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Introduction: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. Methods: All adult patients with MS seen at any RER MS center (2015–2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. Results: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29–1.79). Similar results were found for different classes. No dose-response effect was found. Discussion/Conclusions: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.

Background The differential diagnosis between multiple system atrophy parkinsonism type (MSA-P) and Parkinson's disease with orthostatic hypotension (PD+OH) is difficult because the 2 diseases have a similar clinical picture. The aim of this study is to distinguish MSA-P from PD+OH by immunostaining for abnormal phosphorylated α-synuclein at serine 129 (p-syn) in cutaneous nerves. Method We recruited 50 patients with parkinsonism and chronic orthostatic hypotension: 25 patients fulfilled the diagnostic criteria for MSA-P and 25 patients for PD+OH. The patients underwent a skin biopsy from the cervical area, thigh, and leg to analyze somatic and autonomic skin innervation and p-syn in skin nerves. Results Intraneural p-syn positivity was found in 72% of patients with MSA-P, mainly in distal skin sites. More important, p-syn deposits in MSA-P differed from PD+OH because they were mainly found in somatic fibers of subepidermal plexi, whereas scant autonomic fiber involvement was found in only 3 patients. All patients with PD+OH displayed widely distributed p-syn deposits in the autonomic skin fibers of proximal and distal skin sites, whereas somatic fibers were affected only slightly in 4 patients with PD+OH. Skin innervation mirrored p-syn deposits because somatic innervation was mainly reduced in MSA-P. Sympathetic innervation was damaged in PD+OH but fairly preserved in MSA-P. Conclusions The p-syn in cutaneous nerves allows the differentiation of MSA-P from PD+OH; MSA-P mainly shows somatic fiber involvement with relatively preserved autonomic innervation; and by contrast, PD+OH displays prevalent abnormal p-syn deposits and denervation in autonomic postganglionic nerves. © 2020 International Parkinson and Movement Disorder Society.

Background Depression is considered one of the prodromal symptoms of Parkinson's disease (PD) along with sleep disorders, hyposmia and constipation. Prodromal symptoms refer to the stage wherein early motor symptoms and signs allowing a diagnosis of PD are not yet present. The objective of this study was to investigate the association between the use of antidepressants, as indirect measure of depression, and subsequent PD onset, clinically diagnosed, in the Local Health Trust of Bologna, Italy. Methods Historical cohort study with use of antidepressants as exposure and PD onset as outcome. The cohort considered consisted of inhabitants of Bologna aged ≥35 years in 2005; those who had used antidepressants in the previous 3 years were excluded. Subjects were followed up from 2006 and until PD onset, migration out of Bologna, death or end of the study period (2017), whichever came first. “The ParkLink Bologna” system was used to detect disease onset. “ParkLink Bologna” is a research study including patients with a clinical diagnosis of PD residing in Bologna. Residents that used antidepressants for at least 180 consecutive days within 1 year were considered exposed. Hazard ratios (HR) and 95% confidence interval (CI) were estimated with Cox proportional hazards models, using exposure as time-dependent variable and adjusting for potential confounders: age, gender, use of medical care and comorbidities. Results From 2006 to 2017 199,093 person-years were exposed and 4,286,470 not exposed. Fifty-one subjects with PD were identified in the exposed group and 556 subjects in the non-exposed showing an association of adjusted HR = 1.7 (CI 1.3–2.3). The association was stronger for males (HR 2.2, CI 1.5–3.2) compared to females (HR 1.2, CI 0.8–1.9), for subjects ≤65 years of age (HR 2.4, CI 1.6–3.6) vs. >65 years (HR 1.3, CI 0.8–1.9) and for those with less comorbidities. Age and gender were confounders in the associations between antidepressant use and PD onset. Conclusions The use of antidepressants as indirect measure of depression is associated with the subsequent development of PD. Our findings confirm that depression may precede the onset of motor symptoms in PD. The association is stronger for younger subjects, who are males and with fewer comorbidities.

BackgroundLafora disease (LD) is a rare fatal autosomal recessive form of progressive myoclonus epilepsy. It affects previously healthy children or adolescents, causing pharmacoresistant epilepsy, myoclonus and severe psychomotor deterioration. This work aims to describe the clinical course of LD and identify predictors of outcome by means of a prognostic systematic review with individual participant data meta-analysis.MethodsA search was conducted on MEDLINE and Embase with no restrictions on publication date. Only studies reporting genetically confirmed LD cases were included. Kaplan–Meier estimate was used to assess probability of death and loss of autonomy. Univariable and multivariable Cox regression models with mixed effects (clustered survival data) were performed to evaluate prognostic factors.ResultsSeventy-three papers describing 298 genetically confirmed LD cases were selected. Mean age at disease onset was 13.4 years (SD 3.7), with 9.1% aged ≥ 18 years. Overall survival rates in 272 cases were 93% [95% CI 89–96] at 5 years, 62% [95% CI 54–69] at 10 years and 57% [95% CI 49–65] at 15 years. Median survival time was 11 years. The probability of loss of autonomy in 110 cases was 45% [95% CI 36–55] at 5 years, 75% [95% CI 66–84] at 10 years, and 83% [95% CI 74–90] at 15 years. Median loss of autonomy time was 6 years. Asian origin and age at onset ConclusionsThis study documented that half of patients survived at least 11 years. The notion of actual survival rate and prognostic factors is crucial to design studies on the effectiveness of upcoming new disease-modifying therapies.

