Search

Introduction: Treat-to-target strategies are used in several chronic diseases to improve outcomes. Treatment goals have also been suggested for psoriasis, but there is currently no consensus on targets, and guidance is needed to implement this strategy in clinical practice. The project ‘Treat to Target Italia’ was launched by a scientific board (SB) of 10 psoriasis experts to generate expert consensus recommendations. Methods: On the basis of the published literature, their clinical experience, and the results of a survey among Italian dermatologists, the SB identified four relevant topics: (1) clinical remission; (2) quality of life; (3) abrogation of systemic inflammation; (4) safety. They drafted 20 statements addressing these four topics and submitted them to a panel of 28 dermatologists, in a Delphi process, to achieve consensus (greater than 80% agreement). Results: Consensus was reached on all statements. Treatment goals defining clinical remission should include a 90% improvement from baseline in the Psoriasis Area and Severity Index (PASI90 response) or an absolute PASI score of less than or equal to 3. Patient’s quality of life and satisfaction are important targets. If PASI targets are achieved, there should be no or very low impact of psoriasis on quality of life [Dermatology Life Quality Index (DLQI) score less than or equal to 3]. If PASI or DLQI goals are not achieved within 3–4months, treatment should be changed. Abrogation of systemic inflammation may be crucial for preventing or delaying inflammatory comorbidities. Safety is an equally important target as efficacy. Conclusion: These 20 consensus statements define the parameters of a treat-to-target strategy for psoriasis in Italy. It is hoped that use of these in the management of patients with psoriasis will improve treatment outcomes and patient health-related quality of life.

Objective: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. Background: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. Methods: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18–65years. Each patient was treated with erenumab 70mg, administered monthly. The dose was switched to 140mg in nonresponders and in responders who had become nonresponders for at least 4weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45–48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. Results: A total of 242 patients with migraine received at least one dose of erenumab 70mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3migraine-preventive medication classes. From baseline to Weeks 45–48, erenumab treatment reduced MMD by 4.3±5.3(mean±SD) in patients with HFEM, and MHD by 12.8±8.9 (mean±SD) in subjects with CM. VAS and HIT-6scores were decreased by 1.8±1.9 (mean±SD) and 12.3±11 (mean±SD) in HFEM, and by 3.0±2.2 (mean±SD) and 13.1±11.2 (mean±SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0–13.0) to 5 (IQR 2.0–8.0) in HFEM and from 20.0 (IQR 15.0–30.0) to 6.0 (IQR 3.8–10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52–19.41; p=0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03–8.7; p=0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05–1.20; p=0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15–0.87; p=0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64–0.92; p=0.004). Conclusions: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.

The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P

Objective: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. Background: Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. Methods: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18–65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70mg, administered subcutaneously every 4weeks. Treatment duration was planned to last from 6 to 12months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9–12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). Results: In total, 372 migraine patients were treated with at least one dose of erenumab 70mg. At weeks 9–12, erenumab decreased MMDs by 4.5±4.1days (mean±SD) in patients with HFEM and by 9.3±9.1 (mean±SD) days in those with CM compared to baseline. At weeks 9–12 VAS score was reduced by 1.9±1.9 (mean±SD), HIT score by 10.7±8.8 (mean±SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0–14.0) to 5.0 (IQR 3.0–7.0) in HFEM. In CM patients, VAS was reduced by 1.7±2.0 (mean±SD), HIT by 9.7±10.4 (mean±SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0–30.0) to 8.0 (IQR 5.0–15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24–7.40; p=0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02–1.11; p=0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14–3.52; p=0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20–0.93; p=0.003). Conclusions: Erenumab 70mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

Purpose To describe the impact of a new institutional Code Stroke protocol on ordering volume of head and neck CT angiographies (CTA), and to determine the number and proportion of these studies that resulted in an endovascular or surgical intervention. Methods Clinical and administrative data was collected on all head and neck CTAs ordered within the ED at two high-volume community hospitals and an affiliated urgent care centre during the 6-year period between January 1, 2014, and December 31, 2019. Of those patients who underwent CTA, we identified those who were then transferred to a regional stroke centre for consideration of EVT and those who underwent carotid endarterectomy or stenting within 14 days. Results A total of 4719 CTAs were ordered during the 6-year period. There was nearly a tenfold rise in the yearly number of CTAs ordered per 10,000 ED visits, from 5.3 (in 2014) to 53.1 (in 2019). A total of 164 patients who underwent CTAs (3.5%) were ultimately transferred to a regional tertiary care centre, of whom 43 (0.9%) were transferred to a regional stroke centre for consideration of EVT. A total of 61 (1.3%) patients underwent a carotid intervention within 14 days. Conclusion Little is known of the impacts on healthcare resources that have resulted from the system-wide changes made necessary by the widespread adoption of EVT. Our study shows that at our site, these system changes have resulted in large increases in CTA utilization with very small numbers of patients ultimately undergoing EVT or carotid intervention.

The bla genes identification present in 94 phenotypically resistant Escherichia coli isolated from feces or intestinal contents of young calves with diarrhea or enteritis in Belgium was performed b...

Status epilepticus (SE) is associated with high morbidity and mortality. This multicenter retrospective cohort study aims to identify the factors associated with the occurrence of SE and the predictors of its recurrence in patients with adult-onset seizures.We retrospectively analyzed data of 1115 patients with seizure onset18 years, observed from 1983 to 2020 in 7 Italian Centers (median follow-up 2.1 years). Data were collected from the databases of the Centers. Patients with SE were consecutively recruited, and patients without SE history were randomly selected in a 2:1 ratio. To assess determinants of SE, different clinical-demographic variables were evaluated and included in univariate and multivariate logistic regression model.Three hundred forty-seven patients had a SE history, whereas the remaining 768 patients had either isolated seizures or epilepsy without SE history. The occurrence of SE was independently associated with increasing age at onset of disease (OR 1.02, 95% CI 1.01--1.03, p0.001), female sex (OR 1.39, 95% CI 1.05--1.83, p=0.02) and known etiology (OR 3.58, 95% CI 2.61--4.93, p0.001). SE recurred in 21% of patients with adult-onset SE and recurrence was associated with increasing number of anti-seizure medications taken at last follow-up (OR 1.88, 95% CI 1.31--2.71, p0.001).In patients with adult-onset seizures, SE occurrence is associated with known etiologies, advanced age and female sex. Patients with recurrent SE are likely to have a refractory epilepsy, deserving careful treatment to prevent potentially fatal events.

