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In healthy pancreas, pancreatic stellate cells (PaSCs) synthesize the basement membrane, which is mainly composed of type IV collagen and laminin. In chronic pancreatitis (CP), PaSCs are responsible for the production of a rigid extracellular matrix (ECM) that is mainly composed of fibronectin and type I/III collagen. Reactive oxygen species evoke the formation of the rigid ECM by PaSCs. One source of reactive oxygen species is NADPH oxidase (Nox) enzymes. Nox1 up-regulates the expression of Twist1 and matrix metalloproteinase-9 (MMP-9) in PaSCs from mice with CP. This study determined the functional relationship between Twist1 and MMP-9, and other PaSC-produced proteins, and the extent to which Twist1 regulates digestion of ECM proteins in CP. Twist1 induced the expression of MMP-9 in mouse PaSCs. The action of Twist1 was not selective to MMP-9 because Twist1 induced the expression of types I and IV collagen, fibronectin, transforming growth factor, and α-smooth muscle actin. Luciferase assay indicated that Twist1 in human primary PaSCs increased the expression of MMP-9 at the transcriptional level in an NF-κB dependent manner. The digestion of type I/III collagen by MMP-9 secreted by PaSCs from mice with CP depended on Twist1. Thus, Twist1 in PaSCs from mice with CP induced rigid ECM production and MMP-9 transcription in an NF-κB–dependent mechanism that selectively displayed proteolytic activity toward type I/III collagen.

In the framework of the euroSIG project and within an international collaboration between CNAO, CERN, INFN, and MedAustron, the design of a novel gantry for hadron therapy based on superconducting magnets and a downstream scanning system has been undertaken. The choice of placing the scanning system downstream of the last superconducting dipole plays a crucial role in the overall layout of the gantry, having a direct impact on its radius, weight, and cost. The proposed design for the scanning system considers two separate normal-conducting scanning magnets with a central field in the order of 1 T, three times higher than the current state-of-the-art scanning magnets for hadron therapy. Such a magnetic field value for a fast-pulsed magnet poses interesting questions regarding non-linearities due to the yoke saturation, hysteretic effects, and eddy currents. In this context, it is important to develop reliable models to study the behavior of the magnet at various levels of current and magnetic field. For this reason, we implemented two and three-dimensional simulations of a short dipole with FeCo yoke and we validated them against experimental measurements. In this paper, we focus on the modelization of the hysteretic behavior of this magnet, providing insight into the feasibility of proposed scanning magnets.

Machine learning black boxes, exemplified by deep neural networks, often exhibit challenges in interpretability due to their reliance on complicated relationships involving numerous internal parameters and input features. This lack of transparency from a human perspective renders their predictions untrustworthy, particularly in critical applications. In this paper, we address this issue by introducing the design and implementation of CReEPy, an algorithm for symbolic knowledge extraction based on explainable clustering. Specifically, CReEPy leverages the underlying clustering performed by the ExACT or CREAM algorithms to generate human-interpretable Prolog rules that mimic the behaviour of opaque models. Additionally, we introduce CRASH, an algorithm for the automated tuning of hyper-parameters required by CReEPy. We present experiments evaluating both the human readability and predictive performance of the proposed knowledge-extraction algorithm, employing existing state-of-the-art techniques as benchmarks for comparison in real-world applications.

Cultured epidermal autografts (CEA) have since become more prevalent in the treatment of burn-injured patients with limited available donor sites for adequate wound closure, resulting in decreased mortality rates and an increased number of these patients requiring burn therapy services to achieve optimal functional outcomes at discharge. However, the use and postoperative management of CEA continue to be controversial due large to the physiological fragility and expense of CEA, leading to variable postoperative treatment practices across burn centers. As such, minimal research is available regarding patient outcomes following CEA application, specifically related to burn therapy intervention. Thus, a retrospective chart review was conducted on a series of 10 patients, 18 years of age or older, admitted to a single, American Burn Association verified burn center, between April 2015 and April 2023, who required CEA and received pre- and postoperative treatment by burn therapists in accordance with center-specific burn rehabilitation guidelines. The resulting patient outcomes, in response to early implementation of therapy interventions post-CEA surgery, demonstrated optimal functional status for patients upon discharge and positive long-term implications.

