Metasurface-Based Hybrid Optical Cavities for Chiral Sensing.

Quantum metasurfaces, i.e., two-dimensional subwavelength arrays of quantum emitters, can be employed as mirrors towards the design of hybrid cavities, where the optical response is given by the interplay of a cavity-confined field and the surface modes supported by the arrays. We show that stacked layers of quantum metasurfaces with orthogonal dipole orientation can serve as helicity-preserving cavities. These structures exhibit ultranarrow resonances and can enhance the intensity of the incoming field by orders of magnitude, while simultaneously preserving the handedness of the field circulating inside the resonator, as opposed to conventional cavities. The rapid phase shift in the cavity transmission around the resonance can be exploited for the sensitive detection of chiral scatterers passing through the cavity. We discuss possible applications of these resonators as sensors for the discrimination of chiral molecules. Our approach describes a new way of chiral sensing via the measurement of particle-induced phase shifts.

Budget impact analysis for avatrombopag in the treatment of chronic primary immune thrombocytopenia in adult patients refractory to other treatments.

Introduction: Primary immune thrombocytopenia is a rare autoimmune disease characterised by a decreased platelet count resulting in an increased risk of bleeding events and even life-threatening haemorrhages. Thrombopoietin receptor agonists (TPO-RAs) are the standard of care second-line therapy for adult patients with chronic immune thrombocytopenia. The first TPO-RAs approved and reimbursed in Italy, eltrombopag and romiplostim, while effective, pose some issues in terms of safety (e.g., hepatotoxicity) or general management (e.g., dietary restrictions). Avatrombopag, an effective and well-tolerated TPO-RA, was recently granted reimbursement. Methods: A 3-year (2023-2025) budget impact analysis (BIA) was conducted to estimate its impact on the Italian National Health Service (NHS). Two scenarios were compared, of which one represents the current situation, without avatrombopag, and the other provides for an increasing market share of avatrombopag (up to 26.6%). Results: BIA shows that the increase in the use of avatrombopag correlates with savings for NHS: in the first year, saving would be €1,300,564, increasing to €2,774,210 in the third year, for a total of €6,083,231 over the 3-year period. The sensitivity analysis confirmed these savings in the scenario with avatrombopag. Conclusions: Based on this BIA, the introduction and reimbursement of avatrombopag is an efficient and advantageous choice for the Italian NHS.

Value assessment of medicinal products by the Italian Medicines Agency (AIFA) and French National Authority for Health (HAS): Similarities and discrepancies.

The evaluation of pharmaceutical innovation and therapeutic value is an increasingly complex exercise for which different approaches are adopted at the national level, despite the need for standardisation of processes and harmonisation of public health decisions. The objective of our analysis was to compare the approaches of the AIFA (Agenzia Italiana del Farmaco) and the HAS (Haute Autorité de Santé) in assessing the same medicinal products. In Italy, the 1525/2017 AIFA Deliberation introduces a transparent scheme for the evaluation of innovative status (innovative, conditional, not innovative) based on the therapeutic added value (TAV), therapeutic need, and quality of evidence. In contrast, in France, the HAS makes judgements using the effective clinical benefit (Service Médical Rendu) and improvement of effective clinical benefit (Amélioration du Service Médical Rendu, ASMR). This analysis focused on medicinal products evaluated both by the AIFA and by the HAS from July 2017 to September 2021. Similarities between AIFA and HAS evaluations were investigated in terms of the TAV, recognition of innovativeness, and the ASMR. Both total and partial agreements were considered relevant. Therefore, raw agreement, Cohen's kappa (weighted and unweighted), and Bangdiwala's B-statistic were estimated. A total of 102 medicinal products were included in this study. Out of these, 38 (37.2%) were orphan drugs, while 56 (54.9%) had a clinical indication for the treatment of cancer. The AIFA and HAS reached a higher level of agreement on the innovativeness status compared with the TAV. A moderate total agreement emerged in the recognition of innovativeness (k = 0.463, p-value ≤0.0001), and partial agreement was substantial (equal weight k = 0.547, squared k = 0.638), while a lack of agreement resulted in a comparison of the TAV according to the AIFA and the ASMR recognised by the HAS. Indeed, whereas the AIFA determined the TAV to be important, the HAS considered it to be moderate. In addition, whereas the AIFA identified a bias towards a moderate TAV, the HAS identified a bias towards a minor ASMR. A higher level of agreement was reached, both on the TAV and on innovative status, for less critical medical products (non-cancer-related, or non-orphan, or with a standard European Medicines Agency approval). These results underline the importance of implementing European procedures that are more broadly aligned in terms of value definition criteria.

