Received Speaker Honoraria Research Articles

E049 The Initial Impacts of the UK-Wide Rheumatology Physiotherapy Capabilities Framework

Abstract Background/Aims The Rheumatology Physiotherapy Capabilities Framework, first published September 2021, was developed to describe the physiotherapy-specific skills and knowledge unique to the speciality and to act as a profession standard. Dissemination strategies for the framework included profiling through professional organisations, specialist interest groups and online via Twitter and ResearchGate. This project aims to describe the initial dissemination of the Framework and to provide an evaluation of the areas of impact within rheumatology networks. Methods An appraisal was undertaken in October 2022 on how widely the Rheumatology Physiotherapy Capabilities Framework has been used and embedded in UK clinical practice and service delivery. Evaluation strategies included data on downloads since publication and a brief online survey of a convenience sample of experienced, specialist rheumatology physiotherapists. The open-ended survey question asked for “implementation feedback on your use of the framework” and allowed undirected free-text comments. Responses were analysed using qualitative content and thematic analysis. Results The framework has been downloaded from the British Society for Rheumatology website 154 times and the launch news story on the BSR website has been viewed 4145 times; the Framework has been accessed 354 times from ResearchGate; analysis of impact on the Twitter shows 33 tweets, 238 likes and 95 “re-tweets”. Thematic analysis identified four key areas of use of the framework:(i) Increasing awareness of the physiotherapy role in a Rheumatology service(ii) Personal and team professional development(iii) Recruitment, job matching, re-banding and promotion(iv) Referral pathways and service improvement. Quotes from the survey responses are collated according to these identified themes in Table 1. Conclusion In its first year of publication, this brief survey indicates that the Rheumatology Physiotherapy Capabilities Framework has already started to accomplish many of the aims of its development. The ability for individuals and services to compare their capabilities to an agreed national standard is supporting staff and services in valuable ways. Service improvement projects have been an additional benefit of the framework. It has already become fairly well embedded in UK rheumatology practice; however, further dissemination, awareness-raising strategies and utilisation support are required to fully accomplish its aims. Disclosure W.J. Gregory: Honoraria; W.G. has received honoraria for speaker and advisory board from Abbvie, Novartis and Pfizer. H. Chambers: None. C. McCrum: Honoraria; C.McC. has received speaker honoraria from Novartis. Grants/research support; C.McC. has received a funding grant from Janssen.

P127 Baricitinib Efficacy in Moderate Rheumatoid Arthritis - A Post-hoc Analysis from two Phase III Trials

