basis for high-density single nucleotide polymorphic (SNP) marker implementation in durum wheat.

[Display omitted] • Interventional CMR enables diagnostic RHC under sole CMR guidance. • Interventional CMR allows simultaneous balloon catheter visualization. • CMR-RHC was feasible and safe. • CMR-RHC had a unique clinical impact on diagnosis and therapeutic decision-making. Real-time cardiac magnetic resonance generates spatially and temporally resolved images of cardiac anatomy and function, without the need for contrast agent or X-ray exposure. Cardiac magnetic resonance-guided right heart catheterization (CMR-RHC) combines the benefits of cardiac magnetic resonance and invasive cardiac catheterization. The clinical adoption of CMR-RHC represents the first step towards the development of cardiac magnetic resonance-guided therapeutic procedures. To describe the feasibility, safety and diagnostic yield of CMR-RHC in consecutive all-comer patients with clinical indications for right heart catheterization. From December 2018 to May 2021, 35 consecutive patients with prespecified indications for right heart catheterization were scheduled for CMR-RHC via the femoral route under local anaesthesia in a 1.5T cardiac magnetic resonance suite equipped for interventional cardiac magnetic resonance. The duration of various procedural components and safety data were recorded. Success rate (defined by the ability to record all prespecified haemodynamic measurements and imaging metrics), adverse events and patient/physician perprocedural comfort were assessed. One patient withdrew his consent before the study, and scanner troubleshooting occurred in one case. Among the 33 remaining patients, prespecified cardiac magnetic resonance imaging metrics were obtained in all patients, whereas full CMR-RHC measurements were obtained in 30 patients (91%). A dedicated cardiac magnetic resonance-compatible wire was used in 25/33 procedures. CMR-RHC was completed in 29 ± 16 minutes, and the total duration of the procedure, including conventional cardiac magnetic resonance imaging, was 62 ± 20 minutes. There were no adverse events and no femoral haematomas. Procedural comfort was deemed good by the patients and operators for all procedures. CMR-RHC significantly impacted diagnosis or patient management in 28/33 patients (85%). CMR-RHC seems to be a feasible and safe procedure that can be used in routine daily practice in consecutive adults with an impactful clinical yield. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.

Abstract The Protvino accelerator facility located in the Moscow region, Russia, is in a good position to offer a rich experimental research program in the field of neutrino physics. Of particular interest is the possibility to direct a neutrino beam from Protvino towards the KM3NeT/ORCA detector, which is currently under construction in the Mediterranean Sea 40 km offshore Toulon, France. This proposal is known as P2O. Thanks to its baseline of 2595 km, this experiment would yield an unparalleled sensitivity to matter effects in the Earth, allowing for the determination of the neutrino mass ordering with a high level of certainty after only a few years of running at a modest beam intensity of $$\approx ~90~\hbox {kW}$$ ≈90kW . With a prolonged exposure ($$\approx 1500\hbox { kW}\,\,\hbox {year}$$ ≈1500kWyear ), a $$2\sigma $$ 2σ sensitivity to the leptonic CP-violating Dirac phase can be achieved. A second stage of the experiment, comprising a further intensity upgrade of the accelerator complex and a densified version of the ORCA detector (Super-ORCA), would allow for up to a $$6\sigma $$ 6σ sensitivity to CP violation and a $$10^\circ {-}17^\circ $$ 10∘-17∘ resolution on the CP phase after 10 years of running with a 450 kW beam, competitive with other planned experiments. The initial composition and energy spectrum of the neutrino beam would need to be monitored by a near detector, to be constructed several hundred meters downstream from the proton beam target. The same neutrino beam and near detector set-up would also allow for neutrino-nucleus cross section measurements to be performed. A short-baseline sterile neutrino search experiment would also be possible.

Abstract The ANTARES neutrino telescope has an energy threshold of a few tens of GeV. This allows to study the phenomenon of atmospheric muon neutrino disappearance due to neutrino oscillations. In a similar way, constraints on the 3+1 neutrino model, which foresees the existence of one sterile neutrino, can be inferred. Using data collected by the ANTARES neutrino telescope from 2007 to 2016, a new measurement of Δm 32 2 and θ 23 has been performed — which is consistent with world best-fit values — and constraints on the 3+1 neutrino model have been derived.