The study aims to characterize the epilepsy phenotype of maternally inherited Leigh's syndrome (MILS) and neuropathy, ataxia, retinitis pigmentosa (NARP) due to mutations in the mitochondrial ATP6 gene and to correlate electroclinical features with mutant heteroplasmy load (HL). We investigated 17 individuals with different phenotype, from asymptomatic carriers to MILS: 11 carried the m.8993T>G mutation, 5 the m.8993T>C and one the novel, de novo m.8858G>A mutation. Seizures occurred in 37.5% of patients, EEG abnormalities in 73%. We ranked clinical and EEG abnormalities severity and performed quantitative EEG to estimate Abnormality Ratio (AR) and Spectral Relative Power (SRP). Spearman’s rho and Kruskal–Wallis test were used for correlation with heteroplasmy load (HL). HL correlated with disease severity (Rho=0.63, P=0.012) and was significantly higher in patients with seizures or EEG abnormalities (P=0.014). HL correlated with EEG severity score only for the m.8993T>G (Rho=0.73, P=0.040), showing a trend toward a positive correlation with AR and delta SPR, irrespective of the mutation.

ObjectiveTo compare the diagnostic accuracy of ice pack test (IPT) and single-fiber EMG (SF-EMG) in patients with suspected ocular myasthenia (OM) presenting with ptosis.MethodsWe studied consecutive patients referred for the clinical suspicion of OM. Patients underwent IPT and stimulated SF-EMG on the orbicularis oculi muscle. Receiver operating characteristic curve analysis was performed to determine the accuracy of IPT, SF-EMG, and their combination.ResultsWe included 155 patients, 102 with OM and 53 with other diagnosis (OD). The IPT had a sensitivity of 86% (95% confidence interval [CI] 79–93) and a specificity of 79% (95% CI 68–90). SF-EMG showed a sensitivity of 94% (95% CI 89–98) and a specificity of 79% (95% CI 68–90). Overall, IPT and SF-EMG showed discordant results in 30 cases, 16 OM and 14 OD. The combination of IPT and SF-EMG, using the positivity of at least one test for OM diagnosis, increased the sensitivity to 98% (95% CI 95–100), reducing the specificity to 66% (95% CI 53–78), whereas using the positivity of both tests, we obtained a sensitivity of 82% (95% CI 75–90) and a specificity of 92% (95% CI 85–99). The negativity of both tests had a 94% (95% CI 87–100) negative predictive value. Comparison of the areas under the curve showed no differences in the diagnostic accuracy of IPT, SF-EMG, and their combinations.ConclusionsIPT and SF-EMG have similar diagnostic accuracy in patients with OM presenting with ptosis. The negativity of both tests strongly suggests another diagnosis.Classification of evidenceThis study provides Class I evidence that both the IPT and SF-EMG accurately identify patients with OM.

Background Dysautonomic symptoms (DS) are frequent but often underrecognized in multiple sclerosis (MS) patients, despite the relevant impact on quality of life and physical performance. Objectives To assess frequency and characteristics of DS in our MS population compared with healthy controls (HC). To investigate the relationship between DS and disease characteristics (MS subtype, disease duration, Expanded Disability Status Scale (EDSS), clinical and/or radiological activity, disability progression). Patients and methods Cross-sectional study includes 324 MS patients (mean age 44.9 ± 10.7 years; 66% female) and 190 HC (mean age 40.60 ± 12.83 years; 63% female). DS were assessed using the Italian validated version of the Composite Autonomic Symptom Score-31 (COMPASS-31). Possible confounding factors were considered. Results More than 94% of enrolled MS patients reported alterations in ≥ 2 domains of the COMPASS-31 scale (score > 0) and significantly higher COMPASS-31 total and single domain median scores compared with HC, independently from possible confounding factors (orthostatic intolerance: p = 0.001; vasomotor: p = 0.017; secretomotor: p = 0.040; gastrointestinal: p = 0.047; bladder: p p p p p = 0.01; Rho = 0.25, p = 0.030; Rho = 0.28, p p p p = 0.025), gastrointestinal (p = 0.07), and bladder (p Conclusions Our findings confirm that MS-related DS are frequent and tend to increase paralleling disease duration and clinical worsening, reaching the highest clinical impact in progressive subtypes.

We previously documented that idebenone treatment in OPA1‐Dominant Optic Atrophy (OPA1‐DOA) led to some degrees of visual improvement in seven patients. We here present the results of a cohort study, which investigated the effect of off‐label idebenone administration in a larger OPA1‐DOA group compared with untreated patients. Inclusion criteria were: OPA1‐DOA clinical and molecular diagnosis, baseline visual acuity (VA) greater than/equal to counting fingers and treatment duration greater than 7 months. We found a significant difference between the last visit and baseline VA in favor of stabilization/recovery in idebenone‐treated as compared to untreated patients. This effect was retained after controlling for confounders.

Background: Neurofilament light chain (NfL) is a validated biofluid marker of neuroaxonal damage with great potential for monitoring patients with neurodegenerative diseases. We aimed to further validate the clinical utility of plasma (p) vs. CSF (c) NfL for distinguishing patients with Amyotrophic Lateral Sclerosis (ALS) from ALS mimics. We also assessed the association of biomarker values with clinical variables and survival and established the longitudinal changes of pNfL during the disease course.Methods: We studied 231 prospectively enrolled patients with suspected ALS who underwent a standardized protocol including neurological examination, electromyography, brain MRI, and lumbar puncture. Patients who received an alternative clinical diagnosis were considered ALS mimics. We classified the patients based on the disease progression rate (DPR) into fast (DPR > 1), intermediate (DPR 0.5–1), and slow progressors (DPR < 0.5). All patients were screened for the most frequent ALS-associated genes. Plasma and CSF samples were retrospectively analyzed; NfL concentrations were measured with the SIMOA platform using a commercial kit.Results: ALS patients (n = 171) showed significantly higher pNfL (p < 0.0001) and cNfL (p < 0.0001) values compared to ALS mimics (n = 60). Both cNfL and pNfL demonstrated a good diagnostic value in discriminating the two groups, although cNfL performed slightly better (cNfL: AUC 0.924 ± 0.022, sensitivity 86.8%, specificity 92.4; pNfL: AUC 0.873 ± 0.036, sensitivity 84.7%, specificity 83.3%). Fast progressors showed higher cNfL and pNfL as compared to intermediate (p = 0.026 and p = 0.001) and slow progressors (both p < 0.001). Accordingly, ALS patients with higher baseline cNfL and pNfL levels had a shorter survival (highest tertile of cNfL vs. lowest tertile, HR 4.58, p = 0.005; highest tertile of pNfL vs. lowest tertile, HR 2.59, p = 0.015). Moreover, there were positive associations between cNfL and pNfL levels and the number of body regions displaying UMN signs (rho = 0.325, p < 0.0001; rho = 0.308, p = 0.001). Finally, longitudinal analyses in 57 patients showed stable levels of pNfL during the disease course.Conclusion: Both cNfL and pNfL have excellent diagnostic and prognostic performance for symptomatic patients with ALS. The stable longitudinal trajectory of pNfL supports its use as a marker of drug effect in clinical trials.