Abstract Background/Aims Baricitinib, an oral selective JAK 1/2 inhibitor, is approved for treating adults with moderate-to-severe active rheumatoid arthritis (RA). This analysis aims to report the efficacy of baricitinib in patients with moderate RA at weeks (W)12 and 24 from two phase III studies, RA-BEAM (NCT01710358) and RA-BUILD (NCT01721057). Methods This post-hoc analysis included patients from RA-BEAM (inadequate responders to methotrexate) and RA-BUILD (inadequate responders to conventional synthetic DMARDs) with moderate RA at baseline (defined as Disease Activity Score (DAS)-28 with C-reactive protein (CRP) of > 3.2 and ≤5.1). This analysis reports treatment response as low disease activity (LDA) defined by DAS28-CRP ≤3.2 and >2.6 or remission defined by < 2.6 and presents descriptive data at W12 and W24, including pain (visual analogue scale [VAS]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), physical functioning (Health Assessment Questionnaire-Disability Index [HAQ-DI]), Work Productivity and Activity Impairment (WPAI), duration and severity of morning stiffness, joint pain, and fatigue using daily diaries. Continuous variables are presented as median with interquartile range and categorical variables as frequencies and percentages. Results At baseline, moderate RA was observed in 117 patients on baricitinib 4-mg, 80 on adalimumab, and 133 on placebo in RA-BEAM; and 80 on baricitinib 2-mg, 63 on baricitinib 4-mg, and 73 on placebo in RA-BUILD. In RA-BEAM at W12, 46.2%, 37.5%, and 9.0% of patients on baricitinib 4-mg, adalimumab, and placebo, respectively, achieved remission. In RA-BUILD at W12, 38.8%, 44.4%, and 13.7% of patients on baricitinib 2-mg, baricitinib 4-mg, and placebo, respectively, achieved remission. At W24, a further increase in the percentage of patients achieving remission was reported in both trials (Table). Improvement in pain (VAS), FACIT-F, and HAQ-DI was similar across RA-BEAM and RA-BUILD with baricitinib treatment (Table). In both trials, patients reported improvement in duration and severity of morning stiffness, worst tiredness, and worst joint pain with baricitinib treatment (Table). Additionally, baricitinib treatment yielded numerical improvement in impairment of daily activity and work productivity in RA-BEAM (Table). Conclusion In patients with moderate RA, baricitinib markedly improved signs and symptoms of RA and patient-reported outcomes (PROs) at W12 and W24. Disclosure B.W. Kirkham: Member of speakers’ bureau; B.K. has received speaker’s payments from AbbVie, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, and UCB. Grants/research support; B. K. has received research support from Eli Lilly and Company and Novartis. Other; B. K. has been an adviser for AbbVie, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, and UCB. B. W. has received meeting support payments from Eli Lilly and Company. E. Nikiphorou: Honoraria; E.N. received speaker honoraria from Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Eli Lilly and Company, and Fresenius. Grants/research support; E.N. holds grants from Pfizer and Eli Lilly and Company. Other; E.N. participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Eli Lilly and Company, and Fresenius. E. N. received travel payments from Eli Lilly and Company. C.J. Edwards: Honoraria; C.E received honoraria from Eli Lilly and Company. Grants/research support; C.E. received grant payments from Abbvie, Pfizer, Roche, Biogen, and Eli Lilly and Company. Other; C.E. received personal fees from Abbvie, Astra-Zeneca, BMS, Celltrion, Fresenius, Galapagos, Gilead, GSK, Janssen, Roche, Pfizer, and Sanofi and travel and meeting payments from Eli Lilly and Company. M. Sheesh: Corporate appointments; M. S. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; M. S. is a minor shareholder at Eli Lilly and Company. E. Haladyj: Corporate appointments; E. H. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; E. H. is a minor shareholder at Eli Lilly and Company. J. Gerwien: Corporate appointments; J. G. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; J. G. is a minor shareholder at Eli Lilly and Company. L. Zaremba-Pechmann: Corporate appointments; L. Z-P is a contractor at HaaPACS gmbH. P.C. Taylor: Consultancies; P. T. has been a consultant for AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly and Company, BMS, Pfizer, Roche, Celltrion, Sanofi, Nordic Pharma, Fresenius, and UCB. Grants/research support; P. T. received grant/research support from Galapagos. Other; P. T. has received meeting support payments from Eli Lilly and Company.

Spinocerebellar Ataxia Type 35 Caused by a New TGM6 Variant: Video Documentation of a German Family.

Spinocerebellar Ataxia Type 35 Caused by a New TGM6 Variant: Video Documentation of a German Family.

ISPAD Clinical Practice Consensus Guidelines 2022: Diabetes technologies: Insulin delivery.

J.L.S. reports having received speaker honoraria from Eli Lilly, Insulet, Medtronic, and Zealand and serves on advisory boards of Bigfoot Biomedical, Cecelia Health, Insulet Corporation, Medtronic Diabetes, JDRF T1D Fund, and Vertex. She has been a consultant for Insulet and Medtronic. J.L.S.'s institution received research grant support from JDRF, Medtronic, Insulet, and NIDDK. M.S. reports research grant support, paid to her institution, from Tandem Diabetes Care, Insulet, Medtronic, JDRF, and NIDDK. T.S. has no conflict to disclose. L.R. reports speaker fees from Sanofi, Pfizer, NovoNordisk. T.B. reports speaker fees, consulting honoraria or research support from AstraZeneca, Ascensia, DexCom, Medtronic, NovoNordisk, Roche, Sanofi, and Ypsomed. Since 2021, he is member of the Expert group for medical devices of the European Medicines Agency. A.G. received speaker honoraria from Ypsomed. A.G.'s institution received research support from the European Commission (H2020 program). J.V. has no conflict to disclose. M.E.H. receives research grant support from NIDDK, JDRF, and The Leona M. and Harry B. Helmsley Charitable Trust. C.B. has been a consultant for Insulet. L.A.D. reports that in the last 3 years she has consulted for Vertex and served on a Mannkind, Merck, and Abata adivosry board. She has also recieved research support to her instiution from Caladrius, Lilly, Mannkind, Medtronic, Provention, and Zealand. The peer review history for this article is available at https://publons.com/publon/10.1111/pedi.13421. JLS reviewed the literature, drafted sections of the guidelines, oversaw completion of the first draft of the guidelines, and edited the manuscript. MS, TD, LR, TB, AG, JV, MEH and CB reviewed the literature, provided drafts of sections and edited the manuscript. LAD outlined the guidelines, reviewed the literature, edited the manuscript, and served as the senior author. The authors gratefully acknowledge the editorial assistance of Dr. Leena Priyambada. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Good news for the mdx mouse community: Improved dystrophin restoration after skipping mouse dystrophin exon 23

