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Background Various prediction models have been developed to predict the risk of kidney failure in patients with CKD. However, guideline-recommended models have yet to be compared head to head, their validation in patients with advanced CKD is lacking, and most do not account for competing risks. Methods To externally validate 11 existing models of kidney failure, taking the competing risk of death into account, we included patients with advanced CKD from two large cohorts: the European Quality Study (EQUAL), an ongoing European prospective, multicenter cohort study of older patients with advanced CKD, and the Swedish Renal Registry (SRR), an ongoing registry of nephrology-referred patients with CKD in Sweden. The outcome of the models was kidney failure (defined as RRT-treated ESKD). We assessed model performance with discrimination and calibration. Results The study included 1580 patients from EQUAL and 13,489 patients from SRR. The average c statistic over the 11 validated models was 0.74 in EQUAL and 0.80 in SRR, compared with 0.89 in previous validations. Most models with longer prediction horizons overestimated the risk of kidney failure considerably. The 5-year Kidney Failure Risk Equation (KFRE) overpredicted risk by 10%-\18%. The four- and eight-variable 2-year KFRE and the 4-year Grams model showed excellent calibration and good discrimination in both cohorts. Conclusions Some existing models can accurately predict kidney failure in patients with advanced CKD. KFRE performed well for a shorter time frame (2 years), despite not accounting for competing events. Models predicting over a longer time frame (5 years) overestimated risk because of the competing risk of death. The Grams model, which accounts for the latter, is suitable for longer-term predictions (4 years).

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:276-287 ispartof: location:England status: published

Introduction. Influenza is a widespread acute respiratory disease and represents a serious Public Health problem, both from the NHS and society perspectives. The High Dose quadrivalent influenza vaccine (QIV HD) is a flu vaccine containing 4 times the antigens of a Standard Dose vaccine, resulting in demonstrated superior protection in the population aged 65 years and over. Methods. The analysis has been conducted from the perspective of the NHS. The CEA focuses on the comparison between QIV HD and the QIV SD vaccine. The BIM aims to estimate the potential economic impact for the National Health Service (NHS) resulting from the use of QIV HD in clinical practice in subjects aged 65 or over, when considering its introduction in combination with currently used vaccines, QIV SD and adjuvanted TIV. Results. In a scenario which considers hospitalizations possibly related to influenza, so including cardio-respiratory events, a dominant cost-effectiveness profile emerges in the comparison with QIV SD. In terms of budget impact, overall savings obtained by comparing the two scenarios regarding hospitalizations are equal to 92,766,429 € over the three years’ time horizon considered in the analysis. Conclusions. Nowadays, also considering the state of emergency due to the spread of the SARS-CoV-2 virus, it is crucial to implement innovative health technologies that improve the efficiency and sustainability of the health system. Also, it is essential to protect the elderly population, helping to avoid overload and healthcare systems disruption due to the many COVID-19 hospitalizations.

Background: Opioid use disorder (OUD) is a disorder associated with significant rate of morbidity and mortality. Frequent clinic attendance for supervised consumption of sublingual buprenorphine is common. Prolonged-release buprenorphine (PRB) allows a management based on weekly or monthly subcutaneous injections, thus limiting the burdens of clinic attendance and the risks associated with sublingual formulations. Objective: To determine the price level of PRB that allows to obtain a neutral impact from the point of view of the economic resources absorbed, in comparison with the alternatives currently available in the Italian context for the management of patients suffering from OUD. Methods: The analysis assumes a daily PRB cost of €8.526 (neutral cost). The analysis aims to determine the economic impact associated with the introduction of PRB in the Italian context for the management of OUD patients. Results are expressed in terms of differential resourced absorbed in the alternative scenarios. A one-way sensitivity analysis was also carried out to test the robustness of the results. Results: The introduction of PRB implies an increase in the drug acquisition costs over the 5-year time horizon of €19.563.019,13: such costs are fully compensated by the other cost driver considered in the analysis (drug tests provided, health professionals’ time destined to the provision of the treatment, indirect costs, for savings equal to €6.167.026,94, €9.106.824,67 and €4.289.167,53 respectively) demonstrating its effectiveness in particular by an organizational point of view. Lower price levels for PRB would imply significant savings for the SSN. Conclusions: PRB resulted to be associated to a lower level of resources’ absorption in the Italian sector as compared with the available alternatives thus allowing to re-allocate health founds to other fields of the care sector ensuring greater safety for patients and a decreased misuse and diversion rate.

Background: The current clinical practice for patients affected by chronic myeloid leukemia (CML) is based on the evaluation of second generation alternatives following therapeutic failure that leads to a lengthening of patients’ management times and a consequent negative impact in terms of quality of life. Objective: To determine the economic absorption of resources associated to the management of patients with CML in a scenario in which an early recourse to ponatinib is considered as compared with a scenario based on the current Italian clinical practice characterized by a cyclical recourse to the available therapies. Methods: A Budget Impact model was developed to compare the resources absorbed in the scenarios under assessment considering a 3-year time horizon and the perspective of the Italian National Health Service. Results are expressed in terms of differential resources absorbed in the alternative scenarios. Results: The increase in the recourse to ponatinib allowed a saving of resources for the Italian NHS over the 3-year time horizon of –€ 1,979,322 (€ 825,104,350 vs € 823,125,028). The parameter affecting the most of the results achieved in the base-case is the monthly cost of bosutinib used as a third-line treatment. Conclusions: The increase in the recourse to ponatinib in patients affected by CML that failed to respond to a previous pharmacological therapy resulted to be associated to a lower level of resources’ absorption in the Italian NHS allowing to re-allocate health founds to other fields of the care sector ensuring greater sustainability of the system.

