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In recent years, new treatments have been approved for nonmetastatic castration-resistant prostate cancer (M0CRPC). Because direct comparisons between these treatments are not available to guide treatment decisions, indirect comparisons can be of interest.Our analysis evaluated second-generation hormone treatments proposed for M0CRPC. We searched multiple databases for articles published between 2010 and 2022. Phase-III clinical trials that studied these agents in M0CRPC patients were eligible. Among these, we included trials reporting overall survival (OS) through Kaplan-Meier curves. We performed the reconstruction of individual patient data from Kaplan-Meier graphs, according to the Shiny method, to indirectly compare the efficacy of the different agents. Indirect comparisons included testing for equivalence according to FDA criteria. Confidence intervals (CI) were 95% in all analyses except equivalence testing, where 90%CIs were used.Three studies met these inclusion criteria. Apalutamide (hazard ratio [HR]: 0.75, 95% confidence interval [CI] 0.64-0.88), darolutamide (HR 0.70, 95%CI 0.58-0.84), and enzalutamide (HR 0.77, 95%CI 0.65-0.90) were all significantly more effective than the placebo. Our results showed no difference in OS between any of these three agents, and in testing for equivalence, our estimates of HR met the 0.75-1.33 level.While the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons based on mature OS demonstrated similar efficacy and substantial equivalence among these three second-generation androgen receptor inhibitors.

Biomechanical finite-element study.To directly compare the biomechanical effects of two different techniques for sagittal plane correction of adult spine deformity based on the anterior longitudinal ligament (ALL) resection and use of hyperlordotic cages, namely, the anterior column realignment (ACR) in L3-4, and ALIF in L5-S1 in terms of primary stability and rod stresses using finite-element models.A finite-element model of the thoracolumbar spine was used to perform the analysis. Starting from this "intact" model, three further models were constructed through the insertion of spinal instrumentation, i.e., pedicle screws, rods and cages: 1) posterior instrumentation between T9 and S1 (referred to as "T9-S1"); 2) posterior instrumentation T9-S1 + Hyperlordotic (26°) ALIF cage in L5-S1 ("ALIF"); 3) posterior instrumentation T9-S1 + Hyperlordotic (30°) ACR cage in L3-4 ("ACR"). These models were studied by simulations applying, alternately, a pure moment of 7.5 Nm between the three planes of motion (flexion, extension, lateral bending, and bilateral axial rotation), uniformly distributed over the upper surface of the T9 thoracic vertebra. A total of 24 simulations were performed (6 per models).All models presented a significant reduced ROM when compared to the intact model; the ROM reduction was higher both at L3-4 in the ACR model and at L5-S1 in the ALIF model. At L3-4, the ACR model had, in all cases, the lowest maximum values of Von Mises stresses on the rods, especially in flexion-extension. At L4-5, the ALIF model had the lowest stresses during flexion-extension and axial rotation, while the ACR model had the lowest stresses during lateral bending. At L5-S1, the ALIF model had, in all cases, the lowest stresses on the rods.This finite-element study showed how both ACR at L3-4 and ALIF-ACR at L5-S1 are effective in restoring lumbar lordosis (LL), stabilizing the spine and reducing stress on posterior rods at the index level when compared to a simple fixation model. Interestingly, ALIF-ACR reduces rod stress even at L4-5 in flexion-extension and axial rotation, possibly due to a better distribution of LL, especially on the lower arch, while ACR reduces the stress at L4-5 in lateral bending, possibly thanks to the larger footprint of the cage that increases the area of contact with the lateral side of the endplates.

The attractor Hausdorff dimension is an important quantity bridging information theory and dynamical systems, as it is related to the number of effective degrees of freedom of the underlying dynamical system. By using the link between extreme value theory and Poincare recurrences, it is possible to estimate this quantity from time series of high-dimensional systems without embedding the data. In general $$d \le n$$ , where n is the dimension of the full phase-space, as the dynamics freezes some of the available degrees of freedom. This is equivalent to constraining trajectories on a compact object in phase space, namely the attractor. Information theory shows that the equality $$d=n$$ holds for random systems. However, applying extreme value theory, we show that this result cannot be recovered and that $$d

International audience; A fundamental challenge in climate science is decomposing the con-7 current drivers of weather extremes in observations. Achieving this would pro-8 vide insights into the drivers of individual extreme events as well as into pos-9 sible future changes in extreme event frequencies under greenhouse forcing. 10 In the present work, we exploit recent results from dynamical systems the-11 ory to study the co-variation and recurrence statistics of different atmospheric 12 fields. Specifically, we present a methodology to quantify the recurrences of 13 bivariate fields, the repeated co-occurrences of distinct univariate fields, and 14 the dependence between two fields. The dependence is defined by a coupling 15 parameter, which varies according to the chosen fields, season, and domain 16 and can be understood in terms of the underlying physics of the atmosphere. 17 For suitably chosen fields, this approach enables to decompose the different 18 drivers of weather extremes. Here, we compute the above metrics for near-19 surface temperature and sea level pressure, and use them to study hot or cold 20 days over North America. We first identify states where temperature extremes 21 are strongly and weakly coupled to the large-scale atmospheric circulation, 22 and then elucidate the interplay between coupling and the occurrence of tem-23 perature extremes.