Good news for the mdx mouse community: Improved dystrophin restoration after skipping mouse dystrophin exon 23

Itch-free state in patients with atopic dermatitis treated with ruxolitinib cream: A pooled analysis from two randomized phase 3 studies

Itch-free state in patients with atopic dermatitis treated with ruxolitinib cream: A pooled analysis from two randomized phase 3 studies

6-OR: Vascular Endothelial ROCK2 Deficiency Promotes Browning and Burning of White Adipose Tissue

The accumulation of visceral fat is associated with multiple coronary risk factors such as glucose intolerance, dyslipidemia, and hypertension. We have previously demonstrated that Rho/Rho-associated protein kinase (ROCK) signaling is activated in animal models of diabetes and is involved in the pathogenesis of vascular complications. Specifically, ROCK is implicated in the molecular basis of inflammation- and ischemia-induced tissue damage through the actions on NF-κB dynamics. These findings support the hypothesis that ROCK signaling could be one of the important therapeutic targets for preventing cardiorenal events. However, isoform-specific roles of ROCKs have not been clarified yet. In this study, we aimed to determine the tissue-intrinsic roles of ROCK2 in the setting of obesity. To this end, we generated vascular endothelium-specific ROCK2 knockout mice (ER2KO) by crossing ROCK2 floxed mice with VE-Cadherin-Cre mice. ER2KO mice were fertile and had the same lifespan as wild type mice. Notably, ER2KO gained weight at a slower rate than wild type mice under high-fat diet feeding. Fat composition, as assessed by magnetic resonance imaging, was significantly lower in ER2KO, even though ER2KO displayed increased food intake. The gene expression analysis revealed increased expression of PPARα, a browning-inducing factor, and its downstream components, CIDEA, IL-4, and IL-10, in white adipose tissue obtained from ER2KO mice. ER2KO mice also showed an elevation in body temperature after fasting, suggesting that endothelial ROCK2 may negatively regulate fat browning. In summary, vascular endothelial ROCK2 negatively regulates fat accumulation through the mechanism of browning inhibition. Disclosure Y. Takeda: None. K. Matoba: None. R. Ukichi: None. Y. Nagai: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker's Bureau; Abbott Diabetes, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Terumo Corporation. Funding a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, the MSD Life Science Foundation, the Takeda Science Foundation, the Suzuken Memorial Foundation, Sanofi KK, Tanabe Pharma, and Takeda Pharmaceutical., Kazunori Utsunomiya has received research support from Terumo, Novo Nordisk Pharma, Taisho Pharmaceutical, Böehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, and OPharmaceutical as, Rimei Nishimura has received speaker honoraria from Astellas Pharma, Nippon Boehringer Ingelheim, Eli Lilly Japan KK, Kissei Pharmaceutical, Medtronic Japan, MSD, Novartis Pharma KK, Novo Nordisk Phar.

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework.

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework.

Antibody response to herpes simplex virus-1 is increased in autoimmune encephalitis.

Antibody response to herpes simplex virus-1 is increased in autoimmune encephalitis.

Addendum.

Swartz EE, Register-Mihalik JK, Broglio SP, et al. National Athletic Trainers' Association Position Statement: Reducing Intentional Head-First Contact Behavior in American Football Players. J Athl Train. 2022;57(2):113–124. doi: https://doi.org/10.4085/1062-6050-0062.21Please see the authors' disclosures below.Erik E. Swartz, PhD, ATC, has received grants from the GOG Hawaii Foundation and the Nine Sigma Head Health Challenge and trademark registration for HUTT. Johna K. Register-Mihalik, PhD, LAT, ATC, has received grants from the National Operating Committee on Standards for Athletic Equipment, Department of Defense (DOD), Centers for Disease Control and Prevention (CDC), National Center for Injury Prevention and Control, National Athletic Trainers' Association (NATA) Foundation, National Football League (NFL), and National Collegiate Athletic Association (NCAA)–DOD Mind Matters Research Challenge Award; she is a member of USA Football's Football Development Council. Steven P. Broglio, PhD, ATC, has received funding from the National Institutes of Health, CDC, DOD-USA Medical Research Acquisition Activity, NCAA, NATA Foundation, NFL, Under Armour/GE, Simbex, and ElmindA. He has consulted for the NCAA (travel expenses only), US Soccer, US Cycling (unpaid), and medicolegal litigation and received speaker honoraria and travel reimbursements for talks given. He is on the University of Calgary SHRed Concussions external advisory board (unpaid). Jason P. Mihalik, PhD, CAT(C), ATC, has received grants from the National Institutes of Health, NFL, CDC, and DOD. Kevin M. Guskiewicz, PhD, ATC, has received grants from the NFL (subaward from Boston Children's Hospital) and NCAA and nonfinancial support from the NCAA Scientific Committee. Julian Bailes, MD, is Chairman of the Medical Advisory Committee for Pop Warner Football. Jay L. Myers, PhD, reported no disclosures. Merrill Hoge, BA, has received royalties from Mascot Books for a football-related publication.