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. They are typically characterized by a high incidence of local recurrence, which is the most common cause of death in HNSCC patients. TP53 is the most frequently mutated gene in HNSCC and patients carrying TP53 mutations are associated with a higher probability to develop local recurrence. MiRNAs, which are among the mediators of the oncogenic activity of mt-p53 protein, emerge as an appealing tool for screening, diagnosis and prognosis of cancer. We previously identified a signature of 12 miRNAs whose aberrant expression associated with TP53 mutations and was prognostic for HNSCC. Among them miR-96-5p emerges as an oncogenic miRNAs with prognostic significance in HNSCC. Methods To evaluate the oncogenic role of miR-96-5p in a tumoral context, we performed colony formation, cell migration and cell viability assays in two HNSCC cell lines transfected for miR-96-5p mimic or inhibitor and treated with or without radio/chemo-therapy. In addition, to identify genes positively and negatively correlated to miR-96-5p expression in HNSCC, we analyzed the correlation between gene expression and miR-96-5p level in the subset of TCGA HNSCC tumors carrying missense TP53 mutations by Spearman and Pearson correlation. To finally identify targets of miR-96-5p, we used in silico analysis and the luciferase reporter assay to confirm PTEN as direct target. Results Our data showed that overexpression of miR-96-5p led to increased cell migration and radio-resistance, chemotherapy resistance in HNSCC cells. In agreement with these results, among the most statistically significant pathways in which miR-96-5p is involved, are focal Adhesion, extracellular matrix organization and PI3K-Akt-mTOR-signaling pathway. As a direct target of miR-96-5p, we identified PTEN, the main negative regulator of PI3K-Akt signalling pathway activation. Conclusions These results highlight a new mechanism of chemo/radio-resistance insurgence in HNSCC cells and support the possibility that miR-96-5p expression could be used as a novel promising biomarker to predict radiotherapy response and local recurrence development in HNSCC patients. In addition, the identification of pathways in which miR-96-5p is involved could contribute to develop new therapeutic strategies to overcome radio-resistance.

Traffic-related emissions include gas and particles that can alter air quality and affect human and environmental health. Limited studies have demonstrated that particulate debris thrown off from brakes are toxic to higher plants. The acute phytotoxicity of brake pad wear debris (BPWD) investigated using cress seeds grown in soil contaminated with increasing concentrations of debris. Two types of pads were used: a commercially available phenol based pad and an innovative cement-based pad developed within of the LIFE+ COBRA project. The results suggested that even through the BPWD generated by the two pads were similar in and morphology, debris from traditional pads were more phytotoxic than that from cementitious pads, causing significant alterations in terms of root elongation and loss of plasma membrane integrity. Keywords: Brake pads, Phytotoxicity, Debris, Root damage, LIFE+ COBRA

Abstract Background To compare WBC counts during treatment of localized prostate cancer with either conventionally fractionated (CF) or moderately hypofractionated (HYPO) radiotherapy. Methods Weekly blood test results were extracted from the charts of patients treated within a phase III study comparing HYPO to CF. In order to compare WBC counts at the same nominal dose in both arms and thus to tease out the effect of fractionation, for each recorded WBC value the corresponding cumulative total dose was extracted as well. WBC counts were binned according to percentiles of the delivered dose and three dose levels were identified at median doses of 16, 34.1 and 52 Gy, respectively. A General Linear Model based on mixed design Analysis Of Variance (ANOVA) was used to test variation of WBC counts between the two treatment arms. Results Out of 168 randomized patients, 140 (83.3%) had at least one observation for each one of the selected dose levels and were included in the analysis. Mean counts were lower in the CF than the HYPO arm at all selected dose levels, reaching a statistically significant difference at dose level #3 (5397/mm3 vs 6038/mm3 for CF and HYPO, respectively, p = 0.004). The GLM model confirms that the impact of dose on WBC counts is significantly lower in the HYPO arm over the CF one (Greenhouse-Geisser test, p = 0.04). Interestingly, while WBC counts tend to drop throughout all dose levels in the CF arm, this is the case only in the earlier part of treatment in the HYPO arm. Conclusion This secondary analysis of a phase III study shows that dose fractionation is correlated to WBC drop during treatment of localized prostate cancer, favoring HYPO over CF.

