Spectrum reconstruction from a scattering measurement using the adjoint Boltzmann transport equation for photons

Quality control of medical radiological systems is of fundamental importance, and requires efficient methods for accurately determine the X-ray source spectrum. Straightforward measurements of X-ray spectra in standard operating require the limitation of the high photon flux, and therefore the measure has to be performed in a laboratory. However, the optimal quality control requires frequent in situ measurements which can be only performed using a portable system. To reduce the photon flux by 3 magnitude orders an indirect technique based on the scattering of the X-ray source beam by a solid target is used. The measured spectrum presents a lack of information because of transport and detection effects. The solution is then unfolded by solving the matrix equation that represents formally the scattering problem. However, the algebraic system is ill-conditioned and, therefore, it is not possible to obtain a satisfactory solution. Special strategies are necessary to circumvent the ill-conditioning. Numerous attempts have been done to solve this problem by using purely mathematical methods. In this thesis, a more physical point of view is adopted. The proposed method uses both the forward and the adjoint solutions of the Boltzmann transport equation to generate a better conditioned linear algebraic system. The procedure has been tested first on numerical experiments, giving excellent results. Then, the method has been verified with experimental measurements performed at the Operational Unit of Health Physics of the University of Bologna. The reconstructed spectra have been compared with the ones obtained with straightforward measurements, showing very good agreement.