ObjectiveTo investigate whether the CSF α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay accurately identifies patients with mild cognitive impairment (MCI) due to probable Lewy body (LB) disease.MethodsWe applied α-syn RT-QuIC to 289 CSF samples obtained from 2 independent cohorts, including 81 patients with probable MCI-LB (age 70.7 ± 6.6 years, 13.6% female, Mini-Mental State Examination [MMSE] score 26.1 ± 2.4), 120 with probable MCI due to Alzheimer disease (AD) (age 68.6 ± 7.4 years, 45.8% female, MMSE score 25.5 ± 2.8), and 30 with unspecified MCI (age 65.4 ± 9.3 years, 30.0% female, MMSE score 27.0 ± 3.0). Fifty-eight individuals with no cognitive decline or evidence of neurodegenerative disease and 121 individuals lacking brain α-syn deposits at the neuropathologic examination were used as controls.ResultsRT-QuIC identified patients with MCI-LB against cognitively unimpaired controls with 95% sensitivity, 97% specificity, and 96% accuracy and showed 98% specificity in neuropathologic controls. The accuracy of the test for MCI-LB was consistent between the 2 cohorts (97.3% vs 93.7%). Thirteen percent of patients with MCI-AD also had a positive test; of note, 44% of them developed 1 core or supportive clinical feature of dementia with Lewy bodies (DLB) at follow-up, suggesting an underlying LB copathology.ConclusionsThese findings indicate that CSF α-syn RT-QuIC is a robust biomarker for prodromal DLB. Further studies are needed to fully explore the added value of the assay to the current research criteria for MCI-LB.Classification of EvidenceThis study provides Class III evidence that CSF α-syn RT-QuIC accurately identifies patients with MCI-LB.

BACKGROUND: In many clinical trials endovascular procedures are suggested as the treatment of choice for aneurysmal Subarachnoid Hemorrhage (aSAH) whenever possible. However, in clinical practice this management is often controversial. The aim of this study is to analyze factors involved in this decision. METHODS: Our study included 317 consecutive cases of aSAH between 2010 and 2016, assessing clinical and neuroradiological features to evaluate their role in this choice. RESULTS: In our series coiling was preferred in 119 (37.6%) patients, while 198 (62.4%) were treated surgically. On univariate analysis location of aneurysms (p < 0.001), GCS score on admission (p: 0.105), degree of midline shift (p:0.015), Fisher' score (p: 0.002) and presence of vessels in the aneurysmal neck (p: 0.071) proved the most relevant factors in the choice. Also multivariate analysis confirmed the location and Fisher' grade as influential factors. Conversely, other radiological parameters, such as morphology, aspect and dome-neck ratio, presence of pre-operative vasospasm or hydrocephalus were not associated with this decision. CONCLUSIONS: The decision process in aSAH requires a multidisciplinary team, to singularly evaluate each patient. We found that the location of aneurysms in Vertebro-Basilar circulation, PCoM and ICA, greater GCS score, absence of vessels in the aneurysmal neck, lower midline shift and Fisher' score are factors influencing in choosing coiling. Conversely, morphology, Aspect and Dome-Neck ratio proved not relevant to this decision, due to technological improvement and increasing skills in the endovascular treatment.

PROPAG-AGEING consortium., A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had, This project has received funding from the European Union’s Horizon 2020 research and innovation program Propag‐Ageing under grant agreement no. 634821.

Pediatric type 1 narcolepsy (NT1) is often associated with overweight and obesity. Sodium oxybate (SO), approved for the treatment of narcolepsy with cataplexy from the age of 7 years old in the United States, has been associated with weight loss, although longitudinal pediatric studies are lacking. We report a retrospective cohort of 129 consecutive patients with a 4-year follow-up, to analyze the impact of different pharmacological treatments on body mass index (BMI) z-score. At baseline, the prevalence of obesity and overweight was 26.4% (34/129) and 29.5% (38/129), respectively. Patients were divided into three groups: children treated with SO alone (group 1), with SO-combined therapy (group 2), and without SO (group 3). At the end of the first year of follow-up, group 1 and group 2 showed a significant BMI z-score reduction compared to baseline: from 1.2 ± 1.1 to 0.4 ± 1.4 for group 1 (p < 0.001), and from 1.4 ± 1.1 to 1 ± 1.3 for group 2 (p = 0.002), independently from baseline clinical features. In the second year, only group 2 experienced a further and significant BMI z-score decrease (from 1.0 ± 1.2 to 0.6 ± 1.2, p = 0.037). No further significant BMI z-score changes were observed in SO-treated patients in the following years. Instead, children treated without SO developed a significant weight increase between the second and third year of therapy (BMI z-score from 0.3 ± 0.9 to 0.5 ± 0.9). In conclusion, SO treatment in pediatric NT1 is associated with a favorable weight reduction in the first year of treatment.

Neurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs; p = 0.002 vs MSA; p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs; p = 0.751 vs MSA; p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.