Background: Oropharyngeal squamous cell carcinoma (OPSCC) associated with human papillomavirus (HPV) has higher rates of locoregional control and a better prognosis than HPV-negative OPSCC. These differences are due to some unique biological characteristics that are also visible through advanced imaging modalities. We investigated the ability of a multifactorial model based on both clinical factors and diffusion-weighted imaging (DWI) to determine the HPV status in OPSCC. Methods: The apparent diffusion coefficient (ADC) and the perfusion-free tissue diffusion coefficient D were derived from DWI, both in the primary tumor (PT) and lymph node (LN). First- and second-order radiomic features were extracted from ADC and D maps. Different families of machine learning (ML) algorithms were trained on our dataset using five-fold cross-validation. Results: A cohort of 144 patients was evaluated retrospectively, which was divided into a training set (n = 95) and a validation set (n = 49). The 50th percentile of DPT, the inverse difference moment of ADCLN, smoke habits, and tumor subsite (tonsil versus base of the tongue) were the most relevant predictors. Conclusions: DWI-based radiomics, together with patient-related parameters, allowed us to obtain good diagnostic accuracies in differentiating HPV-positive from HPV-negative patients. A substantial decrease in predictive power was observed in the validation cohort, underscoring the need for further analyses on a larger sample size.

Abstract One of the main objectives of the ANTARES telescope is the search for point-like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliable way to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i.e. the deficit of the atmospheric muon flux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, the Moon shadow is observed with $$3.5\sigma $$ 3.5σ statistical significance. The detector angular resolution for downward-going muons is $$0.73^{\circ }\pm 0.14^{\circ }.$$ 0.73∘±0.14∘. The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location.

This letter presents a combined measurement of the energy spectra of atmospheric νe and νμ in the energy range between ∼100 GeV and ∼50 TeV with the ANTARES neutrino telescope. The analysis uses 3012 days of detector livetime in the period 2007–2017, and selects 1016 neutrinos interacting in (or close to) the instrumented volume of the detector, yielding shower-like events (mainly from νe+ν‾e charged current plus all neutrino neutral current interactions) and starting track events (mainly from νμ+ν‾μ charged current interactions). The contamination by atmospheric muons in the final sample is suppressed at the level of a few per mill by different steps in the selection analysis, including a Boosted Decision Tree classifier. The distribution of reconstructed events is unfolded in terms of electron and muon neutrino fluxes. The derived energy spectra are compared with previous measurements that, above 100 GeV, are limited to experiments in polar ice and, for νμ, to Super-Kamiokande.

Background: passive immunotherapy is a therapeutic alternative for patients with COVID-19. Equine polyclonal antibodies (EpAbs) could represent a source of scalable neutralizing antibodies against SARS-CoV-2. Methods: we conducted a double-blind, randomized, placebo-controlled trial to assess efficacy and safety of EpAbs (INM005) in hospitalized adult patients with moderate and severe COVID-19 pneumonia in 19 hospitals of Argentina. Primary endpoint was improvement in at least two categories in WHO ordinal clinical scale at day 28 or hospital discharge (ClinicalTrials.gov number NCT04494984). Findings: between August 1st and October 26th, 2020, a total of 245 patients were enrolled. Enrolled patients were assigned to receive two blinded doses of INM005 (n = 118) or placebo (n = 123). Median age was 54 years old, 65•1% were male and 61% had moderate disease at baseline. Median time from symptoms onset to study treatment was 6 days (interquartile range 5 to 8). No statistically significant difference was noted between study groups on primary endpoint (risk difference [95% IC]: 5•28% [-3•95; 14•50]; p = 0•15). Rate of improvement in at least two categories was statistically significantly higher for INM005 at days 14 and 21 of follow-up. Time to improvement in two ordinal categories or hospital discharge was 14•2 (± 0•7) days in the INM005 group and 16•3 (± 0•7) days in the placebo group, hazard ratio 1•31 (95% CI 1•0 to 1•74). Subgroup analyses showed a beneficial effect of INM005 over severe patients and in those with negative baseline antibodies. Overall mortality was 6•9% the INM005 group and 11•4% in the placebo group (risk difference [95% IC]: 0•57 [0•24 to 1•37]). Adverse events of special interest were mild or moderate; no anaphylaxis was reported. Interpretation: Albeit not having reached the primary endpoint, we found clinical improvement of hospitalized patients with SARS-CoV-2 pneumonia, particularly those with severe disease.

