bluuebunny/crossref_metadata_2025_split huggingface dataset:
022  Updated safety of cladribine tablets in multiple sclerosis patients: integrated safety analysis and post-approval data
Authors: Cook Stuart , Giovannoni Gavin , Leist Thomas , Comi Giancarlo , Syed Sana , Nolting Axel , Damian Doris , Schick Regina , Jack Dominic 
Published: May 2022

BackgroundThis analysis updates on the previously reported serious treatment emergent adverse event (TEAE) profile of cladribine tablets (CT) 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) following integration of final data from the PREMIERE registry and post-approval safety data from worldwide sources.MethodsThe monotherapy oral cohort (CT3.5, N=923, patient-years [PY]=3936.69; placebo, N=641, PY=2421.47) was derived from the CLARITY, CLARITY Extension and ORACLE-MS trials plus the PREMIERE registry. Adjusted adverse event incidences-per-100PY (Adj-AE-per-100PY) were calculated, cumulative to end of PREMIERE (October 2018).ResultsPatient characteristics were balanced between groups. Adj-AE-per-100PY for ≥1 serious TEAE were:3.80 (CT3.5), 3.05 (placebo); for serious lymphopenia (preferred term [PT]): 0.10 (CT3.5), 0 (placebo); for serious infections and infestations (system organ class): 0.60 (CT3.5), 0.42 (placebo); for serious herpes zoster (PT): 0.05 (CT3.5), 0 (placebo); and malignant tumours: 0.26 (CT3.5), 0.12 (placebo). Post-approval sources reported 1622 AEs in the Periodic Benefit-Risk Evaluation Report (275 were serious); none repre- sented a new safety signal.ConclusionsNo new major safety findings for cladribine tablets were identified in this finalised integrated dataset containing final data from the PREMIERE registry. Findings are consistent with previously published integrated safety analyses. No new safety signals were identified from post-approval safety data. CLARITY:NCT00213135. CLARITY Extension:NCT00641537. ORACLE-MS:NCT00725985. PREMIERE:NCT01013350g.giovannoni@qmul.ac.uk
023  Relapse outcomes with natalizumab Q4W vs switch to Q6W
Authors: Butzkueven Helmut , Kappos Ludwig , Spelman Tim , Trojano Maria , Wiendl Heinz , Su Ray , Hyde Robert , Licata Stephanie , Ho Pei-Ran , Campbell Nolan 
Published: May 2022

IntroductionThe approved dosing of natalizumab (300 mg infusion every 4 weeks [Q4W]) is associated with risk of progressive multifocal leukoencephalopathy. This analysis from the TYSABRI Observational Program (TOP) compared relapse outcomes in patients who switched to natalizumab every 6 weeks (Q6W) after 1 year of Q4W with patients who remained on Q4W.MethodsEligible TOP patients had ≥1 year of natalizumab Q4W. Treatment duration-matched Q6W and Q4W patients (191 pairs) were compared by propensity score matching (PSM). Negative binomial model-estimated annualised relapse rate (ARR) and Kaplan-Meier-estimated relapse risk were compared during the post-switch and exposure-matched follow-up periods.ResultsAfter PSM, 135 pairs of Q6W and Q4W patients were included. Mean treatment duration was4.4 years in both groups. There was no difference in ARR (Q6W: 0.231 [95% confidence interval (CI), 0.145–0.367]; Q4W: 0.254 [0.160–0.402]; P=0.774) or relapse risk (hazard ratio [95% CI], 1.021 [0.583–1.789]; P=0.940) between groups.ConclusionsNo significant difference in relapse outcomes was observed between patients who switched4t6o Q6W and those who remained on Q4W. An ongoing randomized prospective trial of Q4W vs Q6W will inform further on the effectiveness of natalizumab Q6W. Support: Biogen.peiran.ho@biogen.com
031  Long-term efficacy of ocrelizumab in primary progressive multiple sclerosis: 6.5-study years
Authors: Schmierer Klaus , Wolinsky Jerry S , Brochet Bruno , Hartung Hans-Peter , Naismith Robert , Koendgen Harold , Manfrini Marianna , Sauter Annette , Prajapati Kalpesh , Kappos Ludwig 
Published: May 2022

