The Role of Speckle Tracking Echocardiography in the Evaluation of Advanced-Heart-Failure Patients.

Health care is currently showing a fall in heart failure (HF) incidence and prevalence, particularly in developed countries, but with only a subset receiving appropriate therapy to protect the heart against maladaptive processes such as fibrosis and hypertrophy. Appropriate markers of advanced HF remain unidentified, which would help in choosing the most suitable therapy and avoid major compliance problems. Speckle tracking echocardiography (STE) is a good choice, being a non-invasive imaging technique which is able to assess cardiac deformation in a variety of conditions. Several multicenter studies and meta-analyses have demonstrated the clinical application and accuracy of STE in early and late stages of HF, as well as its association with both left ventricular (LV) filling pressures and myocardial oxygen consumption. Furthermore, STE assists in assessing right ventricular free-wall longitudinal strain (RVFWLS), which is a solid predictor of right ventricle failure (RVF) following LV assist device (LVAD) implantation. However, STE is known for its limitations; despite these, it has been shown to explain symptoms and signs and also to be an accurate prognosticator. The aim of this review is to examine the advantages of STE in the early evaluation of myocardial dysfunction and its correlation with right heart catheterization (RHC) parameters, which should have significant clinical relevance in the management of HF patients.

Dapagliflozin Effects on Cardiac Deformation in Heart Failure and Secondary Clinical Outcome.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors were shown to reduce morbidity and mortality in patients with heart failure. OBJECTIVES: This study aims to assess potential effects of dapagliflozin in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with mildly reduced ejection fraction (HFmrEF) on cardiac function assessed by speckle tracking echocardiography (STE). METHODS: This randomized, prospective, single-center, open-label trial compared consecutive nondiabetic outpatients with HFrEF or HFmrEF receiving dapagliflozin with patients treated with optimal medical therapy (OMT) except sodium-glucose cotransporter type 2 inhibitors. Primary endpoint was the presence of a significant modification of left ventricular global longitudinal strain, diastolic function (as peak atrial longitudinal strain) and right ventricular function by STE from baseline to 6 months. Cardiovascular events and parameters of congestion were assessed as safety-exploratory endpoints. RESULTS: Overall, 88 patients (38% HFmrEF) were enrolled and randomized to start dapagliflozin on top of OMT (n = 44) or to continue with OMT (n = 44). All STE values improved in the dapagliflozin group after 6 months, whereas there was a nonsignificant improvement in OMT group. Moreover, when comparing the modification of STE parameters at follow-up in patients with HFrEF and HFmrEF, only the main treatment effect resulted statistically significant in both groups (P < 0.0001), indicating a significant difference between dapagliflozin and OMT. CONCLUSIONS: This study provided randomized data on the beneficial effect of dapagliflozin in nondiabetic patients with HFrEF and HFmrEF in terms of myocardial performance measured by the most sensitive echocardiographic technique, ie, STE. This suggests its usefulness for left ventricular reverse remodeling and better quality of life in patients with HFrEF and HFmrEF. (Effects of Dapagliflozin on cardiac deformation and clinical outcomes in heart failure with reduced and mildly reduced ejection fraction [DAPA ECHO trial]; EudraCT number: 2021-005394-66).

SARS-CoV-2 and influenza vaccine hesitancy during the COVID-19 pandemic in a dynamic perspective.

To investigate the dynamic evolution of vaccine hesitancy toward both COVID-19 and influenza in a context characterized by the compresence of SARS-CoV-2 pandemic and seasonal flu epidemics, a two times repeated cross-sectional exploratory design was performed at Udine Hospital (Italy) following a cohort of 479 adult patients with a previous history of SARS-CoV-2 infection in 2020. Vaccine attitude was assessed through standardized telephone interviews performed at 12 and 18 months after the acute illness. The first interview reported the success of the 2020/21 seasonal influenza immunization with 46.8% (224/479) of the participants showing a positive attitude, especially the elderly and people with comorbidities (p < .001), but the investigation conducted at 18 months showed a drastic drop in flu shot acceptance (30/166, 18.1%). On the other hand, a great increase in vaccinations against SARS-CoV-2 occurred after the introduction of Green Pass (26.7% vs 72.9%). The major drivers of flu vaccine skepticism were represented by the feeling of protection regardless of prevention and by concerns regarding vaccines safety and efficacy; conversely compulsory strategies seemed to play a secondary role, since only a minority of the participants identified in the restrictions induced by the certification the major incentive to get immunized against SARS-CoV-2. The focus on this peculiar historical period helps to take a step forward in the comprehension of the complexity and dynamicity of the vaccine hesitancy phenomenon. Future vaccination campaigns will need to consider the role of personal opinions and emotions, interpreted according to the social and political context.