Assistive strategies for occupational back-support exoskeletons have focused, mostly, on lifting tasks. However, in occupational scenarios, it is important to account not only for lifting but also for other activities. This can be done exploiting human activity recognition algorithms that can identify which task the user is performing and trigger the appropriate assistive strategy. We refer to this ability as exoskeleton versatility. To evaluate versatility, we propose to focus both on the ability of the device to reduce muscle activation (efficacy) and on its interaction with the user (dynamic fit). To this end, we performed an experimental study involving $ 10 $ healthy subjects replicating the working activities of a manufacturing plant. To compare versatile and non-versatile exoskeletons, our device, XoTrunk, was controlled with two different strategies. Correspondingly, we collected muscle activity, kinematic variables and users’ subjective feedbacks. Also, we evaluated the task recognition performance of the device. The results show that XoTrunk is capable of reducing muscle activation by up to $ 40\% $ in lifting and $ 30\% $ in carrying. However, the non-versatile control strategy hindered the users’ natural gait (e.g., $ -24\% $ reduction of hip flexion), which could potentially lower the exoskeleton acceptance. Detecting carrying activities and adapting the control strategy, resulted in a more natural gait (e.g., $ +9\% $ increase of hip flexion). The classifier analyzed in this work, showed promising performance (online accuracy > 91%). Finally, we conducted 9 hours of field testing, involving four users. Initial subjective feedbacks on the exoskeleton versatility, are presented at the end of this work.

A 2-year-old, previously healthy, male presented with an insidious history of intermittent left knee pain and edema who had been evaluated in the emergency department on multiple occasions with unremarkable imaging and normal laboratory results. On the day of presentation, he had mild edema of the left knee and inability to bear weight. Synovial fluid analysis showed an elevated white cell count with neutrophil predominance and mildly elevated inflammatory markers, consistent with septic arthritis. He underwent knee arthrotomy with irrigation and debridement and was initiated on broad spectrum antibiotics. Cultures were negative, polymerase chain reaction for MRSA and Kingella kingae were negative. He was started on a fifth-generation cephalosporin with resolution of symptoms, marked clinical improvement and normalization of inflammatory markers. The identification of the etiologic agent was possible due to detection of bacterial 16S rRNA gene amplification by PCR for Moraxella nonliquefaciens in the synovial fluid. He completed a course of 3 weeks of parenteral antibiotics at home with full recovery.

Vascular endothelial growth factor-A (VEGF-A) has a pathologic role in microvascular diabetic complication, such as diabetic retinopathy (DR). miR-126 plays an important role in vascular development and angiogenesis by regulating the expression of VEGF-A. Since levels of miR-126 have been found downregulated in diabetes, this study is aimed at investigating whether hyperglycemia affects expression of miR-126 in a retinal pigment epithelium cell line. ARPE-19 cells were transfected with miR-126 inhibitor or with miR-126 mimic and the respective scramble negative control. After 24 hours, medium was replaced and cells were cultured for 24 hours in normal (CTR) or diabetic condition (HG). Then, we analyzed mRNA levels of miR-126, VEGF-A, PI3KR2, and SPRED1. We also evaluated protein amount of HIF-1α, PI3KR2, and SPRED1 and VEGF-A secretion. The results showed that exposure of ARPE-19 cells to HG significantly decreased miR-126 levels; mRNA levels of VEGF-A and PI3KR2 were inversely correlated with those of miR-126. Overexpression of miR-126 under HG restored HIF-1α expression and VEGF-A secretion to the level of CTR cells. These results indicate that reduced levels of miR-126 may contribute to DR progression by increasing expression of VEGF-A in RPE cells. In addition, we provide evidence that upregulation of miR-126 in RPE cells counteracts the rise of VEGF-A secretion induced by hyperglycemia. In conclusion, our data support a role of miR-126 mimic-approach in counteracting proangiogenic effects of hyperglycemia.