Summary Background Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. Methods STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov , NCT03461289 (completed). Findings From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p Interpretation STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Funding Novartis Gene Therapies.

Massimo Cesareo,1 Ernesto Di Marco,1 Clarissa Giannini,1 Matteo Di Marino,1 Francesco Aiello,1 Antonio Pisani,2 Mariangela Pierantozzi,3 Nicola Biagio Mercuri,4,5 Carlo Nucci,1 Raffaele Mancino1 1Ophthalmology Unit, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; 3Parkinson’s Center, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 4Neurology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 5Fondazione Santa Lucia I.R.C.C.S, Rome, ItalyCorrespondence: Massimo Cesareo; Ernesto Di MarcoOphthalmology Unit, Department of Experimental Medicine University of Rome “Tor Vergata”, via Montpellier, Rome, 100133, ItalyTel/Fax +39 0620902973Email massimo.cesareo@uniroma2.it; Ernesto2601@hotmail.itPurpose: To assess the structure and function of the retinal posterior pole in patients with early Parkinson’s disease (PD) and to identify possible biomarkers correlated with clinical features.Patients and Methods: A cross-sectional case-control study of 21 patients with PD and 22 age-matched healthy controls (HC) was conducted. All subjects underwent full ophthalmological examinations, fundus perimetry (FP) and spectral domain-OCT (SD-OCT) of the entire retinal posterior pole and peripapillary retinal nerve fiber layer (pRNFL).Results: We analyzed 41 eyes from 21 patients (14 males and 7 females) with early PD (Hoehn and Yahr scale (H&Y) equal to or less than stage 2) and 41 eyes from 22 HC (12 males and 10 females). We found no significant difference in the pRNFL thickness between patients with PD and HC. The statistical analysis of the SD-OCT posterior pole area, consisting of 64 values for each retinal layer, revealed a decrease in the outer nuclear layer (ONL) thickness in patients with PD (p < 0.0001). On the contrary, a significant increase in the thickness of the outer plexiform layer (OPL) (p < 0.0001) and of the retinal pigmented epithelium (RPE) (p= 0.002) compared to healthy controls was detected. Other retinal layers showed no significant statistical differences. The differential light sensitivity (DLS) values measured by FP were significantly lower in patients than the healthy controls (15 [13– 16.2] vs 17.95 [16.08– 18.96] p< 0.0001).Conclusion: Our results showed that DLS and retinal structure differed in the posterior pole between patients with early PD and controls. Thickening of the OPL may represent accumulation of α-synuclein in the OPL of patients with PD.Keywords: Parkinson’s disease, optical coherence tomography, retina, dopamine, alpha-synuclein

Introduction/aims Intrathecal nusinersen administration can be challenging in certain adult spinal muscular atrophy (SMA) patients with difficult spinal anatomy who require imaging techniques (fluoroscopy or computed tomography scans) or invasive approaches (catheter placement, laminotomy) to identify the intrathecal space. We used ultrasound (US) assistance to access the lumbar intrathecal space in patients with SMA who experienced previous difficulties or failures with intrathecal dosing. Methods Eighteen adult patients with difficult spines were enrolled. We used ultrasound assistance and we recorded the successful administrations, number of attempts, procedure times and "patient satisfaction". Results There were 57 consecutive successful nusinersen spinal administrations in all patients enrolled. In 50% of patients 2 or fewer attempts were needed to obtain a successful administration, with 4 or fewer attempts in 83.3%; only 3 patients reported more than 4 attempts because of both severe scoliosis and severe spine rotation (2 patients) and obesity (1 patient). The mean procedure time was 11.8 minutes (range 1.7-28.9). Patient satisfaction was 4.97/5 (range 4-5, median 5) on Likert scale at 5 minutes and at 72 hours. No major adverse events were reported, and 2 post-dural puncture headaches were managed with medical therapy and with complete resolution within 72 hours. Discussion US assistance seems to be a valid option among treatment choices for intrathecal nusinersen administration in patients with difficult spine. The absence of radiation exposure and the lack of need for intravenous sedation or general anesthesia are additional potential advantages to US assisted administration. This article is protected by copyright. All rights reserved.

Introduction This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. Objective We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. Methods Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. Results The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. Conclusions Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01107-6.

Background: Over the last few years there has been increasing attention to detect early signs of impairment in young Duchenne muscular dystrophy boys but less has been reported on whether the delay may also affect the very early aspects of motor development, such as gross motor milestones. Objective: The aim of this study was to retrospectively assess the age when early motor milestones were achieved in Duchenne muscular dystrophy. Methods: The study is a retrospective analysis of data collected as part of a larger natural history project. Information on past medical history, collected at the time the boys were seen for the first time, were recorded and re available on clinical notes and on electronic CRF. Results: Data were collected in 134 DMD boys. Sitting was achieved at 7.04 months. The % of DMD boys not achieving sitting by 9.4 months was 10%, ranging from 2% in the boys with mutations before exon 44 to 33% in those beyond exon 63. Walking was achieved at a mean age of 16.35 months. The % of DMD boys not achieving independent walking by 18 months was 17%, ranging from 9% in the boys with mutations between 44 and 51 to 42% in those beyond exon 63. Conclusions: Our results showed that the risk of a delay in sitting and walking was increasingly high in patients with mutations predictive of the involvement of different brain dystrophin isoforms.

Background JAM3 gene, located on human chromosome 11q25, encodes a member of the junctional adhesion molecule (JAM) family. Mutations of this gene are associated with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC). Case report Herein, we present a newborn male with a prenatal suspicion of bilateral cataracts but without fetal ultrasound findings of cortical malformations. He was postnatally diagnosed with a clinical picture of HDBSCC and Early-onset Developmental and Epileptic Encephalopathy (DEE), associated to a homozygous variant of JAM3 gene. Conclusion Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counseling. To the best of our knowledge, this is the first case reported of a child with a JAM3 variant in Italy, from a different ethnic background than the other reported children until now (Saudi Arabian, Turkish, Afghani, and Moroccan origin). JAM3 screening could be requested in prenatal diagnosis of fetal congenital cataracts and included in Next-Generation DNA Sequencing panels.