Myocardial Work Indices Predict Hospitalization in Patients with Advanced Heart Failure.

BACKGROUND: An increasing proportion of heart failure (HF) patients progress to the advanced stage (AdHF) with high event rates and limited treatment options. Echocardiography, particularly Speckle Tracking-derived myocardial work (MW), is useful for HF diagnosis and prognosis. We aimed to assess MW's feasibility in the prognostic stratification of AdHF. METHODS: We retrospectively screened patients with AdHF who accessed our hospital in 2018-2022. We excluded subjects with inadequate acoustic windows; unavailable brachial artery cuff pressure at the time of the echocardiography; atrial fibrillation; and mitral or aortic regurgitation. We measured standard parameters and left ventricular (LV) strain (LS) and MW. The population was followed up to determine the composite outcomes of all-cause mortality, left ventricular assist device implantation and heart transplantation (primary endpoint), as well as unplanned HF hospitalization (secondary endpoint). RESULTS: We enrolled 138 patients, prevalently males (79.7%), with a median age of 58 years (IQR 50-62). AdHF etiology was predominantly non-ischemic (65.9%). Thirty-five patients developed a composite event during a median follow-up of 636 days (IQR 323-868). Diastolic function, pulmonary pressures, and LV GLS and LV MW indices were not associated with major events. Contrarily, for the secondary endpoint, the hazard ratio for each increase in global work index (GWI) by 50 mmHg% was 0.90 (p = 0.025) and for each increase in global constructive work (GCW) by 50 mmHg% was 0.90 (p = 0.022). Kaplan-Meier demonstrated better endpoint-free survival, with an LV GWI ≥ 369 mmHg%. CONCLUSIONS: GWI and GCW, with good feasibility, can help in the better characterization of patients with AdHF at higher risk of HF hospitalization and adverse events, identifying the need for closer follow-up or additional HF therapy.

Revolutionizing Daptomycin Dosing: A Single 7-11 Hour Sample for Pragmatic Application.

Precision daptomycin dosing faces clinical implementation barriers despite known exposure-safety concerns with the use of twice the regulatory-approved doses. We propose achieving a single 7-11 hour post-dose plasma target concentration of 30 mg/L to 43 mg/L to be a practical starting point to facilitate precision daptomycin dosing.

An Aminoglycoside-Sparing Regimen with Double Beta-Lactam to Successfully Treat Granulicatella adiacens Prosthetic Aortic Valve Endocarditis-Time to Change Paradigm?

(1) Background: Granulicatella adiacens is a former nutritionally variant streptococci (NVS). NVS infective endocarditis (IE) is generally characterized by a higher rate of morbidity and mortality, partially due to difficulties in choosing the most adequate microbiological culture method and the most effective treatment strategy, and partially due to higher rates of complications, such as heart failure, peripheral septic embolism, and peri-valvular abscess, as well as a higher rate of valve replacement. Depending on the affected valve (native valve endocarditisNVE, or prosthetic valve endocarditisPVE), the American Heart Association (AHA) 2015 treatment guidelines (GLs) suggest penicillin G, ampicillin, or ceftriaxone plus gentamicin (2 weeks for NVE and up to 6 weeks for PVE), while vancomycin alone may be a reasonable alternative in patients who are intolerant of ß-lactam therapy. The European Society of Cardiology (ESC) 2023 GLs recommend treating NVE with penicillin G, ceftriaxone, or vancomycin for 6 weeks, suggesting combined with an aminoglycoside (AG) for at least the first 2 weeks only for PVE; likewise, the same recommendations for IE due to Enterococcus faecalis. (2) Methods: Starting from the case of a 51-year-old man with G. adiacens aortic bio-prosthesis IE who was successfully treated with aortic valve replacement combined with double beta-lactams, an AG-sparing regimen, we performed microbiology tests in order to validate this potential treatment change. (3) Results: As for E. faecalis IE, we found that the combination of ampicillin plus cephalosporines (like ceftriaxone or ceftobiprole) showed a synergistic effect in vitro, probably due to wider binding to penicillin-binding proteins (PBPs), thus contributing to enhanced bacterial killing and good clinical outcome, as well as avoiding the risk of nephrotoxicity due to AG association therapy. (4) Conclusions: Further studies are required to confirm this hypothesis, but double beta-lactams and an adequate sourcecontrol could be a choice in treating G. adiacens IE.