Cost analysis of extended half-life recombinant factor IX products in the treatment of haemophilia B in Italy: an update.

Haemophilia B (HB) is a rare disease which may lead to chronic disabling arthropathy, resulting in a significant clinical, social and economic impact. In recent years, new extended half-life (EHL) factor IX concentrates produced by recombinant technology (rFIX) have been developed. They have shown significantly prolonged half-life as compared to other rFIX products and improved bleeding control when used as prophylaxis. To date, EHL rFIX products reimbursed in Italy are a recombinant coagulation factor IX produced with Fc technology (rFIXFc) and a recombinant fusion protein containing rFIX fused with recombinant albumin (rIX-FP). The results of extension studies with injection intervals with a median of almost every 14 days for the complete individualized interval prophylaxis (IP) group on rFIXFc and 21 days for a selected subgroup of patients on rIX-FP have recently been published. The aim of this analysis was to estimate the cost of prophylactic treatment with rFIXFc and rIX-FP in adult patients, in the light of new clinical evidence and current average prices in Italy. The cost of therapy was estimated on the basis of the results of extension studies, the average prices reported in regional drug tenders and assuming an average patient weight of 70 kg. The analysis estimated a cost per patient/year between €224,407 and €230,355 for rFIXFc and between €242,259 and €368,587 for rIX-FP. The sensitivity analysis confirmed the robustness of the results. The use of rFIXFc over rIX-FP proves to be the least expensive choice for the treatment of HB in Italy.

C-Reactive Protein for the Early Assessment of Non-Malarial Febrile Patients: A Retrospective Diagnostic Study.

Biomarkers, especially CRP, have demonstrated their relevance to differentiate viral from bacterial infection, even though a reliable threshold is far to being found. In low- and middle-income countries, affordable and user-friendly rapid diagnostic tests based on biomarkers can be widely adopted to help health workers in the management of non-malarial fever. The primary objective of this study is to assess the best CRP cut-off to distinguish viral from bacterial infections. Other biomarkers were evaluated for the same purpose, alone or in combination with CRP. We retrospectively collected data from two referral hospital departments for infectious and tropical diseases in Italy. Areas under the ROC curve (AUC) were calculated and then compared using the DeLong test. Overall, we included 1193 febrile cases (viral 20.74% vs. bacterial 79.25%). We also collected malaria (n = 202) and intestinal parasite (n = 186) cases to establish their impact on biomarkers. CRP had the best accuracy in differentiating viral from bacterial infections. The best performance of CRP was a cut-off of 11 mg/L. All other biomarkers studied had significantly lower accuracy. Median CRP values were within the normal ranges in parasitic infections, while they were higher in malaria. None of the combinations of CRP with other biomarkers significantly increased the accuracy of CRP alone.

Renormalized Mutual Information for Artificial Scientific Discovery.

We derive a well-defined renormalized version of mutual information that allows us to estimate the dependence between continuous random variables in the important case when one is deterministically dependent on the other. This is the situation relevant for feature extraction, where the goal is to produce a low-dimensional effective description of a high-dimensional system. Our approach enables the discovery of collective variables in physical systems, thus adding to the toolbox of artificial scientific discovery, while also aiding the analysis of information flow in artificial neural networks.

Microsphere kinematics from the polarization of tightly focused nonseparable light.

Recently, it was shown that vector beams can be utilized for fast kinematic sensing via measurements of their global polarization state [Optica2, 864 (2015)10.1364/OPTICA.2.000864]. The method relies on correlations between the spatial and polarization degrees of freedom of the illuminating field which result from its nonseparable mode structure. Here, we extend the method to the nonparaxial regime. We study experimentally and theoretically the far-field polarization state generated by the scattering of a dielectric microsphere in a tightly focused vector beam as a function of the particle position. Using polarization measurements only, we demonstrate position sensing of a Mie particle in three dimensions. Our work extends the concept of back focal plane interferometry and highlights the potential of polarization analysis in optical tweezers employing structured light.

Direct healthcare costs of chronic kidney disease management in Italy: What cost-savings can be achieved with higher biosimilar uptake and more appropriate use of erythropoiesis-stimulating agents?