Late-preterm infants (LPT) are at increased risk for long-term neurodevelopmental sequelae and iron deficiency. The aim of the study is to assess the positive effect of iron supplementation on psychomotor development in healthy LPT. We designed a randomized placebo-controlled double-blind trial dividing the newborns into two groups. Every patient was assessed using the Griffiths Mental Development Scales (GMDS)-II edition at 12-month post-conceptional age. The study was performed at the Neonatology Unit of our Hospital, in Italy. Sixty-six healthy LPT infants born between 340⁄7 and 366⁄7 weeks of gestational age were enrolled in the study. One group received martial prophylaxis from the third week of life to 6 months of post-conceptional age (2 mg/kg/day of iron pidolate), the other received placebo. Fifty-two of the enrolled infants were assessed using the GMDS at 12-month of post-conceptional age. Statistical analysis of the mean scores of the Griffiths subscales was performed. There was a difference in the mean developmental quotient (DQ) (p Conclusions: We recommend that all LPT neonates receive iron supplementation during the first 6 months of life in order to improve their 1-year neurodevelopmental quotient. What is Known:• Late-preterm infants (LPT) are at increased risk for long-term neurodevelopmental sequelae and also for iron deficiency.• Iron deficiency is an independent risk factor for adverse neurological outcomes. What is New:• Healthy late-preterm who received iron supplementation during the first 6 months of life achieved better neurological outcomes at 12-month post-conceptional age than LPT who received placebo.• Our study strongly supports the need for the implementation of martial prophylaxis in LPT neonates.

Head trauma (HT) is emerging as an event anticipating onset of neurodegenerative disorders. However, the potential contribution of HT in young-onset cases (YOPD, age at onset

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. OBJECTIVE: Compare long-term ambulatory function in eteplirsen-treated patients versus controls. METHODS: Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. RESULTS: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, eteplirsen-treated patients demonstrated milder NSAA decline versus controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. CONCLUSION: In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD. ispartof: JOURNAL OF NEUROMUSCULAR DISEASES vol:8 issue:4 pages:469-479 ispartof: location:Netherlands status: published

Spinal muscular atrophy is a progressive, recessively inherited monogenic neurologic disease, the genetic root cause of which is the absence of a functional survival motor neuron 1 gene. Onasemnogene abeparvovec (formerly AVXS-101) is an adeno-associated virus serotype 9 vector-based gene therapy that delivers a fully functional copy of the human survival motor neuron gene. We report anti–adeno-associated virus serotype 9 antibody titers for patients with spinal muscular atrophy when they were screened for eligibility in the onasemnogene abeparvovec clinical trials (intravenous and intrathecal administration) and managed access programs (intravenous). Through December 31, 2019, 196 patients and 155 biologic mothers were screened for anti–adeno-associated virus serotype 9 binding antibodies with an enzyme-linked immunosorbent assay. Of these, 15 patients (7.7%) and 23 biologic mothers (14.8%) had titers >1:50 on their initial screening tests. Eleven patients (5.6%) had elevated titers on their final screening tests. The low percentage of patients with exclusionary antibody titers indicates that most infants with spinal muscular atrophy type 1 should be able to receive onasemnogene abeparvovec. Retesting may identify patients whose antibody titers later decrease to below the threshold for treatment, and retesting should be considered for patients with anti–adeno-associated virus serotype 9 antibody titers >1:50., Graphical abstract, Day and colleagues report that 5.6% of patients screened across the onasemnogene abeparvovec clinical development program and US MAPs were excluded because of elevated anti-adeno-associated virus serotype 9 binding antibody titers, indicating that most patients with spinal muscular atrophy should be able to receive adeno-associated virus serotype 9-based therapy.

Objective We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. Methods Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6‐Minute Walk Test (6MWT) with a mean follow‐up of 1.83 years after nusinersen treatment. Results Over 75% of the 144 patients had a 12‐month follow‐up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12‐month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

Background Adult-onset sporadic chorea includes a wide and heterogeneous group of conditions whose differential diagnosis and treatments are often challenging and extensive. Objectives To analyse retrospectively cases of adult-onset sporadic chorea from a single Italian centre to provide insights for a practical approach in the management of these patients. Methods A total of 11,071 medical charts from a 9-year period (2012–2020) were reviewed, identifying 28 patients with adult-onset sporadic chorea (genetic forms excluded). All available data regarding phenomenology, diagnostic workup, aetiology, treatments, and long-term outcome from this cohort were collected and analysed. Results Adult-onset sporadic chorea occurred more frequently in females and presented with an acute-subacute onset. Cerebrovascular diseases accounted for 68% of aetiology; further causes were structural brain lesions, internal diseases, and other movement disorder syndromes. Clinical course was mild, with spontaneous resolution or minimal disturbances in 82% of cases. Neuroimaging was fundamental to diagnose 76% of adult-onset sporadic chorea, an appropriate clinical examination contributed to the 14% of diagnoses, whereas basic laboratory tests to the 10%. Conclusions Revision of real-world data of adult-onset sporadic chorea patients from a single Italian cohort suggests that an accurate clinical examination, neuroimaging, and routine laboratory tests are useful to identify those cases underlying potentially severe but treatable conditions. Although in the majority of cases adult-onset sporadic chorea has mild clinical course and good response to symptomatic treatments, it is essential to run a fast diagnostic workup.

The aim of the present study is to assess the psychometric properties of the Sleep Disturbance Scale for Children (SDSC) in an Italian population of infants and toddlers.The SDSC was distributed to the primary caregivers of infants aged 6-36 months recruited via nurseries in the urban area of Rome. Reliability analysis for evaluating internal consistency and item-total correlation coefficients, and factor analysis were performed.During a 12-months study period, a total of 193 healthy infants (aged 6-36 months) were evaluated using a 22-item version of the SDSC for Italian infants and toddlers. Three of the 22 original items displayed a low item-total correlation (30) and a low frequency and were eventually removed, resulting in a 19 items questionnaire. Six factors were derived from the factor analysis using the principal component method of extraction and rotated with the varimax method: Difficulty in initiating sleep, Difficulty in maintaining sleep, Sleep breathing disorders, Parasomnias, Disorders of excessive somnolence and Sleep hyperhidrosis. The SDSC adapted for infants and toddlers showed a good level of internal consistency (Cronbach's alpha: 0.83).The statistical analysis, the internal consistency and the factor analysis encourage the use of SDSC as an evaluation tool even at this age. The six factors extracted represent the most common areas of sleep disorders at this age and could therefore help clinicians to detect the areas that need a deeper investigation.