Cubic gold-platinum test-masses (TMs) play the role of free-falling geodesic reference and interferometer end mirrors of the future Laser Interferometer Space Antenna (LISA) observatory for low-frequency gravitational wave detection in space. A similar arrangement has been proposed for the Chinese missions Taiji and TianQin and for the LISA follow-on missions such as ALIA and BBO. The TMs are charged by high-energy particles and photons. The deposited charge couples with stray electric fields surrounding the TMs thus inducing spurious forces that limit the sensitivity of the mission mainly at low frequencies. The TM charging was measured in space in 2016-2017 with LISA Pathfinder (LPF), meant for the testing of the LISA instrumentation. Unfortunately, during the time LPF remained in orbit, no solar energetic particle events or major astrophysical phenomena were observed. We aim at estimating the LISA TM charging attributable to long, short gamma-ray bursts (GRBs) and magnetar flares in comparison to that of charged particles of galactic and solar origin. The contribution of these major astrophysical phenomena to the LISA TM charging is discussed here for the first time. The results found here can be extended to LISA-like missions. The response of the radiation monitors hosted on the three LISA S/C is also evaluated. We show that long, intense extragalactic GRBs and galactic magnetar flares at kpc distances can be detected and monitored through a sudden change from positive to negative charging of the TMs and an increase of the TM charging noise. This is a unique signature since both galactic and solar particles charge positively the LISA TMs. This peculiar behavior of the TM charging would allow monitoring the whole dynamics of GRBs. The suggestion reported in the literature, about the detection of long GRBs and gravitational waves from the same sources, in principle, may apply to LISA and other LISA-like missions since the increase of the TM charging noise during these extreme transient phenomena is estimated to remain below the mission sensitivity while particle detectors are expected to saturate.

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMDmutation type and location, and variants in other genes.Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (–0.80%) and SF (–0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (–11.01?mL/m2, p?=?0.03) while for dp116 were correlated with decreased EF (–4.14%, p?=?<0.001). The rs10880 genotype in the LTBP4gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p?=?0.002, and –10.62?mL/m2, p?=?0.008) with a recessive model.Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4genotype of DCM in DMD.

Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMDmutation type and location, and variants in other genes. We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (–0.80%) and SF (–0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (–11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (–4.14%, p = <0.001). The rs10880 genotype in the LTBP4gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and –10.62 mL/m2, p = 0.008) with a recessive model. We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4genotype of DCM in DMD.

In metal additive manufacturing (AM), inert gases are traditionally used to achieve a controlled atmosphere and mitigate the effects of residual reactive gases. However, the interaction between gases and laser processes, particularly in reactive laser powder bed fusion (RL-PBF) technology, offers the possibility of opening up new avenues for material synthesis. In this experimental work, the authors observed the presence of C3N4in the residual powder during the manufacture of AISI 1070 steel parts by L-PBF, indicating a reactive process occurred during parts production. This investigation revealed the formation in the working chamber of a waste product containing C3N4carbon nitride, due to the reaction between the carbon released from the steel and the nitrogen in the chamber. Remarkably, despite carbon depletion, the final product of AISI 1070 steel complies with the specifications of use. Hence, the L-PBF machine was modified to allow black powder sampling from various locations in the chamber. Authors attempted to enhance the production of the C3N4material by increasing the SED up to 7143 J/mm2to sublimate a pure graphite rod and concurrently manufacture parts in AISI 1070, in a nitrogen atmosphere. The results obtained at higher SED values showed that in both cases (graphite rod or AISI 1070 steel) a C3N4compound in the black powder is formed in the investigated atmosphere by reaction of nitrogen atoms with the carbon atoms vaporized by the laser beam. Thus, the study highlights the novel achievement of synthesizing carbon nitride as a high-value by-product while producing functional AISI 1070 steel parts via L-PBF through reaction with nitrogen atmosphere.

Hydrogenated amorphous silicon (a-Si:H) is a material having an intrinsically high radiation hardness that can be deposited on flexible substrates such as polyimide (PI). For these properties, a-Si:H can be used for the production of flexible sensors. a-Si:H sensors can be successfully utilized in dosimetry, beam monitoring for particle physics (X-ray, electron, gamma ray, and proton detection) and radiotherapy, radiation flux measurement for space applications (study of solar energetic particles and stellar events), and neutron flux measurements. In this article, we have studied the dosimetric X-ray response of n-i-p diodes deposited on PI. We measured the linearity of the photocurrent response to X-rays versus dose rate from which we have extracted the dosimetric X-ray sensitivity at various bias voltages. In particular, low bias voltage operation has been studied to assess the high energy efficiency of these kinds of sensors. A measurement of stability of X-ray response versus time has been shown. The effect of detectors annealing has been studied. Operation under bending at various bending radii is also shown.