PURPOSE: Erythropoiesis-stimulating agents (ESAs), are used for treating chronic kidney disease (CKD)-related anemia, contributing to CKD costs. The study was aimed at investigating direct healthcare costs of CKD patients treated with ESAs and the potential savings achievable by increasing the use of biosimilars and preventing inappropriate ESA use. METHODS: A multi-center, cohort study was conducted using claims databases of five large Italian geographic areas. Yearly mean direct healthcare costs per patient were estimated, stratifying by CKD stage. The total yearly cost and potential savings related to ESA use were estimated: (a) considering 25/50/75% of originator ESA substitution with biosimilars; (b) eliminating inappropriate ESA dispensing. RESULTS: During the study period, the ESA-related yearly mean cost represented 17% of total yearly costs in stage I-III, decreasing to 13% in stage IV-V and 6% in dialysis. Among originator users, assuming a 25% of biosimilar uptake, the annual cost-savings of ESA treatment would represent 10.5% of total ESA costs in CKD stage I-V and 7.7% in dialysis. Among incident ESA users for which hemoglobin levels were available, 9% started inappropriately ESA treatment, increasing to 62.0% during the first year of maintenance therapy. Hypothesizing prevention of the first inappropriate ESA dispensing, the total yearly cost-savings would amount to €35 772, increasing to €167 641 eliminating the inappropriate dispensing during maintenance therapy. CONCLUSIONS: Higher use of lowest cost ESA, prevention of inappropriate ESA use as well as other strategies aimed at slowing down the progressive renal impairment are essential for minimizing clinical and economic burden of CKD.

Economic impact of ferric carboxymaltose in haemodialysis patients / Impatto economico dell'utilizzo di carbossimaltosio ferrico nei pazienti in emodialisi

Intravenous iron supplementation is essential in hemodialysis (HD) patients to recover blood loss and to meet the requirements for erythropoiesis and, in patients receiving erythropoietin, to avert the development of iron deficiency. In a recent real-world study, Hofman et al. showed that a therapeutic shift from iron sucrose (IS) to ferric carboxymaltose (FCM) in HD patients improves iron parameters while reducing use of iron and erythropoietin. The objective of this economic analysis is to compare the weekly cost of treatment of FCM vs IS in hemodialysis patients in Italy. The consumption of drugs (iron and erythropoietin) was derived from Hofman's data, while the value was calculated at Italian ex-factory prices. The analysis was carried on the total patient sample and in two subgroups: patients with iron deficiency and patients anemic at baseline. In addition, specific sensitivity analyses considered prices currently applied at the regional level, simulating the use of IS vs iron gluconate (FG) and epoetin beta vs epoetin alfa. In the base-case analysis, the switch to FCM generates savings of -€12.47 per patient/week (-21%) in all patients, and even greater savings in the subgroups with iron deficiency -€17.28 (-27%) and in anemic patients -€23.08 (-32%). Sensitivity analyses were always favorable to FCM and confirmed the robustness of the analysis. FCM may represent a cost-saving option for the NHS, and Italian real-world studies are needed to quantify the real consumption of resources in dialysis patients.

Budget impact analysis of extended half-life recombinant factor IX (rFIXFc) in the treatment of haemophilia B.

Introduction: Prophylaxis with factor IX (FIX) concentrates, produced by recombinant DNA technology (rFIX) or human plasma-derived concentrates, is the treatment of choice for haemophilia B (HB); rFIX covalently fused to the Fc domain of human immunoglobulin G1 (rFIXFc) allows for prophylaxis/treatment with one infusion every 7-14 days. The purpose of this study is to quantify the financial impact of prophylaxis with rFIXFc vs. other approved rFIX and reimbursed for treatment of HB in Italy. Methods: The number of patients was estimated according to Italian epidemiological data and use of rFIX. Dose and frequency of administration used for weekly prophylaxis were those recommended in the Summary of Product Characteristics (SPC), while clinical trials and literature data were used to calculate bleeding rates and management. Drug costs were calculated using regional ex-factory net prices. In the model, a reference scenario (Reference) vs. an alternative scenario (Alternative) were created to account for introduction of rFIXFc, estimating an increasing trend of the market share of rFIXFc in a 3-year timeframe. The analysis was developed in the perspective of the National Health Service and included healthcare costs related to rFIX for prophylaxis and resolution of bleeding events. Results: The model estimated an overall cumulative expenditure (years 1-3) of €209,453,646 for the Reference and €207,465,568 for Alternative scenarios, with calculated cumulative savings of €1,988,068. Conclusions: The increasing use of rFIXFc as a substitute for other rFIX concentrates in the treatment of HB can represent a financially viable choice for the Italian National Health Service while ensuring effective control of bleeding.