Non-motor symptoms (NMS) frequently impact health-related quality of life (HRQoL) in patients with Parkinson's Disease (PD). Sleep problems represent one of the main NMS complained by PD patients. In this observation study, sleep problems measured by Parkinson's Disease Sleep Scale - 2nd version (PDSS-2), and HRQoL measured by Parkinson's Disease Questionnaire-39 (PDQ39) were quantified in patients with PD ranging from mild to moderate-advanced disease stages, and correlated to motor impairment and anti-PD therapy.We included idiopathic PD patients who underwent PDSS-2 and PDQ39. Moreover, we assessed patients' motor symptoms by rating the Unified Parkinson's Disease Rating Scale (UPDRS) - III section (motor examination), patients' PD status following HY stage, and levodopa equivalent daily dose (LEDD).One-hundred and fifty-four patients with PD were included and distributed for HY stage. PDSS-2 and PDQ39 total and sub-items scores significantly increased with the HY stage. PDSS-2 total score significantly correlated with PDQ39 total score (γ = 0.63, P 0.01). Finally, distributing PD patients according to the PDSS-2 cut-off for detecting sleep disturbances, we found in poor sleepers (n = 58) higher PDQ39 scores than good sleepers (n = 89).Sleep problems are very common in patients with PD and severely impact on HRQoL. Sleep impairment and low HRQoL occur from the early stages of the disease and deteriorate along disease progression. Further studies investigating sleep and quality of life should be planned for targeting sleep improvement to increase HRQoL and possibly reduce motor impairment.

Background Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (Online Mendelian Inheritance in Man [OMIM] #277000) is a congenital condition characterized by the total or partial agenesis of vagina and uterus. Agenesis can be isolated (MRKH 1) or associated with other renal, vertebral or cardiac defects (MRKH 2). Case presentation In this paper, we report a case of a Caucasian patient showing the clinical signs associated with MRKH. Array-based comparative genomic hybridization (a-CGH) analysis revealed a microduplication of approximately 3.01 megabases (Mb) located on the long arm of chromosome 22 (22q11.21). Microduplications affecting the 22q11.21 region have been shown to be associated with MRKH syndrome and Müllerian aplasia. The phenotype of patients with 22q11.2 duplication (OMIM #608363) appears extremely variable, ranging from apparently normal to mild learning difficulties or with multiple defects, sharing features with DiGeorge/velocardiofacial (DGS/VCFS) syndrome. Conclusions The altered gene expression together with other genetic, nongenetic, epigenetic or environmental factors can cause the extremely variable phenotype in patients carrying such duplication. Therefore, we can consider MRKH syndrome to be one of the clinical features of DGS/VCFS syndrome.

Background Acromegaly is a rare disease due to chronic growth hormone (GH) excess and the consequent increase in insulin-like growth factor-1 (IGF-1) levels. Both GH and IGF-1 play a role in intermediate metabolism affecting glucose homeostasis. The association between hyperinsulinemia/impaired glucose tolerance and an increased risk of cancer has been clarified. Insulin has a mitogenic effect through its interaction with the IGF-1 receptor (IGF-1R) that also binds IGF-1. On the other hand, metformin, an anti-hyperglycemic drug that decreases serum levels of insulin and IGF-1, could have a protective role in the treatment of endocrine tumors. Methods A retrospective, observational, multicenter study in 197 acromegalic patients, receiving/not receiving metformin, was performed to assess whether the prevalence of neoplasms might be correlated with insulin resistance and could eventually be modified by metformin treatment. Results In general, the occurrence of secondary neoplasia among our patients was significantly (pV = 0.035) associated with a positive family history of malignancy and with disease duration; a trend towards significance was observed in patients aged > 50 years. Acromegalic subjects who had undergone surgery showed a lower probability of developing a malignant tumor, whereas a higher prevalence of malignancies was observed in obese patients. No significant statistical difference was found when comparing metformin-treated or -untreated subjects for the presence of a second tumor. More interestingly, a trend towards statistical significance (pV = 0.065) was demonstrated in the metformin-treated group for the onset of a benign neoplasm. Conclusion Metformin could act directly on tumor cell metabolism and may have an adjuvant role in benign lesion progression.

We measured α-Klotho in CSF and serum of PD patients at early stage of the disease, finding two distinct pools, the first increased, the second reduced. CSF α-Klotho was inversely associated with CSF α-synuclein levels. Our preliminary results suggest α-Klotho as potential biomarker or therapeutic target in PD.

Systemic comorbidity precipitates the risk for dementia. To comprehend the underlying mechanisms into a therapeutic perspective, we analyzed how comorbidity affects neurodegeneration-related cerebrospinal fluid (CSF) biomarkers of 55 cognitively intact subjects. The Charson Comorbidity Index (CCI) was correlated with CSF amyloid-β42 (Aβ42), amyloid-β40, total-tau, 181-phosphorylated-tau (p-tau), the Aβ42/p-tau ratio, neurogranin, and lactate. The age-related brain lesions at imaging were also considered. CCI had a raw association with Aβ42/p-tau and p-tau, and a stronger, age-independent correlation with lactate. These preliminary findings suggested that, in normal subjects, systemic comorbidity might increase CNS oxidative stress and, together with aging, contribute to develop an Alzheimer’s disease-like biochemical profile.