Safety of fertility preservation techniques before and after anticancer treatments in young women with breast cancer: a systematic review and meta-analysis.

Safety of fertility preservation techniques before and after anticancer treatments in young women with breast cancer: a systematic review and meta-analysis.

Persistence with insulin pump therapy among children and young adults with type 1 diabetes in Germany: An update.

Persistence with insulin pump therapy among children and young adults with type 1 diabetes in Germany: An update.

Parents’ Experiences of Using a Hybrid Closed-Loop System to Care for a Very Young Child With Type 1 Diabetes: Qualitative Study

Background: We explored parents’ experiences of using a hybrid closed-loop system when caring for a very young child with type 1 diabetes. Our objectives were to understand the impact of using this technology on users’ quality of life and inform its use in routine clinical care. Methods: Interviews were conducted with parents of 30 children (aged 1-7 years) who participated in a randomised controlled trial comparing closed-loop insulin delivery with sensor-augmented pump therapy. Findings: Parents reported major clinical benefits to using the closed-loop system, including more time being spent in range. Parents welcomed opportunities to collaborate with the system (using Ease-off and Boost functions) when their own knowledge could enhance its efficacy. Parents also reported a lessened need for health professional input after the initial transition onto the system had been made. Parents described wide-ranging quality-of-life benefits to using a system that automatically regulated blood glucose. Parents reported sleeping better, worrying less about their child and feeling more confident entrusting their child’s care to others, and how these individuals were more willing to assume caregiving responsibilities. Parents also described how their child felt more normal and experienced better sleep, mood and concentration, and lessened distress. Siblings also benefitted from parents’ time and attention being less focused on diabetes management. While parents highlighted multiple benefits to being able to administer insulin using a smartphone, difficulties were experienced stowing this device on the child’s body. Interpretation: Using a hybrid closed-loop system in very young children can have potentially life-changing consequences and may result in a lessened demand for health professionals’ input. Systems may need to be customised for use in very young children. Funding Information: The European Commission within the Horizon 2020 Framework Programme under the grant agreement number 731560 funded this work. Declaration of Interests: RH reports having received speaker honoraria from Eli Lilly and Novo Nordisk, serving on advisory panels for Eli Lilly and Novo Nordisk, receiving licence fees from BBraun and Medtronic. RH reports patent patents, patent applications, shareholding and directorship at CamDiab. FC has attended Advisory Boards and obtained speaking fees for Abbott, Medtronic, Lilly, and NovoNordisk. EFR reports having received speaker honoraria from Eli Lilly and Novo Nordisk, and serving on advisory boards for Eli Lilly and Sanofi. SH declares having received speakers honoraria from Eli Lilly, Sanofi and Pfizer. TMK has received speaking honoraria from Eli Lilly and MerckSerono, and consulted Sanofi for a transition brochure. BRM has received speaker honoraria from Abbott Diabetes Care, Eli Lilly, Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi and Menarini, and has been on the advisory boards of Roche Diabetes Care and Abbott Diabetes Care. The Authors JL, DR, RIH, CKB, JF, JMA, AT, US and BK declare that there is no conflict of interest. Ethics Approval Statement: Participants were consented into the interview study when they were consented into the trial. Approval was received from relevant Ethics Committees in participating sites/countries and relevant national regulatory authorities.

The Role of Mobility Endpoints in Marketing Authorisation of Drugs: What Gets the EMA Moving?