BackgroundEfficacy/safety of ocrelizumab in primary progressive multiple sclerosis were demonstrated in the ORATORIO (NCT01194570) double-blind period (DBP). Here we assessed the efficacy of switching to, or earlier initiation of, ocrelizumab after 6.5-study years (312 weeks), in the open-label extension (OLE).MethodsDuring the DBP, patients were randomised to ocrelizumab or placebo for ≥120 weeks until a prespecified number of confirmed disability progression (CDP) events occurred. Patients continued blinded treatment until the outcome was ascertained (extended controlled period [ECP]). At OLE initia- tion, patients continued ocrelizumab (OCR-OCR) or switched from placebo to ocrelizumab (PBO-OCR). Time to onset of 24-week-CDP and time-to-wheelchair-confinement (Expanded Disability Status Scale≥7.0) were analysed.ResultsDuring the DBP, ocrelizumab reduced the risk of 24-week-CDP by 25% (p=0.037) vs placebo. At Week 168 (12 weeks after the first patients entered the OLE), the proportion of patients with 24-week-CDP in PBO-OCR and OCR-OCR was 44.7% vs 33.3% (Δ=11.4%; p=0.005), and at Week 312 was 64.8% vs 51.7% (Δ=13.1%; p=0.002), respectively. During DBP+ECP+OLE, risk of wheelchair confinement was 42% lower (p=0.011) and of 24-week-CDP was 28% lower (p=0.002) in OCR-OCR vs PBO-OCR.ConclusionsCompared with PBO-OCR, initiating ocrelizumab 3–5 years earlier significantly reduced the risk of wheelchair confinement and 24-week-CDP.k.schmierer@qmul.ac.uk
035  Diagnosis of secondary progressive multiple sclerosis in UK centres: results from the SPECTRUM project
Authors: Duddy Martin , Wilkinson Carmel , Rhys Katherine , Medhurst Steve 
Published: May 2022

BackgroundAs new treatment approaches emerge for progressive forms of multiple sclerosis (MS), it is important to understand the factors underlying current practice.MethodsWe used a structured questionnaire to interview 59 healthcare professionals (HCPs) from geo- graphically-dispersed UK MS centres about current disease modifying therapy (DMT) management of patients with suspected/confirmed secondary progressive MS (SPMS).ResultsOf the HCPs who used a definition of SPMS, a minority used the Lublin 2014 phenotype criteria (n=2/36, 6%), the remainder used a variety of other definitions (n=34/36, 94%). The most important element considered for SPMS diagnosis was expanded disability status scale (EDSS) score increase and absence of relapse (n=21/59, 36%), however many other criteria were also used. The median estimated time between first suspecting and diagnosing SPMS was 12.0 months (IQR 12.0–24.0, n=45). The most common explanations for reluctance to diagnose SPMS were concerns over withdrawing DMTs (n=49/59, 83%) and psychological impact on patients (n=39/59, 66%).ConclusionsThere is substantial variation in the UK in how HCPs define and diagnose SPMS. Diagnosis is often made at advanced levels of disability and can take a year or longer from first suspicion of SPMS.katherine.rhys@novartis.com
044  Safety and efficacy of dimethyl fumarate in ESTEEM UK cohort
Authors: Ford Helen L , Su Ray , Parks Becky , Syndercombe Fiona , Jones Cynthia J 
Published: May 2022

