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Summary: Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

Background/Objectives: Waste milk harbors many bacteria and antibiotic residues. Calves fed with untreated waste milk have a higher incidence of scours and an increased risk of developing antimicrobial-resistant bacteria. This study aimed to evaluate the efficacy of treatment with copper ions on bacteria and antibiotics contained in bovine waste milk. Methods: Waste milk samples were collected from a dairy farm for seven weeks and were subjected to treatment with copper ions. Total bacterial counts, coliforms, Streptococcus, and Staphylococcus were assessed before and after treatment. Additionally, metagenomic analysis was performed to determine microbial diversity. Results: Before treatment, the total bacterial count average was 4.0 × 106 CFU/mL, 1.7 × 104 CFU/mL for coliforms, 2.6 × 106 CFU/mL for Streptococcus, and 5.4 × 102 CFU/mL for Staphylococcus Copper treatment significantly reduced bacterial counts within 15 min. Total bacteria decreased from 4.0 × 106 CFU/mL to 1.1 × 102 CFU/mL after 30 min; meanwhile, other groups were not detected. The most abundant groups were Lactococcus (29.94%), Pseudomonas (28.89%), and Enterobacteriaceae (21.19%). Beta-lactams were detected in five-sevenths samples, and in one sample they were detected before and at 15 min of treatment but not after 30 min. Conclusions: The effect of treatment with copper ions on the different bacterial groups was significantly effective but showed limited effect on the detection of antibiotics.

Abstract Background & Objectives Calcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine. It is understood that they act peripherally, which raises the question whether treatment merely interferes with the last stage of headache generation or, alternatively, causes secondary adaptations in the central nervous system and might thus possess disease modifying potential. This study addresses this question by investigating the nociceptive blink reflex (nBR), which is closely tied to central disease activity, before and after treatment with CGRP antibodies. Methods We enrolled 22 patients suffering episodic migraine (21 female, 46.2 ± 13.8 years of age) and 22 age-/gender-matched controls. Patients received assessments of the nBR (R2 component, 10 trials, 6 stimuli/trial) before (V0) and three months (V3) after treatment with CGRP antibodies started, controls were assessed once. The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) of the stimulated/non-stimulated side (_s/_ns) following repeated supraorbital stimulation provide a direct readout of brainstem excitability and habituation as key mechanisms in migraine. Results All patients showed a substantial reduction of headache days/month (V0: 12.4±3.3, V3: 6.6 ± 4.9). R2a_s (Fglobal=5.86, p

Abstract Background Although migraine is less common in older people, preventive treatment of migraine in these individuals may be more challenging due to the presence of multiple comorbidities and polypharmacy. Additionally, evidence for migraine treatment efficacy, safety, and tolerability is limited in this population. We evaluated efficacy, safety, and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene–related peptide (CGRP), in clinical trial participants aged ≥60 years with episodic migraine (EM) or chronic migraine (CM). Methods This analysis included data from 3 randomized, double-blind, placebo-controlled phase 3 studies: the HALO EM study, HALO CM study, and FOCUS study in participants with EM or CM and prior inadequate response to 2–4 migraine preventive medication classes. Participants in all studies were randomized 1:1:1 to receive 12 weeks of subcutaneous treatment with quarterly fremanezumab (Months 1/2/3: EM/CM, 675 mg/placebo/placebo), monthly fremanezumab (Months 1/2/3: EM, 225 mg/225 mg/225 mg; CM, 675 mg/225 mg/225 mg), or matched monthly placebo. Results These pooled analyses included 246 participants aged ≥60 years. Reductions in monthly migraine days from baseline over 12 weeks were significantly greater with fremanezumab (least-squares mean change from baseline [standard error]: quarterly fremanezumab, − 4.3 [0.59]; monthly fremanezumab, − 4.6 [0.54]) versus placebo (placebo, − 2.3 [0.57]; both P

Abstract Background Persistent postural-perceptual dizziness (PPPD) is the most common functional vestibular disorder. A multisensory mismatch altered by psychological influences is considered to be an important pathophysiological mechanism. Increased cortical and subcortical excitability may play a role in the pathophysiology of PPPD. We hypothesized that decreased motion perception thresholds reflect one mechanism of the abnormal vestibular responsiveness in this disorder. We investigated the vestibular perception thresholds and the vestibular ocular reflex with a rotatory chair experiment to gain insights in the processing and adaption to vestibular provocation. Methods In this cross-sectional study 26 female PPPD patients and 33 healthy female age matched controls (HC) were investigated sitting in a motorized rotary chair shielded regarding visual and acoustic stimuli. The chair was rotated for 20 minutes with slowly increasing velocity to a maximum of 72°/s. We functionally tested motion perception thresholds and vegetative responses to rotation as well as vestibular-ocular reflex thresholds. We additionally investigated several psychological comorbidities (i.e. depression, anxiety, somatosensory amplification) using validated scores. Conventional dizziness scores were obtained to quantify the experienced dizziness and impact on daily life. Results PPPD patients showed a significant reduced vestibulo-perceptual threshold (PPPD: 10.9°/s vs. HC: 29.5°/s; p