Background: Mobility is defined as the ability to independently move around the environment and is a key contributor to quality of life. The aim of this study was to evaluate the use of mobility as a decisive outcome for the marketing authorisation of drugs by the European Medicines Agency (EMA). Methods: Fifteen therapeutic areas which commonly lead to mobility impairments and alter the quantity and/or the quality of walking were selected: two systemic neurological diseases, four conditions primarily affecting exercise capacity, seven musculoskeletal diseases, and two conditions representing sensory impairments. European Public Assessment Reports (EPARs) published by the EMA up to September 2020 were examined for mobility endpoints included in their ‘main studies’, defined as those which were decisive for EU approval. Clinical study registries and primary scientific publications for these studies were also reviewed. Findings: 484 EPARs yielded 186 relevant documents with 402 ‘main studies’. The EPARs reported 153 primary and 584 secondary endpoints which considered mobility; 70 different assessment tools (38 patient-reported outcomes, 13 clinician-reported outcomes, 8 performance outcomes, and 13 composite endpoints) were used. Importantly, only 15·7% of those tools distinctly informed on patients’ mobility status. 105/402 (26·1%) of the ‘main studies’ did not have any mobility assessment and none of these studies included a digital mobility outcome. The supplementary review of study registries and primary publications revealed only five uses of mobility assessments not reported by EPARs. Interpretation: For conditions with a high impact on mobility, distinct mobility assessment was given little consideration in the marketing authorisation of drugs by the EMA. Where mobility impairment was considered to be a relevant outcome, questionnaires or composite scores were predominantly used. Reporting biases for such outcomes presents challenges for the interpretation of study results. Funding: Mobilise-D (Innovative Medicines Initiative) and Robert Bosch Stiftung, Germany. Declaration of Interest: SJ is partly supported by the Robert Bosch Stiftung Stuttgart. MW reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. DS reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. MC reports personal fees from Takeda Pharmaceuticals, during the conduct of the study; personal fees from Takeda Pharmaceuticals, outside the submitted work. JK reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. JGA reports grants from HORIZON2020 IMI No. 820820, and from AstraZeneca, Chiesi, Esteve, outside the submitted work. WM receives or received funding from the European Union, the German Federal Ministry of Education of Research, Michael J. Fox Foundation, Robert Bosch Foundation, Neuroalliance, Lundbeck and Janssen. He received speaker honoraria from Abbvie, Bayer, GlaxoSmithKline, Licher MT, Rolke Pharma and UCB, was invited to Advisory Boards of Abbvie, Biogen, Lundbeck and Market Access & Pricing Strategy GmbH, and is an advisory board member of the Critical Path for Parkinson's Consortium. He serves as the co-chair of the MDS Technology Task Force. MP reports grants from HORIZON2020 IMI No. 820820, outside the submitted work. MS is supported by the Robert Bosch Stiftung Stuttgart and reports grants from HORIZON2020 IMI 2 Mobilise D, during the conduct of the study, and grants and non-financial support from Green Cross WellBeing Co. Ltd., Gilead Sciences Inc., Robert Bosch GmbH, and CORAT Therapeutics GmbH , as well as other from Agena Bioscience GmbH, outside the submitted work. CB disclosed consultation from E. Lilly and speaker fees from Amgen, Nutricia and Pfizer reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. RT, BS, LL, LR, SCR declare no competing interests.

The Effect of Different National Treatment Strategies on Disability Outcome in Relapsing-Remitting Multiple Sclerosis: A Propensity Score Adjusted Comparison between Denmark and Sweden