IntroductionESTEEM (NCT02047097) is an ongoing 5-year, global study characterizing long-term safety and effectiveness of routinely prescribed dimethyl fumarate (DMF) in multiple sclerosis (MS) patients. We report results from an analysis of the UK cohort of ESTEEM.MethodsThe primary objective of ESTEEM is to assess the incidence, type, and patterns of serious adverse events (SAEs), and AEs leading to discontinuation of DMF in routine practice. Secondary objectives include assessment of annualized relapse rate (ARR) and proportion of patients without relapse at 6 and 12 months.ResultsOf 238 UK patients (median age 42 years, 187[79%] female), SAEs were reported in 14(6%) patients. AEs leading to discontinuation occurred in n=53(22.3%) patients; the most common of these were gas- trointestinal disorders (n=20;8.4%). Unadjusted ARR declined by 84%(95%confidence interval [CI]=68– 100%;P<0.0001), from 0.74(95%CI=0.63–0.85) 12 months before enrollment to 0.12(95%CI=0.07–0.16) the year after enrollment. The proportion of relapse-free patients was 93.8%(n=223) and 87.9%(n=209) at 6 and 12 months, respectively.ConclusionsNo new safety signals were observed in patients treated with DMF routinely for one year. ARR was significantly reduced vs the year prior to enrollment. Safety/efficacy results were similar between the UK and overall ESTEEM populations.SupportBiogen; disclosures detailed on poster.fiona.syndercombe@biogen.com
045  Effect of siponimod on cortical grey matter and thalamic volume in secondary progressive multiple sclerosis
Authors: Arnold Douglas L , Fox Robert J , Bar-Or Amit , Cree Bruce AC , Giovannoni Gavin , Gold Ralf , Vermersch Pat- rick , Meier Daniela Piani , Arnould Sophie , Kappos Ludwig 
Published: May 2022

BackgroundGrey matter (GM) loss is associated with cognitive decline and physical disability in multiple sclerosis (MS). In Phase 3 EXPAND study, siponimod significantly reduced disability progression, cognitive decline and whole brain volume loss in patients with secondary progressive MS (SPMS).MethodsMagnetic resonance imaging (MRI) from EXPAND were pooled and analysed using high reso- lution T1 and conventional MRI. Analysis included intent-to-treat population (full analysis set, FAS) and per protocol set (PPS). Change from baseline in cortical grey matter (cGM) and thalamic volumes were assessed.ResultsIn the FAS, adjusted mean percent change in volume from baseline at M12 and M24, respectively, was −0.07 versus −0.59 (88% reduction vs placebo, p<0.0001) and −0.51 versus −0.90 (43% reduction; p<0.0001) for cGM; −0.54 versus −1.01 (47% reduction; p< 0.0001) and −1.20 versus −1.74 (31% reduction; p=0.0001) for the thalamus. PPS values were 0.01 versus −0.60 (100% reduction; p< 0.0001) and −0.39 versus−1.04 (63% reduction; p< 0.0001) for cGM; −0.47 vs −0.94 (50% reduction; p< 0.0001) and −1.02 versus −1.77 (42% reduction; p< 0.0001) for the thalamus.ConclusionsSiponimod significantly reduced cGM and thalamic volume loss compared with placebo in patients with SPMS.g.giovannoni@qmul.ac.uk
049  Hypertension is uncommon during alemtuzumab treatment for relapsing-remit- ting multiple sclerosis
Authors: Ong Hui Ching , Shields Aoife , Leary Siobhan , Brownlee Wallace J 
Published: May 2022

BackgroundHaemorrhagic cerebrovascular events have been reported during Alemtuzumab treatment for relapsing-remitting multiple sclerosis (RRMS) leading to changes in the marketing authorisation in Europe. Hypertension is the proposed mechanism.AimsTo characterise systolic blood pressure (SBP) changes during Alemtuzumab administration and the frequency of significant hypertension.MethodWe recorded SBP measurements during Alemtuzumab infusions from a random sample of RRMS patients. Mean SBP changes were calculated for each day and the 5-day treatment course. Common Terminology Criteria for Adverse Events was used to grade hypertension.Results2412 SBP measurements from 50 RRMS patients (mean age 35.9 years; 70% female) were recorded. No patients had premorbid hypertension. The mean (SD) SBP change was -0.7 (7.59) mmHg over 5 days. Two (4%) patients developed sustained grade III hypertension (SBP ≥160mmHg) over two or more readings >15 minutes apart, which resolved spontaneously. No patients had immediate cerebrovascular complications.ConclusionsClinically-significant hypertension is uncommon during Alemtuzumab treatment and should prompt close clinical observation. Slowing (or stopping) the rate of infusion should be considered in patients with sustained hypertension.hui.chingong@nhs.net
054  The individual costs of multiple sclerosis
Authors: Nicholas R , Middleton R , Tuite-Dalton K , Rogers W , Craig E , Chevli M , Pulikottil-Jacob M , Heaven M 
Published: May 2022