Atrial fibrillation increases the risk of stroke, which can be mitigated by anticoagulant prescription. We evaluated local emergency physician anticoagulation practice for patients discharged from the emergency department with atrial fibrillation, along with 90-day incidence of stroke and major bleeding. This was a health record review of patients diagnosed with new onset atrial fibrillation in two emergency departments between 2014 and 2017. We collected data on CHADS65 scores, contraindications to direct oral anticoagulant (DOAC) prescription and initiation of anticoagulation in the ED. Patient charts were reviewed for the diagnosis of stroke, transient ischemic attack (TIA), systemic embolism or major bleeding within 90 days. We identified 399 patients, median age 68 (IQR 57–79), 213 (53%) male. Only 299/399 patients had an indication for anticoagulation (CHADS65-positive). Of these 299, 27 had a contraindication to or were already prescribed anticoagulation. 45/272 (17%, 95% confidence interval 12–22%) patients eligible for initiation of anticoagulation left the emergency department with a prescription for anticoagulation. During 90-day follow-up, seven patients had stroke or TIA. Four stroke/TIA patients had been eligible to start an anticoagulant but were not started, two left the emergency department with prescriptions for an anticoagulant and one patient had a contraindication to initiating anticoagulation in the emergency department. There were no major bleeding episodes. Few eligible patients were prescribed anticoagulation and the 90-day stroke rate was high. Physicians should become familiar with the CAEP Acute AF Best Practices Checklist AF which offers guidance on anticoagulation prescription.

BACKGROUND: Evidence-based guidelines advise excluding pulmonary embolism (PE) diagnosis using d-dimer in patients with a lower probability of PE. Emergency physicians frequently order computed tomography (CT) pulmonary angiography without d-dimer testing or when d-dimer is negative, which exposes patients to more risk than benefit. Our objective was to develop a conceptual framework explaining emergency physicians’ test choices for PE. METHODS: We conducted a qualitative study using in-depth interviews of emergency physicians in Canada. A nonmedical researcher conducted in-person interviews. Participants described how they would test simulated patients with symptoms of possible PE, answered a knowledge test and were interviewed on barriers to using evidence-based PE tests. RESULTS: We interviewed 63 emergency physicians from 9 hospitals in 5 cities, across 3 provinces. We identified 8 domains: anxiety with PE, barriers to using the evidence (time, knowledge and patient), divergent views on evidence-based PE testing, inherent Wells score problems, the drive to obtain CT rather than to diagnose PE, gestalt estimation artificially inflating PE probability, subjective reasoning and cognitive biases supporting deviation from evidence-based tests and use of evidence-based testing to rule out PE in patients who are very unlikely to have PE. Choices for PE testing were influenced by the disease, environment, test qualities, physician and probability of PE. INTERPRETATION: Analysis of structured interviews with emergency physicians provided a conceptual framework to explain how these physicians use tests for suspected PE. The data suggest 8 domains to address when implementing an evidence-based protocol to investigate PE.

Aim: SNPs in miRNA machinery genes may affect miRNA function by impacting their biogenesis. Here, we investigated the association between three SNPs in miRNA machinery genes ( DICER rs1057035, DROSHA rs10719 and XPO5 rs11077) and bicuspid aortic valve (BAV). Materials & methods: Three polymorphisms were analyzed in 177 BAV patients and 414 healthy subjects by using a TaqMan®SNP assay. Results: The frequencies of XPO5 rs11077 genotype were significantly different between BAV patients and controls (p = 0.022). On multivariate logistic regression analysis, the XPO5 rs11077 C allele resulted a significant predictor of BAV (odds ratioadjusted = 0.65; CI: 0.42–0.98; p = 0.047). Conclusion: The XPO5 rs11077 SNP was associated with a decreased BAV risk supporting the causative role of miRNAs in aortic valve development.

International audience; In a previous Phase 2 study, olesoxime had a favorable safety profile. Although the primary endpoint was not met, analyses suggested that olesoxime might help in the maintenance of motor function in patients with Types 2/3 SMA. This open-label extension study (OLEOS) further characterizes the safety, tolerability and efficacy of olesoxime over longer therapy durations. In OLEOS, no new safety risks were identified. Compared to matched natural history data, patients treated with olesoxime demonstrated small, non-significant changes in motor function over 52 weeks. Motor function scores were stable for 52 weeks but declined over the remainder of the study. The greatest decline in motor function was seen in patients ≤15 years old, and those with Type 2 SMA had faster motor function decline versus those with Type 3 SMA. Previous treatment with olesoxime in the Phase 2 study was not protective of motor function in OLEOS. Respiratory outcomes were stable in patients with Type 3 SMA >15 years old but declined in patients with Type 2 SMA and in patients with Type 3 SMA ≤15 years old. Overall, with no stabilization of functional measures observed over 130 weeks, OLEOS did not support significant benefit of olesoxime in patients with SMA.

Atopic dermatitis (AD) is a chronic inflammatory disease that may involve any cutaneous site; involvement of the genital area may greatly impair patients' quality of life but, as the inspection of genitals is not usually conducted during the routine physical examination of patients with AD, the genital presentation of AD is frequently neglected and under-reported. We decided to evaluate the incidence of genital AD in patients with moderate-severe AD and the relative response to anti-interleukin (IL)-4/IL-13 dupilumab. In our study, a high incidence of genital AD emerged but the use of dupilumab allowed a generalized improvement.

AIMS: To assess hyperreflective foci (HF) number in angioid streaks (AS) by means of spectral-domain optical coherence tomography (SD-OCT). METHODS: Observational and cross-sectional study. Sixty-two eyes with AS and 62 controls underwent best-corrected visual acuity (BCVA), fundoscopy, and SD-OCT. HF were assessed on the horizontal scan of a six-line radial OCT, in the fovea (1500-μm diameter) and parafovea (500 μm external to the fovea), and sub-classified as retinal or choroidal, small or large. Eyes were distributed in one of four groups, as carrying foveal AS without choroidal neovascularization (CNV) (14 eyes), extra-foveal AS without CNV (14), active CNV (20), and inactive CNV (14). Primary outcome was HF assessment in AS. Secondary outcomes included their correlations with BCVA. RESULTS: AS-affected eyes had higher HF numbers. Our sub-analysis revealed that patients with active CNV had a larger number of retinal and choroidal HF than all the other groups, whereas retinal and choroidal foci were significantly increased in inactive CNV only with respect to controls. Interestingly, patients with foveal AS showed HF number increase in the choroid and fovea. BCVA deterioration positively correlated with the total HF number found in the fovea and the choroid. CONCLUSION: HF are significantly increased in patients with AS. Despite being especially evident in active CNV, the increasing number in eyes without CNV might suggest new pathogenetic aspects of the disease.