COVID-19 pneumonia represents a global threatening disease, especially in severe cases. Chest imaging, with X-ray and high-resolution computed tomography (HRCT), plays an important role in the initial evaluation and follow-up of patients with COVID-19 pneumonia. Chest imaging can also help in assessing disease severity and in predicting patient’s outcome, either as an independent factor or in combination with clinical and laboratory features. This review highlights the current knowledge of imaging features of COVID-19 pneumonia and their temporal evolution over time, and provides recent evidences on the role of chest imaging in the prognostic assessment of the disease.

IntroductionDespite overlaying an irreplaceable role as a key diagnostic tool in modern medicine, the role of radiologist still appears to be unclear to patients.Methods We conducted a survey in outpatient clinic of Radiological Sciences Department of the University Hospital “A. Gemelli” in Rome, aiming to assess how correct patients identify the figure of the radiologist. The patients were interviewed by the trained physician using structured questionnaire.Results We included the number of 259 patients. Majority were female 63.3%, most were 60-69 years old (24.3%), have finished second grade secondary school (35.1%) and were subjected to magnetic resonance (28.6%) while the least were subjected to chest X-ray (8.1%). Only 38.7% answered correctly to question No 1 “Who performed your examination?”, and only 30.9% correctly identified the radiologist as a person interpreting the exam (question No 2 “Who is going to interpret your radiological examination?”). Overall, 16.8% responded correctly to the both questions. Significantly less patients with primary school (OR: 0.18, CI 95% 0.06-0.49) and first grade secondary school (OR: 0.37, CI 95% 0.18-0.75) correctly addressed the question No 1 in compare to those with second grade secondary school. The first grade secondary education (OR: 0.43, CI 95% 0.20-0.92) was inversely associated with correct answer to question No 2. Patients with primary education were significantly less prone to give both correct answers (OR: 0.12, CI 95% 0.02-0.60).Conclusion We report insufficient knowledge among patients on radiologist’s role in healthcare system. The level of knowledge is associated with level of education.

The present investigation examined the longitudinal effects of Child-Parent Psychotherapy (CPP) for toddlers and their mothers with depression on: a) maternal affective expression, b) child affective expression, and c) mother-child cohesion. Mothers with depression (Mage = 31.7 years; 92.8% White, 3.5% Black, 2.1% Hispanic, 2.3% other) and their toddlers were randomized to receive CPP (DI; n = 66) or to a control group (DC; n = 64). Mothers without depression and their toddlers (NC; n = 68) were recruited as an additional comparison group. Dyads were assessed at baseline (T1; 20 months old), post-intervention (T2; 36 months old), and follow-up (T3; 9 years old). Data from a mother-child conflict task was coded as a measure of observed outcome variables. Change in post-intervention attachment security assessed via the Strange Situation was evaluated as a mediator between intervention condition and maternal and child affective expression and dyadic cohesion at T3. Change to secure attachment post-intervention significantly mediated the association between intervention condition and T3 maternal warmth and child anger/problem behavior. Toddlers of mothers with depression who received CPP showed higher rates of change to secure attachment compared to those in both the DC and NC groups. Dyads who changed to secure attachment at T2 displayed higher levels of maternal warmth at T3 and lower levels of child anger and problem behavior at T3. Implications for the use of CPP as a preventive intervention and the importance of attachment as a mediator of long-term outcomes are discussed.

Introduction: Osteoarthritis (OA) is a common chronic joint disease characterized by pain, deformity, instability, reduction of motion and function. It is one of the main causes of disability in older adults, affecting about 10% of men and 18% of women over the age of sixty. There are several Guidelines that support the general clinical decision-making process. However, it is necessary to define an integrated management model for patients with OA to ensure an appropriate and quality healthcare. Methods: The objective of the analysis is to determine the economic burden linked to the prevalence and incidence of OA in the acute and chronic phases from the perspective of the National Health Service (NHS) and the entire society. A comparison was made between the management according to the clinical practice and the appropriate management according to National and International Guidelines, determining for each scenario the level of resources absorbed. Results: Patients who started a nonsteroidal anti-inflammatory drug (NSAID)-based therapy in clinical practice resulted in a higher absorption of resources of €363.87 than the same patient managed by referring to National and International Guidelines. Conclusions: OA is associated with a high economic burden and it is a priority problem for public health internationally. The savings resulting from our research, if generalized to the entire Italian population, would lead to a significant reduction of OA economic burden, thus allowing a reallocation of the available resources to other NHS’ sectors.

BACKGROUND Computed tomography (CT) plays a key role in evaluation of paranasal sinus inflammation, but improved, and standardized, objective assessment is needed. Computerized volumetric analysis has benefits over visual scoring, but typically relies on manual image segmentation, which is difficult and time-consuming, limiting practical applicability. We hypothesized that a convolutional neural network (CNN) algorithm could perform automatic, volumetric segmentation of the paranasal sinuses on CT, enabling efficient, objective measurement of sinus opacification. In this study we performed initial clinical testing of a CNN for fully automatic quantitation of paranasal sinus opacification in the diagnostic workup of patients with chronic upper and lower airway disease. METHODS Sinus CT scans were collected on 690 patients who underwent imaging as part of multidisciplinary clinical workup at a tertiary care respiratory hospital between April 2016 and November 2017. A CNN was trained to perform automatic segmentation using a subset of CTs (n = 180) that were segmented manually. A nonoverlapping set (n = 510) was used for testing. CNN opacification scores were compared with Lund-MacKay (LM) visual scores, pulmonary function test results, and other clinical variables using Spearman correlation and linear regression. RESULTS CNN scores were correlated with LM scores (rho = 0.82, p < 0.001) and with forced expiratory volume in 1 second (FEV1 ) percent predicted (rho = -0.21, p < 0.001), FEV1 /forced vital capacity ratio (rho = -0.27, p < 0.001), immunoglobulin E (rho = 0.20, p < 0.001), eosinophil count (rho = 0.28, p < 0.001), and exhaled nitric oxide (rho = 0.40, p < 0.001). CONCLUSION Segmentation of the paranasal sinuses on CT can be automated using a CNN, providing truly objective, volumetric quantitation of sinonasal inflammation.