Purpose: This article summarizes the short lecture on gantries given at the “Hadrontherapy: status and perspectives. Development of a hadrontherapy facility: learning from the existing” event. Methods and materials: An introduction to gantries is given describing what a gantry is and which are the main difficulties and choices for an ion gantry. The gantry design activities ongoing at CNAO are shortly described. Results: The first part of the lecture and of the article describes some of the main choices to be made when designing a carbon ion gantry. The second part of the lecture reports shortly about the activities ongoing at CNAO within the HITRIplus and the EuroSIG projects. Conclusions: Carbon ion gantries are large, complicated and expensive objects and presently only three gantries for carbon are operational worldwide. The design of a gantry can be optimized in many ways and in many respects. In the paper, without the ambition of being exhaustive, some of the main choices are illustrated and the pros and cons of the possible options are discussed. Finally the gantry design activities ongoing in the EuroSIG collaboration and in the HITRIplus project are shortly reported.

Nowadays, in the most developed countries, modern society is moving towards scenarios in which the self-sufficiency elderly people live alone in their homes. An automatic remote monitoring system using wearable sensors is becoming even more important in Ambient Assisted Living applications. For this type of services, it is important that IoT sensors networks, which are generally composed of devices with limited computing power and storage, implement reliable communication among sensors and the Internet. There are several specialized protocols for the Internet of Things proposed by the scientific community, each characterized by its own levels of Quality of Services. The emergence of new protocols forces the need for developing proxying systems able to intermediate among different types of networks and to translate the relative protocols. In this paper, we propose a complete architecture for monitoring and managing wearable devices, and, in particular, fall detection ones. Our system uses a cross protocol proxy and a device with CoAP and MQTT as application level protocols, while it exploits the NB-IoT at physical and data-link levels. The goal of this work is the performance evaluation of the proposed solution in terms of Throughput, Round Trip Time and Delay. The results highlight the low latency reached by the proposed system architecture thanks to the implemented protocols.

The rapid worldwide aging makes necessary the development of advanced technologies for the objective identification of diseases and disabilities onset. Accordingly, we need to regard the biological age as an alternative and more reliable indicator of the physiological decline of individuals, respect to the simple chronological age. In this paper, we present an eHealth system for estimate the biological age of elderly people starting from the assessment of the frailty phenotype. The frailty phenotype evaluation is made possible using a standard protocol for data acquisition and a cloud application for processing and storing data. The proposed eHealth system is also equipped with wireless, small and non-invasive wearable sensors for an objective evaluation of the mobility of a subject. The eHealth system is tested on a reference population in order to have an amount of data necessary for defining a model to estimate the biological age. The use of the presented system on a reference population, and the availability of data regarding their mobility, allow the validation of the proposed model for the computation of the biological age via simple and objective frailty phenotype assessment.

In the frame of the Next Generation Europe program, the EU program to boost after-COVID recovery, the Italian Minister of University and Research has funded a project called Innovative Research Infrastructure for applied Superconductivity (IRIS). New laboratories will be built or upgraded in six poles: Milan (hub of the infrastructure), Genoa, Frascati, Naples, Salerno, and Lecce, to carry out basic research on magnetism and superconducting materials, test of wires, tapes, and large current cables, superconducting magnets construction with advanced instrumentation, power tests of magnets, and a special facility for high current-high voltage superconducting lines. The program will be executed over three years and then will operate for at least 10 years. It includes two first demonstrators: one HTS magnet to be operated at 10–20 K and a superconducting line of 1 GW (40 kA–25 kV) about 140 m long. The demonstrators anticipate the main scope of the investment in the IRIS infrastructure: to support the use of superconductivity for improving sustainability by decreasing the energy consumption without compromising performance. This article describes the global IRIS project.

As opaque decision systems are being increasingly adopted in almost any application field, issues about their lack of transparency and human readability are a concrete concern for end-users. Amongst existing proposals to associate human-interpretable knowledge with accurate predictions provided by opaque models, there are rule extraction techniques, capable of extracting symbolic knowledge out of opaque models. The quantitative assessment of the extracted knowledge’s quality is still an open issue. For this reason, we provide here a first approach to measure the knowledge quality, encompassing several indicators and providing a compact score reflecting readability, completeness and predictive performance associated with a symbolic knowledge representation. We also discuss the main criticalities behind our proposal, related to the readability assessment and evaluation, to push future research efforts towards a more robust score formulation.