ObjectiveTo describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).MethodsThis was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy.ResultsThere were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8–16.6) and 15.1 (13.8–16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes.ConclusionsIn SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

OBJECTIVE: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments. RESULTS: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (ß = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (ß = -1.15, p < 0.0001) and IIIB (ß = -0.69, p = 0.002). INTERPRETATION: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117.

Purpose The purpose of the present study was to report the temporomandibular joint (TMJ) alloplastic reconstruction (TMJR) revision and/or replacement rates and associated complication outcomes data gathered from experienced TMJ surgeons and to review the recent relevant data. Materials and Methods A 21-question anonymous on-line survey was sent to all Commission on Dental Accreditation–approved oral and maxillofacial surgery program directors and to members of the European Society of TMJ Surgeons and the American Society of Temporomandibular Joint Surgeons. Results Of the surgeons sent the survey, 22% completed the full questionnaire. Most responses were from surgeons who routinely perform TMJR surgery (93.5%). Of the respondents, 28.3% had more than 30 years of experience and 73.9% were full-time academic faculty. A total of 4638 TMJR procedures were recorded and analyzed. The incidence of TMJR revision (keeping the same device) was 3% and that of replacement (placing a new device) was 4.9%. The most common reason for revision was heterotopic ossification (27.5%). The most common reason for replacement was infection (21.1%). Revision was successful in 86.7% and replacement in 94.6% of the patients at the longest follow-up reported. Conclusions The data from the present study have shown that the incidence is low and the success rate is high for TMJR revision and replacement.

Spinal muscular atrophy (SMA) used to be one of the most common genetic causes of infant mortality. New disease modifying treatments have changed the disease trajectories and most impressive results are seen if treatment is initiated in the presymptomatic phase of the disease. Very recently, the European Medicine Agency approved Onasemnogene abeparvovec (Zolgensma®) for the treatment of patients with SMA with up to three copies of the SMN2 gene or the clinical presentation of SMA type 1. While this broad indication provides new opportunities, it also triggers discussions on the appropriate selection of patients in the context of limited available evidence. To aid the rational use of Onasemnogene abeparvovec for the treatment of SMA, a group of European neuromuscular experts presents in this paper eleven consensus statements covering qualification, patient selection, safety considerations and long-term monitoring., Highlights • Onasemnogene abeparvovec (Zolgensma®) is the first approved gene therapy for a neuromuscular disease. • Treatment with Onasemnogene abeparvovec requires a thorough risk-benefit analysis for each individual patient. • Gene therapy with Onasemnogene abeparvovec should only be used by qualified neuromuscular expert centres. • Systematic real-world data collection and additional clinical trials are needed to fill evidence gaps concerning safety and efficacy.

The aim of this study was to survey an international group of temporomandibular joint surgeons regarding their outcomes with alloplastic total joint replacement in skeletally immature patients and to review the literature linked to autogenous reconstruction and alloplastic replacement of the temporomandibular joint (TMJR) in this population. A total of 24 custom/patient-specific TMJ Concepts devices were implanted into 14 patients (eight male and six female). Their mean age was 14 years (range 7-17 years). Nine (64.3%) had bilateral devices and five (35.7%) had unilateral devices. The most prevalent diagnosis was idiopathic condylar resorption (33.3%), followed by ankylosis (16.7%). Concurrent orthognathic surgery was performed in four patients (28.6%). The TMJR was completed as a one-stage procedure in 11 patients (78.6%) and in two stages in three patients (21.4%). All surgeons reported improvements in maximum incisal opening with good function. The respondents reported no asymmetric mandibular growth or retrognathia after either bilateral or unilateral TMJR implantation. This pilot study indicates that the use of TMJR in the growing patient may be a useful modality in select cases. The encouraging results of experienced surgeons demonstrate and support the need for further studies on the utilization of TMJR in this patient population.

SUMMARY BACKGROUND: Recurrent laryngeal papillomatosis, caused by the Human Papilloma Virus, has a significant economic impact worldwide and there are no epidemiological data of this disease in Brasil. OBJECTIVE: The objective of the study was to estimate the incidence and prevalence of laryngeal papillomatosis of some otorhinolaryngology centers in São Paulo State (Brasil). METHODS: A questionnaire containing data on the number of new and follow-up cases diagnosed with laryngeal papillomatosis was sent to the Otorhinolaryngology services (n=35) of São Paulo State (Brasil). RESULTS: A total of 20 otorhinolaryngology centers answered the questionnaire. Of these, the five largest regional health centers were selected as follows: Campinas (42 cities – 4,536,657 inhabitants), Sao Jose do Rio Preto (102 cities – 1,602,845 inhabitants), Ribeirão Preto (26 cities – 1,483,715 inhabitants), Bauru (68 cities – 1,770,427 inhabitants), and Sorocaba (47 cities – 2,478,208 inhabitants). The incidence and prevalence of each regional health centers were, respectively: Campinas (5.51;7.27), Sorocaba (2.02;6.86), São José do Rio Preto (1.87;7.49), Ribeirão Preto (11.46;22.92), and Bauru (3.95;7.91). CONCLUSION: The incidence and prevalence of the laryngeal papillomatosis of the five largest regional health centers of the interior of São Paulo State (Brasil) varied between 1.87 to 11.46 and 6.86 to 22.92 per 1,000,000 inhabitants, respectively for a total population of 11,871,852 inhabitants. RESUMO CONTEXTO: A papilomatose recorrente da laringe, causada pelo vírus do papiloma humano, tem um impacto econômico significativo em todo o mundo e não existem dados epidemiológicos dessa doença no Brasil. OBJETIVO: O objetivo do estudo foi estimar a incidência e prevalência de papilomatose laríngea em alguns centros de otorrinolaringologia do estado de São Paulo (Brasil). MÉTODOS: Um questionário contendo dados sobre o número de casos novos e de retornos diagnosticados com papilomatose laríngea foi enviado aos serviços de otorrinolaringologia (n-35) do estado de São Paulo (Brasil). RESULTADOS: Vinte centros de otorrinolaringologia responderam ao questionário e, destes, os cinco maiores centros regionais de saúde foram selecionados da seguinte forma: Campinas (42 cidades - 4.536.657 habitantes), São José do Rio Preto (102 cidades - 1.602.845 habitantes), Ribeirão Preto (26 cidades - 1.483.715 habitantes), Bauru (68 cidades - 1.770.427 habitantes) e Sorocaba (47 cidades - 2.478.208 habitantes). A incidência e prevalência de cada centro de saúde regional foram, respectivamente: Campinas (5,51; 7,27), Sorocaba (2,02; 6,86), São José do Rio Preto (1,87; 7,49), Ribeirão Preto (11,46; 22,92), Bauru (3,95; 7,91). CONCLUSÃO: A incidência e prevalência da papilomatose laríngea dos cinco mais importantes centros regionais de saúde do interior do estado de São Paulo (Brasil) variaram entre 1,87 e 11,46 e 6,86 e 22,92, por 1.000.000 de habitantes, respectivamente, para uma população total de 11.871.852 habitantes.