Purpose: To adapt the management of prostate malignancy in response to the COVID-19 pandemic. Methods: In according to the recommendations of the European Association of Urology, we have developed practical additional document on the treatment of prostate cancer. Results: Low-Risk Group Watchful Waiting should be offered to patients >75 years old, with a limited life expectancy and unfit for local treatment. In Active Surveillance (AS) patients re-biopsy, PSA evaluation and visits should be deferred for up to 6 months, preferring non-invasive multiparametric-MRI. The active treatment should be delayed for 6–12 months. Intermediate-Risk Group AS should be offered in favorable-risk patients. Short-course neoadjuvant androgen deprivation therapy (ADT) combined with ultra-hypo-fractionation radiotherapy should be used in unfavorable-risk patients. High-Risk Group Neoadjuvant ADT combined with moderate hypofractionation should be preferred. Whole-pelvis irradiation should be offered to patients with positive lymph nodes in locally advanced setting. ADT should be initiated if PSA doubling time is < 12 months in radio-recurrent patients, as well as in low priority/low volume of metastatic hormone sensitive prostate cancer. If radiotherapy cannot be delayed, hypo-fractionated regimens should be preferred. In high priority class metastatic disease, treatment with androgen receptor-targeted agents should be offered. When palliative radiotherapy for painful bone metastasis is required, single fraction of 8 Gy should be offered. Conclusions: In Covid-19 Era, the challenge should concern a correct management of the oncologic patient, reducing the risk of spreading the virus without worsening tumor prognosis.

L'Autore si sofferma sulla discussa figura del datore di lavoro plurale riconosciuta dall’ordinamento spagnolo, non solo livello normativo, ma anche giurisprudenziale, considerandola formula preferenziale per la cooperazione interaziendale, soprattutto in seguito allo sviluppo di processi produttivi globali dominati dall’ascesa dei gruppi d'imprese e delle reti d’impresa. Il contributo esplora i numerosi profili giuridici nonché i delicati problemi che nascono dalla configurazione unica del rapporto di lavoro complesso , dove al lavoratore, unico debitore della prestazione e un unico creditore della retribuzione, si contrappongono tutti i datori di lavoro che condividono la posizione di datore di lavoro.

Global health trainees rely on immersive experiences to apply their classroom knowledge in real-world settings. However, during the COVID-19 pandemic travel has come to a halt and short-term experiences are no longer available in their current form. As with didactic material, global health programs have an opportunity to innovate the delivery of applied learning, providing trainees with robust, mentored experiences that promote the acquisition of core global health competencies. We provide a series of practical solutions for remote applied learning including case-based learning, pathfinder pedagogy, virtual reality simulations, and twinning. We further describe the role of these approaches in addressing common criticisms of short-term experiences and their potential for creating new win-win dynamics between institutions and trainees.