Different right ventricular dysfunction and pulmonary coupling in acute heart failure according to the left ventricular ejection fraction.

BACKGROUND: Right ventricular (RV) dysfunction and pulmonary uncoupling are two acknowledged features associated with poor outcome, however few data defined RV adaptation across the different left ventricular ejection fraction (EF) cut-off. Additionally, less data are reported in patients with acute heart failure (AHF). AIMS: The aim of present study was to analyse RV function in AHF patients presenting with either reduced or preserved EF. METHODS: This is a multi-center observational study including 380 patients affected by AHF: 235 had AHF with reduced EF (AHFrEF) and 145 had AHF with preserved EF (AHFpEF). Pulmonary artery systolic pressure (PASP), tricuspid annular plane systolic excursion (TAPSE), S' wave velocity, and the RV end-diastolic diameter (RVEDD) were measured by echocardiography. TAPSE/PASP and S'/PASP ratios were calculated as non-invasive surrogates of RV-pulmonary arterial coupling. RESULTS: Factors associated with poor outcome were higher values of PASP (45 [40-55] mmHg vs 40 [35-46] mmHg; p < 0.001), RVEDD (44 [38-47] mm vs 37 [35-42] mm; p < 0.001), lower TAPSE values (17 [15-20] mm vs 20 [18-22] mm; p < 0.001) and S' wave (10 [8-12] cm/s vs 11 [10-13] cm/s; p < 0.001), reduced TAPSE/PASP (0.37 [0.29-0.47] vs 0.50 [0.40-0.60]; p < 0.001) and S'/PASP ratios (0.22 [0.18-0.28] vs 0.28 [0.22-0.34]; p < 0.001). However, the prognostic parameters differed according to the LVEF value: in AHFpEF S'/PASP between 0.22 and 0.29 and > 0.29 demonstrated a protective prognostic value (Respectively HR 0.29 (0.16-0.53), p < 0.001 and HR 0.22 [0.12-0.42], p < 0.001). Conversely, in AHFrEF, TAPSE <16 mm (HR 2.59 [1.67-4.03], p < 0.001), ICV > 21 mm (HR 1.17 [1.17-1.28], p = 0.001) and TAPSE/PASP <0.49 HR 1.92 [1.10-3.37], p = 0.023) were related to adverse outcome. CONCLUSIONS: RV adaptation and RV pulmonary coupling differ in AHF according to the level of LVEF. S' wave, and S'/PASP are associated with adverse outcome in patients with preserved EF; reduced TAPSE and TAPSE/PASP are better prognostic predictors in patients with reduced EF.

CO2 Reduction by Nanosecond-Plasma Discharges: Revealing the Dissociation's Time Scale and the Importance of Pulse Sequence.

Power-to-chemical technologies with CO2 as feedstock recycle CO2 and store energy into value-added compounds. Plasma discharges fed by renewable electricity are a promising approach to CO2 conversion. However, controlling the mechanisms of plasma dissociation is crucial to improving the efficiency of the technology. We have investigated pulsed nanosecond discharges, showing that while most of the energy is deposited in the breakdown phase, CO2 dissociation only occurs after an order of microsecond delay, leaving the system in a quasi-metastable condition in the intervening time. These findings indicate the presence of delayed dissociation mechanisms mediated by CO2 excited states rather than direct electron impact. This "metastable" condition, favorable for an efficient CO2 dissociation, can be prolonged by depositing more energy in the form of additional pulses and critically depends on a sufficiently short interpulse time.

Lactococcus lactis blood products contamination resulting in fatal human case: insights from a forensic case.

Lactococcus species are micro-aerophilic Gram positive bacteria characterized by low virulence features and other biotechnological properties of industrial interest. They are thus widely employed in food fermentation processes. Despite its low pathogenic potential and food grade safety, L. lactis may, however, rarely cause infections, especially among immunocompromised hosts. Moreover, the growing complexity of patients implies increased detections of such infections. This said, there is a paucity of data concerning L. lactis infections from infusion of blood transfusion products. To our knowledge, this is the first case of L. lactis infection from transfusion of blood products, as observed in an 82-year-old Caucasian male undergoing weekly platelet and blood transfusion due to sustained severe thrombocytopenia. Albeit minimally pathogenic, L. lactis should be considered for thorough testing, especially in the case of human-derived infusion products such as platelets due to their storage requirements for extended times at room temperature and their use in immunocompromised and critically ill subjects.