Background: Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The objective was to investigate the influence of such differences on disease modifying treatment (DMT) and disability outcome. Methods: Patients with RRMS commencing their first DMT 2013-2016 were retrospectively included from the Swedish and Danish MS registries. Time to the 24-week confirmed disability worsening (CDW, primary outcome) and 24-week confirmed disability improvement (CDI, secondary outcome) and milestone expanded disability status scale (EDSS) score 3 and 4 end-points (secondary outcomes) were analyzed using Inverse Probability of Treatment Weighting (IPTW)-based Cox regression models with robust standard errors. The IPTW model used a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the two countries. Findings: A total of 2700 patients from the Swedish registry and 2161 patients from the Danish MS registry commencing a first DMT between 2013 and 2016 were included in the analysis and observed for an average of 4 years. The proportion of patients initiating with a low-moderate as compared to highly effective DMT was 92.4% (teriflunomide 42%) and 7.6% in Denmark and 62.4% (teriflunomide 2.4%) and 35% in Sweden, respectively. Swedish patients were associated with a 29% reduction in the rate of post-baseline 24-week CDW relative to Danish patients (IPTW HR 0.71; 95% CI 0.57-0.90; p=0.004). The Swedish cohort was associated with a 27% and 26% reduction in the rate of reaching EDSS 3 and 4 respectively, relative to Danish patients (HR 0.73; 95% CI 0.62-0.85; p<0.001; and 0.74; 95% CI 0.59-0.93; p=0.009, reference = Denmark). Interpretation: We show for the first time that differences in treatment strategies of RRMS have an impact on disability outcomes at a national level. Escalation of treatment efficacy seemed inferior to using more efficacious DMT as initial treatment. Funding Statement: This study was supported by the Swedish Research Council, the Swedish Brain foundation, the Karolinska University Hospital & the Patient-Centered Outcomes Research Institute (PCORI), the Swedish Multiple Sclerosis Research Foundation, the Swedish Federal Government (LUA/ALF Agreement ALFGBG-722081), the Swedish Association of Persons with Neurological Disabilities, the Research Foundation of the Multiple Sclerosis Society of Gothenburg, the Edit Jacobson Foundation, and NEURO Sweden. Declaration of Interests: TS has received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen Inc; speaker honoraria from Novartis. MM has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie, has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. FP has received research grants from Biogen and Novartis. AS reports no conflicts of interest FS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. PVR has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, and Alexion, has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, has received support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. MK reports no conflicts of interest HJ has received honoraria for participating in advisory board from Biogen. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis and speaker’s fees from Biogen, Novartis, Merck-Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, BiogenIdec, Merck- Serono, TEVA, Sanofi-Genzyme and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation JL has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, Roche and SanofiGenzyme; has served on scientific advisory boards for Biogen, Novartis, Merck, Roche, BSM and SanofiGenzyme; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, and Novartis. Ethics Approval Statement: The study was approved by the The Swedish Ethical Review Authority (Dnr: 2019-00839/1199-18), and The Danish Data Protection Authority (Org. number 202100 2973).

Employment, Health Care Utilization, Mental Health, and Mortality in Parents With a Chronically Ill Child: A Nationwide Population-Based Cohort Study

Background: Chronic diseases in children can impact their parents; this may be overlooked in a clinical setting. Our objective was to investigate associations of chronic diseases in children with their parents’ employment, health care utilization, mental health, and mortality. Methods: In a matched cohort study using nationwide and population-based data in Denmark we included parents to children (<18 years) with acute disseminated encephalomyelitis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease and rheumatoid arthritis during 2008–15. The reference group was parents to sex- and age-matched unaffected children. Outcomes were employment (early retirement, cash benefits, income), health care utilization (e.g. general practitioner, or hospital visits), mental health (visits to psychiatry/psychology clinics, antidepressant drug redemptions), and mortality. Findings: We included 13,769 parents with a chronically ill child and 138,606 control parents. One-parent families had an increased annual income after the child’s disease onset. Two-parent families had increased hazard of early retirement of 25% (95% CI=1∙01–1∙54, p=0∙04). Parents with a chronically ill child had a) increased rate of antidepressant drug redemptions or psychology/psychiatry visits (hazard ratio 1∙37; 95% CI=1∙28‒1∙46 at 1-year follow-up); b) increased health care utilization, with an increased marginal mean in primary care of 1% (95% CI=1∙00–1∙02; p=0∙005), hospital-affiliated visits of 19% (95% CI=1∙14–1∙24; p<0∙0001), and hospital admissions of 14% (95% CI=1∙09–1∙20; p<0∙0001); c) 69% increased mortality hazard (95% CI 1∙30–2∙18, p<0∙0001) in parents younger than 50 years with no comorbidities, albeit small in absolute numbers. Interpretation: Pediatric chronic diseases were negatively associated with parental employment, mental health, and increased health care utilization. Parents to a chronically ill child who were younger than 50 years and who had no comorbidities also had increased mortality hazard. Funding Statement: Danish MS Society, Dagmar Marshalls Fond, Axel Muusfeldts Fond, Bent Boghs Fond, Viggo Bruuns Fond. Declaration of Interests: Dr. Boesen has served on a scientific advisory board for Teva; has received speaker honoraria for lecturing from Novartis, and support for congress participation from Teva, Novartis and Roche. Dr. Blinkenberg has served on scientific advisory boards for Genzyme, Roche, Biogen, Merck, Novartis and Teva; has received speaker honoraria from Genzyme, Biogen, Merck, Novartis, Teva and Roche; has received consulting honoraria from the Danish Multiple Sclerosis Society, Biogen, Teva, Roche and Merck; and has received funding for travel from Genzyme, Roche and Biogen. Dr. Thygesen has received honoraria for lecturing from Rigshospitalet (Copenhagen, Denmark), Statistics Denmark and Sanofi Aventis. Dr. Uldall reports no disclosures. Dr. Born has received speaker honoraria from Novartis and has served on advisory boards for Biogen, Novartis and Roche. Dr Magyari has served on the scientific advisory board for Biogen, Sanofi, Teva, Roche, Novartis, and Merck; has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and support for congress participation from Biogen, Genzyme, Teva, and Roche. Dr. Eriksson reports no disclosures. Ethics Approval Statement: The Danish Health and Medicines Authority waived the requirement for patient informed consent to access medical records (case number: 3-3013-896/1). The study was approved by the Danish Data Protection Agency (30-1423/03567) and the Danish Health Data Authority (FSEID: 00003621/DST: 707103).