IntroductionEpilepsy is a chronic condition requiring consistent follow-up aimed at seizure control, and monitoring of anti-seizure medication (ASM) levels and side effects. Telemedicine (TM) offers invaluable support to patient follow-up, guaranteeing the prompt availability of a team of experts for persons with epilepsy (PWE) widely distributed across the country. Although many health institutions have endorsed the use of TM, robust data on effectiveness, safety and costs of TM applied to epilepsy are lacking. TELEmedicine for EPIlepsy Care (TELE-EPIC) will evaluate the effectiveness of video consultation (VC) via TM compared with usual care (UC) for the monitoring of PWE (TELE-EPIC_RCT). Moreover, TELE-EPIC will apply an innovative Volumetric Absorptive Microsampling (VAMS) device for quantitation of ASM through finger prick blood sampling as an alternative to venipuncture sampling (TELE-EPIC_VAMS).Methods and analysisTELE-EPIC_RCT is a multicentre, open, pragmatic two-arm randomised controlled trial prospectively including adult and paediatric outpatients with established diagnosis of epilepsy consecutively attending the Epilepsy Centres of Bologna and Rome, respectively. The primary outcome is the non-inferiority of VC on seizure control compared with UC after an 18-month follow-up. Secondary outcomes are adherence to treatment, ASM-related adverse events, quality of life, mood disorders, patient and caregiver satisfaction, safety and costs. TELE-EPIC_VAMS is a cross-validation study for blood ASM quantitation through a novel, VAMS-based device, comparing (1) VAMS versus plasma samples (reference standard method); and (2) nurse-collected versus self-collected blood by VAMS device.Ethics and disseminationThe study has been approved by the local ethics committee (349-2019-SPER-AUSLBO). Complete information about the state of project, relevant events and results will be regularly updated on the project’s webpage on ClinicalTrials.gov. The project’s results and data on the potential impact of TM in epilepsy will be disseminated on social media. A closeout meeting will be convened for the communication and dissemination of the project, highlighting its main achievements and impacts.Trial registration numberNCT04496310

Introduction : Data on seizure course during pregnancy in women with epilepsy are limited. In particular, little is known about the causes underlying possible seizure worsening in this population. We therefore set out to explore worsening, in pregnancy, of sleep-related hypermotor epilepsy (SHE), a syndrome in which seizures are known to be triggered by sleep fragmentation, a condition common in pregnancy. Methods : From a cohort of consecutive patients with epilepsy who had one or more deliveries between January 2008 and March 2018, we retrospectively compared the rates of seizure worsening during pregnancy in SHE versus other epilepsies (NSHE). Worsening was defined as an increase in seizure frequency compared with the rate for the year prior to conception, including seizure recurrence after a year of seizure freedom, and/or new occurrence of tonic-clonic seizures. Results : We considered data on 11 pregnancies in women with SHE and 104 pregnancies in women with NSHE. Seizures worsened in six SHE pregnancies (54.5%) versus 18 NSHE ones (17.3%) (OR adjusted for preconception seizure frequency and polytherapy = 5.7, 95% CI = 1.6–20.8, p = 0.019). Conclusions : Women with SHE have a higher risk of seizure worsening in pregnancy. This finding should be considered from the perspective of patient counseling.

Epilepsy with Auditory Features (EAF) is a focal epilepsy syndrome mainly of unknown aetiology. LGI1 and RELN have been identified as the main cause of Autosomal Dominant EAF and anecdotally reported in non-familial cases. Pathogenic variants in SCN1A and DEPDC5 have also been described in a few EAF probands belonging to families with heterogeneous phenotypes and incomplete penetrance. We aimed to estimate the contribution of these genes to the disorder by evaluating the largest cohort of EAF. We included 112 unrelated EAF cases (male/female: 52/60) who underwent genetic analysis by next-generation sequencing (NGS) techniques. Thirty-three (29.5%) were familial cases. We identified a genetic diagnosis for 8% of our cohort, including pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI: 0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and DEPDC5 (0.9%; CI 0-4.9).This study shows that the contribution of each of the known genes to the overall disorder is limited and that the genetic background of EAF is still largely unknown. Our data emphasize the genetic heterogeneity of EAF and will inform the diagnosis and management of individuals with this disorder.

Background Depression is more frequently associated with akinetic-rigid/postural instability gait difficulty subtypes of Parkinson's disease than with tremor-dominant subtype. Objectives The aim of the study is to investigate the frequency of exposure to antidepressant drugs, as proxy of depression, before motor onset according to Parkinson's disease subtypes. Method Based on a historical cohort design, the exposure to antidepressant drugs before Parkinson's disease motor onset was obtained from the drug prescription database and assessed in the resident population of the Local Healthcare Trust of Bologna (443,117 subjects older than 35 years). Diagnosis of Parkinson's disease and subtype (tremor dominant, non-tremor dominant) at onset were recorded by neurologists and obtained from the “ParkLink Bologna” record linkage system. Exposure to antidepressants was compared both to the general population and between the two subtypes. Results From 2006 to 2018, 198 patients had a tremor dominant subtype at onset whereas 450 did not. Comparison with the general population for antidepressant exposure showed an adjusted hazard ratio of 0.86 (95% CI 0.44–1.70) for the tremor dominant subtype and 1.66 (1.16–2.39) for the non-tremor dominant subtype. Comparison of non-tremor dominant with tremor dominant subtypes showed an adjusted odds ratio of 1.86 (1.05–3.95) for antidepressant exposure. Conclusions In our study, non-tremor dominant Parkinson's disease at onset was significantly associated with exposure to antidepressants in comparison to the general population and in comparison with the tremor dominant subtype. These results support the hypothesis of different biological substrates for different Parkinson's disease subtypes even before motor onset.

