Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?

The mammalian target of rapamycin (mTOR) signalling pathway regulates fundamental metabolic processes such as inflammation, autophagy and apoptosis, all of which influence cell fate. Recent experimental data suggest that mTOR signalling is involved in many diseases, including lung diseases, but with contrasting data. Overexpression of mTOR and its signalling proteins have been linked to lung cell senescence and development of emphysema, pulmonary hypertension and inflammation. On the other hand, mTOR inhibitors, as rapamycin and/or its derivatives, restore corticosteroid sensitivity in peripheral blood mononuclear cells from chronic obstructive pulmonary disease (COPD) patients, and overexpression of mTOR suppresses cigarette smoke-induced inflammation and emphysema, suggesting that induction of mTOR expression/activity might be useful to treat COPD. This apparent discrepancy is due to complex and heterogenic enzymatic pathway of mTOR. Translation of pre-clinical positive data on the use of mTOR inhibitors to COPD therapy needs a more in-depth knowledge of mTOR signalling

Lifestyle interventions in prevention and comprehensive management of COPD

Chronic respiratory diseases are among the four major human chronic diseases. Tobacco smoke as well as environmental pollutants, infections, physical activity and nutritional status play a role in the prevalence, development and/or progression of chronic obstructive pulmonary disease (COPD). Changes in lifestyle are possible and may be beneficial in prevention and comprehensive management of COPD. Population-level interventions aimed at early diagnosis, promotion of vaccinations and prevention of infections, and reductions in smoking, environmental pollutants, physical inactivity, obesity and malnutrition may increase the number of life-years lived in good health. Educational aims To improve awareness of the influence of lifestyle on natural history of COPD. To describe the effects of some interventions to modify lifestyle in prevention and management. To provide information on the main clinical results. To define recommendations and limitations

Home-Based Adaptation to Night-Time Non-Invasive Ventilation in Patients with Amyotrophic Lateral Sclerosis: A Randomized Controlled Trial

Background: Initiation to Non-Invasive Ventilation (NIV) in amyotrophic lateral sclerosis (ALS) can be implemented in an inpatient or outpatient setting. Aims: We aimed to evaluate the efficacy of adaptation (the number of needed sessions) to home-based NIV compared to an outpatient one in ALS in terms of arterial carbon dioxide (PaCO2) improvement. NIV acceptance (mean use of ≥5 h NIV per night for three consecutive nights during the adaptation trial), adherence (night-time NIV usage for ≥150 h/month), quality of life (QoL), and caregiver burden were secondary outcomes. Methods: A total of 66 ALS patients with indications for NIV were involved in this randomized controlled trial (RCT): 34 underwent NIV initiation at home (home adaptation, HA) and 32 at multiple outpatient visits (outpatient adaptation, OA). Respiratory function tests were performed at baseline (the time of starting the NIV, T0) together with blood gas analysis, which was repeated at the end of adaptation (T1) and 2 (T2) and 6 (T3) months after T1. NIV adherence was measured at T2 and T3. Overnight cardiorespiratory polygraphy, Short Form Health Survey (SF-36), Caregiver Burden Inventory (CBI), Caregiver Burden Scale (CBS), and Zarit Burden Interview (ZBI) were performed at T0, T2, and T3. Results: Fifty-eight participants completed the study. No differences were found between groups in PaCO2 at T1 (p = 0.46), T2 (p = 0.50), and T3 (p = 0.34) in acceptance (p = 0.55) and adherence to NIV at T2 and T3 (p = 0.60 and p = 0.75, respectively). At T2, the patients’ QoL, assessed with SF-36, was significantly better in HA than in OA (p = 0.01), but this improvement was not maintained until T3 (p = 0.17). Conclusions: In ALS, adaptation to NIV in the patient’s home is as effective as that performed in an outpatient setting regarding PaCO2, acceptance, and adherence, which emphasizes the need for further studies to understand the role of the environment concerning NIV adherence