Introduction: Achieving haemostasis is critical in surgical procedures. Surgical bleeding is associated with an increased risk of mortality and morbidity with consequences at both clinical and organizational level, and with significant economic implications. In addition to conventional methods for controlling intraoperative bleeding, many topical adjunctive hemostatic products are available; among them Floseal® (Baxter Healthcare Corporation), a gelatin-based hemostatic matrix. The aim of this study is to provide an updated systematic literature review of Floseal® in cardiac surgery and estimate its associated economic impact in an Italian hospital. Methods: A literature search was conducted in MEDLINE and the Cochrane Library over the period 2013-2016 to identify new publications related to Floseal® in cardiac surgery, in addition to those already included in the systematic review of Echave et al. Furthermore, we investigated the economic impact of the use of Floseal® adapting the model elaborated by Tackett et al. to the Italian NHS. Four new studies were selected. Results: High variability in surgical procedures, choice of hemostatic products compared to Floseal® and outcome definition is confirmed. Clinical, organizational, and economics endpoints were investigated. A cost-consequence analysis estimated relevant savings. A scenario analysis, despite showing a high variability in patient level savings (€ 441-2.831), confirmed economic advantages associated with Floseal®. Discussion: Results support prior research both in terms of heterogeneity of evidence on the effectiveness of Floseal® in cardiac surgery and cost implications. The use of Floseal® achieves substantial cost savings in a hypothetical Italian hospital with a cardiac surgery unit.

Software in modern vehicles consists of multi-criticality functions, where a function can be safety-critical with stringent real-time requirements, less critical from the vehicle operation perspective, but still with real-time requirements, or not critical at all. Next-generation autonomous vehicles will require higher computational power to run multi-criticality functions and such a power can only be provided by parallel computing platforms such as multi-core architectures. However, current model-based software development solutions and related modelling languages have not been designed to effectively deal with challenges specific of multi-core, such as core-interdependency and controlled allocation of software to hardware. In this paper, we report on the evolution of the Rubus Component Model for the modelling, analysis, and development of vehicular software systems with multi-criticality for deployment on multi-core platforms. Our goal is to provide a lightweight and technology-preserving transition from model-based software development for single-core to multi-core. This is achieved by evolving the Rubus Component Model to capture explicit concepts for multi-core and parallel hardware and for expressing variable criticality of software functions. The paper illustrates these contributions through an industrial application in the vehicular domain.

Aim To describe the methods and feasibility of the nutritional intervention carried out within the SPRINTT Randomized cotrolled trial. We also illustrate how nutrition interventionists identified participants at risk of malnutrition and the lessons learnt from the nutrition intervention. Findings SPRINTT nutrition intervention was well-received by the majority of the participants. It was mainly carried out using tailored nutrition counselling, but also other means of delivering the intervention were successfully used. Compared with a standard nutrition prescription, an individualized protocol to diagnose malnutrition and follow-up by tailored nutrition counselling helped achieve nutritional targets more effectively in spite of diversity of population in nutritional habits and in some cases reluctance to accept changes. Message The SPRINTT nutrition intervention was feasible and allowed flexibility to the varying needs and cultural differences of this heterogeneous population of frail, older Europeans. It may serve as a model to educate and improve nutrition among community-dwelling older people at risk of mobility limitations. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-020-00438-4., Background The “Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies” (SPRINTT) project sponsored a multi-center randomized controlled trial (RCT) with the objective to determine the effect of physical activity and nutrition intervention for prevention of mobility disability in community-dwelling frail older Europeans. We describe here the design and feasibility of the SPRINTT nutrition intervention, including techniques used by nutrition interventionists to identify those at risk of malnutrition and to carry out the nutrition intervention. Methods SPRINTT RCT recruited older adults (≥ 70 years) from 11 European countries. Eligible participants (n = 1517) had functional limitations measured with Short Physical Performance Battery (SPPB score 3–9) and low muscle mass as determined by DXA scans, but were able to walk 400 m without assistance within 15 min. Participants were followed up for up to 3 years. The nutrition intervention was carried out mainly by individual nutrition counseling. Nutrition goals included achieving a daily protein intake of 1.0–1.2 g/kg body weight, energy intake of 25–30 kcal/kg of body weight/day, and serum vitamin D concentration ≥ 75 mmol/L. Survey on the method strategies and feasibility of the nutrition intervention was sent to all nutrition interventionists of the 16 SPRINTT study sites. Results Nutrition interventionists from all study sites responded to the survey. All responders found that the SPRINTT nutrition intervention was feasible for the target population, and it was well received by the majority. The identification of participants at nutritional risk was accomplished by combining information from interviews, questionnaires, clinical and laboratory data. Although the nutrition intervention was mainly carried out using individual nutritional counselling, other assisting methods were used as appropriate. Conclusion The SPRINTT nutrition intervention was feasible and able to adapt flexibly to varying needs of this heterogeneous population. The procedures adopted to identify older adults at risk of malnutrition and to design the appropriate intervention may serve as a model to deliver nutrition intervention for community-dwelling older people with mobility limitations. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-020-00438-4.