Objective: We describe a multicenter experience with VNS implantation in pediatric patients with epileptic encephalopathy. Our goal was to assess VNS efficacy and identify potential predictors of favorable outcome. Methods: This was a retrospective study. Inclusion criteria were: ≤18 years at the time of VNS implantation and at least one year of follow-up. All patients were non-candidates for excisional procedures. Favorable clinical outcome and effective VNS therapy were defined as seizure reduction >50%. Outcome data were reviewed at one, two, three and five years after VNS implantation. Fisher's exact test, Kaplan-Meier and multiple logistic regression analysis were employed. Results: Twenty-seven patients met inclusion criteria. Responder rate (seizure frequency reduction ≥ 50%) at one-year follow-up was 25.9%, and 15.3% at last follow-up visit. The only variable significantly predicting favorable outcome was time to VNS implantation, with the best outcome achieved when VNS implantation was performed within five years of seizure onset (overall response rate of 83.3% at one year of follow-up and 100% at five years). In total, 63% of patients evidenced improved QOL at last follow-up visit. Only one patient exited the study due to an adverse event at two years from implantation. Significance: Early VNS implantation within five years of seizure onset was the only predictor of favorable clinical outcome in pediatric patients with epileptic encephalopathy. Improved QOL and a very low incidence of adverse events were observed.

Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mild-moderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.

ObjectiveTo compare the diagnostic accuracy and the prognostic value of blood and cerebrospinal fluid (CSF) tests across prion disease subtypes.MethodsWe used a single-molecule immunoassay to measure tau and neurofilament light chain (NfL) protein levels in the plasma and assessed CSF total(t)-tau, NfL and protein 14-3-3 levels in patients with prion disease (n=336), non-prion rapidly progressive dementias (n=106) and non-neurodegenerative controls (n=37). We then evaluated each plasma and CSF marker for diagnosis and their association with survival, taking into account the disease subtype, which is a strong independent prognostic factor in prion disease.ResultsPlasma tau and NfL concentrations were higher in patients with prion disease than in non-neurodegenerative controls and non-prion rapidly progressive dementias. Plasma tau showed higher diagnostic value than plasma NfL, but a lower accuracy than the CSF proteins t-tau and 14-3-3. In the whole prion cohort, both plasma (tau and NfL) and CSF (t-tau, 14-3-3 and NfL) markers were significantly associated with survival and showed similar prognostic values. However, the intrasubtype analysis revealed that only CSF t-tau in sporadic Creutzfeldt-Jakob disease (sCJD) MM(V)1, plasma tau and CSF t-tau in sCJD VV2, and plasma NfL in slowly progressive prion diseases were significantly associated with survival after accounting for covariates.ConclusionsPlasma markers have lower diagnostic accuracy than CSF biomarkers. Plasma tau and NfL and CSF t-tau are significantly associated with survival in prion disease in a subtype-specific manner and can be used to improve clinical trial stratification and clinical care.

Objective: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy characterized by seizures occurring mostly during sleep, ranging from brief seizures with paroxysmal arousals (SPAs) to hyperkinetic seizures and ambulatory behaviors. SPAs are brief and stereotypic seizures representing the beginning of a major seizure. Distinguishing SPAs from disorders of arousal (DOAs) and their briefest episodes called simple arousal movements (SAMs) is difficult. We performed a characterization of SPAs and SAMs to identify video-polysomnographic (VPSG) features that can contribute to the diagnosis of SHE or DOA. Methods: Fifteen SHE, 30 DOA adult patients, and 15 healthy subjects underwent full-night VPSG. Two neurologist experts in sleep disorders and epilepsy classified all the sleep-related movements and episodes recorded. For each SPAs and SAMs, sleep stage at onset, duration, limb involvement, progression, and semiology have been identified. Results: A total of 121 SPAs were recorded, emerging mostly during stage 1-2 non–rapid eye movement (NREM) sleep (median duration: 5seconds). At the beginning, the SPAs motor pattern was hyperkinetic in 78 cases (64%), involving more than three non-contiguous or all body parts. The standard was a constant progression of movements during SPAs without any motor arrests. In DOA patients a total of 140 SAMs were recorded (median duration: 12seconds) mostly emerging during stage 3 NREM sleep. In SAMs, we did not observe any tonic/dystonic or hypermotor patterns or stereotypy; motor arrest was present over the course of about half of the episodes. In comparison with both DOA and healthy subjects, SHE patients showed a higher number of sleep-related movements per night and a reduction of sleep efficiency. Significance: SPAs and SAMs present different semiological and clinical features. Their recognition could be useful to drive the diagnosis when major episodes are not recorded during VPSG in patients with a clear clinical history of SHE or DOA.

Background In neurodegenerative dementias (NDs) such as prion disease, Alzheimer’s disease (AD), and frontotemporal lobar degeneration (FTLD), protein misfolding leads to the tissue deposition of protein aggregates which, in turn, trigger neuroinflammation and neurodegeneration. Cerebrospinal fluid (CSF) biomarkers have the potential to reflect different aspects of these phenomena across distinct clinicopathological subtypes and disease stages. Methods We investigated CSF glial markers, namely chitotriosidase 1 (CHIT1), chitinase-3-like protein 1 (YKL-40) and glial fibrillary acidic protein (GFAP) in prion disease subtypes (n = 101), AD (n = 40), clinicopathological subgroups of FTLD (n = 72), and controls (n = 40) using validated, commercially available ELISA assays. We explored glial biomarker levels’ associations with disease variables and neurodegenerative CSF biomarkers and evaluated their diagnostic accuracy. The genotype of the CHIT1 rs3831317 polymorphic site was also analyzed. Results Each ND group showed increased levels of CHIT1, YKL-40, and GFAP compared to controls with a difference between prion disease and AD or FTLD limited to YKL-40, which showed higher values in the former group. CHIT1 levels were reduced in both heterozygotes and homozygotes for the CHIT1 24-bp duplication (rs3831317) in FTLD and controls, but this effect was less significant in AD and prion disease. After stratification according to molecular subgroups, we demonstrated (i) an upregulation of all glial markers in Creutzfeldt-Jakob disease VV2 compared to other disease subtypes, (ii) a difference in CHIT1 levels between FTLD with TAU and TDP43 pathology, and (iii) a marked increase of YKL-40 in FTLD with amyotrophic lateral sclerosis (ALS) in comparison with FTLD without ALS. In prion disease, glial markers correlated with disease stage and were already elevated in one pre-symptomatic case of Gerstmann-Sträussler-Scheinker disease. Regarding the diagnostic value, YKL-40 was the only glial marker that showed a moderate accuracy in the distinction between controls and NDs. Conclusions NDs share a CSF profile characterized by increased levels of CSF CHIT1, YKL-40, and GFAP, which likely reflects a common neuroinflammatory response to protein misfolding and aggregation. CSF glial markers of neuroinflammation demonstrate limited diagnostic value but have some potential for monitoring the clinical and, possibly, preclinical phases of NDs.