In evaluating 3 or more comparators, pharmacoeconomic analyses can be improved by using the methodology of net monetary benefit (NMB) as opposed to incremental cost-effectiveness ratio (ICER). NMB is particularly suitable for managing competitive tenders that evaluate 3 or more devices in the same lot. For scientific purposes, the methodology of NMB is perfectly adequate. However, when tenders are managed in European countries, the Public Procurement Directive states that the tender score for price should be kept separate from that of clinical benefits. As a result, the traditional mathematical approach of NMB must be rearranged to comply with this administrative requirement. In this report, we describe how the classic equations of NMB should be modified to achieve this purpose. The mathematical principle of proportionality, which is typical of the ICER, must be replaced by the principle of mathematical additivity, which is typical of NMB. Furthermore, to rearrange the scale of benefits according to the NMB, an estimate is needed of the minimum acceptable benefit converted into monetary units, which is associated with 0 in the benefit scale. A detailed example is presented to explain the practical application of these mathematical equations. These equations are widely applicable in the field of implantable devices. Since the expenditure for medical devices in European hospitals is close to that of hospital medicines, tenders for the in-hospital procurement of devices may represent a decisive tool to manage sustainability and ensure access to innovation. In this context, the methodology for managing clinical outcomes through tenders requires a specific mathematical approach that we have described in the present article.

Esophageal cancer is the seventh most common cancer globally, accounting more than a half million deaths per year. Despite several therapeutic options in neoadjuvant setting, including chemoradiotherapy and surgery, no adjuvant treatment has been established for patients at high risk of recurrence. Even so, findings from the recently published CheckMate 577 trial seem to suggest an important clinical impact, in terms of disease-free progression, for the use of adjuvant nivolumab, a PDL-1 inhibitor, in resected esophageal cancer or gastroesophageal junction cancer. The authors reported a benefit for the treatment arm of 22.4 months compared with 11.0 in the placebo group. Although median is commonly used as an endpoint in survival studies, it can be influenced by the timing of a few events in the descending portion of the Kaplan-Meier curve. Restricted mean survival time (RMST) considers the entire time-course of the curve and does not assume that event risks are constant over the follow-up. This may be helpful to a more realistic interpretation of survival outcomes. In this letter, we re-analyzed the study curves of the CheckMate 577 trial by application of RMST. While confirming the disease-free progression benefits for nivolumab compared with placebo (28.54 months for the treatment arms versus 22.70 for the controls), our analysis allows us to interpret the survival benefit in a more conservative manner.

The Mediterranean region is projected to be significantly affected by climate change through warming and drying. The Eastern Mediterranean (EM) is particularly vulnerable since the bulk of the prec ...

In this study, covalently cross-linked network strategy has been applied to prepare new triple-shape memory polymers (TSPs) based on poly(l-lactide) (PLA)/poly(ɛ-caprolactone) (PCL) blends. The TSPs were fabricated by adding di-cumyl peroxide, with triallyl isocyanurate as a coagent for performing the cross-linking reaction. The differential scanning calorimetry (DSC) analysis demonstrated that all the PLA/PCL blends show two melting points (Tm,PCL and Tm,PLA), which can be employed as the transition temperature (Ttrans) to induce triple-shape memory behavior. The scanning electron microscopy (SEM) analysis indicated that there are two immiscible morphologies: co-continuous structure and matrix-droplet. The influence of temperature on the crystalline phase changes was analyzed by X-ray diffraction at various temperatures. The results revealed that during the heating–cooling cycle, the degree of crystallinity decreased when the temperature increased and at higher temperature, the crystallization peaks of PCL disappeared. Multiple thermal–mechanical tests were performed and the results showed that the composition ratio of the two phases plays an important role in the triple-shape memory behavior. The results confirmed that the excellent shape memory behavior was obtained for the sample containing 50 wt% PCL.

Several cases of expensive drugs designed for large patient populations (e.g. sofosbuvir) have raised a complex question in terms of drug pricing. Even assuming value-based pricing, the treatment with these drugs of all eligible patients would have an immense budgetary impact, which is unsustainable also for the richest countries. This raises the need to reduce the prices of these agents in comparison with those suggested by the value-based approach and to devise new pricing methods that can achieve this goal. The present study discusses in detail the following two methods: (i) The approach based on setting nation-wide budget thresholds for individual innovative agents in which a fixed proportion of the historical pharmaceutical expenditure represents the maximum budget attributable to an innovative treatment; (ii) The approach based on nation-wide price-volume agreements in which drug prices are progressively reduced as more patients receive the treatment. The first approach has been developed in the USA by the Institute for Clinical and Economic Review and has been applied to PCSK9 inhibitors (alirocumab and evolocumab). The second approach has been designed for the Italian market and has found a systematic application to manage the price of ranibizumab, sofosbuvir, and PCSK9 inhibitors. While, in the past, price-volume agreements have been applied only on an empirical basis (i.e. in the absence of any quantitative theoretical rule), more recently some explicit mathematical models have been described. The performance of these models is now being evaluated on the basis of the real-world experiences conducted in some European countries, especially Italy.