Recently new opportunities are emerging for improving the way patients with Haemophilia A are treated. Among these opportunities, efmoroctocog alfa is a first-in-class recombinant factor VIII-Fc fusion protein (rFVIIIFc) produced by recombinant DNA technology with an extended half-life compared with conventional FVIII preparations. The available evidence coming from an Italian HTA report indicates that efmoroctocog alfa provides an effective alternative to conventional FVIII preparations (including standard rFVIIIs) for the management of Haemophilia A. Moreover, by reducing the frequency of injections required, it has the potential to reduce treatment burden, and hence improve adherence to prophylaxis and patient Quality-of-Life.

Among the well-known physiological consequences of early adverse environments is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. A number of studies demonstrate that negative parenting and living with parents with a history of substance abuse and mental health problems may be associated with HPA axis dysregulation in children. In contrast, studies of more delayed effects in adult offspring, especially prospective, are still scarce. This study was a prospective longitudinal investigation of the association between maternal mental illnesses/substance abuse and maternal negative parenting/parental stress on one side and, on the other side, adult offspring outcomes 10 years later-specifically, we studied the activity of offspring's neuroendocrine (cortisol) and autonomic (heart rate) systems when exposed to a mild psychological stressor. Children of mothers with mental illnesses and/or substance abuse were exposed to more disadvantaged conditions (higher negative parenting and community violence). Despite this, maternal risk groups (having a mother with mental illnesses and/or substance abuse) were not associated with any of the indicators of stress systems activity. Regardless of the risk group, participants with dysregulated HPA axis activity experienced a higher level of negative parenting. Altogether, our study provides evidence that negative parenting may have long-lasting effects on stress-sensitive physiological mechanisms.

A class of lightweight spherical-axicon-like dielectric lenses suitable for enhancing broadband antennas performances is presented. The proposed lenses, sized according to a reference massive lens, are formed by thin dielectric sheets spaced equiangularly on the azimuth plane (petal-shaped lens), or regularly orthogonally arranged along the lens axis (disks-shaped lens), thus yielding construction simplicity and significant weight reduction. While petal-shaped dielectric lenses are shown to yield mild gain increase, lenses made by thin dielectric disks, orthogonally periodically arranged along the lens optical axis, offer performances much closer to those achieved by comparable massive refractive spherical-axicon dielectric lenses. The time-domain and the focusing characteristics of the proposed lenses are investigated. Then, a Floquet’s mode-based model is proposed to describe the stop-band characteristics of stacked-disk lenses, illustrating the mechanism underpinning their sudden performance degradation observed at the stop-band onset frequency. Full-wave analyses, based on a locally conformal finite integration technique (FIT), implemented in CST Studio Suite™ and validated by measurements or highly accurate FEM simulations, illustrate the excellent characteristics of the proposed lenses to operate with narrowband as well as ultra-wideband (UWB) waveforms.

Interstitial lung disease (ILD) are a large group of diffuse lung diseases characterized by similar clinical, pathological and radiological features. High resolution computed tomography (HRCT) has a central role in ILD diagnosis and management. In the last few years, computer-aided methods as Quantitative Computer Tomography (QCT) and Artificial Intelligence (AI) software were proposed as a source of reliable quantitative imaging biomarkers. The present review aimed to summarize and describe the current QCT and AI methods and to evaluate their potential diagnostic and prognostic role. The first attempt to a quantitative analysis of HRCT in ILD is represented by the density histogram analysis with the definition of two new parameter, Kurtosis and Skewness. Then texture analysis tools were developed as Adaptive Multiple Features Method (AMFM), Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER), Quantitative Lung Fibrosis (QLF) and Automated Quantification System (AQS). The introduction of AI technologies further increased the amount of objective and reproducible biomarkers. The diagnostic and prognostic role of QCT and AI methods was analyzed and confirmed in various studies, as reported in the review. QCT and AI technologies application led to the introduction of new objective biomarkers with relevant diagnostic and prognostic implications. However, there is still the need for more prospective study and the creation of open-source datasets would help to assess QCT and AI methods efficacy and to compare them.

BACKGROUND This study analyzes patient health-related quality of life (QoL) 24-month after prostate cancer (PCa) diagnosis within the PROState cancer monitoring in ITaly from the National Research Council (Pros-IT CNR) study. METHODS Pros-IT CNR is an ongoing, longitudinal and observational study, considering a convenience sample of patients enrolled at PCa diagnosis and followed at 6, 12, 24, 36, 48 and 60 months from the diagnosis. Patients were grouped according to the treatment received: nerve sparing radical prostatectomy (NSRP), non-nerve sparing radical prostatectomy (NNSRP), radiotherapy (RT), radiotherapy plus androgen deprivation (RT plus ADT) and active surveillance (AS). QoL was measured through the Italian versions of SF-12 and UCLA-PCI questionnaires at diagnosis and at 6-12 and 24-month. The minimal clinically important difference (MCID) was defined as half a standard deviation of the baseline domain. RESULTS Overall, 1 537 patients were included in the study. The decline in urinary function exceeded the MCID at each timepoint only in the NSRP and NNSRP groups (at 24 months -14.7, p

Prostate Cancer (PCa) is one of the most frequently identified urological cancers. PCa patients are often over-diagnosed due to still not highly specific diagnostic methods. The need for more accurate diagnostic tools to prevent overestimated diagnosis and unnecessary treatment of patients with non-malignant conditions is clear, and new markers and methods are strongly desirable. Extracellular vesicles (EVs) hold great promises as liquid biopsy-based markers. Despite the biological and technical issues present in their detection and study, these particles can be found highly abundantly in the biofluid and encompass a wealth of macromolecules that have been reported to be related to many physiological and pathological processes, including cancer onset, metastasis spreading, and treatment resistance. The present study aims to perform a technical feasibility study to develop a new workflow for investigating EVs from several biological sources. Serum and urinary supernatant EVs of PCa, benign prostatic hyperplasia (BPH) patients, and healthy donors were isolated and investigated by a fast, easily performable, and cost-effective cytofluorimetric approach for a multiplex detection of 37 EV-antigens. We also observed significant alterations in serum and urinary supernatant EVs potentially related to BPH and PCa, suggesting a potential clinical application of this workflow.

