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Introduction: Dalbavancin (DAL) is a long-acting lipoglycopeptide active against Gram-positive bacteria, including multidrug-resistant isolates. A growing body of evidence supports its efficacy in various difficult-to-treat infections. DAL shows time-dependent bactericidal activity in vitro at free drug concentrations equal to 4×MIC values. However, the optimal dosing scheme for achieving the PK/PD target in multidose treatment has not been fully established. Methods: Pharmacokinetic analysis was based on a nonlinear mixed effects modelling approach performed in NONMEM v7.5/Pirana, while R was used for data management and graphical summaries. Final model parameters were used to simulate the plasma disposition of DAL by Monte Carlo simulations to determine the multidose DAL regimen associated with a 90% target attainment of 100% f T > 4×MIC. Results: A two-compartmental model with first-order elimination and allometric-scaled bodyweight best described DAL disposition in patients with CLcr > 30 mL/min. Monte Carlo simulations showed that two 1500 mg DAL doses 7 days apart granted an optimal PTA > 90% of 100% f T > 4×MIC up to 5, 4, and 3 weeks in patients weighting from 40-80 kg, 80-120 kg and 120-200 kg, respectively. An additional third 1500 mg dose at the above time points by weight bands may extend the optimal PTA up to 9, 7, and 6 weeks of total treatment. Conclusions: Two 1500 mg DAL doses administered 7 days apart could be a valuable starting strategy for patients of all weight classes with CLcr > 30 mL/min. In patients requiring long-term DAL treatment, the optimal timing of additional administrations should be guided by routine TDM or empirically through patients' total body weight when TDM is unavailable.

Background: The combination of ivacaftor, tezacaftor and elexacaftor (ETI) is approved for patients with cystic fibrosis (CF) aged two years and older and at least one F508del mutation in the CFTR gene. Variability in ETI treatment response has been repeatedly reported, and its reasons are unclear and understudied. Objectives: We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the rapid and simultaneous quantification of ETI in plasma, dried plasma spots (DPS), and whole blood volumetric absorptive microsampling (VAMS). Methods: The method utilizes a rapid extraction protocol with 200 μL methanol after the addition of deuterated internal standards. Chromatographic separation was achieved using a reversed-phase Hypersil Gold aQ column (Thermo Fisher Scientific). The method was validated according to ICH (International Council on Harmonisation) guidelines M10 for bioanalytical method validation, demonstrating linearity in the concentration range 0.020-12.000 µg/mL. It was also proved accurate and reproducible with no matrix effect. This method was applied to anonymized samples from patients undergoing ETI treatment: eight plasma and DPS and five VAMS samples were analyzed. Results: ETI concentrations measured in plasma and DPS were interchangeable, whereas ETI concentrations in VAMS were lower than in plasma, as expected for molecules with high plasma protein binding (99%). A correction factor based on the hematocrit value was used to calculate the equivalent plasma concentration from VAMS concentrations. Conclusions: This method is suitable for pharmacokinetic (PK) studies and could facilitate the centralization of samples to specialized laboratories, supporting multicenter studies.

Background : Oncological surgery of the parotid gland or of the temporal bone may require the contemporary sacrifice of the facial nerve (FN). In such cases, the immediate repair of the sacrificed FN is recommended. The aim of this study is to evaluate the impact of facial rehabilitation (FR) and, secondarily, of post-operative radiotherapy (PORT) on the FN outcome after FN sacrifice and reconstruction via cable graft. Methods : This is a multicentric retrospective study including patients affected by malignant tumors whose surgical excision required FN sacrifice and contextual FN reconstruction with a cable graft. Other FN reconstruction techniques were excluded. FN function was assessed using both House-Brackmann and Sunnybrook grading systems. Results : A total of 28 patients were included. Most of the patients underwent a total parotidectomy. The greater auricular nerve was the main donor for cable graft. FR and PORT were performed in 22 and 15 patients, respectively. In particular, 20 patients underwent neuro-muscular retraining (NMR). Patients who underwent FR had better FN outcomes compared to those who did not ( p = 0.02 at 12 months and p = 0.0002 at 24 months). In contrast, there was no statistically significant difference between patients who underwent PORT and those who did not ( p > 0.05). Pre-operative FN palsy is a risk factor of worse FN function outcomes after cable graft. Conclusions : Our study, even though it was limited to only 28 cases, may demonstrate that cable graft failure is not due to PORT, as widely believed among clinicians, but to the absence of a rehabilitation program. Moreover, we suggest that the key to obtaining the best possible FN function results after FN sacrifice is the association of a technically correct FN reconstruction with a proper and targeted FR.

Objectives: We aim to investigate cognitive phenotype distribution and MRI correlates across pediatric-, elderly-, and adult-onset MS patients as a function of disease duration., Methods: In this cross-sectional study, we enrolled 1262 MS patients and 238 healthy controls, with neurological and cognitive assessments. A subset of 222 MS patients and 92 controls underwent 3T-MRI scan for brain atrophy and lesion analysis. Multinomial probabilistic models identified likelihood of belonging to cognitive phenotypes ("preserved-cognition," "mild verbal memory/semantic fluency," "mild multi-domain," "severe attention/executive," and "severe multi-domain") and experiencing MRI abnormalities based on disease duration and age at onset., Results: In all groups, the likelihood of "preserved-cognition" phenotype decreased, whereas "mild multi-domain" increased with longer disease duration. In pediatric- and adult-onset patients, the likelihood of "mild verbal memory/semantic fluency" phenotypes decreased with longer disease duration, and that of "severe multi-domain" increased with longer disease duration. Only in adult-onset patients, the likelihood of "severe executive/attention" phenotype increased with longer disease duration. All groups displayed escalating probabilities of cortical, thalamic, hippocampal, and deep gray matter atrophy over disease course. Compared to adult, pediatric-onset patients showed lower probability of experiencing thalamic atrophy with longer disease duration, while elderly-onset showed higher probability of experiencing cortical and hippocampal atrophy., Interpretation: Age at MS onset significantly influences the distribution of cognitive phenotypes and the patterns of regional gray matter atrophy throughout the disease course., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Supraglottic squamous cell carcinoma (SCC) is a significant portion of head and neck cancers, with the management of clinically negative necks (cN0) through selective neck dissection (SND) being debated due to potential morbidities and low metastasis rates in levels IIb and IV., Methods: This study is a retrospective, multicenter examination of the potential feasibility of limited neck dissection (LND), including only levels IIa and III in cN0 supraglottic SCC patients. It analyzed occult metastasis rates and explored relapse occurrences alongside potential predictors of lymph node metastasis., Results: Among 425 patients, predominantly male (85.6%) with a mean age of 63 years, the occult metastasis rate was 28.9%, and 13.7% experienced relapses during a mean follow-up of 52 months. Advanced clinical stage, higher grading, and other risk factors emerged as predictors of occult lymph node metastasis at level IIb., Conclusions: The study supports LND potential feasibility for cN0 supraglottic SCC, suggesting level IIb dissection can be omitted in specific early-stage cases to reduce morbidity without affecting outcomes., (© 2025 The Author(s). Head & Neck published by Wiley Periodicals LLC.)