The XAI community is currently studying and developing symbolic knowledge-extraction (SKE) algorithms as a means to produce human-intelligible explanations for black-box machine learning predictors, so as to achieve believability in human-machine interaction. However, many extraction procedures exist in the literature, and choosing the most adequate one is increasingly cumbersome, as novel methods keep on emerging. Challenges arise from the fact that SKE algorithms are commonly defined based on theoretical assumptions that typically hinder practical applicability. This paper focuses on hypercube-basedSKE methods, a quite general class of extraction techniques mostly devoted to regression-specific tasks. We first show that hypercube-based methods are flexible enough to support classification problems as well, then we propose a general model for them, and discuss how they support SKE on datasets, predictors, or learning tasks of any sort. Empirical examples are reported as well –based upon the PSyKE framework –, showing the applicability of hypercube-based methods to actual classification tasks.

A concomitant drug-based score was developed by our group and externally validated for prognostic and predictive purposes in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). The model considers the use of three classes of drugs within a month before initiating ICI, assigning score 1 for each between proton pump inhibitor and antibiotic administration until a month before immunotherapy initiation and score 2 in case of corticosteroid intake. In the present analysis, the drug score was validated in a prospective population of 305 patients with metastatic renal cell carcinoma treated with ipilimumab plus nivolumab in the first-line setting. The value of the model in predicting overall survival and progression-free survival was statistically significant and clinically meaningful, with an overall survival rate at 12 months of 73% vs. 44% (P<0.0001), and median progression-free survival of 11.6 (95% CI: 9.1–14.1) months versus 4.8 (95% CI: 2.7–7.0) months (P=0.002), respectively, for patients belonging to the favorable group (score 0–1) versus the unfavorable (score 2–4). Further development will be represented by the gut microbiome analysis according to the drug-based model classification and to the outcome of patients to ICI therapy to demonstrate the link between drug exposure and immune sensitivity.

The emergency department serves as a vital source of health care for residents in the United States, including as a safety net. However, patients from minoritized racial and ethnic groups have historically experienced disproportionate barriers to accessing health care services and lower quality of services than White patients. Quality measures and their application to quality improvement initiatives represent a critical opportunity to incentivize health care systems to advance health equity and reduce health disparities. Currently, there are no nationally recognized quality measures that track the quality of emergency care delivery by race and ethnicity and no published frameworks to guide the development and prioritization of quality measures to reduce health disparities in emergency care. To address these gaps, the American College of Emergency Physicians (ACEP) convened a working group of experts in quality measurement, health disparities, and health equity to develop guidance on establishing quality measures to address racial and ethnic disparities in the provision of emergency care. Based on iterative discussion over 3 working group meetings, we present a summary of existing emergency medicine quality measures that should be adapted to track racial and ethnic disparities, as well as a framework for developing new measures that focus on disparities in access to emergency care, care delivery, and transitions of care.

BackgroundTransgender women sex workers (TGW-SW) are disproportionally affected by HIV and have reduced access to testing. Moreover, information regarding their behaviours and health needs is scarce.MethodsA behavioural survey and a targeted testing programme in prostitution sites were conducted in Milan and Monza areas. The non-profit organisation ‘ALA Milano Onlus’ and ‘San Gerardo’ Hospital (Monza) implemented a mobile HIV testing unit involving a TGW peer educator, four physicians, a counsellor, a psychologist and a cultural mediator. All TGW-SW were offered anonymous HIV and hepatitis C virus (HCV) oral testing and asked to fill a questionnaire on sexual habits, drug abuse, and knowledge and attitudes towards HIV and STDs.ResultsBetween May and July 2017, 130 TGW-SW, predominantly migrants, were contacted during 15 street visits; among them, 78 (60%) were interviewed. HIV and HCV testing were accepted by 53 (42%) and 67 (52%) TGW-SW, respectively. Twenty-five (19.8%) subjects who reported already established HIV infection were not retested. Seven patients received a new diagnosis of HIV, while nobody tested positive for HCV. Overall, HIV prevalence was 13.2% (25% including those with already known HIV infection). Recent arrival in Italy and young age were associated with risk of undiagnosed HIV infection. Inconsistent condom use was commonly reported during commercial sex (27%) and with non-commercial partners (64%). Alcohol and cocaine abuse were common problems which facilitated risky behaviours.ConclusionsOral rapid HIV and HCV testing for TGW-SW in outreach settings were feasible and acceptable and led to a considerable number of new diagnoses. Interventions tailored to TGW-SW, focused on HIV prevention, testing and engagement in care, are fundamental.