Objective Quantitative EEG (qEEG) is an established technique used as objective measure for evaluating the effect of antiseizure medications (ASMs) on EEG background activity and monitoring cognitive effects of ASMs. Perampanel (PER) has been associated with relatively more tolerable cognitive effects in patients with epilepsy. The primary aim of the present study was to verify the effect of PER as first add-on ASM on qEEG in child and adult patients affected by epilepsy. The secondary aim of this study was to verify the effectiveness of the drug as first add-on treatment in both child and adult patients with epilepsy. Methods We collected data from 17 adults and 10 children treated with PER as first add-on treatment, who underwent qEEG analysis before starting PER and at 3-month follow-up under stable treatment. Results PER resulted with significant effectiveness in reducing seizures in both children and adults. Considering qEEG analysis, we observed at follow-up the significant increase in beta1 and beta total bands both in children and adult patients. In particular, children showed the significant increase of beta band frequencies predominantly in the occipital regions, whereas adults showed a widespread increase of beta activity. Moreover, we documented in both child and adult patients the global reduction of delta bands activity. Conclusions This qEEG study documented the relative increase of cortical EEG fast activity in both children and adult patients affected by epilepsy and treated by PER. This result may suggest a potential less negative impact of PER on cognition in patients affected by epilepsy, other than demonstrating effectiveness of the drug when used as first add-on treatment in both children and adult patients.

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (-7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619.

Background Biotinidase deficiency (BTD) is an autosomal recessive inborn error of metabolism provoking progressive biotin depletion, which causes, in turn, multiple carboxylase deficiency. Its infantile onset is characterized by intractable seizures associated with lethargy, psychomotor regression, hypotonia, feeding and respiratory problems, and cutaneous abnormalities. Case description We describe a 52-month-old female whose clinical and neuroradiological pictures were consistent with myelopathy, which is generally more frequent in older patients, as well as with symptoms of an infantile onset of biotinidase deficiency, revealed at 17 months. Results A biochemical biotinidase test revealed a profound deficiency of biotinidase detecting a 10% residual enzymatic activity, which led to the diagnosis of BTD. Gene sequencing revealed a compound heterozigous mutation (c.454A > C/c.1612C > T). Conclusion Our findings suggest that even if myelopathy is uncommonly reported in BTD, and generally occurs in older children, its presence in childhood-onset floppiness should always be considered as a possible marker for an atypical presentation of BTD. Although, until recently, BTD myelopathy was believed to be prevalent in older children, a spinal cord involvement has also been described in at least nine cases in early infancy. Thus, another early diagnosis suggests that myelopathy may be more frequent than previously thought, and it is probably underdiagnosed because spinal MRI is not always routinely performed on these children. Early recognition of BTD disease is important as it would lead to prompt treatment, preventing irreversible brain damage and increasing the chances of complete recovery.

Purpose Although concerns regarding implant-related metal hypersensitivity exist, no guidelines have been accepted for screening or treatment of patients with metal sensitivity before temporomandibular joint replacement (TMJR). The present study aimed to determine the trends in TMJR metal sensitivity screening and the effect of positive test results on patient treatment. Materials and Methods A questionnaire was distributed to members of the American Society of Temporomandibular Joint Surgeons and the European Society of Temporomandibular Joint Surgeons using a web-based data collection and analysis tool. The questions aimed to establish the screening methods used to establish a diagnosis of metal hypersensitivity and any changes in management when metal hypersensitivity had been documented. Results A total of 72 responses (32.43%) were collected through the survey, with respondents primarily practicing in the United States (47.22%). Of the participants, 75% believed that metal hypersensitivity occurs with TMJR and only 2.77% did not. Most agreed that patients should be questioned about any metal sensitivities before consideration for TMJR (91.66%), and 80.55% routinely asked their patients if they had a previous sensitivity to any metals. Nickel was the most commonly encountered metal allergen (64.28%). If a metal allergy were reported, 44.28% of surgeons would refer the patient to determine the specific metal allergen. The diagnosis for metal allergy was based primarily on patient signs and symptoms (52.85%) and an allergist or dermatologist consultation (44.28%). The lymphocyte transformation test was the test most used by respondents to confirm the diagnosis. Of the surgeons, 41.42% would choose to observe/monitor as their first choice for patients testing positive for metal hypersensitivity. In the case of a “mild” reaction to metal hypersensitivity testing, 54.28% would alter their implant choice to a nonreactive metal component. For “severe” reactions to preoperative metal hypersensitivity testing, 62.85% would alter their implant choice to a nonreactive metal component, and 22.85% would choose not to perform TMJR. Conclusions The results from the present study have demonstrated that respondent TMJ surgeons agree that metal hypersensitivity occurs with TMJR. However, their approaches to screening and managing metal hypersensitivity vary. Further research of this topic is required to eventually develop specific management pre- and postoperative guidelines for the treatment of patients with metal sensitivities.

