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A bstract We study freeze-in production of Higgs portal dark matter (DM) at temperatures far below the dark matter mass. The temperature of the Standard Model (SM) thermal bath may have never been high such that dark matter production via thermal emission has been Boltzmann-suppressed. This allows for a significant coupling between the Higgs field and DM, which is being probed by the direct DM detection experiments and invisible Higgs decay searches at the LHC. We delineate the corresponding parameter space in the Higgs portal framework with dark matter of spin 0, 1/2 and 1.

A bstract We consider an extension of the Standard Model that explains the neutrino masses and has a rich dark matter phenomenology. The model has two dark matter candidates, a vector WIMP and a fermion FIMP, and the sum of their relic densities matches the total dark matter abundance. We extensively study the dark matter production mechanisms and its connection with the neutrino sector, together with various bounds from present and future experiments. The extra scalar field in the model may induce a first-order phase transition in the early Universe. We study the production of stochastic gravitational waves associated with the first-order phase transition. We show that the phase transition can be strong, and thus the model may satisfy one of the necessary conditions for a successful electroweak baryogenesis. Detectability of the phase transition-associated gravitational waves is also discussed.

A bstract We consider an extension of the Standard Model that accounts for the muon g − 2 tension and neutrino masses and study in detail dark matter phenomenology. The model under consideration includes a WIMP and a FIMP scalar dark matter candidates and thus gives rise to two-component dark matter scenarios. We discuss different regimes and mechanisms of production, including the novel freeze-in semi-production, and show that the WIMP and FIMP together compose the observed relic density today. The presence of the extra scalar fields allows phase transitions of the first order. We examine the evolution of the vacuum state and discuss stochastic gravitational wave signals associated with the first-order phase transition. We show that the gravitational wave signals may be probed by future gravitational wave experiments which may serve as a complementary detection signal.

Obstructive sleep apnea (OSA) is a risk factor for several diseases and is correlated with other non-medical consequences that increase the disease's clinical and economic burden. However, OSA's impact is highly underestimated, also due to substantial diagnosis gaps. This study aims at assessing the economic burden of OSA in the adult population in Italy by performing a cost-of-illness analysis with a societal perspective. In particular, we aimed at estimating the magnitude of the burden caused by conditions for which OSA is a proven risk factor. A systematic literature review on systematic reviews and meta-analyses, integrated by expert opinion, was performed to identify all clinical and non-clinical conditions significantly influenced by OSA. Using the Population Attributable Fraction methodology, a portion of their prevalence and costs was attributed to OSA. The total economic burden of OSA for the society was estimated by summing the costs of each condition influenced by the disease, the costs due to OSA's diagnosis and treatment and the economic value of quality of life lost due to OSA's undertreatment. Twenty-six clinical (e.g., diabetes) and non-clinical (e.g., car accidents) conditions were found to be significantly influenced by OSA, contributing to an economic burden ranging from €10.7 to €32.0 billion/year in Italy. The cost of impaired quality of life due to OSA undertreatment is between €2.8 and €9.0 billion/year. These costs are substantially higher than those currently borne to diagnose and treat OSA (€234 million/year). This study demonstrates that the economic burden due to OSA is substantial, also due to low diagnosis and treatment rates. Providing reliable estimates of the economic impact of OSA at a societal level may increase awareness of the disease burden and help to guide evidence-based policies and prioritisation for healthcare, ultimately ensuring appropriate diagnostic and therapeutic pathways for patients.