BackgroundThe UK Multiple Sclerosis Register (UKMSR) captures data from multiple sources including directly from people with MS (pwMS) via online questionnaires. There is little research into the non-medical (personal) costs of MS. In partnership with Sanofi we investigated healthcare resource use and costs (excluding drugs), including who bears these costs, by disease severity and typeMethodsA cost of illness questionnaire was deployed to 3035 pwMS on the UKMSR. Respondent’s answers were linked to retrospective UKMSR data. Resource consumption was categorised as being direct (medical) or indirect (non-medical) and costed by NHS and Social Services estimates for 2018.Results£509,003 was calculated as non-medical costs over a year and £435,488 in medical costs generated over 3 months (n=537, 6935 interventions). PwMS reported self-funding 75% of non-medical costs these were mainly home modifications. Costs, increased with disability but those with indirect costs (n=138) had higher medical costs, were more disabled and were more likely to be unemployed than those with medical interventions only (n=399).ConclusionsThe importance of disability in driving costs is again clearly illustrated with balance between indirect and direct costs consistent with the UK health environment as a whole. PwMS and their families fund 75% of non-medical costs that can facilitate early discharge and reduce the need to rehabilita- tion/nursing home services.richard.nicholas@btinternet.com
059  Secondary progressive MS in the UK: a prospective cohort study
Authors: Harding Katharine , Joseph Fady , Pickersgill Trevor , Tomassini Valentina , Tallantyre Emma , Robertson Neil 
Published: May 2022

BackgroundAlthough most people with relapsing onset multiple sclerosis (R-MS) eventually transition to secondary progressive multiple sclerosis (SPMS), little is known about disability progression in SPMS.MethodsAll R-MS patients in the Cardiff MS registry were included. Cox proportional hazards regression was used to examine a) hazard of converting to SPMS and b) hazard of attaining EDSS 6.0 and 8.0 in SPMS.Results1611 R-MS patients were included. Older age at MS onset (hazard ratio [HR] 1.02, 95%CI 1.01–1.03), male sex (HR 1.71, 95%CI 1.41–2.08), and residual disability after onset (HR 1.38, 95%CI 1.11–1.71) were asso- ciated with increased hazard of SPMS. Male sex (EDSS 6.0 HR 1.41 [1.04–1.90], EDSS 8.0 HR 1.75 [1.14–2.69]) and higher EDSS at SPMS onset (EDSS 6.0 HR 1.31 [1.17–1.46]; EDSS 8.0 HR 1.38 [1.19–1.61]) were associated with increased hazard of reaching disability milestones, while older age at SPMS was associated with a lower hazard of progression (EDSS 6.0 HR 0.94 [0.92–0.96]; EDSS 8.0: HR 0.92 [0.90–0.95]).ConclusionsDifferent factors are associated with hazard of SPMS compared to hazard of disability progres- sion after SPMS onset. These data may be used to plan services, and provide a baseline for comparison for future interventional studies and has relevance for new treatments for SPMSRobertsonNP@cardiff.ac.uk
061  T cell-mediated cerebellitis after ipilimumab for small cell lung cancer
Authors: Guillochon Remi , Nolan Luke , Nicoll James , Jogai Sanjay , Joseph-Pietras Deborah , Arriola Edurne , Ottensmeier Christian , Galea Ian 
Published: May 2022

Ipilimumab is an anti-CTLA4 antibody in evaluation for the treatment of small cell lung cancer. We report a case of rapidly progressive fatal cerebellitis occurring eight months after first dosing. Pre-treatment weakly positive anti-Yo antibodies did not change. Clinically asymptomatic anti-voltage-gated calcium channel antibodies developed after ipilimumab treatment, despite lack of expression by the tumour. The patient died three weeks into the neurological illness. Post-mortem examination revealed a T cell-mediated cerebellitis, with CD8 cytotoxicity towards Purkinje cells. This demonstrates the potential for CD8 T cells to trigger neuronal autoimmunity, offering insight into the early events in paraneoplastic neurological disease.remi.guillochon@nhs.net
062  A case of autoimmune facial swelling, weakness and sensorineuropathy with lower limb myositis
Authors: Ur Rashid Sk Mamun , Warner Graham 
Published: May 2022