Cefditoren: a clinical overview.

Cefditoren is an oral third-generation cephalosporin with a large spectrum activity against Gram-negative and Gram-positive bacteria which are reported to be responsible for respiratory tract and skin and skin structure infections. In this work we reviewed the pharmacodynamics, pharmacokinetics, and the main clinical indications of cefditoren. Similarly to other beta-lactams, cefditoren is a time-dependent antibiotic, and its "best" PK/PD target is probably 40% dosing interval time > 4- 5-fold MIC and 40-70% dosing interval time > 4- 5-fold MIC for bacteriostatic and bactericidal effect, respectively. In fasting patients oral bioavailability is low and increases when the drug is taken with food. This cephalosporin has significant bactericidal activity against S. pneumoniae (both penicillin-susceptible and penicillin-resistant strains), S. pyogenes, H. Influenzae and M. catarrhalis, as well as methicillin-susceptible S. aureus (MSSA). Regarding Enterobacterales, cefditoren has very low MICs90 against K. pneumoniae andE. coli but is not active against AmpC-, ESBL- and carbapenemase-producer' strains. Licensed indications are treatment of exacerbations of chronic bronchitis,acute rhinosinusitis, otitis media, upper respiratory tract infections (pharyngitis/tonsillitis), lower community-acquired respiratory tract infections (LRTIs), and skin and skin-structure infections (SSTI). Cefditoren might have a role in switching from parenteral to oral therapy in acute pyelonephritis and LRTIs. with a reduction of adverse effects and hospital costs. Eventually, due to its supposed binding to enterococcal penicillin binding proteins (PBPs) cefditoren, in combination with other beta-lactams, might have a role in partial oral enterococcal endocarditis treatment..

Fragmentation of interstellar methanol by collisions with He˙+: an experimental and computational study.

Methanol is a key species in astrochemistry as its presence and reactivity provides a primary route to the synthesis of more complex interstellar organic molecules (iCOMs) that may eventually be incorporated in newly formed planetary systems. In the interstellar medium, methanol is formed by hydrogenation of CO ices on grains, and its fate upon collisions with interstellar ions should be accounted for to correctly model iCOM abundances in objects at various stages of stellar evolution. The absolute cross sections (CSs) and branching ratios (BRs) for the collisions of He˙+ ions with CH3OH are measured, as a function of the collision energy, using a Guided Ion Beam Mass Spectrometer (GIB-MS). Insights into the dissociative electron (charge) exchange mechanism have been obtained by computing the entrance and exit multidimensional Potential Energy Surfaces (PESs) and by modelling the non-adiabatic transitions using an improved Landau-Zener-Stückelberg approach. Notably, the dynamical treatment reproducing the experimental findings includes a strong orientation effect of the system formed by the small He˙+ ion and the highly polar CH3OH molecule, in the electric field gradient associated to the strongly anisotropic intermolecular interaction. This is a stereodynamical effect that plays a fundamental role in collision events occurring under a variety of conditions, with kinetic energy confined within intervals ranging from the sub-thermal to the hyper-thermal regime.

The Selective Role of Long-Range Forces in the Stereodynamics of Ion-Molecule Reactions: The He+ +Methyl Formate Case From Guided-Ion-Beam Experiments.

Long-range intermolecular forces play a crucial role in controlling the outcome of ion-molecule chemical reactions, such as those determining the disappearance of organic or inorganic "complex" molecules recently detected in various regions of the interstellar medium due to collisions with abundant interstellar atomic ions (e.g. H+ and He+ ). Theoretical treatments, for example, based on simple capture models, are nowadays often adopted to evaluate the collision-energy dependence of reactive cross sections and the temperature dependent rate coefficients of many ion-molecule reactions. The obtained results are widely used for the modelling of phenomena occurring in different natural environments or technological applications such as astrophysical and laboratory plasmas. Herein it is demonstrated, through a combined experimental and theoretical investigation on a prototype ion-molecule reaction (He+ +methyl formate), that the dynamics, investigated in detail, shows some intriguing features that can lead to rate coefficients at odds with the expectations (e.g. Arrhenius versus anti-Arrhenius behaviour). Therefore, this study casts light on some new and general guidelines to be properly taken into account for a suitable evaluation of rate coefficients of ion-molecule reactions.

Prevalence of Catatonia and Its Moderators in Clinical Samples: Results from a Meta-analysis and Meta-regression Analysis.