Background and purpose Receiving clear, complete and up-to-date information and having a satisfying relationship with the health professional (HP) are of primary importance for MS patients. Healthcare organization plays a key role in promoting an effective relationship and communication between patients and HPs. The present study aims to explore which care organization and service characteristics provided by Italian MS centres best predict patients’ satisfaction with healthcare. Methods Eighty-one centres and 707 patients (502 women, mean age 40.5 years, SD 10.2; mean education 12.2 years, SD 3.6; time since diagnosis 5.9 years, SD 1.5) were included in the analysis. The care organization and service provided by each centre were evaluated in comparison with the National Institute for Health and Care Excellence (NICE) guidelines on management of MS. Patients’ satisfaction with care was measured using the patient self-assessed questionnaire ‘Comunicazione medico-paziente nella Sclerosi Multipla, revised’ section 2 (COSM-R section 2). Results The clinical characteristics of patients significantly affected their satisfaction. A multivariate regression model showed that higher patients’ satisfaction (COSM-R score) was inversely associated with hospital size (number of patients under care) (β = −0.21, 95% confidence interval −0.35; −0.07) and directly associated with psychological interventions (β = 2.44, 95% confidence interval 0.29; 4.59). Conclusions Multiple sclerosis patients from larger hospitals are less satisfied with the information received and the relationship with HPs. Building an individualized relationship between patients and HPs and tailoring the communication of information improve patients’ satisfaction. Such a goal is probably less likely to be accomplished in larger centres with many incoming patients. Moreover, when the centres also provide structured psychological interventions, the patients are more satisfied.

Introduction: After the European Medicines Agency (EMA) warning on the use of valproate (VPA) in female patients, we explored the antiepileptic drug (AED) prescribing attitudes of Italian epileptologists with regard to sex and VPA use in patients with epilepsy. Material and methods: A specifically designed 30-item questionnaire was distributed at the annual multicenter meeting of the Italian League Against Epilepsy (LICE), held in Rome on January 2018. One hundred and sixty-nine physicians answered the questionnaire. Results: In females, VPA was significantly less prescribed as first-choice AED in childhood absence epilepsy (22% females vs 64% males, p < 0.001), Dravet syndrome (54% vs 71%, p = 0.01), juvenile myoclonic epilepsy (JME) (2% vs 74%, p < 0.001), and undetermined epilepsy (0% vs 32%, p < 0.001). Ninety-six percent of the respondents inform teenage girls of the detrimental effects of intrauterine exposure to VPA; 74% recommend contraceptive measures when prescribing VPA. All the respondents stated that they were aware of the recommendations on VPA in female patients, and 64% claimed to have had difficulties in implementing them. Conclusions: The main challenges were represented by women with JME, who were seizure-free on VPA and failed to respond to levetiracetam and lamotrigine, and by little girls for whom VPA was considered the best choice. According to many Italian epileptologists, the decision to withdraw VPA should be shared with the patient.

Disorders of arousal include confusional arousals, sleepwalking and sleep terrors. The diagnosis of disorders of arousal is based on the clinical criteria established in the International Classification of Sleep Disorders, third edition, although the interobserver reliability of these criteria has never been investigated. The aim of this study was to estimate the inter-rater reliability of the diagnostic criteria for disorders of arousal throughout the whole life in order to understand their feasibility in clinical daily activity and in multicenter observational studies. Three raters interviewed 126 subjects (patients complaining of sleep disorders, headache, and healthy subjects), aged 18–80 years, with a standardized questionnaire created by applying the International Diagnostic Criteria for Disorders of Arousal. An “almost perfect” inter-rater reliability for disorders of arousal criteria and the final diagnosis was found among the raters (kappa 0.89 for confusional arousals, 0.87 for sleepwalking, and 0.87 for sleep terrors). The International Classification of Sleep Disorders, Third Edition criteria are adequate for a reliable diagnosis of disorders of arousal. Further validation studies, confirming DOA diagnosis with video polysomnography, are needed to investigate the predictive value of ICSD-3 criteria.

Background: Anger is involved in the emotional experience of pain. Individuals with migraine are more likely to hold their anger-in than controls. However, only one study evaluated anger in cluster headache (CH). The objective is to compare anger between migraine and CH patients. Methods: One hundred thirty-five migraine and 108 CH patients completed the State Trait Anger Expression Inventory (STAXI-2), composed of 7 subscales. State Anger measures the intensity of the individual’s angry feelings at the time of testing. Trait Anger evaluates general predisposition to become angry. Anger Expression Out and Anger Expression In measure the extent to which anger could be overtly expressed or suppressed. Anger Control Out and Anger Control In evaluate how individual try to control the outward or inward expression of anger. Anger Expression Index is a general index. Results: CH patients have higher median scores than migraine patients in State Anger (46 vs 44, p = 0.012). CH patients have lower scores in Anger Control Out (44 vs 50, p = 0.016). In subgroup analysis, CH patients during the cluster period have higher scores than chronic migraine patients in State Anger (47 vs 44, p = 0.035), while CH patients in headache-free period did not differ from migraine patients. Conclusions: Migraine and CH patients differ in state anger, indicating that CH patients experienced higher intensity of anger during the time of testing. These data add new information about emotional regulation in headache patients and could support the hypothesis of different emotional and behavioral responses to pain in migraine and CH patients.