This study systematically reviews costing studies of seasonal influenza-like illness (ILI) in high-income countries. Existing reviews on the economic impact of ILI do not report information on drug consumption and its costs, nor do they provide data on the overall cost per episode. The PRISMA-P checklist was used to design the research protocol. Studies included were cost of illness analysis (COI) and modeling studies that estimated the cost of ILI episodes. Records were searched from January 2000 to December 2016 in electronic bibliographic databases including Medline, Embase, Science Direct, the Cochrane Library, the Centre for Reviews and Disseminations of the University of York, and Google scholar. References from the included studies were hand-searched for completion. Abstract screening, full-text analysis and data extraction were performed by two reviewers independently and discrepancies were resolved by discussion with a third reviewer. A standardized, pre-piloted form was used for data extraction. All costs were converted to 2015 US$ Purchasing Power Parities. The literature search identified 5,104 records. After abstract and title screening, 76 studies were analyzed full-text and 27 studies were finally included in the review. Full estimates of the cost per episode range from US$19 in Korea to US$323 in Germany. Particularly, the cost per episode of laboratory confirmed influenza cases was estimated between US$64 and US$73. Inpatient and outpatient services account for the majority of the costs. Differences in the estimates may reflect country-specific characteristics, as well as other study-specific features including study design, identification strategy of ILI cases, study populations and types of costs included in the analysis. Children usually register higher costs, whereas evidence for the elderly is less conclusive. Patients risk-profile, co-morbidities and complications are the other important cost-drivers. None of the papers considered appropriateness in resource use (e.g. abuse of antibiotics). Despite cost of illness studies have ultimately a descriptive role, evidence on (in)appropriateness is useful for policy-makers.

Background Vaccines development in this millennium started by the milestone work on Neisseria meningitidis B , reporting the invention of Reverse Vaccinology (RV), which allows to identify vaccine candidates (VCs) by screening bacterial pathogens genome or proteome through computational analyses. When NERVE (New Enhanced RV Environment), the first RV software integrating tools to perform the selection of VCs, was released, it prompted further development in the field. However, the problem-solving potential of most, if not all, RV programs is still largely unexploited by experimental vaccinologists that impaired by somehow difficult interfaces, requiring bioinformatic skills. Results We report here on the development and release of NERVE 2.0 (available at: https://nerve-bio.org ) which keeps the original integrative and modular approach of NERVE, while showing higher predictive performance than its previous version and other web-RV programs (Vaxign and Vaxijen). We renewed some of its modules and added innovative ones, such as Loop-Razor , to recover fragments of promising vaccine candidates or Epitope Prediction for the epitope prediction binding affinities and population coverage. Along with two newly built AI (Artificial Intelligence)-based models: ESPAAN and Virulent . To improve user-friendliness, NERVE was shifted to a tutored, web-based interface, with a noSQL-database to consent the user to submit, obtain and retrieve analysis results at any moment. Conclusions With its redesigned and updated environment, NERVE 2.0 allows customisable and refinable bacterial protein vaccine analyses to all different kinds of users.

Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor prevents ischaemic events after coronary stenting, but increases bleeding. Guidelines support weighting bleeding risk before the selection of treatment duration, but no standardised tool exists for this purpose. A total of 14 963 patients treated with DAPT after coronary stenting—largely consisting of aspirin and clopidogrel and without indication to oral anticoagulation—were pooled at a single-patient level from eight multicentre randomised clinical trials with independent adjudication of events. Using Cox proportional hazards regression, we identified predictors of out-of-hospital Thrombosis in Myocardial Infarction (TIMI) major or minor bleeding stratified by trial, and developed a numerical bleeding risk score. The predictive performance of the novel score was assessed in the derivation cohort and validated in patients treated with percutaneous coronary intervention from the PLATelet inhibition and patient Outcomes (PLATO) trial (n=8595) and BernPCI registry (n=6172). The novel score was assessed within patients randomised to different DAPT durations (n=10 081) to identify the effect on bleeding and ischaemia of a long (12–24 months) or short (3–6 months) treatment in relation to baseline bleeding risk. The PRECISE-DAPT score (age, creatinine clearance, haemoglobin, white-blood-cell count, and previous spontaneous bleeding) showed a c-index for out-of-hospital TIMI major or minor bleeding of 0·73 (95% CI 0·61–0·85) in the derivation cohort, and 0·70 (0·65–0·74) in the PLATO trial validation cohort and 0·66 (0·61–0·71) in the BernPCI registry validation cohort. A longer DAPT duration significantly increased bleeding in patients at high risk (score ≥25), but not in those with lower risk profiles (pinteraction=0·007), and exerted a significant ischaemic benefit only in this latter group. The PRECISE-DAPT score is a simple five-item risk score, which provides a standardised tool for the prediction of out-of-hospital bleeding during DAPT. In the context of a comprehensive clinical evaluation process, this tool can support clinical decision making for treatment duration. None.