IMPORTANCE: Clinical trials play a critical role in the development of novel cancer therapies, and precise estimates of the frequency with which older adult patients with cancer participate in clinical trials are lacking. OBJECTIVE: To estimate the proportion of older adult Medicare Fee-for-Service (FFS) beneficiaries with cancer who participate in interventional cancer clinical trials, using a novel population-based methodology. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study evaluating clinical trial participation among older adult patients with cancer from January 1, 2014, through June 30, 2020, claims data from Medicare FFS were linked with the ClinicalTrials.gov to determine trial participation through the unique National Clinical Trial (NCT) identifier. The proportion of patients with newly diagnosed or newly recurrent cancer in 2015 participating in an interventional clinical trial and receiving active cancer treatment from January 2014 to June 2020 was estimated. Data analysis was performed from November 18, 2020, to November 1, 2021. EXPOSURES: Patients with cancer aged 65 years or older with Medicare FFS insurance, with and without active cancer treatment. MAIN OUTCOMES AND MEASURES: Enrollment in clinical trials among all patients with cancer 65 years and older and among patients receiving active cancer treatments as defined by the presence of at least 1 NCT identifier corresponding to an interventional cancer clinical trial in Medicare claims. RESULTS: Among 1 150 978 patients (mean [SD] age, 75.7 [8.4] years; 49.9% men and 50.1% women) with newly diagnosed or newly recurrent cancer in 2015, 12 028 (1.0%) patients had a billing claim with an NCT identifier indicating enrollment in an interventional cancer clinical trial between January 2014 and June 2020. In a subset of 429 343 patients with active cancer treatment, 8360 (1.9%) were enrolled in 1 or more interventional trials. Patients enrolled in a trial tended to be younger, male, a race other than Black, and residing in zip codes with high median incomes. CONCLUSIONS AND RELEVANCE: Findings of this cohort study show that clinical trial enrollment among older adult patients with cancer remains low, with only 1.0% to 1.9% of patients with newly diagnosed or recurrent cancer in 2015 participating in an interventional cancer clinical trial as measured by the presence of NCT identifiers in Medicare claims. These data provide a contemporary estimate of trial enrollment, persistent disparities in trial participation, and only limited progress in trial access over the past 2 decades.

Background: NETosis is a neutrophil-mediated defense mechanism during which DNA and enzymes are extruded forming a network (NETs) trapping and killing different pathogens. NETosis is reduced in both mice and humans during aging. Aims: We explored the difference in the efficacy of NETs released in elderly (> 65 years) versus adults (20–50 years) subjects in inhibiting Staphylococcus aureusgrowth and activating the growth of keratinocytes. Methods: Neutrophil granulocytes, obtained from venous blood both in healthy elderly and adult subjects, were stimulated by LPS (0–250 µg/ml) to induce the formation of NET. NETs were quantified by SYBR Green staining and growth inhibition of S. aureuswas evaluated by disk diffusion test. Furthermore, NETs (0–500 ng/ml) were added to immortalized human keratinocytes (HaCaT cells), and their proliferation was evaluated by MTT assay after 24 h. Finally, the DNA size of NETs was evaluated by flow cytometry after SYBR Green staining. Results: Greater production of NETs was observed in elderly subjects than in adults, but these NETs showed reduced bactericidal capacity and HaCaT cells’ proliferation stimulation. The activities of the NETs are related to the size of the extruded DNA threads, and when NETs size was analyzed, DNA from elderly showed a higher size compared to that obtained by adults. Discussion: Unexpected results showed aging-related NETs structural modification resulting in both a lower antimicrobial activity and keratinocyte proliferation stimulation compared to NETs obtained from adults. Conclusions: The NETs DNA size observed in elderly subjects has not been previously reported and could be part of other pathogenic mechanisms observed in aging.