Objective: To investigate predictors of patient-reported urinary incontinence (PRUI) in the first 2 years after post-prostatectomy radiotherapy (PORT) with particular emphasis on possible dose-effect relationships.Patients and Methods: Two-hundred-thirteen patients, whose clinical and dosimetric data were prospectively collected within a registered multi-institutional cohort study, underwent PORT with adjuvant (n = 106) or salvage (n = 107) intent with conventional (n = 123, prescribed dose to the prostatic bed: 66.6–79.8Gy in 1.8–2.0Gy/fr) or moderately hypo- (n = 90, 65.8–76.8Gy in 2.1–2.7Gy/fr) fractionation during the period 2011–2017. PRUI was evaluated through the ICIQ-SF questionnaire filled in at baseline and every 6 months thereafter. The analysis focused on three ICIQ-based clinically relevant endpoints: (a) very frequent leakage (FREQUENCY, ICIQ3 score >3), (b) moderate to severe amount of urine loss (AMOUNT, ICIQ4>2) (c) objective severe symptoms (OBJECTIVE, ICIQ3+4>5). Predictors of the incidence within 2 years for the three endpoints were investigated focusing only on patients without endpoint symptoms at baseline. A uni-variable logistic regression analysis was performed in order to determine the best dose metrics describing PRUI risk in terms of 2-Gy equivalent dose (EQD2) calculated with different α/β values reported in the literature (0.8, 3, 5Gy), and to identify the most significant clinical variables. Variables showing p < 0.20 at uni-variable analysis were entered into a backward stepwise multi-variable logistic regression analysis. Lastly, the goodness of fit and model calibration were evaluated and internally validated.Results: Patients without symptoms at baseline experienced (a), (b), and/or (c) within 2 years in 41/130 (32%), 40/192 (21%), and 41/129 (32%) of the cases, respectively. EQD2 for α/β = 0.8Gy was the best dose metric associated with PRUI. Multi-variable analysis identified baseline incontinence levels as the strongest predictor for all endpoints (p < 0.006). Both FREQUENCY and OBJECTIVE were significantly influenced also by EQD2(α/β = 0.8Gy). The goodness of fit was excellent, as was the calibration; internal calibration confirmed apparent performance.Conclusion: Baseline mild urinary incontinence symptoms strongly modulate the 2-year risk of PRUI. In addition, FREQUENCY is characterized by a marked dose-effect relationship also influencing the trend of OBJECTIVE, with results more reliable than AMOUNT as an objective index. A strong impact of fractionation on severe PRUI after post-prostatectomy radiotherapy also emerged.

Neutrino detectors participate in the indirect search for the fundamental constituents of dark matter (DM) in form of weakly interacting massive particles (WIMPs). In WIMP scenarios, candidate DM particles can pair-annihilate into Standard Model products, yielding considerable fluxes of high-energy neutrinos. A detector like ANTARES, located in the Northern Hemisphere, is able to perform a complementary search looking towards the Galactic Centre, where a high density of dark matter is thought to accumulate. Both this directional information and the spectral features of annihilating DM pairs are entered into an unbinned likelihood method to scan the data set in search for DM-like signals in ANTARES data. Results obtained upon unblinding 3170 days of data reconstructed with updated methods are presented, which provides a larger, and more accurate, data set than a previously published result using 2101 days. A non-observation of dark matter is converted into limits on the velocity-averaged cross section for WIMP pair annihilation.

Cachexia is a complex metabolic syndrome that determines a severe body weight loss characterized by a marked reduction in muscle mass. About 80% of patients with advanced cancer develop cachexia due to both the tumor itself and cancer treatment (radiotherapy and/or chemotherapy), which is associated to a worse prognosis. Despite its clinical relevance, this syndrome is still under-diagnosed and it lacks effective treatments. Radio-chemotherapy treatment is essential in patients with advanced head and neck cancers (HNSCC). Although this treatment has improved patients’ life expectancy, it has also dramatically increased their need for assistance and support. The management of adverse symptoms, including cachexia, is of great importance in order to avoid delays in therapy, reduction of dosages and hospitalizations. MicroRNAs (miRNAs) are small non-coding RNA molecules, which have emerged as powerful biomarkers in stratifying human cancers. Due to their high stability in body fluids, miRNAs might be excellent non-invasive biomarkers for the early detection and follow-up of cancer patients. Here, we will summarize the current knowledge and debate the strong need to identify circulating biomarkers for the early diagnosis of cachexia. We will propose circulating non-coding RNAs as biomarkers for detecting early cachexia and implementing specific treatment. We will also discuss the potential use of circulating miRNAs as biomarkers of cachexia in HNSCC patients’ blood samples collected before and after radio-chemotherapy treatment. Our intent is to pave the way to the identification of specific circulating miRNAs associated to cachexia occurrence and to the design of specific interventions aimed at improving the quality of life of cancer patients.