Erratum: Optimal Frames for Polarization State Reconstruction [Phys. Rev. Lett. 115, 263901 (2015)].

This corrects the article DOI: 10.1103/PhysRevLett.115.263901.

Diagnostic Yield of 2 Strategies for Adult Celiac Disease Identification in Primary Care.

GOALS: To compare the diagnostic yield and cost-consequences of 2 strategies, screening regardless of symptoms versus case finding (CF), using a point-of-care test (POCT), for the detection of celiac disease (CD) in primary care, to bridge the diagnostic gap of CD in adults. MATERIALS AND METHODS: All subjects under 75 years of age who consecutively went to their general practitioners' offices were offered POCT for anti-transglutaminase immunoglobulin A antibodies. The POCT was performed on all subjects who agreed, and then a systematic search for symptoms or conditions associated with higher risk for CD was performed, immediately after the test but before knowing the test results. The 2 resulting groups were: (a) POCT positive and (b) symptomatic subject at CF. Subjects were defined as symptomatic at CF in the presence of 1 or more symptoms. All POCT-positive or symptomatic subjects at CF were referred to the CD Centers for confirmation of CD. Data on resource consumption were gathered from patients' charts. Cost of examinations, and diagnostic and laboratory tests were estimated with regional outpatient tariffs (Sicily), and a price of &OV0556;2.5 was used for each POCT. RESULTS: Of a total of 2197 subjects who agreed to participate in the study, 36 (1.6%) and 671 (30.5%) were POCT positive and symptomatic at CF, respectively. The yield from the screening and CF was 5 new celiac patients. The total cost and mean cost for each new CD case were &OV0556;7497.35 and &OV0556;1499.47 for the POCT screening strategy, and &OV0556;9855.14 and &OV0556;1971.03 for the CF strategy, respectively. Assuming consecutive use of both strategies, performing POCT only in symptomatic subjects at CF, the calculated yield would be 4 new diagnoses with a total cost of &OV0556;2345.84 and a mean cost of &OV0556;586.46 for each newly diagnosed patient. Only 1 patient was celiac despite a negative POCT. CONCLUSIONS: Testing symptomatic subjects at CF only by POCT seems the most cost-effective strategy to bridge the diagnostic gap of adult CD in primary care.

Cost-effectiveness analysis of ibrutinib in patients with Waldenström macroglobulinemia in Italy.

Background and Objective: Ibrutinib has recently been approved in Europe for Waldenström Macroglobulinemia (WM) in symptomatic patients who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy. The aim of the study is to estimate the incremental cost-effectiveness ratio (ICER) of ibrutinib in relapse/refractory WM, compared with the Italian current therapeutic pathways (CTP). Methods: A Markov model was adapted for Italy considering the National Health System perspective. Input data from literature as well as global trials were used. The percentage use of therapies, and healthcare resources consumption were estimated according to expert panel advice. Drugs ex-factory prices and national tariffs were used for estimating costs. The model had a 15-year time horizon, with a 3.0% discount rate for both clinical and economic data. Deterministic and probabilistic sensitivity analyses were performed to test the results strength. Results: Ibrutinib resulted in increased Life Years Gained (LYGs) and increased costs compared to CTP, with an ICER of €52,698/LYG. Sensitivity analyses confirmed the results of the BaseCase. Specifically, in the probabilistic analysis, at a willingness to pay threshold of €60,000/LYG ibrutinib was cost-effective in 84% of simulations. Conclusions: Ibrutinib has demonstrated a positive cost-effectiveness profile in Italy.

Unraveling beam self-healing.

We show that, contrary to popular belief, diffraction-free beams may not only reconstruct themselves after hitting an opaque obstacle but also, for example, Gaussian beams. We unravel the mathematics and the physics underlying the self-reconstruction mechanism and we provide for a novel definition for the minimum reconstruction distance beyond geometric optics, which is in principle applicable to any optical beam that admits an angular spectrum representation. Moreover, we propose to quantify the self-reconstruction ability of a beam via a newly established degree of self-healing. This is defined via a comparison between the amplitudes, as opposite to intensities, of the original beam and the obstructed one. Such comparison is experimentally accomplished by tailoring an innovative experimental technique based upon Shack-Hartmann wave front reconstruction. We believe that these results can open new avenues in this field.