In this paper, we report on a case study in an industrial setting where code is generated from models, and, for various reasons, that generated code is then manually modified. To enhance the maintainability of both models and code, consistency between them is imperative. A first step towards establishing that consistency is to identify the manual changes that were made to the code after it was generated and deployed. Identifying the delta is not straightforward and requires pre-processing of the artifacts. The main mechanics driving our solution are higher-order transformations, which make the implementation scalable and robust to small changes in the modeling language. We describe the specific industrial setting of the problem, as well as the experiences and lessons learned from developing, implementing, and validating our solution together with our industrial partner.

Background The COVID-19 pandemic has necessitated the social isolation of the population and the rapid implementation of remote care for patients with neurodegenerative diseases. The objective of this study was to explore the perceived impact of confinement in patients with Parkinson's disease and document the effects of gender and living environment. Methods We recruited two cohorts from the Canadian provinces of Quebec and Alberta, which differed in the dynamics of COVID-19 spreading at the time of the study, and administered a questionnaire on the perceived effects of confinement on daily living and disease management. Results The data reveals that approximately half of the patients experienced a change in one or more clinical symptoms, with differences observed between gender (e.g. day-to-day changes in slowness in men, aggravated headaches in women) and geographic location (e.g. increased depression in Alberta but reduced sleep quality in Quebec). Furthermore, participants identifying as women or living in Alberta implemented more frequently home or online exercise. Lastly, high levels of satisfaction with phone or video consultations did not translate into a sustained interest to pursue this mode of healthcare. Conclusions This study suggests that COVID-19-related confinement affected Parkinson's disease manifestation and management. Patients also reported varying levels of interest to continue remote care. A number of differences reported in our study were seemingly related to gender and living environment.

International audience; The advent of complex Cyber-Physical Systems (CPSs) creates the need for more efficient engineering processes. Recently, DevOps promoted the idea of considering a closer continuous integration between system development (including its design) and operational deployment. Despite their use being still currently limited, Artificial Intelligence (AI) techniques are suitable candidates for improving such system engineering activities (cf. AIOps). In this context, AIDOaRT is a large European collaborative project that aims at providing AI-augmented automation capabilities to better support the modelling, coding, testing, monitoring, and continuous development of CPSs. The project proposes to combine Model Driven Engineering principles and techniques with AI-enhanced methods and tools for engineering more trustable CPSs. The resulting framework will 1) enable the dynamic observation and analysis of system data collected at both runtime and design time and 2) provide dedicated AI-augmented solutions that will then be validated in concrete industrial cases. This paper describes the main research objectives and underlying paradigms of the AIDOaRt project. It also introduces the conceptual architecture and proposed approach of the AIDOaRt overall solution. Finally, it reports on the actual project practices and discusses the current results and future plans.

Proton therapy is increasing in utilization worldwide at a rapid rate. With process improvements in costs, footprints, and continued advances in the delivery of care, including intensity modulation and image guidance, proton therapy may evolve into standard treatment with photon radiation therapy. This chapter reviews process improvements in proton therapy and the application in modern care.

Italy has a well-established prominent system of national registries to support managed entry agreements (MEAs), monitoring innovative medicinal products (MPs) with clinical as well as economic uncertainties to ensure appropriate use and best value for money. The technological architecture of the registries is funded by pharmaceutical companies, but fully governed by the national medicines agency (AIFA). A desktop analysis was undertaken of data over a 15-year timeframe of all AIFA indication-based registries and associated EMA information. The characteristics of registries were evaluated, comparing orphan MPs vs. all MPs exploring cancer and non-cancer indications. OMP (orphan medicinal product) registries’ type vs. AIFA innovation status and EMA approval was reviewed. Of the 283 registries, 182 are appropriateness registries (35.2% relate to OMPs, with an almost equal split of cancer vs. non-cancer for OMPs and MPs), 35 include financial-based agreements [20% OMPs (2 non-cancer, 5 cancer)], and 60 registries are payment by result agreements [23.3% OMPs (4 non-cancer, 10 cancer)]. Most OMPs (53/88) came through the normal regulatory route. With the strengthening of the system for evaluation of innovation, fewer outcomes-based registries have been instigated. AIFA has overcome many of the challenges experienced with MEA through developing an integrated national web-based data collection system: the challenge that remains for AIFA is to move from using the system for individual patient decisions about treatment to reviewing the wealth of data it now holds to optimize healthcare.