Parameters and algorithms to evaluate cardiac mechanics by conductance catheter

This work is structured as follows: In Section 1 we discuss the clinical problem of heart failure. In particular, we present the phenomenon known as ventricular mechanical dyssynchrony: its impact on cardiac function, the therapy for its treatment and the methods for its quantification. Specifically, we describe the conductance catheter and its use for the measurement of dyssynchrony. At the end of the Section 1, we propose a new set of indexes to quantify the dyssynchrony that are studied and validated thereafter. In Section 2 we describe the studies carried out in this work: we report the experimental protocols, we present and discuss the results obtained. Finally, we report the overall conclusions drawn from this work and we try to envisage future works and possible clinical applications of our results. Ancillary studies that were carried out during this work mainly to investigate several aspects of cardiac resynchronization therapy (CRT) are mentioned in Appendix. -------- Ventricular mechanical dyssynchrony plays a regulating role already in normal physiology but is especially important in pathological conditions, such as hypertrophy, ischemia, infarction, or heart failure (Chapter 1,2.). Several prospective randomized controlled trials supported the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with moderate or severe heart failure and ventricular dyssynchrony. CRT resynchronizes ventricular contraction by simultaneous pacing of both left and right ventricle (biventricular pacing) (Chapter 1.). Currently, the conductance catheter method has been used extensively to assess global systolic and diastolic ventricular function and, more recently, the ability of this instrument to pick-up multiple segmental volume signals has been used to quantify mechanical ventricular dyssynchrony. Specifically, novel indexes based on volume signals acquired with the conductance catheter were introduced to quantify dyssynchrony (Chapter 3,4.). Present work was aimed to describe the characteristics of the conductancevolume signals, to investigate the performance of the indexes of ventricular dyssynchrony described in literature and to introduce and validate improved dyssynchrony indexes. Morevoer, using the conductance catheter method and the new indexes, the clinical problem of the ventricular pacing site optimization was addressed and the measurement protocol to adopt for hemodynamic tests on cardiac pacing was investigated. In accordance to the aims of the work, in addition to the classical time-domain parameters, a new set of indexes has been extracted, based on coherent averaging procedure and on spectral and cross-spectral analysis (Chapter 4.). Our analyses were carried out on patients with indications for electrophysiologic study or device implantation (Chapter 5.). For the first time, besides patients with heart failure, indexes of mechanical dyssynchrony based on conductance catheter were extracted and studied in a population of patients with preserved ventricular function, providing information on the normal range of such a kind of values. By performing a frequency domain analysis and by applying an optimized coherent averaging procedure (Chapter 6.a.), we were able to describe some characteristics of the conductance-volume signals (Chapter 6.b.). We unmasked the presence of considerable beat-to-beat variations in dyssynchrony that seemed more frequent in patients with ventricular dysfunction and to play a role in discriminating patients. These non-recurrent mechanical ventricular non-uniformities are probably the expression of the substantial beat-to-beat hemodynamic variations, often associated with heart failure and due to cardiopulmonary interaction and conduction disturbances. We investigated how the coherent averaging procedure may affect or refine the conductance based indexes; in addition, we proposed and tested a new set of indexes which quantify the non-periodic components of the volume signals. Using the new set of indexes we studied the acute effects of the CRT and the right ventricular pacing, in patients with heart failure and patients with preserved ventricular function. In the overall population we observed a correlation between the hemodynamic changes induced by the pacing and the indexes of dyssynchrony, and this