Cost-effectiveness of bedaquiline in MDR and XDR tuberculosis in Italy.

Objective: To evaluate the cost-effectiveness of bedaquiline plus background drug regimens (BR) for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in Italy. Methods: A Markov model was adapted to the Italian setting to estimate the incremental cost-effectiveness ratio (ICER) of bedaquiline plus BR (BBR) versus BR in the treatment of MDR-TB and XDR-TB over 10 years, from both the National Health Service (NHS) and societal perspective. Cost-effectiveness was evaluated in terms of life-years gained (LYG). Clinical data were sourced from trials; resource consumption for compared treatments was modelled according to advice from an expert clinicians panel. NHS tariffs for inpatient and outpatient resource consumption were retrieved from published Italian sources. Drug costs were provided by reference centres for disease treatment in Italy. A 3% annual discount was applied to both cost and effectiveness. Deterministic and probabilistic sensitivity analyses were conducted. Results: Over 10 years, BBR vs. BR alone is cost-effective, with ICERs of €16,639/LYG and €4081/LYG for the NHS and society, respectively. The sensitivity analyses confirmed the robustness of the results from both considered perspectives. Conclusion: In Italy, BBR vs. BR alone has proven to be cost-effective in the treatment of MDR-TB and XDR-TB under a range of scenarios.

Experimental generation of amplitude squeezed vector beams.

We present an experimental method for the generation of amplitude squeezed high-order vector beams. The light is modified twice by a spatial light modulator such that the vector beam is created by means of a collinear interferometric technique. A major advantage of this approach is that it avoids systematic losses, which are detrimental as they cause decoherence in continuous-variable quantum systems. The utilisation of a spatial light modulator (SLM) gives the flexibility to switch between arbitrary mode orders. The conversion efficiency with our setup is only limited by the efficiency of the SLM. We show the experimental generation of Laguerre-Gauss (LG) modes with radial indices 0 or 1 and azimuthal indices up to 3 with complex polarization structures and a quantum noise reduction up to -0.9dB±0.1dB. The corresponding polarization structures are studied in detail by measuring the spatial distribution of the Stokes parameters.

Single-mode squeezing in arbitrary spatial modes.

As the generation of squeezed states of light has become a standard technique in laboratories, attention is increasingly directed towards adapting the optical parameters of squeezed beams to the specific requirements of individual applications. It is known that imaging, metrology, and quantum information may benefit from using squeezed light with a tailored transverse spatial mode. However, experiments have so far been limited to generating only a few squeezed spatial modes within a given setup. Here, we present the generation of single-mode squeezing in Laguerre-Gauss and Bessel-Gauss modes, as well as an arbitrary intensity pattern, all from a single setup using a spatial light modulator (SLM). The degree of squeezing obtained is limited mainly by the initial squeezing and diffractive losses introduced by the SLM, while no excess noise from the SLM is detectable at the measured sideband. The experiment illustrates the single-mode concept in quantum optics and demonstrates the viability of current SLMs as flexible tools for the spatial reshaping of squeezed light.

Spontaneous generation of singularities in paraxial optical fields.

In nonrelativistic quantum mechanics, the spontaneous generation of singularities in smooth and finite wave functions is a well understood phenomenon also occurring for free particles. We use the familiar analogy between the two-dimensional Schrödinger equation and the optical paraxial wave equation to define a new class of square-integrable paraxial optical fields that develop a spatial singularity in the focal point of a weakly focusing thin lens. These fields are characterized by a single real parameter whose value determines the nature of the singularity. This novel field enhancement mechanism may stimulate fruitful research for diverse technological and scientific applications.

Quantum uncertainty in the beam width of spatial optical modes.

We theoretically investigate the quantum uncertainty in the beam width of transverse optical modes and, for this purpose, define a corresponding quantum operator. Single mode states are studied as well as multimode states with small quantum noise. General relations are derived, and specific examples of different modes and quantum states are examined. For the multimode case, we show that the quantum uncertainty in the beam width can be completely attributed to the amplitude quadrature uncertainty of one specific mode, which is uniquely determined by the field under investigation. This discovery provides us with a strategy for the reduction of the beam width noise by an appropriate choice of the quantum state.