Recent political events and policy changes in the United States have fueled antirefugee/immigrant rhetoric and an increase of xenophobic harassment and intimidation, which together present a significant threat to the physical and mental health of refugee/immigrant children and families. This article aims to provide an overview of how the current sociopolitical context threatens the public health of refugee and immigrant communities and to describe the role of psychologists in advocating for social justice and responding to this urgent public health need through interprofessional collaboration and translation of scientific knowledge into multilevel intervention development. The case study of the You're Not Alone (YNA) initiative describes swiftly mobilized advocacy efforts (e.g., press conference, webinars, resources development and dissemination) and participatory development and roll-out of community capacity-building trainings to address the needs of refugee/immigrant children and families. Trainings aimed to raise awareness of the refugee/immigrant experience and to equip refugee/immigrant community members and providers across a variety of public sectors to implement culturally responsive and trauma-informed strategies to promote resilience, respond to distress, and prevent mental health crises. Between March 2017 and June 2018, a total of 1,642 individuals attended 48 training events. The role of psychologists in future policy and advocacy efforts to promote mental health among refugee/immigrant families is discussed as well as implications for how other marginalized communities affected by the current sociopolitical climate might benefit from broadening the scope of this public health response. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In the context of space missions, where science is the most important goal, careful planning and detailed commanding are fundamental. The planning and commanding phases are activities whose complexity depends on the instrument characteristics, environmental constraints and scientific goals. The purpose of this work is to describe in detail these activities for the Jovian Infrared Auroral Mapper (JIRAM) on board the Juno spacecraft, a NASA mission to Jupiter. To maximize the scientific return, we fully employ the flexibility offered by the JIRAM operational modes to efficiently plan observations of various Jovian targets, in spite of the harsh Jovian radiation environment and the spinning state of the Juno spacecraft. Moreover, the JIRAM observations are limited by the challenging pointing and timing scheme of the mission, which impose constraints on both the observation planning and instrumental commanding.

Background Genetic, biologic and clinical data suggest that Parkinson's disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository. Objective To present the QPN and to perform preliminary analysis of the QPN data. Methods A total of 1,070 consecutively recruited PD patients were included in the analysis. Demographic and clinical data were analyzed, including comparisons between males and females, PD patients with and without RBD, and stratified analyses comparing early and late-onset PD and different age groups. Results QPN patients exhibit a male:female ratio of 1.8:1, an average age-at-onset of 58.6 years, an age-at-diagnosis of 60.4 years, and average disease duration of 8.9 years. REM-sleep behavior disorder (RBD) was more common among men, and RBD was associated with other motor and non-motor symptoms including dyskinesia, fluctuations, postural hypotension and hallucinations. Older patients had significantly higher rates of constipation and cognitive impairment, and longer disease duration was associated with higher rates of dyskinesia, fluctuations, freezing of gait, falls, hallucinations and cognitive impairment. Since QPN's creation, over 60 studies and 30 publications have included patients and data from the QPN. Conclusions The QPN cohort displays typical PD demographics and clinical features. These data are open-access upon application (http://rpq-qpn.ca/en/), and will soon include genetic, imaging and bio-samples. We encourage clinicians and researchers to perform studies using these resources.

Una ripresa secondo una dimensione pubblica del dibattito sulla giustizia distributiva in Sanità si è verificata in tempi recenti con l’introduzione dei nuovi farmaci antivirali ad azione diretta per il trattamento dei pazienti affetti da epatite C, estremamente efficaci nel curare la patologia ma dai costi esorbitanti. Obiettivo del presente contributo è di fornire un breve approfondimento sul tema dei c.d. “farmaci insostenibili”, esaminato sotto un particolare modello di giustizia distributiva, ossia l’egualitarismo, e secondo la prospettiva intergenerazionale. La conclusione è che ad oggi i sistemi sanitari stanno affrontando il problema della sostenibilità attraverso l’ottimizzazione della spesa farmaceutica, ma non sembrano ancora ben equipaggiati per affrontare l’eventualità di una divaricazione inaggirabile tra domanda e offerta di questa tipologia di farmaci. Quest’ultima va affrontata in riferimento all’idea di giustizia distributiva che ha una società, e più specificatamente, alla quantità di risorse che una società è disposta a pagare per la cura di un suo membro. Da ultimo, in termini di giustizia distributiva, l’idea – spesso supportata dalle analisi di farmacoeconomia – che sia giustificabile spendere una cifra molto elevata oggi per ricavare risparmi nel lungo periodo non è di per sé coerente con le principali teorie della giustizia, e necessita di argomenti a sostegno estrinseci ai loro presupposti teorici.

Purpose: The aim of this work was to determine how the spatial pattern of dose in the ano-rectal wall is related to late gastro-intestinal toxicity for prostate cancer patients treated with mainly IMRT. Patients and methods: Patients from the DUE-01 multicentre study with patient-reported (prospective) follow-up and available dosimetric data were included. Conventionally fractionated patients received 74–80 Gy and hypofractionated patients received 65–75.2 Gy. A large majority of the patients were treated with intensity-modulated radiotherapy (IMRT). Dose-surface maps (DSMs) for the anal canal and rectum as a single structure, and for the anal canal and the rectum separately, were co-registered rigidly in two dimensions and, for the patients with and without toxicity, respectively, the mean value of the dose in each pixel was calculated. A pixel-wise t-test was used to highlight the anatomical areas where there was a significant difference between the ‘mean dose maps’ of each group. Univariate models were also fitted to a range of spatial parameters. The endpoints considered were a mean grade ≥1 late fecal incontinence and a maximum grade ≥2 late rectal bleeding. Results: Twenty-six out of 213 patients had fecal incontinence, while 21/225 patients had rectal bleeding. Incontinence was associated with a higher dose in the caudal region of the anal canal; the most relevant spatial parameter was the lateral extent of the low and medium isodoses (5–49 Gy in EQD2). Bleeding was associated with high isodoses reaching the posterior rectal wall. The spatial dose parameters with the highest AUC value (.69) were the lateral extent of the 60–70 Gy isodoses. Conclusions: To avoid fecal incontinence it is important to limit the portion of the anal canal irradiated. Our analysis confirms that rectal bleeding is a function of similar spatial dose parameters for patients treated with IMRT, compared to previous studies on patients treated with three-dimensional conformal radiotherapy.