Catatonia is an independent syndrome that co-occurs with several mental and medical conditions. We performed a systematic literature review in PubMed/Scopus until February 2017 and meta-analyzed studies reporting catatonia prevalence. Across 74 studies (cross-sectional = 32, longitudinal = 26, retrospective = 16) providing data collected from 1935 to 2017 across all continents, mean catatonia prevalence was 9.0% (k = 80, n = 110764; 95% CI = 6.9-11.7, I2 = 98%, publication bias P < .01), decreasing to 7.8% (k = 19, n = 7612, 95% CI = 7-8.7, I2 = 38.9%) in a subgroup with low heterogeneity. Catatonia prevalence was 23.9% (k = 8, n = 1168, 95% CI = 10-46.9, I2 = 96%) in patients undergoing ECT/having elevated creatinine phosphokinase. Excluding ECT samples, the catatonia prevalence was 8.1% (k = 72, n = 109606, 95% CI = 6.1-10.5, I2 = 98%, publication bias P < .01), with sensitivity analyses demonstrating that country of study origin (P < .001), treatment setting (P = .003), main underlying condition (P < .001), and sample size (P < .001)moderated catatonia prevalence, being highest in Uganda (48.5%, k = 1) and lowest in Mexico (1.9%, 95% CI = 0.4-8.8, I2 = 67%, k = 2), highest in nonpsychiatric out- or inpatient services (15.8%, 95% CI = 8.1-28.4, I2 = 97%, k = 15)and lowest in psychiatric outpatients services (3.2%, 95% CI = 1.7-6.1, I2 = 50%, k = 3), highest in presence of medical or neurological illness with no comorbid psychiatric condition (20.6%, 95% CI = 11.5-34.2, I2 = 95%, k = 10)and lowest in mixed psychiatric samples (5.7%, 95% CI = 4.2-7.7, I2 =98%, k = 43), highest in studies with sample sizes <100 (20.7%, 95% CI = 12.8-31.6, I2 = 90%, k = 17) and lowest in studies with sample sizes >1000 (2.3%, 95% CI = 1.3-3.9, I2 = 99%, k = 16). Meta-regression showed that smaller sample size (P < .01) and less major depressive disorder (P = .02) moderated higher catatonia prevalence. Year of data collection did not significantly moderate the results. Results from this first meta-analysis of catatonia frequencies across time and disorders suggest that catatonia is an epidemiologically and clinically relevant condition that occurs throughout several mental and medical conditions, whose prevalence has not decreased over time and does not seem to depend on different rating scales/criteria. However, results were highly heterogeneous, calling for a cautious interpretation.

Characterisation of volatile organic compounds (VOCs) released by the composting of different waste matrices.

The complaints arising from the problem of odorants released by composting plants may impede the construction of new composting facilities, preclude the proper activity of existing facilities or even lead to their closure, with negative implications for waste management and local economy. Improving the knowledge on VOC emissions from composting processes is of particular importance since different VOCs imply different odour impacts. To this purpose, three different organic matrices were studied in this work: dewatered sewage sludge (M1), digested organic fraction of municipal solid waste (M2) and untreated food waste (M3). The three matrices were aerobically biodegraded in a bench-scale bioreactor simulating composting conditions. A homemade device sampled the process air from each treatment at defined time intervals. The samples were analysed for VOC detection. The information on the concentrations of the detected VOCs was combined with the VOC-specific odour thresholds to estimate the relative weight of each biodegraded matrix in terms of odour impact. When the odour formation was at its maximum, the waste gas from the composting of M3 showed a total odour concentration about 60 and 15,000 times higher than those resulting from the composting of M1 and M2, respectively. Ethyl isovalerate showed the highest contribution to the total odour concentration (>99%). Terpenes (α-pinene, ß-pinene, p-cymene and limonene) were abundantly present in M2 and M3, while sulphides (dimethyl sulphide and dimethyl disulphide) were the dominant components of M1.

Experimental investigation of the reaction of helium ions with dimethyl ether: stereodynamics of the dissociative charge exchange process.