Striatal Atrophy and Hypometabolism in Drug-Resistant Non-Ketotic Hyperglycemic Chorea-Ballism.

Non-ketotic hyperglycemic chorea-ballism (NKHCB) is a rare movement disorder associated with poorly controlled type-2 diabetes,1 in the majority of cases characterized by: unilateral hemicorea-hemiballism, contralateral striatum hyperintensity on T1-weighted magnetic resonance imaging (MRI), and clinical and radiological improvement after blood glucose correction.2 Herein, we present a case of NKHCB with following evidence of striatal atrophy. A 56-year-old woman presented to the emergency department of another hospital because of sudden onset of involuntary movements of the left limbs attenuated during rest. She had a recent history of type-2 diabetes mellitus treated with poor glycemic control. A computed tomography scan showed striatal hyperdensity. Routine laboratory findings were normal, despite a fasting blood glucose level of 167 mg/dL and glycate hemoglobin level of 130 mmol/mol (14%). MRI scan showed striatal T1-weighted hyperintensity with a corresponding hyperintensity in T2-weighted (Fig. 1A and B) and fluid attenuated inversion recovery (FLAIR) scans. The patient was diagnosed with NKHCB. Glucose control was optimized and anti-choreic therapy was started with haloperidol 5 mg/day and tetrabenazine 25 mg/day with a slight clinical benefit. The patient arrived at our attention 4 months after symptom onset for diagnostic re-evaluation. The motor impairment persisted and involuntary movements worsened insidiously. The neurological examination showed choreoatetosic and ballic movements of the left body side. Involuntary movements increased with distraction maneuvers and resolved during rest at bed. Blood fasting glucose was 126 mg/dL and glycated hemoglobin was 62 mmol/mol (7.8%). MRI scan showed the resolution of the striatal alteration, but highlighted atrophic evolution (Fig. 1C and D). A fluorodeoxyglucose positron emission tomography scan showed an intense hypometabolism consistent with morphological MRI atrophy findings (Fig. 1E and F). Haloperidol was discontinued and clinical improvement was obtained with tetrabenazine 25 mg thrice/day, piracetam 3 g/day and topiramate 25 mg twice/day. The comparison of MRI volumes at the two timepoints showed, on the right side, a decrease in caudate head and putamen volumes and an increase in the lateral ventricle volume. The two main pathophysiological mechanisms proposed for NKHCB are related to metabolic dysfunction and to microvascular damage.3, 4 Our findings may be explained by irreversible metabolic or vascular damage. The microvascular hypothesis might explain the prevalent unilateral clinical onset. The prognostic implication of our observation is related to the high variability in outcomes.1 Extended lesions at MRI were associated with prolonged involuntary movements.5 Our findings of focal atrophy strengthen these results, suggesting a role of the pathological disease severity, in-vivo assessed by MRI, to determine the persistence of the disorder. We hypothesize that a mild disorder, solved with anti-chorea treatment, might be associated with a lower degree of atrophy, unrecognized without a volumetric analysis. In conclusion, our case of NKHCB showed focal striatal atrophy and hypometabolism after radiological resolution in a 4-month follow-up, associated with poor response to glucose-control and anti-chorea treatment. To date, for the first time we documented nuclear volume changes with a quantitative approach demonstrating irreversible pathological changes in NKHCB, explaining drug-resistant cases. (1) Research project: A. Conception, B. Organization, C. Execution. (2) Statistical Analysis: A. Design, B. Execution, C: Review and Critique. (3) Manuscript: A. Writing of the first draft, B. Review and Critique. P.G.S.: 1A, 1B, 1C, 2A, 2B, 3A F.A.: 1A, 1B, 2C, 3B N.A.: 1C, 3B M.A.V.: 1A, 1B, 1C, 2C, 3B M.F.: 1A, 1B, 2C, 3B This study has been approved by the Ethics Committee of IRCCS San Raffaele Hospital and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The patient provided written informed consent to be anonymously included in this report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No funding was received for this work and the authors have no conflicts of interest to report. P.G. Scamarcia, N. Anzalone, and M.A. Volontè have nothing to disclose. F. Agosta is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Philips, Novartis and Biogen Idec; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. M. Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Distinct Patterns of Humoral and Cellular Immune Responses Following SARS-CoV-2 mRNA Vaccination in Patients With Immune-Mediated Neurological Disorders on Anti-CD20 Therapy: A Prospective Cohort Study