The production of extracellular vesicles (EV) is a ubiquitous feature of eukaryotic cells but pathological events can affect their formation and constituents. We sought to characterize the nature, profile and protein signature of EV in the plasma of Parkinson's disease (PD) patients and how they correlate to clinical measures of the disease. EV were initially collected from cohorts of PD (n = 60; Controls, n = 37) and Huntington's disease (HD) patients (Pre-manifest, n = 11; manifest, n = 52; Controls, n = 55) – for comparative purposes in individuals with another chronic neurodegenerative condition – and exhaustively analyzed using flow cytometry, electron microscopy and proteomics. We then collected 42 samples from an additional independent cohort of PD patients to confirm our initial results. Through a series of iterative steps, we optimized an approach for defining the EV signature in PD. We found that the number of EV derived specifically from erythrocytes segregated with UPDRS scores corresponding to different disease stages. Proteomic analysis further revealed that there is a specific signature of proteins that could reliably differentiate control subjects from mild and moderate PD patients. Taken together, we have developed/identified an EV blood-based assay that has the potential to be used as a biomarker for PD.

To assess risk factors for 28-day mortality and cost implications in intensive care unit (ICU) patients with complicated intra-abdominal infections (cIAIs).Single-center retrospective cohort study of prospectively collected data analysing ICU patients with a microbiologically confirmed complicated intra-abdominal infections.137 complicated intra-abdominal infections were included and stratified according to the adequacy of antimicrobial therapy (initial inadequate antimicrobial therapy [IIAT], n = 44; initial adequate antimicrobial therapy [IAAT], n = 93). The empirical use of enterococci/methicillin-resistant Staphylococcus aureus active agents and of carbapenems was associated with a higher rate of therapeutic adequacy (p = 0.016 and p = 0.01, respectively) while empirical double gram-negative and antifungal therapy did not. IAAT showed significantly lower mortality at 28 and 90 days and increased clinical cure and microbiological eradication (p 0.01). In the logistic and Cox-regression models, IIAT and inadequate source control were the unique predictors of 28-day mortality. No costs differences were related to the adequacy of empirical therapy and source control. The empirical double gram-negative and antifungal therapy (p = 0.03, p = 0.04) as well as the isolation of multidrug-resistant (MDR) bacteria and the microbiological failure after targeted therapy were drivers of increased costs (p = 0.004, p = 0.04).IIAT and inadequate source control are confirmed predictors of mortality in ICU patients with complicated intra-abdominal infections. Empirical antimicrobial strategies and MDR may drive hospital costs.

The aim of this study is to present the results of the Italian survey on the management of pulmonary nodules incidentally identified at computed tomography (CT). An online electronic survey, consisting of 23 multiple-choice questions, was created using the SurveyMonkey web-based tool. The questionnaire was developed by the Board of the Italian College of Chest Radiology of the Italian Society of Medical and Interventional Radiology (SIRM) and by an experienced group of Italian Academic Chest Radiologists. The link to the online electronic survey was submitted by email to all the SIRM members. A total of 767 radiologists, corresponding to 7.5% of all the SIRM members, participated in the online survey. The majority of participants (92%) routinely describe the attenuation of pulmonary nodules in the report, and 84.1% recommend the further follow-up, with 92.7% of respondents taking CT nodule morphological features into consideration. The 57.7% of participants adhere to the Fleischner Society guidelines for the management of incidental pulmonary nodules. However, 56.6% and 75.6% of respondents have a more cautious approach than that recommended by the guidelines and tend to use a shorter follow-up for both solid and ground-glass nodules, respectively. Finally, 94.5% of participants favor congresses and refresher courses dedicated to insights on lung nodule diagnosis and management. This survey demonstrates that the management of pulmonary nodules incidentally detected on CT is still complex and controversial. The majority of SIRM members express a need for an update on this topic.

Telemedicine in diabetes care has been evolving over several years, particularly since the advent of cloud-connected technologies for diabetes management, such as glucose monitoring devices, including continuous glucose monitoring (CGM) systems, that facilitate sharing of glucose data between people with diabetes and their healthcare professionals in near-real time. Extreme social distancing and shielding in place for vulnerable patients during the COVID-19 pandemic has created both the challenge and the opportunity to provide care at a distance on a large scale. Available evidence suggests that glucose control has in fact improved during this period for people with diabetes who are able to use CGM devices for remote glucose monitoring. The development of telemedicine as part of the standard of care in diabetes faces significant challenges in the European context, particularly in terms of providing consistent and effective care at a distance to large populations of patients while using robust systems that can be supported by large regional and national healthcare services. These challenges include a fragmented approach to healthcare technology assessment and reimbursement, lack of eHealth education and literacy, particularly amongst healthcare professionals, lack of data integration, as well as concerns about electronic health records, patient consent and privacy. Here we review the benefits of and challenges to wider application of telemedicine and telemonitoring in the post-pandemic future, with the aim to ensure that the value of these eHealth services is provided to patients, healthcare providers and health systems.