Introduction Vitiligo is an acquired, idiopathic disorder clinically characterized by amelanotic lesions on the skin which cause significant impairment of patients' quality of life. A variety of treatments have been proposed, with inconsistent results. In the last decades, the use of platelet-rich plasma (PRP) is receiving increasing interest as a potential effective technique in the treatment of several dermatological diseases, including vitiligo. Objective We conducted a review with the aim to identify studies that documented the use of PRP for vitiligo. Materials and methods Electronic databases of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2019 have been searched using different combinations of the following terms: "platelet-rich plasma", "platelet gel", "platelet-rich fibrin", "PRP" and "vitiligo". Results We identified 6 clinical studies consistent with our research, with a total of 253 patients, listing and discussing the obtained results. In all reports, all treated patients showed a stable vitiligo, and a significantly higher improvement in the PRP groups was always observed compared to control groups. Regarding the side effects, PRP in vitiligo patients is useful and without important side effects. Conclusion PRP is a promising treatment for stable vitiligo lesions in different body sites. The possible use of PRP in combination with traditional therapeutic options and the standardization of processing protocols represents a very fertile field for future research. Larger clinical trials with longer time of observation would provide solid evidence regarding the effectiveness of PRP for the treatment of vitiligo.

Introduction:Increasing evidence demonstrates the relevant association between Parkinson's disease (PD) and vascular diseases/risk factors, as well as a worse clinico-pathological progression in those patients with vascular comorbidity. The mechanisms underlying this relationship have not been clarified yet, although their comprehension is critical in a perspective of disease-modifying treatments development or prevention. Methods:We performed an experimental protocol of ischemic injury (glucose-oxygen deprivation, OGD) on PTEN-induced kinase 1 knockout (PINK1-/-) mice, a well-established PD model, looking at both electrophysiological and morphological changes in basal ganglia. In addition, 253 PD patients were retrospectively analysed, to estimate the prevalence of vascular risk factors. Results:In PINK1-/-mice, the OGD protocol induced electrophysiological (prolonged depolarization) and morphological alterations (picnotic cells, cellular loss and swelling, thickening of nuclear chromatin) in striatal medium spiny neurons and nigral dopaminergic neurons. Vascular comorbidity occurred in 75% of PD patients. Conclusions:The ischemic injury precipitates neuronal vulnerability in basal ganglia of PINK1-/-mice, probably through an impairment of mitochondrial metabolism and higher oxidative stress. These experimental data may provide a potential mechanistic explanation for both the association between vascular diseases and PD and their reciprocal interactions in determining the clinico-pathological burden of PD patients.

Background The advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Main text Three longitudinal natural history studies, two performed in the United States and one in Italy, were identified. The different study design of these three studies made it possible for the cumulative dataset to include the full spectrum of severity; from infants with neonatal onset to those with a milder phenotype that were not always included in the individual natural history studies. The cumulative analysis confirmed that, even in a larger cohort, there was never an improvement on the CHOP INTEND over time. This was true for all the infants, irrespective of their age or baseline CHOP INTEND scores. Infants with neonatal onset had low CHOP INTEND scores and a fast decline. The relatively large number of patients allowed us to calculate the rate of progression in subgroups identified according to SMN2 copy number and baseline CHOP INTEND scores. Conclusion A detailed understanding of the existing data is important, as it will be difficult to acquire new systematic longitudinal history data because of the availability of disease modifying therapies. The cumulative findings in this review help to better understand the variability of natural history data in untreated patients and will be of use for comparison to the real world patients treated with the recently approved therapies that have shown encouraging results in clinical trials.

BACKGROUND AND OBJECTIVE: To compare morphologic and functional status at age 4 years for patients treated in one eye with laser photocoagulation and the other eye with intravitreal bevacizumab (IVB) injection for Type 1 retinopathy of prematurity (ROP). PATIENTS AND METHODS: In this single-center, randomized, controlled trial, best-corrected visual acuity (BCVA) in logMAR was obtained along with spherical equivalent refraction (SER), fluorescein angiography (FA), optical coherent tomography (OCT), and OCT angiography (OCTA). RESULTS: Eighteen babies (36 eyes) were selected for this study. BCVA and SER were similar in the two groups, but six patients had anisometropia of 4 diopters or more. IVB-treated eyes tended to have thinner foveal thickness than laser-treated eyes (mean difference: −5.33 pixels; 95% confidence interval, −9.62 to −1.05). CONCLUSION: Although the differences found here are minimal between the IVB-treated and laser-treated groups, further long-term evaluation of not only FA, but also OCT and OCTA, are needed in larger studies. [ Ophthalmic Surg Lasers Imaging Retina . 2020;51:180–186.]

Idiopathic condylar resorption (ICR), alternatively called progressive condylar resorption, is an uncommon aggressive form of degenerative disease of the temporomandibular joint seen mostly in adolescent and young women. ICR occurring before the completion of growth results in a shorter mandibular condyloid process, ramus and body, compensatory growth at the gonial angle and coronoid process, as well as an increase in anterior facial vertical dimension. Management options discussed include oral appliances, orthodontics, medical management, orthognathic surgery with and without disc repositioning, and alloplastic temporomandibular joint replacement.

Introduction: The Carney complex (CC) is an autosomal dominant syndrome, characterized by multiple endocrine neoplasms, pigmented skin lesions, endocrine hyper-activity and myxomas. Case study: C. E., 71 years old, was addressed to our center in August 1994, following the finding of a sellar enlargement in a skull radiography performed after an accident. A pituitary tomography showed the presence of a lesion extended up to the optic chiasm, a macroadenoma that was treated with transsphenoidal endoscopic surgery. A histological diagnosis of a “GH secreting macroadenoma” was performed. An echocardiographic study highlighted an atrial isolated myxoma that was subsequently removed. A contrast-enhanced abdominal magnetic resonance imaging (MRI) excluded adrenal lesions. In 2001, in relation to relapse of Acromegaly, the patient started therapy with somatostatin analogues which was replaced, in 2008, by Pegvisomant to obtain biochemical control of the disease. Conclusions: At the time of initial screening, it is important not to underestimate the possibility that certain clinical features fall within the context of more complex syndromes. The knowledge of how Acromegaly presents itself in relation to CC and its associated characteristics such as cardiac myxoma or typical skin lesions, will help clinicians to timely diagnose this rare disease and treat it appropriately.