BackgroundClinical features of Sjögren’s Syndrome (SS) and Systemic Lupus Erythematosus (SLE) often overlap. We present a case with facial sensory neuropathy & myositis.Clinical presentation: A 45-year-old lady with 14 years of fleeting myalgia/polyarthralgia, recurrent chest infections, oral ulcers, hair loss, and recent onset jaw and facial pain was initially diagnosed as having GCA/PMR but unresponsive to prednisolone. Developing new slurred speech, salivation pain, left facial weakness and vomiting a year later, SLE was diagnosed (investigations below). Neurological scrutiny five months after found bilateral sensory trigeminal neuropathy, asymmetric bifacial weakness, and ten- derness of TMJs, overlying the mandibular rami, shoulders, and extremities but no neurological deficits beyond painful dysarthria.Immunology showed a raised ESR, a positive ANA, anti-Ro and anti-La with negative antiphospholipid antibodies. Initial testing reported normal CT chest and brain MRI but mild lymphocytic infiltration on temporal artery biopsy. Biochemistry showed CK of 2300 with upward trend. MRI and EMG showed myositis in hamstrings, quadriceps and adductors. PET-CT did not show any occult neoplasms. Retrospectively initial MRI revealed enlarged bilateral parotid glands well before serology testing.ConclusionMajor salivary gland enlargement occurs in 25%-66% of primary-SS. These are rare with sec- ondary-SS yet best explain facial clinical phenomena here.Myositis overlaps between SS and SLE but commoner with primary-SS. It is uncommon in lupus. SLE can have diffuse symptoms, including alopecia, oral ulcers and neuropsychiatric symptoms.skmamunur@yahoo.co.uk
Dark matter and low scale leptogenesis in a flavor symmetric neutrino two Higgs doublet model ($$\nu $$2HDM)
Authors: Sarma Lavina , Boruah Bichitra Bijay , Das Mrinal Kumar 
Published: May 2022

AbstractWe have studied dark matter (DM) phenomenology, neutrinoless double beta decay (NDBD) and realized low scale leptogenesis in an extension of Standard Model (SM) with three neutral fermions, a scalar doublet and a dark sector incorporating a singlet scalar and a Dirac singlet fermion. A generic model based on $$A_4\times Z_4$$

A
4

×

Z
4

flavor symmetry including five flavons is used to explain both normal and inverted hierarchy mass patterns of neutrino and also to accommodate the dark matter mass. In this extension of the $$\nu $$
ν
2HDM, the effective neutrino mass observed in $$0\nu \beta \beta $$

0
ν
β
β

is well within the experimental limit provided by KamLAND-ZEN. In order to validate DM within this model, we have checked relic abundance and free streaming length of the dark sector component, i.e. a Dirac singlet fermion constraining its mass in keV range. More importantly we have also realised low scale leptogenesis simultaneously within this framework and also the Dirac CP phase gets constrained with the results. Bound from LFV is also incorporated in order to constrain the Yukawa couplings. More importantly, we have analyzed the dependence of various phenomenology with decay parameter for different choice of arbitrary complex angles.
Linear Nash-Greene fluctuations on the evolution of $$S_8$$ and $$H_0$$ tensions
Authors: Capistrano Abraão J. S. , Cabral Luís A. , Marão José A. P. F. , Coimbra-Araújo Carlos H. 
Published: May 2022