A Comprehensive Update on Late-Onset Pompe Disease

Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the GAA gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ in age of onset, organ involvement, and severity of disease. Assessment of acid alpha-glucosidase activity on a dried blood spot is the first-line screening test, which needs to be confirmed by genetic analysis in case of suspected deficiency. LOPD is a multi-system disease, thus requiring a multidisciplinary approach for efficacious management. Enzyme replacement therapy (ERT), which was introduced over 15 years ago, changes the natural progression of the disease. However, it has limitations, including a reduction in efficacy over time and heterogeneous therapeutic responses among patients. Novel therapeutic approaches, such as gene therapy, are currently under study. We provide a comprehensive review of diagnostic advances in LOPD and a critical discussion about the advantages and limitations of current and future treatments

Early initiation of nighttime NIV in an outpatient setting. A randomized non inferiority study in ALS patients

BACKGROUND: In patients with amyotrophic lateral sclerosis (ALS), non-invasive ventilation (NIV) is usually initiated in an in-hospital regime. AIM: We investigated if NIV initiated in an outpatient setting can be as effective as regards patients' acceptance/adherence. We also evaluated factors predicting NIV acceptance and adherence and disease progression. DESIGN: Prospective randomized study. SETTING: Outpatient vs inpatient rehabilitation. POPULATION: ALS patients. METHODS: ALS patients were randomized to two groups for NIV initiation: outpatient vs. inpatient. At baseline (T0), end of NIV trial program (T1) and after 3 months from T1 (T2), respiratory function tests, blood gas analysis, and sleep study were performed. At T1, we assessed: NIV acceptance (>4 h/night), and dyspnea symptoms (day/night) by Visual analogue scale (VAS), staff and patients' experience (how difficult NIV was to accept, how difficult ventilator was to manage, satisfaction); at T2: NIV adherence (>120 h/month) and patients' experience. RESULTS: Fifty patients participated. There were no differences in acceptance failure (p=0.733) or adherence failure (p=0.529). At T1, outpatients had longer hours of nocturnal ventilation (p<0.02), at T2 this was similar (p=0.34). Female gender and spinal onset of the disease were predictors for NIV acceptance/adherence failure. There were no between-group differences in progression of respiratory impairment, symptoms and sleep quality. CONCLUSIONS: Early outpatient initiation of NIV in ALS is as effective as inpatient initiation

Diagnostic flow chart for targered detection of Alpha-1-antitrypsin deficiency.

SummaryBackgroundAlpha1-antitrypsin (AAT) deficiency is under-recognized, probably because many individuals affected show no clinical impairment. The targeted detection is a tool to increase its recognition.MethodsWe prospectively submitted to AAT serum levels determination, phenotyping and, if doubtful, genotyping: (i) patients with the early onset of emphysema, emphysema in absence of recognized risk or pneumothorax (path P), antineutrophil cytoplasm antibodies (ANCA) positive vasculitis (path V), cervical artery dissection (path A), Periodic acid-Schiff (PAS) positive bodies in the liver cell or unexplained abnormal transaminase level (Path L) [index cases: IC] and (ii) subjects with low-serum alpha1-globulin (path e) and close relatives of patients with AAT deficiency (path r) [non index cases: NIC]. We determined and compared gender, age, AAT serum levels values, the ratio between AAT deficiency subjects identified and all subjects examined (identified/examined). Receiver operating characteristic (ROC) curve was plotted to find the best threshold for AAT serum levels.ResultsTwo hundred and eighty-five individuals were examined and 211 with AAT deficiency identified: 66 were IC and 145 NIC. The ratio identified/examined resulted 0.74. A serum level of 120mg/dL was able to identify AAT deficiency with a specificity of 73% and a sensitivity of 97%. IC showed male prevalence (P=0.005), more advanced age (P=0.02), lower AAT serum levels (P=0.008).ConclusionsOur protocol is effective to detect AAT deficiency in a selected population. About 120mg/dL (nephelometric method) is a reliable AAT serum level cut-off for selecting subjects/patients to submit to phenotype or genotype; as compared to NIC, IC are older, mostly male and with lower AAT serum levels

Formare i Public Historian (Dialoghi della Public History 5 ; 7 dicembre 2020)