Background: Patients with neuroimmunological disorders on anti-CD20 therapy are at increased risk of severe COVID-19. However, little is known about SARS-CoV-2 vaccine efficacy in this cohort. In particular, the impact of B cell depletion on humoral and cellular immune responses to SARS-CoV-2 vaccination remains poorly defined. No study has addressed vaccine responses to the SARS-CoV-2 delta variant in immunocompromised individuals so far.Methods: In this prospective cohort study we investigated humoral and cellular responses in serial samples from 164 individuals after SARS-CoV-2 mRNA vaccination (82 patients with neuroimmunological disorders on anti-CD20 therapy and 82 healthy controls). Antibodies were quantified using the Elecsys anti-SARS-CoV-2 S immunoassay against the receptor-binding (RBD) domain. T cell responses against the SARS-CoV-2 Wuhan strain and the delta variant were assessed by IFN-g enzyme-linked immunosorbent spot assays. Findings: Following vaccination, SARS-CoV-2 –specific antibodies were detected in 57/82 (70%) patients compared to 82/82 (100%) healthy controls (pInterpretation: Humoral immunity following SARS-CoV-2 mRNA vaccination can be achieved in patients on anti-CD20 therapy once B cells start to repopulate. In the absence of B cells, a robust and stable T cell response is generated which may provide a potent defense against severe COVID-19 in this high-risk patient population. Funding Information: Funded partly by a Medical-Scientific fund of the Major of the federal capital of Vienna (grant Covid003).Declaration of Interests: BK has received honoraria for speaking and for consulting from Biogen, BMS-Celgene, Johnson&Johnson, Merck, Novartis, Roche, Teva and Sanofi-Genzyme outside of the submitted work. No conflict of interest with respect to the present study. FL has received honoraria for speaking and consulting from Almirall, Biogen-Idec, Celgene BMS, MedDay, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Genzyme, Santhera; Schering, Teva-Ratiopharm. There are no conflicts of interest with respect to the present study, PR has received honoraria for speaking and for consulting from Alexion, Almirall, Amicus, Biogen, Merck, Novartis, Roche, Teva, Sandoz, and Sanofi Genzyme outside of the submitted work. He has received research grants from Amicus, Biogen, Merck and Roche outside the submitted work. GZ recieved speaking honoria from biogen and has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. No conflict of interest regarding this study, GB has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Novartis, Roche, Sanofi-Genzyme and Teva. He has received financial support in the past 12 months by unrestricted research grants (Celgene/BMS, Novartis). No conflict of interest with respect to the present study, ADB declares no conflict of interest related to the content of this article. Independent of this study, ADB has participated in meetings sponsored by or received speaker honoraria or travel funding from Biogen, Merck, Novartis, Roche, Celgene (BMS), and Sanofi. She has received an unrestricted grant from Merck GmbH, an affiliate of Merck KGaA and is currently supported by a research grant from Biogen. TB has no particular conflicts of interest regarding the present study. In general, he has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Bayer, Biogen, Biologix, Bionorica, Genzyme, GSK, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, TG Pharmaceuticals, TEVA ratiopharm and UCB. His institution has received financial support in the last 12 months by unrestricted research grants (Biogen, Bayer, Merck, Novartis, Sanofi/Genzyme, and TEVA ratiopharm) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, and TEVA. LS, HH, RT, FZ, WR, KZ, IW, AS, MG, MM, KR, SW, JHA, ST report no conflicts of interest.Ethics Approval Statement: Subjects gave written informed consent. The study was approved by the ethics committee of the Medical University of Vienna, Austria, EK Nr. 1073/2021.

Pulmonary Aspergillosis in Critically Ill Coronavirus Disease 2019 Patients– A Multinational Observational Study by the European Confederation of Medical Mycology

Pulmonary Aspergillosis in Critically Ill Coronavirus Disease 2019 Patients– A Multinational Observational Study by the European Confederation of Medical Mycology

Age-Related Outcomes after Transcatheter Aortic Valve Implantation: Insights from the SwissTAVI Registry

Age-Related Outcomes after Transcatheter Aortic Valve Implantation: Insights from the SwissTAVI Registry