may have practical implications for hemodynamic-guided device implantation. The optimal ventricular pacing site for patients with conventional indications for pacing remains controversial. The majority of them do not meet current clinical indications for CRT pacing. Thus, we carried out an analysis to compare the impact of several ventricular pacing sites on global and regional ventricular function and dyssynchrony (Chapter 6.c.). We observed that right ventricular pacing worsens cardiac function in patients with and without ventricular dysfunction unless the pacing site is optimized. CRT preserves left ventricular function in patients with normal ejection fraction and improves function in patients with poor ejection fraction despite no clinical indication for CRT. Moreover, the analysis of the results obtained using new indexes of regional dyssynchrony, suggests that pacing site may influence overall global ventricular function depending on its relative effects on regional function and synchrony. Another clinical problem that has been investigated in this work is the optimal right ventricular lead location for CRT (Chapter 6.d.). Similarly to the previous analysis, using novel parameters describing local synchrony and efficiency, we tested the hypothesis and we demonstrated that biventricular pacing with alternative right ventricular pacing sites produces acute improvement of ventricular systolic function and improves mechanical synchrony when compared to standard right ventricular pacing. Although no specific right ventricular location was shown to be superior during CRT, the right ventricular pacing site that produced the optimal acute hemodynamic response varied between patients. Acute hemodynamic effects of cardiac pacing are conventionally evaluated after stabilization episodes. The applied duration of stabilization periods in most cardiac pacing studies varied considerably. With an ad hoc protocol (Chapter 6.e.) and indexes of mechanical dyssynchrony derived by conductance catheter we demonstrated that the usage of stabilization periods during evaluation of cardiac pacing may mask early changes in systolic and diastolic intra-ventricular dyssynchrony. In fact, at the onset of ventricular pacing, the main dyssynchrony and ventricular performance changes occur within a 10s time span, initiated by the changes in ventricular mechanical dyssynchrony induced by aberrant conduction and followed by a partial or even complete recovery. It was already demonstrated in normal animals that ventricular mechanical dyssynchrony may act as a physiologic modulator of cardiac performance together with heart rate, contractile state, preload and afterload. The present observation, which shows the compensatory mechanism of mechanical dyssynchrony, suggests that ventricular dyssynchrony may be regarded as an intrinsic cardiac property, with baseline dyssynchrony at increased level in heart failure patients. To make available an independent system for cardiac output estimation, in order to confirm the results obtained with conductance volume method, we developed and validated a novel technique to apply the Modelflow method (a method that derives an aortic flow waveform from arterial pressure by simulation of a non-linear three-element aortic input impedance model, Wesseling et al. 1993) to the left ventricular pressure signal, instead of the arterial pressure used in the classical approach (Chapter 7.). The results confirmed that in patients without valve abnormalities, undergoing conductance catheter evaluations, the continuous monitoring of cardiac output using the intra-ventricular pressure signal is reliable. Thus, cardiac output can be monitored quantitatively and continuously with a simple and low-cost method. During this work, additional studies were carried out to investigate several areas of uncertainty of CRT. The results of these studies are briefly presented in Appendix: the long-term survival in patients treated with CRT in clinical practice, the effects of CRT in patients with mild symptoms of heart failure and in very old patients, the limited thoracotomy as a second choice alternative to transvenous implant for CRT delivery, the evolution and prognostic significance of diastolic filling pattern in CRT, the selection of candidates to CRT with echocardiographic criteria and the prediction of response to the therapy.