Objective: Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF Aβ42 values invivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF Aβ42/Aβ40 ratio. We compared CSF Aβ42 and Aβ42/Aβ40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death. Methods: We measured CSF Aβ40 and Aβ42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt-Jakob disease (n=159), AD (n=12), dementia with Lewy bodies (DLB, n=4), AD/DLB mixed pathologies (n=5), and various other pathologies (n=31). Results: The score reflecting the severity of Aβ pathology showed a better correlation with ln(Aβ42/Aβ40) (R 2 =0.506, β=−0.713, P&nbsp

Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic seizures arising from sleep. Awake seizures occasionally occur and are associated with a worse prognosis, with important implications for driving and quality of life. We evaluated the clinical features and sleep/wakefulness distribution of seizures at onset and lifelong in a large cohort of clinical/confirmed SHE. Chi-square test and a multivariate logistic regression model were used to identify predictors of awake seizures lifelong (primary endpoint). Positive and negative likelihood ratio (LR+, LR-) were calculated. We included 165 patients (male/female: 105/60) with a 27.6-year median follow-up. Most (67.9%) presented with seizures exclusively from sleep; 32.1% presented with seizures both while asleep and while awake, or exclusively during wakefulness. Presentation with seizures in wakefulness shows a sensitivity of 62.5% and a specificity of 96.5% to predict the occurrence of awake seizures lifelong, with an LR+of 18 (95% confidence interval [CI] = 5.75-55) and LR- of 0.39 (95% CI = 0.29-0.52). On multivariate analysis, distribution of sleep/awake seizures at onset was confirmed as an independent risk factor of awake seizures lifelong (odds ratio = 56.7). Patients presenting with awake seizures have a 94% probability of awake seizures lifelong, whereas in those presenting with asleep seizures only, the percentage lowers to 27%. This aspect should be mentioned during physician-to-patient communication about prognosis.

The angiogenic pathway plays a pivotal role in tumor growth, invasiveness and metastasis. The most important actors in the angiogenic pathway are VEGFA and its receptors VEGFR1, 2 and 3. These genes are polymorphic, and the presence of single nucleotide polymorphisms may result in angiogenic deregulation. Herein, we hypothesized that germline variants may affect sunitinib efficacy (TTP and OS) and/or toxicity. Therefore, we investigated 19 polymorphisms, in four genes, in 54 GIST patients, treated with second-line sunitinib and 147 healthy controls. Through a multiple candidate gene approach, we also investigated, for the first time, any possible significant associations with GIST susceptibility and clinical pathological features. The most important result shows two associations between polymorphisms in VEGFR3 rs6877011 (CC vs. CG, OR 9.7, 95% CI 3.31-28.4; P < 0.001) and rs7709359 (AA+AG vs. GG, OR 5.01, 95% CI 1.33-18.8; P = 0.017) and TTP. Interestingly, the association between VEGFR3 rs6877011 and TTP maintained the significance after applying the Bonferroni correction for multiple testing (P = 0.017). We also highlighted the association with sunitinib-related toxicity; in particular, VEGFA polymorphism rs3025039 (CT+TT vs. CC, OR 15.3, 95% CI 2.2-102.1; P = 0.005) is associated with severe toxicity, with the presence of the variant T allele associated with a grade a 3 AE. Because of the small sample size and large number of tests performed, we cannot ignore the possibility that some associations have been retrieved by chance. However, the influence of VEGF polymorphisms in angiogenesis is a hypothesis worthy of exploration in cellular models and confirmation in a sizeable cohort of patients.

Objective: Pituitary macroadenomas (PAs) are usually defined as benign intracranial tumors. However, they may present local aggressive course. High Ki67 labelling index (LI) values have been related to an aggressive tumor behavior. A recent clinicopathological classification of PA based on local invasiveness and proliferation indexes, divided them in groups with different prognosis. We evaluated the utility of conventional MRI (cMRI) and diffusion-weighted imaging (DWI), in predicting the Ki67- LI according the clinicopathological classification. Methods: 17 patients (12 M and 5 F) who underwent surgical removal of a PA were studied. cMRI features, quantification of T1W and T2W signal intensity, degree of contrast uptake (enhancement ratio, ER) and apparent diffusion coefficient (ADC) values were evaluated by using a 3 T scan. Statistics included Mann–Whitney test, Spearman’s test, and receiver operating characteristic analysis. A value of p ≤ 0.05 was considered significant for all the tests. Results: Negative correlations were observed between Ki-67 LI, ADCm (ρ = - 0.67, p value = 0.005) and ER values (ρ = −0.62; p = 0.008). ER values were significantly lower in the proliferative PA group (p = 0.028; p = 0.017). ADCm showed sensitivity and specificity of 90 and 85% respectively into predict Ki67-LI value. A value of ADCm ≤0, 711 x 10–6 mm2 emerged as a cut-off of a value of Ki67-LI ≥ 3%. Conclusion: Adding quantitative measures of ADC values to cMRI could be used routinely as a non-invasive marker of specific predictive biomarker of the proliferative activity of PA. Advances in knowledge: Routinely use of DWI on diagnostic work-up of pituitary adenomas may help in establish the likely biological aggressive lesions.