The fate of dimethyl ether (DME, CH3OCH3) in collisions with He+ ions is of high relevance for astrochemical models aimed at reproducing the abundances of complex organic molecules in the interstellar medium. Here we report an investigation on the reaction of He+ ions with DME carried out using a Guided Ion Beam Mass Spectrometer (GIB-MS), which allows the measurement of reactive cross-sections and branching ratios (BRs) as a function of the collision energy. We obtain insights into the dissociative charge (electron) exchange mechanism by investigating the nature of the non-adiabatic transitions between the relevant potential energy surfaces (PESs) in an improved Landau-Zener approach. We find that the large interaction anisotropy could induce a pronounced orientation of the polar DME molecule in the electric field generated by He+ so that at short distances the collision complex is confined within pendular states, a particular case of bending motion, which gives rise to intriguing stereodynamic effects. The positions of the intermolecular potential energy curve crossings indicate that He+ captures an electron from an inner valence orbital of DME, thus causing its dissociation. In addition to the crossing positions, the symmetry of the electron density distribution of the involved DME orbitals turns out to be a further major point affecting the probability of electron transfer. Thus, the anisotropy of the intermolecular interaction and the electron densities of the orbitals involved in the reaction are the key "ingredients" for describing the dynamics of this dissociative charge transfer.

Emergency department triage performance timing. A regional multicenter descriptive study in Italy.

OBJECTIVES: We explored the time employed by nurses to perform the ED triage process in the clinical setting. Moreover, we assessed the influences on triage timing performance exerted by variables related to nurses, local EDs' features, and by interruptions. METHODS: This is a multicenter prospective descriptive-explorative study performed in 11 EDs of the Tuscany region (Italy), using a 5 tier triage system. The sample was made up of 1/3 of nurses working in each ED. Sampling was performed by a stratified proportional randomization (length of service classes: <5 years; 5-10 years; >10 years). Triage nurses were observed during their triage work-shift. RESULTS: In 2014, 120 nurses were observed, during 1114 triage processes. The timings of triage phases were: waiting time to triage, median 2.55 min (IQR 1.28-5.03 min; range 0.1-56.25 min); triage duration, median 2.58 min (IQR 1.36-4.35 min; range 0.07-50 min). 400 interruptions were recorded (35.9%). In 9.9% there were 2 interruptions at least. There were significant differences in the medians of triage duration among the years of nurses' triage experience (P < 0.001). The presence of interruption was significantly associated with the increasing of the time intervals in all the triage phases (P < 0.0001). Finally, we recorded significant differences in all the triage time phases between the EDs. CONCLUSION: We found that the nurses triage time performances are similar to other triage systems in the world.

A current-carrying coil design with improved liquid cooling arrangement.

The design of an electromagnet requires the compliance with a number of constraints such as power supply characteristics, coil inductance and resistance, and, above all, heat dissipation, which poses the limit to the maximum achievable magnetic field. A common solution consists in using copper tubes in which a coolant flows. This approach, however, introduces further hydrodynamic concerns. To overcome these difficulties, we developed a new kind of electromagnet in which the pipe concept is replaced by a duct formed by the windings. Here we report on the realization and characterization of a compact model system in which the conductors carry a current that is one order of magnitude higher than the current allowable with conventional designs.

Efficient genotype elimination via adaptive allele consolidation.

We propose the technique of Adaptive Allele Consolidation, that greatly improves the performance of the Lange-Goradia algorithm for genotype elimination in pedigrees, while still producing equivalent output. Genotype elimination consists in removing from a pedigree those genotypes that are impossible according to the Mendelian law of inheritance. This is used to find errors in genetic data and is useful as a preprocessing step in other analyses (such as linkage analysis or haplotype imputation). The problem of genotype elimination is intrinsically combinatorial, and Allele Consolidation is an existing technique where several alleles are replaced by a single "lumped" allele in order to reduce the number of combinations of genotypes that have to be considered, possibly at the expense of precision. In existing Allele Consolidation techniques, alleles are lumped once and for all before performing genotype elimination. The idea of Adaptive Allele Consolidation is to dynamically change the set of alleles that are lumped together during the execution of the Lange-Goradia algorithm, so that both high performance and precision are achieved. We have implemented the technique in a tool called Celer and evaluated it on a large set of scenarios, with good results.

Detection, identification and quantification of a new de-fluorinated impurity in casopitant mesylate drug substance during late phase development: an analytical challenge involving a multidisciplinary approach.

During late phase development of the selective NK1 receptor antagonist casopitant mesylate, a de-fluorinated impurity was discovered and quantified by an orthogonal analytical approach, using NMR and LC-MS. A dedicated (19)F NMR method was initially developed for first line identification and semi-quantification of the impurity. Subsequently, a more accurate quantification was achieved by means of a selective normal-phase LC-MS method, which was fully validated. The results obtained on the development batches of the drug substance were used by the project team to set up a suitable control strategy and ultimately to ensure patient safety and the progression of the project.