Primary stability in cementless total hip replacement: measurement techniques and aided-surgery

Primary stability of stems in cementless total hip replacements is recognized to play a critical role for long-term survival and thus for the success of the overall surgical procedure. In Literature, several studies addressed this important issue. Different approaches have been explored aiming to evaluate the extent of stability achieved during surgery. Some of these are in-vitro protocols while other tools are coinceived for the post-operative assessment of prosthesis migration relative to the host bone. In vitro protocols reported in the literature are not exportable to the operating room. Anyway most of them show a good overall accuracy. The RSA, EBRA and the radiographic analysis are currently used to check the healing process of the implanted femur at different follow-ups, evaluating implant migration, occurance of bone resorption or osteolysis at the interface. These methods are important for follow up and clinical study but do not assist the surgeon during implantation. At the time I started my Ph.D Study in Bioengineering, only one study had been undertaken to measure stability intra-operatively. No follow-up was presented to describe further results obtained with that device. In this scenario, it was believed that an instrument that could measure intra-operatively the stability achieved by an implanted stem would consistently improve the rate of success. This instrument should be accurate and should give to the surgeon during implantation a quick answer concerning the stability of the implanted stem. With this aim, an intra-operative device was designed, developed and validated. The device is meant to help the surgeon to decide how much to press-fit the implant. It is essentially made of a torsional load cell, able to measure the extent of torque applied by the surgeon to test primary stability, an angular sensor that measure the relative angular displacement between stem and femur, a rigid connector that enable connecting the device to the stem, and all the electronics for signals conditioning. The device was successfully validated in-vitro, showing a good overall accuracy in discriminating stable from unstable implants. Repeatability tests showed that the device was reliable. A calibration procedure was then performed in order to convert the angular readout into a linear displacement measurement, which is an information clinically relevant and simple to read in real-time by the surgeon. The second study reported in my thesis, concerns the evaluation of the possibility to have predictive information regarding the primary stability of a cementless stem, by measuring the micromotion of the last rasp used by the surgeon to prepare the femoral canal. This information would be really useful to the surgeon, who could check prior to the implantation process if the planned stem size can achieve a sufficient degree of primary stability, under optimal press fitting conditions. An intra-operative tool was developed to this aim. It was derived from a previously validated device, which was adapted for the specific purpose. The device is able to measure the relative micromotion between the femur and the rasp, when a torsional load is applied. An in-vitro protocol was developed and validated on both composite and cadaveric specimens. High correlation was observed between one of the parameters extracted form the acquisitions made on the rasp and the stability of the corresponding stem, when optimally press-fitted by the surgeon. After tuning in-vitro the protocol as in a closed loop, verification was made on two hip patients, confirming the results obtained in-vitro and highlighting the independence of the rasp indicator from the bone quality, anatomy and preserving conditions of the tested specimens, and from the sharpening of the rasp blades. The third study is related to an approach that have been recently explored in the orthopaedic community, but that was already in use in other scientific fields. It is based on the vibration analysis technique. This method has been successfully used to investigate the mechanical properties of the bone and its application to evaluate the extent of fixation of dental implants has been explored, even if its validity in this field is still under discussion. Several studies have been published recently on the stability assessment of hip implants by vibration analysis. The aim of the reported study was to develop and validate a prototype device based on the vibration analysis technique to measure intra-operatively the extent of implant stability. The expected advantages of a vibration-based device are easier clinical use, smaller dimensions and minor overall cost with respect to other devices based on direct micromotion measurement. The prototype developed consists of a piezoelectric exciter connected to the stem and an accelerometer attached to the femur. Preliminary tests were performed on four composite femurs implanted with a conventional stem. The results showed that the input signal was repeatable and the output could be recorded accurately. The fourth study concerns the application of the device based on the vibration analysis technique to several cases, considering both composite and cadaveric specimens. Different degrees of bone quality were tested, as well as different femur anatomies and several levels of press-fitting were considered. The aim of the study was to verify if it is possible to discriminate between stable and quasi-stable implants, because this is the most challenging detection for the surgeon in the operation room. Moreover, it was possible to validate the measurement protocol by comparing the results of the acquisitions made with the vibration-based tool to two reference measurements made by means of a validated technique, and a validated device. The results highlighted that the most sensitive parameter to stability is the shift in resonance frequency of the stem-bone system, showing high correlation with residual micromotion on all the tested specimens. Thus, it seems possible to discriminate between many levels of stability, from the grossly loosened implant, through the quasi-stable implants, to the definitely stable one. Finally, an additional study was performed on a different type of hip prosthesis, which has recently gained great interest thus becoming fairly popular in some countries in the last few years: the hip resurfacing prosthesis. The study was motivated by the following rationale: although bone-prosthesis micromotion is known to influence the stability of total hip replacement, its effect on the outcome of resurfacing implants has not been investigated in-vitro yet, but only clinically. Thus the work was aimed at verifying if it was possible to apply to the resurfacing prosthesis one of the intraoperative devices just validated for the measurement of the micromotion in the resurfacing implants. To do that, a preliminary study was performed in order to evaluate the extent of migration and the typical elastic movement for an epiphyseal prosthesis. An in-vitro procedure was developed to measure micromotions of resurfacing implants. This included a set of in-vitro loading scenarios that covers the range of directions covered by hip resultant forces in the most typical motor-tasks. The applicability of the protocol was assessed on two different commercial designs and on different head sizes. The repeatability and reproducibility were excellent (comparable to the best previously published protocols for standard cemented hip stems). Results showed that the procedure is accurate enough to detect micromotions of the order of few microns. The protocol proposed was thus completely validated. The results of the study demonstrated that the application of an intra-operative device to the resurfacing implants is not necessary, as the typical micromovement associated to this type of prosthesis could be considered negligible and thus not critical for the stabilization process. Concluding, four intra-operative tools have been developed and fully validated during these three years of research activity. The use in the clinical setting was tested for one of the devices, which could be used right now by the surgeon to evaluate the degree of stability achieved through the press-fitting procedure. The tool adapted to be used on the rasp was a good predictor of the stability of the stem. Thus it could be useful for the surgeon while checking if the pre-operative planning was correct. The device based on the vibration technique showed great accuracy, small dimensions, and thus has a great potential to become an instrument appreciated by the surgeon. It still need a clinical evaluation, and must be industrialized as well. The in-vitro tool worked very well, and can be applied for assessing resurfacing implants pre-clinically.