OBJECTIVES:To investigate the correlation between histogram-based Dynamic Contrast-Enhanced magnetic resonance imaging (DCE-MRI) parameters and positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG-PET) values in oropharyngeal squamous cell carcinoma (OPSCC), both in primary tumors (PTs) and in metastatic lymph nodes (LNs). METHODS:52 patients with a new pathologically-confirmed OPSCC were included in the present retrospective cohort study. Imaging including DCE-MRI and 18F-FDG PET/CT scans were acquired in all patients. Both PTs and the largest LN, if present, were volumetrically contoured. Quantitative parameters, including the transfer constants, Ktrans and Kep, and the volume of extravascular extracellular space, ve, were calculated from DCE-MRI. The percentiles (P), P10, P25, P50, P75, P90, and skewness, kurtosis and entropy were obtained from the histogram-based analysis of each perfusion parameter. Standardized uptake values (SUV), SUVmax, SUVpeak, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated applying a SUV threshold of 40%. The correlations between all variables were investigated with the Spearman-rank correlation test. To exclude false positive results under multiple testing, the Benjamini-Hockberg procedure was applied. RESULTS:No significant correlations were found between any parameters in PTs, while significant associations emerged between Ktrans and 18F-FDG PET parameters in LNs. CONCLUSIONS:Evident relationships emerged between DCE-MRI and 18F-FDG PET parameters in OPSCC LNs, while no association was found in PTs. The complex relationships between perfusion and metabolic biomarkers should be interpreted separately for primary tumors and lymph-nodes. A multiparametric approach to analyze PTs and LNs before treatment is advisable in head and neck squamous cell carcinoma (HNSCC).

The Importance of Neuroscience in the Study of ReligiosityThe article aims to determine whether neuroscience is relevant for a better comprehension of religious activities. The answer to this problem emphasizes the distinction between mental operations and their intentional content. Neurobiological studies, I argue, can be important to evaluate the psychological and neural dimension of religious acts, with caution due to their great complexity, but not to evaluate the truth and genuineness of their content, neither to solve objective religious problems. Neuroscience may be helpful for the discernment of some extraordinary religious experiences and to study pseudo-religious pathologies as well.

Abstract Background Functional magnetic resonance imaging may provide several quantitative indices strictly related to distinctive tissue signatures with radiobiological relevance, such as tissue cellular density and vascular perfusion. The role of Intravoxel Incoherent Motion Diffusion Weighted Imaging (IVIM-DWI) and Dynamic Contrast-Enhanced (DCE) MRI in detecting/predicting radiation-induced volumetric changes of parotids both during and shortly after (chemo)radiotherapy of oropharyngeal squamous cell carcinoma (SCC) was explored. Methods Patients with locally advanced oropharyngeal SCC were accrued within a prospective study offering both IVIM-DWI and DCE-MRI at baseline; IVIM-DWI was repeated at the 10th fraction of treatment. Apparent diffusion coefficient (ADC), tissue diffusion coefficient Dt, perfusion fraction f and perfusion-related diffusion coefficient D* were estimated both at baseline and during RT. Semi-quantitative and quantitative parameters, including the transfer constant Ktrans, were calculated from DCE-MRI. Parotids were contoured on T2-weighted images at baseline, 10th fraction and 8th weeks after treatment end and the percent change of parotid volume between baseline/10th fr (∆Vol10fr) and baseline/8th wk. (∆Volpost) computed. Correlations among volumetric changes and patient-, treatment- and imaging-related features were investigated at univariate analysis (Spearman’s Rho). Results Eighty parotids (40 patients) were analyzed. Percent changes were 18.2 ± 10.7% and 31.3 ± 15.8% for ∆Vol10fr and ∆Volpost, respectively. Among baseline characteristics, ∆Vol10fr was correlated to body mass index, patient weight as well as the initial parotid volume. A weak correlation was present between parotid shrinkage after the first 2 weeks of treatment and dosimetric variables, while no association was found after radiotherapy. Percent changes of both ADC and Dt at the 10th fraction were also correlated to ∆Vol10fr. Significant relationships were found between ∆Volpost and baseline DCE-MRI parameters. Conclusions Both IVIM-DWI and DCE-MRI can help to detect/predict early (during treatment) and shortly after treatment completion the parotid shrinkage. They may contribute to clarify the correlations between volumetric changes of parotid glands and patient−/treatment-related variables by assessing individual microcapillary perfusion and tissue diffusivity.