Value-based pricing (VBP) is well established in markets for common goods and services, but wide consensus on VBP for pharmaceuticals is lacking. In principle, VBP implies that prices are mainly driven by a drug's value (value for money) and that the impact on budget (sustainability) is a second-order driver of price regulation. Although the literature provides descriptive analyses on regulations governing medicine price negotiation, there are few insights on whether and how price negotiation regulations have been implemented. The goal of this article was to cover this information gap for 5 European countries and the United States. VBP has been applied according to two models: (1) direct models in which cost-effectiveness is a driver; and (2) indirect, multi-attribute models characterized by greater discretion on the integration between the different value domains and the evaluation of consistency between costs and value. In these models, cost-effectiveness is not a driver. In addition, it is hard to evaluate within these models the actual implementation of VBP. Identifying whether and how VBP is applied requires a clear predefined link between added value and the premium price, as well as transparency in the way added value is converted into a premium price. In general, for these countries, it remains difficult to determine whether pricing is mostly driven by value (value-for-money) or impact on budget (sustainability). In instances in which thresholds on the incremental cost-effectiveness ratio are used, it becomes easier to understand whether VBP has been implemented. If VBP relies on a multi-criteria approach, greater transparency on which criteria have been used to assess a new drug and how they have been converted into a reasonable price may help in understanding whether a value-based approach has been used.

PurposeWe present an automated method for extracting anatomical parameters from biplanar radiographs of the spine, which is able to deal with a wide scenario of conditions, including sagittal and coronal deformities, degenerative phenomena as well as images acquired with different fields of view.MethodsThe location of 78 landmarks (end plate centers, hip joint centers, and margins of the S1 end plate) was extracted from three-dimensional reconstructions of 493 spines of patients suffering from various disorders, including adolescent idiopathic scoliosis, adult deformities, and spinal stenosis. A fully convolutional neural network featuring an additional differentiable spatial to numerical (DSNT) layer was trained to predict the location of each landmark. The values of some parameters (T4–T12 kyphosis, L1–L5 lordosis, Cobb angle of scoliosis, pelvic incidence, sacral slope, and pelvic tilt) were then calculated based on the landmarks’ locations. A quantitative comparison between the predicted parameters and the ground truth was performed on a set of 50 patients.ResultsThe spine shape predicted by the models was perceptually convincing in all cases. All predicted parameters were strongly correlated with the ground truth. However, the standard errors of the estimated parameters ranged from 2.7° (for the pelvic tilt) to 11.5° (for the L1–L5 lordosis).ConclusionsThe proposed method is able to automatically determine the spine shape in biplanar radiographs and calculate anatomical and posture parameters in a wide scenario of clinical conditions with a very good visual performance, despite limitations highlighted by the statistical analysis of the results.Graphical abstractThese slides can be retrieved under Electronic Supplementary Material.

In space applications, the required levels of performance and reliability drive up hardware costs. Reducing the efforts related to device development and validation may help balance the budget. A versatile transmitter for space telemetry is implemented here that may help in this respect. Such a device can switch across different linear and continuous phase modulation schemes just by modifying its parameters, while maintaining the same hardware structure. Results from an extensive campaign of experimental test measurements of the device are reported. A GNURadio-implemented receiver is developed to test performance of the actual transmitter by considering all the main blocks of the receiver chain and computing the bit error rate (BER) at the receiver. After testing different configurations, results confirm that the BER of the improved one-filter modulated signal is lower than the BER obtained using only the first Laurent decomposition component.