Measurement of the atmospheric muon charge ratio with the OPERA detector

The atmospheric muon charge ratio, defined as the number of positive over negative charged muons, is an interesting quantity for the study of high energy hadronic interactions in atmosphere and the nature of the primary cosmic rays. The measurement of the charge ratio in the TeV muon energy range allows to study the hadronic interactions in kinematic regions not yet explored at accelerators. The OPERA experiment is a hybrid electronic detector/emulsion apparatus, located in the underground Gran Sasso Laboratory, at an average depth of 3800 meters water equivalent (m.w.e.). OPERA is the first large magnetized detector that can measure the muon charge ratio at the LNGS depth, with a wide acceptance for cosmic ray muons coming from above. In this thesis, the muon charge ratio is measured using the spectrometers of the OPERA detector in the highest energy region. The charge ratio was computed separately for single and for multiple muon events, in order to select different primary cosmic ray samples in energy and composition. The measurement as a function of the surface muon energy is used to infer parameters characterizing the particle production in atmosphere, that will be used to constrain Monte Carlo predictions. Finally, the experimental results are interpreted in terms of cosmic ray and particle physics models.

Gait analysis using a single wearable inertial measurement unit

Procedures for quantitative walking analysis include the assessment of body segment movements within defined gait cycles. Recently, methods to track human body motion using inertial measurement units have been suggested. It is not known if these techniques can be readily transferred to clinical measurement situations. This work investigates the aspects necessary for one inertial measurement unit mounted on the lower back to track orientation, and determine spatio-temporal features of gait outside the confines of a conventional gait laboratory. Apparent limitations of different inertial sensors can be overcome by fusing data using methods such as a Kalman filter. The benefits of optimizing such a filter for the type of motion are unknown. 3D accelerations and 3D angular velocities were collected for 18 healthy subjects while treadmill walking. Optimization of Kalman filter parameters improved pitch and roll angle estimates when compared to angles derived using stereophotogrammetry. A Weighted Fourier Linear Combiner method for estimating 3D orientation angles by constructing an analytical representation of angular velocities and allowing drift free integration is also presented. When tested this method provided accurate estimates of 3D orientation when compared to stereophotogrammetry. Methods to determine spatio-temporal features from lower trunk accelerations generally require knowledge of sensor alignment. A method was developed to estimate the instants of initial and final ground contact from accelerations measured by a waist mounted inertial device without rigorous alignment. A continuous wavelet transform method was used to filter and differentiate the signal and derive estimates of initial and final contact times. The technique was tested with data recorded for both healthy and pathologic (hemiplegia and Parkinson’s disease) subjects and validated using an instrumented mat. The results show that a single inertial measurement unit can assist whole body gait assessment however further investigation is required to understand altered gait timing in some pathological subjects.

Kinematic models of interseismic deformation from inversion of GPS and InSAR measurements to estimate fault parameters and coupling degree

We have used kinematic models in two Italian regions to reproduce surface interseismic velocities obtained from InSAR and GPS measurements. We have considered a Block modeling, BM, approach to evaluate which fault system is actively accommodating the occurring deformation in both considered areas. We have performed a study for the Umbria-Marche Apennines, obtaining that the tectonic extension observed by GPS measurements is explained by the active contribution of at least two fault systems, one of which is the Alto Tiberina fault, ATF. We have estimated also the interseismic coupling distribution for the ATF using a 3D surface and the result shows an interesting correlation between the microseismicity and the uncoupled fault portions. The second area analyzed concerns the Gargano promontory for which we have used jointly the available InSAR and GPS velocities. Firstly we have attached the two datasets to the same terrestrial reference frame and then using a simple dislocation approach, we have estimated the best fault parameters reproducing the available data, providing a solution corresponding to the Mattinata fault. Subsequently we have considered within a BM analysis both GPS and InSAR datasets in order to evaluate if the Mattinata fault may accommodate the deformation occurring in the central Adriatic due to the relative motion between the North-Adriatic and South-Adriatic plates. We obtain that the deformation occurring in that region should be accommodated by more that one fault system, that is however difficult to detect since the poor coverage of geodetic measurement offshore of the Gargano promontory. Finally we have performed also the estimate of the interseismic coupling distribution for the Mattinata fault, obtaining a shallow coupling pattern. Both of coupling distributions found using the BM approach have been tested by means of resolution checkerboard tests and they demonstrate that the coupling patterns depend on the geodetic data positions.

Accuracy of liver stiffness measurement using fibroscan ® to predict the response to antiviral therapy in patients with chronic hepatitis c viral infection

Introduction: Antiviral therapy can prevent disease progression in patients with chronic hepatitis C . Transient Elastografy (TE; Fibroscan) is an accurate surrogate marker to liver fibrosis, by measuring liver stiffness (LS). LS decrease has been associated with sustained virologic response (SVR). Aim: to assess the changes of LS measurments in CHC patients during and one year after Interferon (IFN)-based antiviral therapy (IFN/ribavirin) or (telaprevir+IFN/ribavirin). Methods: consecutive 69 CHC patients (53.6% females, mean age 57.9 ± 11.4) who underwent antiviral therapy for at least 20 weeks were enrolled. LS was measured using FibroScan at baseline, after three months, at the end of treatment and one year after treatment discontinuation. Fibrosis was graded using METAVIR score. Results: twenty patients treated with triple therapy and 49 with IFN/ribavirin. Fifty patients had SVR and 19 were non-responders. SVR patients: F0-F1, F2 and F3 patients (39.1%, 7.2% and 17.4%; respectively) showed no significant LS decrease (P= 0.186, 0.068 and 0.075; respectively). Conversely, in F4 patients (36.2%) LS was significantly decreased (P=0.015) after one year of treatment completion. In all patients with no SVR, no significant decrease in LS was observed. Interestingly, all Patients with F4 fibrosis (even non-responders) showed an initial significant decrease in LS (P=0.024) at 3 months after the start of treatment. However, this decrease was not predictive of SVR; area under the ROC curve 0.369 (CI %: 0.145-0.592) P= 0.265. Conclusion: Our study showed that initial decrease in LSM, especially in patients with higher baseline fibrosis score is unlikely to predict an SVR. In addition no significant association was found between clinical or virological parameters and fibrosis improvement. Further studies are needed to delineate the most appropriate clinical scenarios for the LSM by Fibroscan in chronic hepatitis C and its role in monitoring the response to antiviral treatment.