AIM: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi). MATERIALS AND METHODS: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in ≥10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC). RESULTS: Among 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints. CONCLUSIONS: Our method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models. ispartof: RADIOTHERAPY AND ONCOLOGY vol:159 pages:241-248 ispartof: location:Ireland status: published

Background: Radiation-induced xerostomia is one of the most prevalent adverse effects of head and neck cancer treatment, and it could seriously affect patients’ qualities of life. It results primarily from damage to the salivary glands, but its onset and severity may also be influenced by other patient-, tumour-, and treatment-related factors. We aimed to build and validate a predictive model for acute salivary dysfunction (aSD) for locally advanced nasopharyngeal carcinoma (NPC) patients by combining clinical and dosimetric factors. Methods: A cohort of consecutive NPC patients treated curatively with IMRT and chemotherapy at 70 Gy (2–2.12 Gy/fraction) were utilised. Parotid glands (cPG, considered as a single organ) and the oral cavity (OC) were selected as organs-at-risk. The aSD was assessed at baseline and weekly during RT, grade ≥ 2 aSD chosen as the endpoint. Dose-volume histograms were reduced to the Equivalent Uniform Dose (EUD). Dosimetric and clinical/treatment features selected via LASSO were inserted into a multivariable logistic model. Model validation was performed on two cohorts of patients with prospective aSD, and scored using the same schedule/scale: a cohort (NPC_V) of NPC patients (as in model training), and a cohort of mixed non-NPC head and neck cancer patients (HNC_V). Results: The model training cohort included 132 patients. Grade ≥ 2 aSD was reported in 90 patients (68.2%). Analyses resulted in a 4-variables model, including doses of up to 98% of cPG (cPG_D98%, OR = 1.04), EUD to OC with n = 0.05 (OR = 1.11), age (OR = 1.08, 5-year interval) and smoking history (OR = 1.37, yes vs. no). Calibration was good. The NPC_V cohort included 38 patients, with aSD scored in 34 patients (89.5%), the HNC_V cohort included 93 patients, 77 with aSD (92.8%). As a general observation, the incidence of aSD was significantly different in the training and validation populations (p = 0.01), thus impairing calibration-in-the-large. At the same time, the effect size for the two dosimetric factors was confirmed. Discrimination was also satisfactory in both cohorts: AUC was 0.73, and 0.68 in NPC_V and HNC_V cohorts, respectively. Conclusion: cPG D98% and the high doses received by small OC volumes were found to have the most impact on grade ≥ 2 acute xerostomia, with age and smoking history acting as a dose-modifying factor. Findings on the development population were confirmed in two prospectively collected validation populations.

Motivational digital systems offer capabilities to engage and motivate end-users to foster behavioral changes towards a common goal. In general these systems use gamification principles in non-games contexts. Over the years, gamification has gained consensus among researchers and practitioners as a tool to motivate people to perform activities with the ultimate goal of promoting behavioural change, or engaging the users to perform activities that can offer relevant benefits but which can be seen as unrewarding and even tedious. There exists a plethora of heterogeneous application scenarios towards reaching the common good that can benefit from gamification. However, an open problem is how to effectively combine multiple motivational campaigns to maximise the degree of participation without exposing the system to counterproductive behaviours. We conceive motivational digital systems as multi-agent systems: self-adaptation is a feature of the overall system, while individual agents may self-adapt in order to leverage other agents' resources, functionalities and capabilities to perform tasks more efficiently and effectively. Consequently, multiple campaigns can be run and adapted to reach common good. At the same time, agents are grouped into micro-communities in which agents contribute with their own social capital and leverage others' capabilities to balance their weaknesses. In this paper we propose our vision on how the principles at the base of the autonomous and multi-agent systems can be exploited to design multi-challenge motivational systems to engage smart communities towards common goals. We present an initial version of a general framework based on the MAPE-K loop and a set of research challenges that characterise our research roadmap for the implementation of our vision., 7 pages, 1 figure

Decades of research on the prion protein and its associated diseases have caused a paradigm shift in our understanding of infectious agents. More recent years have been marked by a surge of studies supporting the application of these findings to a broad array of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Here, we present evidence to suggest that Huntington's disease, a monogenic disorder of the central nervous system, shares features with prion disorders and that, it too, may be governed by similar mechanisms. We further posit that these similarities could suggest that, like other common neurodegenerative disorders, sporadic forms of Huntington's disease may exist.

Oncology clinical trials provide opportunity to advance care for patients with cancer. Bridging basic science with bedside care, cancer clinical trials have brought new and updated scientific knowledge at a rapid pace. Managing subject data in translation science requires a sophisticated informatics infrastructure that will enable harmonized datasets across all areas that could influence outcomes. Successful translational science requires that all relevant information be made readily available in a digital format that can be queried in a facile manner. Through a translational science prism, we look at past issues in cancer clinical trials and the new National Institutes of Health/National Cancer Institute initiative to address the need of database availability at an enterprise level.

As a founder of the field of applied developmental psychology, Dr Edward Zigler promoted public policy that translated scientific knowledge into real-world programs to improve the outcomes of high-risk children and families. Many researchers, practitioners, and public policy proponents have sought to carry on his legacy through integration of empirical research, evidence-based prevention and intervention, and advocacy to address a range of challenges facing families with young children. To advance the field of child maltreatment, a multidisciplinary team of investigators from the Universities of Rochester and Minnesota partnered with the Eunice Kennedy Shriver National Institute of Child Health and Human Development to create the Translational Research that Adapts New Science FOR Maltreatment Prevention Center (Transform). Building on state-of-the-art research methodologies and clinical practices, Transform leverages theoretically grounded research and evidence-based interventions to optimize outcomes for individuals across the life span who have experienced, or may be at risk for, maltreatment. Inspired by the work of Dr Zigler, Transform is committed to bridging science and real-world practice. Therefore, in addition to creating new science, Transform's Community Engagement Core provides translational science to a broad audience of investigators, child-serving professionals, and parental and governmental stakeholders. This article describes Transform's purpose, theoretical framework, current activities, and future directions.