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BACKGROUND AND OBJECTIVES: The understanding of the natural history of Friedreich ataxia (FRDA) has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this study was to acknowledge the broad genetic diversity of the population, especially for younger individuals, and to provide analyses stratified by age to guide population selection in future studies. METHODS: Based on a large natural history study, the FRDA Clinical Outcome Measures study that at the current data cut enrolled 1,115 participants, followed up for 5,287 yearly visits, we present results from the modified FRDA Rating Scale and its subscores. The secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk, and the 9-hole peg test. Long-term progression was modeled using slope analyses within early-onset, typical-onset, intermediate-onset, and late-onset FRDA. To reflect recruitment in clinical trials, short-term changes were analyzed within age-based subpopulations. All analyses were stratified by ambulation status. RESULTS: Long-term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages at onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability subscore of the mFARS. The analyses of short-term changes showed slower progression with increasing population age due to decreasing genetic severity. Future clinical studies could reduce population diversity, interpatient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification. DISCUSSION: The understanding of the diversity within FRDA populations and their patterns of functional decline provides an essential foundat

INTRODUCTION: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. METHODS: 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. DISCUSSION: Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease tr

There has been an increase in surgical interventions in frailer elderly with concomitant chronic diseases. The purpose of this paper was to evaluate the impact of aging and comorbidities on outcomes in patients who underwent surgery for the treatment of colorectal cancer (CRC) in Veneto Region (Northeastern Italy). This is a retrospective cohort study in patients ≥ 40 years who underwent elective or urgent CRC surgical resection between January 2013 and December 2015. Independent variables included: age, sex, and comorbidities. We analyzed variables associated with the surgical procedure, such as stoma creation, hospitalization during the year before the index surgery, the surgical approach used, the American Society of Anesthesiologists (ASA) score, and the Charlson Comorbidity Index score. Eight thousand four hundred and forty-seven patients with CRC underwent surgical resection. Patient age affected both pre- and post-resection LOS as well as the overall survival (OS); however, it did not affect the 30-day readmission and reoperation rates. Multivariate analysis showed that age represented a risk factor for longer preoperative and postoperative LOS as well as for 30-day and 365-day mortality, but it was not associated with an increased risk of 30-day reoperation and 30-day readmission. Chronic Heart Failure increased the 30-day mortality risk by four times, the preoperative LOS by 51%, and the postoperative LOS by 33%. Chronic renal failure was associated with a 74% higher 30-day readmission rate. Advanced age and comorbidities require a careful preoperative evaluation and appropriate perioperative management to improve surgical outcomes in older patients undergoing elective or urgent CRC resection.

OBJECTIVE: Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. METHODS: We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. RESULTS: One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. INTERPRETATION: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.

Il volume offre un quadro aggiornato degli sviluppi della politica sociale europea a quattro anni dalla solenne proclamazione a Goteborg del Pilastro europeo dei diritti sociali. Benché non giuridicamente vincolante, questo documento ha segnato l’avvio di una intensa fase propulsiva della politica sociale europea, poiché la Commissione l’ha utilizzato sia nell’ambito del Semestre europeo, sia per programmare le proprie iniziative legislative e di sostegno all’azione degli Stati membri. In particolare, dopo un’ampia riflessione introduttiva sul significato del pilastro europeo per il diritto sociale dell’UE, l’opera fa il punto su alcune delle novità più interessanti della politica sociale europea degli ultimi anni, dalla direttiva sulle condizioni trasparenti e prevedibili alla riforma della disciplina del distacco transnazionale, dalla direttiva sulla conciliazione vita-lavoro alle prospettive della partecipazione dei lavoratori, dai progetti sul quadro europeo in materia di salari minimi al regolamento sull’Autorità europea del lavoro. Conclude il volume un saggio sulla politica sociale della Russia contemporanea, partner fondamentale dell’Unione nello spazio euroasiatico. Gli autori del volume sono tutti affermati studiosi di Università italiane e di altri Paesi europei., The volume deals with the European Pillar of social rights, solemnly proclaimed in Goteborg in 2017, by analysing it and the directive the EU approved following its implementation.

Si tratta dell'introduzione al volume dedicato al Pilastro europeo dei diritti sociali: l'autore ritiene che il Pilastro, nonostante le forti perplessità iniziali di una parte della dottrina, abbia consentito un notevole avanzamento del diritto sociale dell'UE., The contribution represents the introduction of the editor to the volume. The author is convinced that the European Pillar, in spite of the initial doubts of the legal scholars, has helped EU social law progress.

Il saggio ricostruisce l'evoluzione del diritto dell'Unione europea in materia di partecipazione dei lavoratori, segnalando come in questo campo il Pilastro europeo dei diritti sociali non abbia per ora contribuito a significativi avanzamenti., The article deals with the evolution of EU Labour Law in the field of employee participation, by pointing out that here the European Pillar of social rights has not brought about significant improvement yet.

Il volume si propone di ricostruire in concreto il contenuto delle norme emanate dall'Organizzazione Internazionale del Lavoro e il loro impatto sull'ordinamento interno, così da offrire un bilancio del primo secolo di vita dell'Organizzazione., The book aims to concretely reconstruct the content of the ILO labour standards and their impact on the national legal system in order to offer a balance-sheet of the International Labour Organization's first century of life.