Measurement of the $B^0$ - $\bar{B}^0$ and $B^0_s$ - $\bar{B}^0_s$ production asymmetries in pp collisions at $\sqrt{s}=7$ TeV and $\sqrt{s}=8$ TeV with the LHCb experiment

The production rate of $b$ and $\bar{b}$ hadrons in $pp$ collisions are not expected to be strictly identical, due to imbalance between quarks and anti-quarks in the initial state. This phenomenon can be naively related to the fact that the $\bar{b}$ quark produced in the hard scattering might combine with a $u$ or $d$ valence quark from the colliding protons, whereas the same cannot happen for a $b$ quark. This thesis presents the analysis performed to determine the production asymmetries of $B^0$ and $B^0_s$. The analysis relies on data samples collected by the LHCb detector at the Large Hadron Collider (LHC) during the 2011 and 2012 data takings at two different values of the centre of mass energy $\sqrt{s}=7$ TeV and at $\sqrt{s}=8$ TeV, corresponding respectively to an integrated luminosity of 1 fb$^{-1}$ and of 2 fb$^{-1}$. The production asymmetry is one of the key ingredients to perform measurements of $CP$ violation in b-hadron decays at the LHC, since $CP$ asymmetries must be disentangled from other sources. The measurements of the production asymmetries are performed in bins of $p_\mathrm{T}$ and $\eta$ of the $B$-meson. The values of the production asymmetries, integrated in the ranges $4 < p_\mathrm{T} < 30$ GeV/c and $2.5<\eta<4.5$, are determined to be: \begin{equation} A_\mathrm{P}(\B^0)= (-1.00\pm0.48\pm0.29)\%,\nonumber \end{equation} \begin{equation} A_\mathrm{P}(\B^0_s)= (\phantom{-}1.09\pm2.61\pm0.61)\%,\nonumber \end{equation} where the first uncertainty is statistical and the second is systematic. The measurement of $A_\mathrm{P}(B^0)$ is performed using the full statistics collected by LHCb so far, corresponding to an integrated luminosity of 3 fb$^{-1}$, while the measurement of $A_\mathrm{P}(B^0_s)$ is realized with the first 1 fb$^{-1}$, leaving room for improvement. No clear evidence of dependences on the values of $p_\mathrm{T}$ and $\eta$ is observed. The results presented in this thesis are the most precise measurements available up to date.

Assessment of gait spatio-temporal parameters in neurological disorders using wearable inertial sensors

Movement analysis carried out in laboratory settings is a powerful, but costly solution since it requires dedicated instrumentation, space and personnel. Recently, new technologies such as the magnetic and inertial measurement units (MIMU) are becoming widely accepted as tools for the assessment of human motion in clinical and research settings. They are relatively easy-to-use and potentially suitable for estimating gait kinematic features, including spatio-temporal parameters. The objective of this thesis regards the development and testing in clinical contexts of robust MIMUs based methods for assessing gait spatio-temporal parameters applicable across a number of different pathological gait patterns. First, considering the need of a solution the least obtrusive as possible, the validity of the single unit based approach was explored. A comparative evaluation of the performance of various methods reported in the literature for estimating gait temporal parameters using a single unit attached to the trunk first in normal gait and then in different pathological gait conditions was performed. Then, the second part of the research headed towards the development of new methods for estimating gait spatio-temporal parameters using shank worn MIMUs on different pathological subjects groups. In addition to the conventional gait parameters, new methods for estimating the changes of the direction of progression were explored. Finally, a new hardware solution and relevant methodology for estimating inter-feet distance during walking was proposed. Results of the technical validation of the proposed methods at different walking speeds and along different paths against a gold standard were reported and showed that the use of two MIMUs attached to the lower limbs associated with a robust method guarantee a much higher accuracy in determining gait spatio-temporal parameters. In conclusion, the proposed methods could be reliably applied to various abnormal gaits obtaining in some cases a comparable level of accuracy with respect to normal gait.