Physical interaction with a partner plays an essential role in our life experience and is the basis of many daily activities. When two physically coupled humans have different and partly conflicting goals, they face the challenge of negotiating some type of collaboration. This requires that both participants understand their partner's state and current actions. But, how would the collaboration be affected if information about their partner were unreliable or incomplete? We designed an experiment in which two players (a dyad) are mechanically connected through a virtual spring, but cannot see each other. They were instructed to perform reaching movements with the same start and end position, but through different via-points. In different groups of dyads we varied the amount of information provided to each player about his/her partner: haptic only (the interaction force perceived through the virtual spring), visuo-haptic (the interaction force is also displayed on the screen), and partner visible (in addition to interaction force, partner position is continuously displayed on the screen). We found that incomplete information about the partner affects not only the speed at which collaboration is achieved (less information, slower learning), but also the actual collaboration strategy. In particular, incomplete or unreliable information leads to an interaction strategy characterized by alternating leader-follower roles. Conversely, more reliable information leads to more synchronous behaviors, in which no specific roles can be identified. Simulations based on a combination of game theory and Bayesian estimation suggested that synchronous behaviors correspond to optimal interaction (Nash equilibrium). Roles emerge as sub-optimal forms of interaction, which minimize the need to account for the partner. These findings suggest that collaborative strategies in joint action are shaped by the trade-off between the task requirements and the uncertainty of the information available about the partner.

Abstract Cherenkov light induced by radioactive decay products is one of the major sources of background light for deep-sea neutrino telescopes such as ANTARES. These decays are at the same time a powerful calibration source. Using data collected by the ANTARES neutrino telescope from mid 2008 to 2017, the time evolution of the photon detection efficiency of optical modules is studied. A modest loss of only 20% in 9 years is observed. The relative time calibration between adjacent modules is derived as well.

Abstract Background Cancer and coagulation activation are tightly related. The extent to which factors related to both these pathologic conditions concur to patient prognosis intensely animates the inherent research areas. The study herein presented aimed to the development of a tool for the assessment and stratification of risk of death and disease recurrence in early breast cancer. Methods Between 2008 and 2010, two hundreds thirty-five (N: 235) patients diagnosed with stage I–IIA breast cancer were included. Data on patient demographics and clinic-pathologic features were collected in course of face-to-face interviews or actively retrieved from clinical charts. Plasma levels of plasminogen activator inhibitor type 1 (PAI-1), fragment 1 + 2 (F1 + 2), thrombin antithrombin complex (TAT), factor VIII (FVIII), and D-dimer (DD) were measured at breast cancer diagnosis and prior to any therapeutic procedure, including breast surgery. The risk of death was computed in terms of overall survival (OS), which was the primary outcome. For a subset of patients (N = 62), disease free survival (DFS) was also assessed as a measure of risk of disease recurrence. Results Median follow up was 95 months (range 6–112 months). Mean age at diagnosis was 60.3 ± 13.4 years. Cancer cases were more commonly intraductal carcinomas (N: 204; 86.8%), pT1 (131; 55.7%), pN0 (141; 60%) and G2 (126; 53.6%). Elevated levels of PAI-1 (113; 48.1%) represented the most frequent coagulation abnormality, followed by higher levels of F1 + 2 (97; 41.3%), DD (63; 27.0%), TAT (34; 40%), and FVIII (29; 12.3%). In univariate models of OS, age, pT, DD, FVIII were prognostically relevant. In multivariate models of OS, age (p = 0.043), pT (p = 0.001), levels of DD (p = 0.029) and FVIII (p = 0.087) were confirmed. In the smaller subgroup of 62 patients, lymph node involvement, percent expression of estrogen receptors and levels of FVIII impacted DFS significantly. Conclusions We developed a risk assessment tool for OS including patient- and cancer-related features along with biomarkers of coagulation activation in a cohort of early BC patients. Further studies are warranted to validate our prognostic model in the early setting and eventually extend its application to risk evaluation in the advanced setting for breast and other cancers.

The passive acoustic monitoring of cetaceans is a research method that can provide unique information on the animal’s behaviour since the animals can be studied at great depths and at a long-range without interference. Nevertheless, the real-time data collection, transfer, and analysis using these techniques are difficult to implement and maintain. In this paper, a review of several experiments that have used this approach will be provided. The first class of detectors consists of hydrophone systems housed under buoys on the sea surface with wireless data transmission, while the second type comprises several acoustic detector networks integrated within submarine neutrino telescopes cabled to the shore.