The grapevine source-to-sink ratio and berry exposure to solar radiation both influence grape flavonoid biosynthesis and accumulation. Here, we compared these concepts on cv. Merlot in two different growing locations (Michigan (MI) and Friuli-Venezia Giulia (FVG), IT) to understand whether the environment influences flavonoid sensitivity to these parameters. Three levels of leaf removal (LR0, LR5, LR8) were implemented at the pea-size phenological stage to compare conditions of increased cluster light exposure with a decreasing vine source-to-sink ratio on berry flavonoid accumulation. Treatments did not affect total soluble solids (TSSs) or pH, but titratable acidity (TA) was lower in LR8 at harvest in both locations. LR5 increased anthocyanins and flavonols in MI but decreased most phenolics in FVG. The decreased expression of VviLAR1 and VviF3′5′Hhduring ripening supported the lower concentrations of flavan-3-ol monomers and anthocyanins in FVG. In summary, flavonoid biosynthesis and accumulation were more sensitive to solar radiation than the source-to-sink ratio, and the vineyard environment dictated whether solar radiation was beneficial or detrimental to flavonoid biosynthesis.

A common practice in modern explainable AI is to post-hocexplain black-box machine learning (ML) predictors – such as neural networks – by extracting symbolicknowledge out of them, in the form of either rule lists or decision trees. By acting as a surrogate model, the extracted knowledge aims at revealing the inner working of the black box, thus enabling its inspection, representation, and explanation. Various knowledge-extraction algorithms have been presented in the literature so far. Unfortunately, running implementations of most of them are currently either proofs of concept or unavailable. In any case, a unified, coherent software framework supporting them all – as well as their interchange, comparison, and exploitation in arbitrary ML workflows – is currently missing. Accordingly, in this paper we discuss the design of PSyKE, a platform providing general-purpose support to symbolic knowledge extraction from different sorts of black-box predictors via many extraction algorithms. Notably, PSyKE targets symbolic knowledge in logic form, allowing the extraction of first-order logic clauses. The extracted knowledge is thus both machine- and human-interpretable, and can be used as a starting point for further symbolic processing—e.g. automated reasoning.

IMPORTANCE: For adults with appendicitis, several randomized clinical trials have demonstrated that antibiotics are an effective alternative to appendectomy. However, it remains unknown how the characteristics of patients in such trials compare with those of patients who select their treatment and whether outcomes differ. OBJECTIVE: To compare participants in the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) randomized clinical trial (RCT) with a parallel cohort study of participants who declined randomization and self-selected treatment. DESIGN, SETTING, AND PARTICIPANTS: The CODA trial was conducted in 25 US medical centers. Participants were enrolled between May 3, 2016, and February 5, 2020; all participants were eligible for at least 1 year of follow-up, with all follow-up ending in 2021. The randomized cohort included 1094 adults with appendicitis; the self-selection cohort included patients who declined participation in the randomized group, of whom 253 selected appendectomy and 257 selected antibiotics. In this secondary analysis, characteristics and outcomes in both self-selection and randomized cohorts are described with an exploratory analysis of cohort status and receipt of appendectomy. INTERVENTIONS: Appendectomy vs antibiotics. MAIN OUTCOMES AND MEASURES: Characteristics among participants randomized to either appendectomy or antibiotics were compared with those of participants who selected their own treatment. RESULTS: Clinical characteristics were similar across the self-selection cohort (510 patients; mean age, 35.8 years [95% CI, 34.5-37.1]; 218 female [43%; 95% CI, 39%-47%]) and the randomized group (1094 patients; mean age, 38.2 years [95% CI, 37.4-39.0]; 386 female [35%; 95% CI, 33%-38%]). Compared with the randomized group, those in the self-selection cohort were less often Spanish speaking (n = 99 [19%; 95% CI, 16%-23%] vs n = 336 [31%; 95% CI, 28%-34%]), reported more formal education (some college or more, n = 355 [72%; 95% CI, 68%-76%] vs n = 674 [63%; 95% CI, 60%-65%]), and more often had commercial insurance (n = 259 [53%; 95% CI, 48%-57%] vs n = 486 [45%; 95% CI, 42%-48%]). Most outcomes were similar between the self-selection and randomized cohorts. The number of patients undergoing appendectomy by 30 days was 38 (15.3%; 95% CI, 10.7%-19.7%) among those selecting antibiotics and 155 (19.2%; 95% CI, 15.9%-22.5%) in those who were randomized to antibiotics (difference, 3.9%; 95% CI, −1.7% to 9.5%). Differences in the rate of appendectomy were primarily observed in the non-appendicolith subgroup. CONCLUSIONS AND RELEVANCE: This secondary analysis of the CODA RCT found substantially similar outcomes across the randomized and self-selection cohorts, suggesting that the randomized trial results are generalizable to the community at large. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02800785