AbstractWe present the perturbation equations in an embedded four space-time from the linear Nash-Greene fluctuations of background metric. In the context of a five-dimensional bulk, we show that the cosmological perturbations are only propagated by the gravitational tensorial field equation. In Newtonian conformal gauge, we study the matter density evolution in sub-horizon regime and on how such scale may be affected by the extrinsic curvature. We apply a joint likelihood analysis to the data by means of the Markov Chain Monte Carlo (MCMC) method for parameter estimation using a pack of recent datasets as the Pantheon Supernovae type Ia, the Baryon Acoustic Oscillations (BAO) from DR12 galaxy sample and Dark Energy Survey (DESY1). We discuss the tensions on the Hubble constant$$H_0$$H0and the growth amplitude factor$$S_8$$S8of the observations from Planck 2018 Cosmic Microwave Background (CMB) and the local measurements of$$H_0$$H0with Hubble Space Telescope (HST) photometry and Gaia EDR3. As a result, we obtain an alleviation below$$\sim 1\sigma $$∼1σin the contours ($$S_8$$S8-$$\varOmega _m$$Ωm) at$$68.4\%$$68.4%confidence level (CL) when compared with DESY1 data. On the other hand, the$$H_0$$H0tension persists with$$\sim 2.6\sigma $$∼2.6σat$$68.4\%$$68.4%CL and$$1.95\sigma $$1.95σat$$95.7\%$$95.7%CL, aggravated with the inclusion of BAO data.
Higgs boson production at the LHC: fast and precise predictions in QCD at higher orders
Authors: Camarda Stefano , Cieri Leandro , Ferrera Giancarlo , Urtasun-Elizari Jesús 
Published: May 2022

AbstractWe present a new numerical program, , which provides fast and numerically precise predictions for Higgs boson production cross sections. The present version of the code implements the perturbative QCD expansion up to the next-to-next-to-leading order also combined with the resummation of the large logarithmic corrections at small transverse momenta up to next-to-next-to-leading logarithmic accuracy and it includes the Higgs boson production through gluon fusion and decay in two photons with the full dependence on the final-state kinematics. Arbitrary kinematical cuts can be applied to the final states in order to obtain fiducial cross sections and associated kinematical distributions. We present a benchmark comparison with the predictions obtained with the numerical programs and programs for which represents an improved reimplementation.
Generalizability of the EAST‐AFNET 4 Trial: Assessing Outcomes of Early Rhythm‐Control Therapy in Patients With Atrial Fibrillation
Authors: Dickow Jannis , Kirchhof Paulus , Van Houten Holly K. , Sangaralingham Lindsey R. , Dinshaw Leon H. W. , Friedman Paul A. , Packer Douglas L. , Noseworthy Peter A. , Yao Xiaoxi 
Published: May 2022

Background
EAST‐AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) demonstrated clinical benefit of early rhythm‐control therapy (ERC) in patients with new‐onset atrial fibrillation (AF) and concomitant cardiovascular conditions compared with current guideline‐based practice. This study aimed to evaluate the generalizability of EAST‐AFNET 4 in routine practice.

Methods and Results

Using a US administrative database, we identified 109 739 patients with newly diagnosed AF during the enrollment period of EAST‐AFNET 4. Patients were classified as either receiving ERC, using AF ablation or antiarrhythmic drug therapy, within the first year after AF diagnosis (n=27 106) or not receiving ERC (control group, n=82 633). After propensity score overlap weighting, Cox proportional hazards regression was used to compare groups for the primary composite outcome of all‐cause mortality, stroke, or hospitalization with the diagnoses heart failure or myocardial infarction. Most patients (79 948 of 109 739; 72.9%) met the inclusion criteria for EAST‐AFNET 4. ERC was associated with a reduced risk for the primary composite outcome (hazard ratio [HR], 0.85; 95% CI, 0.75–0.97 [
P
=0.02]) with largely consistent results between eligible (HR, 0.89; 95% CI, 0.76–1.04 [
P
=0.14]) or ineligible (HR, 0.77; 95% CI, 0.60–0.98 [
P
=0.04]) patients for EAST‐AFNET 4 trial inclusion. ERC was associated with lower risk of stroke in the overall cohort and in trial‐eligible patients.

Conclusions
This analysis replicates the clinical benefit of ERC seen in EAST‐AFNET 4. The results support adoption of ERC as part of the management of recently diagnosed AF in the United States.