Measurement of CP violation with $B^0_{(s)} \to h^+ h^{\prime-}$ decays, $|V_{cb}|$ with $B^0_{s}\to D^{(*)-}_s \mu^+ \nu_\mu$ decays, and simulation and characterisation of the LHCb Upgrade II ECAL

The time-dependent CP asymmetries of the $B^0\to\pi^+\pi^-$ and $B^0_s\toK^+K^-$ decays and the time-integrated CP asymmetries of the $B^0\toK^+\pi^-$ and $B^0_s\to\pi^+K^-$ decays are measured, using the $p-p$ collision data collected with the LHCb detector and corresponding to the full Run2. The results are compatible with previous determinations of these quantities from LHCb, except for the CP-violation parameters of the $B^0_s\to K^+K^-$ decays, that show a discrepancy exceeding 3 standard deviations between different data-taking periods. The investigations being conducted to understand the discrepancy are documented. The measurement of the CKM matrix element $|V_{cb}|$ using $B^0_{s}\to D^{(*)-}_s\mu^+ \nu_\mu$ is also reported, using the $p-p$ collision data collected with the LHCb detector and corresponding to the full Run1. The measurement leads to $|V_{cb}| = (41.4\pm0.6\pm0.9\pm1.2)\times 10^{-3}$, where the first uncertainty is statistical, the second is systematic, and the third is due to external inputs. This measurement is compatible with the world averages and constitutes the first measurement of $|V_{cb}|$ at a hadron collider and the absolute first one with decays of the $B^0_s$ meson. The analysis also provides the very first measurements of the branching ratio and form factors parameters of the signal decay modes. The study of the characteristics ruling the response of an electromagnetic calorimeter (ECAL) to profitably operate in the high luminosity regime foreseen for the Upgrade2 of LHCb is reported in the final part of this Thesis. A fast and flexible simulation framework is developed to this purpose. Physics performance of different configurations of the ECAL are evaluated using samples of fully simulated $B^0\to \pi^+\pi^-\pi^0$ and $B^0\to K^{*0}e^+e^-$ decays. The results are used to guide the development of the future ECAL and are reported in the Framework Technical Design Report of the LHCb Upgrade2 detector.

Analytical approaches for the measurement of sulfide in biological and pharmaceutical fields

Hydrogen sulfide (H2S) is a widely recognized gasotransmitter, with key roles in physiological and pathological processes. The accurate quantification of H2S and reactive sulfur species (RSS) may hold important implications for the diagnosis and prognosis of various diseases. However, H2S species quantification in biological matrices is still a challenge. Among the sulfide detection methods, monobromobimane (MBB) derivatization coupled with reversed phase high-performance liquid chromatography (RP-HPLC) is one of the most reported. However, it is characterized by a complex preparation and time-consuming process, which may alter the actual H2S level. Moreover, quantitative validation has still not been described based on a survey of previously published works. In this study, we developed and validated an improved analytical protocol for the MBB RP-HPLC method. Main parameters like MBB concentration, temperature, reaction time, and sample handling were optimized, and the calibration method was further validated using leave-one-out cross-validation (CV) and tested in a clinical setting. The method shows high sensitivity and allows the quantification of H2S species, with a limit of detection (LOD) of 0.5 µM and a limit of quantification (LOQ) of 0.9 µM. Additionally, this model was successfully applied in measurements of H2S levels in the serum of patients subjected to inhalation with vapors rich in H2S. In addition, a properly procedure was established for H2S release with the modified MBB HPLC-FLD method. The proposed analytical approach demonstrated the slow-release kinetics of H2S from the multilayer Silk-Fibroin scaffolds with the combination of different H2S donor’s concentration with respect to the weight of PLGA nanofiber. In the end, some efforts were made on sulfide measurements by using size exclusion chromatography fluorescence/ultraviolet detection and inductively coupled plasma-mass spectrometry (SEC-FLD/UV-ICP/MS). It’s intended as a preliminary study in order to define the feasibility of a separation-detection-quantification platform to analyze biological samples and quantify sulfur species.