Background/Objectives: Waste milk harbors many bacteria and antibiotic residues. Calves fed with untreated waste milk have a higher incidence of scours and an increased risk of developing antimicrobial-resistant bacteria. This study aimed to evaluate the efficacy of treatment with copper ions on bacteria and antibiotics contained in bovine waste milk. Methods: Waste milk samples were collected from a dairy farm for seven weeks and were subjected to treatment with copper ions. Total bacterial counts, coliforms, Streptococcus, and Staphylococcus were assessed before and after treatment. Additionally, metagenomic analysis was performed to determine microbial diversity. Results: Before treatment, the total bacterial count average was 4.0 × 106 CFU/mL, 1.7 × 104 CFU/mL for coliforms, 2.6 × 106 CFU/mL for Streptococcus, and 5.4 × 102 CFU/mL for Staphylococcus Copper treatment significantly reduced bacterial counts within 15 min. Total bacteria decreased from 4.0 × 106 CFU/mL to 1.1 × 102 CFU/mL after 30 min; meanwhile, other groups were not detected. The most abundant groups were Lactococcus (29.94%), Pseudomonas (28.89%), and Enterobacteriaceae (21.19%). Beta-lactams were detected in five-sevenths samples, and in one sample they were detected before and at 15 min of treatment but not after 30 min. Conclusions: The effect of treatment with copper ions on the different bacterial groups was significantly effective but showed limited effect on the detection of antibiotics. [ABSTRACT FROM AUTHOR]

BackgroundDigitalization and electronic health (eHealth) offer new treatment approaches for patients with migraine. Current smartphone applications (apps) for migraine patients include a wide spectrum of functions ranging from digital headache diaries to app-based headache treatment by, among others, analysis of the possible triggers, behavioral therapy approaches and prophylactic non-drug treatment methods with relaxation therapy or endurance sport. Additional possibilities arise through the use of modern, location-independent communication methods, such as online consultations. However, there is currently insufficient evidence regarding the benefits and/or risks of these electronic tools for patients. To date, only few randomized controlled trials have assessed eHealth applications.MethodsSMARTGEM is a randomized controlled trial assessing whether the provision of a new digital integrated form of care consisting of the migraine app M-sense in combination with a communication platform (with online consultations and medically moderated patient forum) leads to a reduction in headache frequency in migraine patients, improving quality of life, reducing medical costs and work absenteeism (DRKS-ID: DRKS00016328).DiscussionSMARTGEM constitutes a new integrated approach for migraine treatment, which aims to offer an effective, location-independent, time-saving and cost-saving treatment. The design of the study is an example of how to gather high quality evidence in eHealth. Results are expected to provide insightful information on the efficacy of the use of electronic health technology in improving the quality of life in patients suffering from migraine and reducing resource consumption.

Abstract Background Calcitonin gene related peptide (CGRP) monoclonal antibodies (mAB) are the first specific migraine prophylactic medication. Erenumab is the only CGRP mAB targeting the CGRP receptor. Clinical data regarding efficacy and tolerability of erenumab in highly therapy-refractory patients are not available, yet, although many patients treated with CGRP mAB under real world conditions can be considered as highly therapy-refractory. Methods Clinical routine data of highly therapy-refractory migraine patients treated with erenumab 70 mg for 3 months between November 2018 and December 2019 in the West German Headache Center, University Hospital Essen, Germany, were analysed. Monthly migraine days (MMD), monthly headache days (MHD) and days of acute medication intake (AMD) were assessed. Statistical analysis was performed using the Wilcoxon test. Descriptive statistics were performed to evaluate changes of vegetative symptoms, acute medication response, side effects, as well as treatment satisfaction. Results Complete clinical data were available for 26 episodic (EM) and 74 chronic (CM) migraineurs. Sixty-six % (n = 49) of CM patients had an additional medication overuse headache (MOH). After 3 months 57.7% of EM patients and 41.9% of CM patients had a 50% or greater reduction of MMD. The mean number of MMD was reduced by 3.43 (SE 1.26) in EM, and by 4.72 (SE 0.87) in CM. Thirty-nine patients (52.7%) returned from chronic to episodic course of migraine. After 3 months, 23 patients (46.9%) were not suffering from a MOH anymore. Conclusions Erenumab seems to be a promising therapeutic option in highly therapy-refractory migraine patients. Trial registration Retrospective registered.