La figura del Public Historian è in via di definizione, ma ormai sono chiare alcune competenze imprescindibili: elevata formazione come storico su uno spettro cronologico ampio, alta capacità comunicativa, grande consapevolezza delle problematiche inerenti l’uso e l’abuso della storia. Vi sono però altre competenze che di volta in volta, a seconda dei progetti che propone o in cui è coinvolto, risultano essenziali: uso consapevole di media diversi, strumenti digitali e relative problematiche metodologiche, capacità di lavorare in team e di gestire progetti complessi, conoscenza profonda del territorio in cui opera. Si tratta di un ventaglio ampio di conoscenze e competenze: quali enti possono fornirle, a che livello e con quali formule didattiche

Home-Based Adaptation to Night-Time Non-Invasive Ventilation in Patients with Amyotrophic Lateral Sclerosis: A Randomized Controlled Trial

Background: Initiation to Non-Invasive Ventilation (NIV) in amyotrophic lateral sclerosis (ALS) can be implemented in an inpatient or outpatient setting. Aims: We aimed to evaluate the efficacy of adaptation (the number of needed sessions) to home-based NIV compared to an outpatient one in ALS in terms of arterial carbon dioxide (PaCO2) improvement. NIV acceptance (mean use of ≥5 h NIV per night for three consecutive nights during the adaptation trial), adherence (night-time NIV usage for ≥150 h/month), quality of life (QoL), and caregiver burden were secondary outcomes. Methods: A total of 66 ALS patients with indications for NIV were involved in this randomized controlled trial (RCT): 34 underwent NIV initiation at home (home adaptation, HA) and 32 at multiple outpatient visits (outpatient adaptation, OA). Respiratory function tests were performed at baseline (the time of starting the NIV, T0) together with blood gas analysis, which was repeated at the end of adaptation (T1) and 2 (T2) and 6 (T3) months after T1. NIV adherence was measured at T2 and T3. Overnight cardiorespiratory polygraphy, Short Form Health Survey (SF-36), Caregiver Burden Inventory (CBI), Caregiver Burden Scale (CBS), and Zarit Burden Interview (ZBI) were performed at T0, T2, and T3. Results: Fifty-eight participants completed the study. No differences were found between groups in PaCO2 at T1 (p = 0.46), T2 (p = 0.50), and T3 (p = 0.34) in acceptance (p = 0.55) and adherence to NIV at T2 and T3 (p = 0.60 and p = 0.75, respectively). At T2, the patients’ QoL, assessed with SF-36, was significantly better in HA than in OA (p = 0.01), but this improvement was not maintained until T3 (p = 0.17). Conclusions: In ALS, adaptation to NIV in the patient’s home is as effective as that performed in an outpatient setting regarding PaCO2, acceptance, and adherence, which emphasizes the need for further studies to understand the role of the environment concerning NIV adherence

May an early integrated care program with NIV adaptation delay NIV failure in patients with ALS?

The most recent European Guidelines propose the start of non invasive ventilation (NIV) when the amyotrophic lateral sclerosis (ALS) patient\u2019s sitting Forced Vital Capacity (FVC% prd) is less than the value of 80%. The aim of our study was to assess whether an early integrated care program with adaptation to NIV (patient with FVC%> 80) can lengthen free interval of NIV failure (tracheostomy and/or death). This retrospective study was conducted in 3 italian facilities on a cohort of 213 subjects with ALS with at least 36 months of follow-up from the NIV start. The subjects were then divided into two groups according to the sitting FVC% value prd (Late group = LG with FVC <80% and Early group = EG with FVC> 80%) at the time of NIV prescription. For each group we analyzed clinical and respiratory functional data, time free from \u201cfailure of NIV " (tracheotomy need/death) starting from the first symptoms, the ALS diagnosis and the NIV prescription. 167 patients failed NIV after 36 months of follow-up (in LG 125 and 42 in the EG). After one year from the NIV prescription, the % of failure rate was 50% in LG and about 10% in the EG while after three years by NIV prescription % of failure in the LG was 86% compared to 62% in the EG. When compared with the LG, the EG showed a lower probability of NIV failure starting from a) the time of NIV prescription (p = 0.0000) b) first symptoms (p = 0.001) (figure 1) c) diagnosis (p = 0.0003). An early integrated care with NIV prescription seems to prolong free interval to the some NIV failure (tracheotomy and/or death). Only robust randomized controlled trials will confirm our working hypothesis