The early detection of colorectal cancer (CRC) can significantly improve the prognosis of affected patients. The loss of genomic stability and the resulting gene alteration play an important role in the molecular pathological steps that occur early in tumorigenesis of CRC. Thus, the identification of non-invasive biomarkers, whose function may provide useful insights into critical early events in the CRC process, is of great interest. In this regard, micronucleus (MN) frequency in peripheral blood lymphocytes (PBL) has become one of the most established biomarkers for studying DNA damage in the human population. This study investigated the MN frequency in the PBL of 82 subjects (30 females and 52 males; aged 50-70 years) who were participating in a screening programme for CRC prevention. All 82 patients were positive in fecal occult blood tests and they were subsequently classified, according to colonoscopy and histological findings, as patients with CRC, patients with colon polyps or subjects without intestinal lesion, referred to as study controls. This study also examined the relationship between the plasma clastogenic activity and the frequency of micronuclei of the study population. The MN frequency was significantly higher in CRC patients than in both colon polyp patients (16.82 ± 6.56 versus 12.23 ± 1.88; P = 0.002) and controls (16.82 ± 6.56 versus 8.00 ± 1.77; P < 0.001). An increased MN frequency was detected in the lymphocytes of the polyp group in comparison to the control group, although this was lower than that observed in CRC patients (12.23 ± 1.88 versus 8.00 ± 1.77; P < 0.001). In the overall study population, the increase of MN frequency, which was observed in the lymphocytes of the subjects involved, was significantly associated with the clastogenic activity detected in their plasma (r = 0.594, P < 0.001). Overall, the results suggest that the MN test can become a promising biomarker for the early detection of CRC.

BACKGROUND: The outcomes of patients admitted to a respiratory ICU (RICU) have been evaluated in the past, but no study has considered the influence of location prior to RICU admission. METHODS: We analyzed prospectively collected data from 326 consecutive patients admitted to a 7-bed RICU. The primary end points were survival and severity of morbidity-related complications, evaluated according to the patient's location prior to RICU admission. Three admission pathways were considered: step-down for patients transferred from the ICUs of our hospital; step-up for patients coming from our respiratory wards or other medical wards; and directly for patients coming from the emergency department. The secondary end point was the potential influence of several risk factors for morbidity and mortality. RESULTS: Of the 326 subjects, 92 (28%) died. Overall, subjects admitted in a step-up process had a significantly higher mortality ( P < .001) than subjects in the other groups. The mortality rate was 64% for subjects admitted from respiratory ward, 43% for those from medical wards, and 18% for subjects from both ICU and emergency department (respiratory ward vs medical ward P = .04, respiratory ward vs emergency department P < .001, respiratory ward vs ICU P < .001, medical ward vs emergency department P < .001, and medical ward vs ICU P < .001). Subjects admitted from a respiratory ward had a lower albumin level, and Simplified Acute Physiology Score II was significantly higher in subjects following a step-up admission. About 30% of the subjects admitted from a respiratory ward received noninvasive ventilation as a “ceiling treatment.” The highest odds ratios related to survival were subject location prior to RICU admission and female sex. Lack of use of noninvasive ventilation, younger age, female sex, higher albumin level, lower Simplified Acute Physiology Score II, higher Barthel score, and absence of chronic heart failure were also statistically associated with a lower risk of death. CONCLUSIONS: The pathway of admission to a RICU is a determinant of outcome. Patients following a step-up pattern are more likely to die. Other major determinants of survival are age, nutritional status and female sex.

Background Socio-economic, cultural and environmental factors are becoming increasingly important determinants of chronic obstructive pulmonary disease (COPD). We conducted a study to investigate socio-demographic, lifestyle and clinical factors, and to assess their role as predictors of acute events (mortality or hospitalization for respiratory causes) in a group of COPD patients. Methods Subjects were recruited among outpatients who were undertaking respiratory function tests at the Pneumology Unit of the Sant’Orsola-Malpighi Hospital, Bologna. Patients were classified according to the GOLD Guidelines. Results 229 patients with COPD were included in the study, 44 with Mild, 68 Moderate, 52 Severe and 65 Very Severe COPD (GOLD stage). Significant differences among COPD stage, in terms of smoking status and fragility index, were detected. COPD stage significantly affected the values of all clinical tests (spirometry and ABG analysis). Kaplan-Meier estimates showed a significant difference between survival curves by COPD stage with lower event-free probability in very severe COPD stage. Significant risk factors for acute events were: underweight (HR = 4.08; 95% CI 1.01–16.54), having two or more comorbidities (HR = 4.71; 95% CI 2.52–8.83), belonging to moderate (HR = 3.50; 95% CI 1.01–12.18) or very severe COPD stage (HR = 8.23; 95% CI 2.35–28.85). Conclusions Our findings indicate that fragility is associated with COPD stage and that comorbidities and the low body mass index are predictors of mortality or hospitalization. Besides spirometric analyses, FeNO measure and comorbidities, body mass index could also be considered in the management and monitoring of COPD patients.

The two basic mainstays of gastrointestinal stromal tumours (GIST) treatment are surgery and imatinib, a selective tyrosine kinase inhibitor that allows achieving a stable or responding disease in about 80% of patients with unresectable/metastatic GIST. Response to imatinib mainly depends from KIT and PDGFRα mutational status. Nevertheless, some patients with a potentially responsive genotype do not respond, and others develop a pattern of resistance to imatinib which is not associated with secondary mutations. This emphasizes the presence of mechanisms of resistance other than the receptor-related genotype, and the need of biological predictors to select the optimal therapeutic strategy, particularly now that other potent inhibitors are available. We investigated a panel of 31 polymorphisms in 11 genes, potentially associated with the pharmacogenetics of imatinib, in a group of 54 unresectable/metastatic GISTs treated with imatinib 400 mg daily as first line therapy. Included in this analysis were polymorphisms in the transporters’ family SLC22 , SLCO , ABC , and in the metabolizing genes CYP - 3A4 and - 3A5 . Time to progression was significantly improved in presence of the C allele in SLC22A4 (OCTN1 rs1050152), and the two minor alleles (G) in SLC22A5 (OCTN2 rs2631367 and rs2631372). Importantly, multivariate analysis, adjusting for age, gender, KIT / PDGFRα mutational status, and tumour size, revealed that all the three genotypes maintained independent predictive significance. In conclusion, in this study we showed that SLC22A4 and SLC22A5 genotypes may be an important predictor of time to progression in GIST patients receiving imatinib therapy. Further investigations are required in an attempt to further personalize GIST therapy.