•Substrate properties modulate olive tree response to salt stress.•The use of inert substrates like perlite acts as an inefficient buffer compared to peat.•Physiological and biometric data showed a more pronounced reduction of plant growth with perlite.•Metabolomics indicate that differences are due to substrate and salt stress severity.•The metabarcoding analysis confirmed that the 100 mM NaCl treatment differs in holobiont composition.

•Drought represents one of the most environmental stressors of industrial crops.•Biochar application and AMF inoculation may mitigate the impact of drought stress.•Biochar combined with AMF increased antioxidant enzymes and phenolic compounds.•Biochar and AMF regulate physiological and biochemical traits of lavander.

AimsAccording to The Cancer Genome Atlas (TCGA), around 9% of bladder carcinomas usually show abnormalities of the murine double minute 2 (MDM2) gene, but a few studies have been investigated them. We profiled MDM2 gene amplification in a series of urothelial carcinomas (UC) considering the molecular subtypes and expression of programmed death ligand 1 (PD-L1).Methods117 patients with muscle-invasive UC (pT2-3) without (N0) or with (N+) lymph-node metastases were revised. Only cases with availability of in toto specimens and follow-up were studied. Tissue microarray was built. p53, ER, RB1, GATA-3, CK20, CK5/6, CD44 and PD-L1 (clone sp263) immunoexpression was evaluated. Fluorescent in situ hybridisation was assessed by using the HER-2/neu, FGFR-3, CDKN2A and MDM2 probes. True (ratio 12q/CEP12 >2) MDM2 gene amplification was distinguished from polyploidy/gains (ratio <2, absolute copy number of MDM-2 >2). MDM2 and PD-L1 values were correlated to the TCGA molecular phenotypes. Statistical analysis was performed.Results6/50 (12%) cases (5 N0 and 1 N+) were amplified for MDM2 without matching to molecular phenotypes. Of 50, 14 (37%) cases expressed PD-L1 at 1% cut-off; 3/50 (9%) at >50% cut-off; of these, 2 cases on side of neoplasia among inflammatory cells. Only one out of six (17%) cases amplified for MDM2 showed expression (>50% cut-off) of PD-L1. MDM2 amplification was independent to all documented profiles (k test=0.3) and was prevalent in recurrent UC.ConclusionMDM2 amplification has been seen in both PD-L1 positive and negative muscle-invasive bladder UC independently from the TCGA molecular phenotypes. MDM2 and PD-L1 might be assessed in order to predict a better response to combo/single targeted therapies.

Pediatric acute lymphoid leukemias (ALL) is the most common childhood cancer, and cytotoxic chemotherapy remains the primary treatment option. Chemotherapic drugs act by oxidative stress generation, but their clinical meaning is poorly understood. During the chemotherapy schedule, this study evaluated the antioxidant profile of peripheral blood samples from 34 patients diagnosed with type B-cell ALL (B-ALL). Peripheral blood samples were collected at diagnosis (D0) and during the induction, consolidation, and maintenance phases. The plasma total antioxidant capacity (TRAP) was determined using the high-sensitivity chemiluminescence technique. Antioxidant levels were higher on D0 compared to day 7 after treatment starting (D7) in the induction phase (28.68–1194.71 μM Trolox, p = 0.0178) and in the high-risk group (age > ten years and/or with white blood cell counts and/or > 50,000 white blood cells/m3 at diagnosis) concerning low-risk patients (253.79–1194.71 μM Trolox, p = 0.0314). Reduced TRAP was also detected in patients who died compared to those who survived (392.42–1194.71 μM Trolox, p = 0.0278). Patients under consolidation (56.14–352.05 μM Trolox, p=<0.0001) and maintenance (30.48–672.99 μM Trolox, p=<0.0001) showed a significant reduction in TRAP levels compared to those from the induction phase (28.68–1390.26 μM Trolox), reaching levels similar to cured patients out of treatment (64.82–437.82 μM Trolox). These findings suggest that the variation of the total antioxidant capacity in B-ALL during chemotherapy is a parameter that correlates to some predictors of disease prognosis.