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Hexagonal boron nitride (h-BN) nanosheets are grown at room temperature by pulsed laser deposition that exhibits remarkable functional properties, creating a scenario for “h-BN on demand” under a frugal thermal budget, essential for nanotechnology.

BACKGROUND: Academic teaching institutions perform approximately one third of all orthopedic procedures in the United States. Revision total knee arthroplasty (rTKA) is a complex and challenging procedure that requires expertise and extensive planning, however the impact of resident involvement on outcomes is poorly understood. The aim of the study was to investigate whether resident involvement in rTKA impacts postoperative complication rates, operative time, and length of hospital stay (LOS). METHODS: The American College of Surgeons National Surgical Quality Improvement Program registry was queried to identify patients who underwent rTKA procedures from 2006-2012 using CPT codes 27486 and 27487. Cases were classified as resident involved or attending only. Demographics, comorbidities, and 30-day postoperative complications were analyzed. Multiple logistic regression analysis was performed to identify independent risk factors for increased 30-day postoperative complications. Wilcoxon rank sum tests were performed to determine the impact of resident involvement on operative time and LOS with significance defined as p

Background and ObjectivesTo explore efficacy/safety of natalizumab, a humanized monoclonal anti–α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy.MethodsParticipants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed.ResultsOf 32 and 34 participants dosed in the natalizumab 300 mg and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period, respectively (one participant was randomized to receive natalizumab but not dosed due to IV complications). Estimated relative change in seizure frequency of natalizumab over placebo was −14.4% (95% confidence interval [CI] –46.1%–36.1%; p = 0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency was 31.3% for natalizumab and 17.6% for placebo (odds ratio 2.09, 95% CI 0.64–6.85; p = 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo.DiscussionAlthough the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted.Trial Registration InformationThe ClinicalTrials.gov registration number is NCT03283371.Classification of EvidenceThis study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab.

This report presents new findings of exchange bias and related structural and magnetic properties in iron carbide/magnetite (Fe5C2/Fe3O4) core/shell nanoparticles. The exchange bias emerges from an energetic landscape, namely a first-order phase transition–the Verwey transition at 125 K, during which the Fe3O4 shell changes from the cubic to monoclinic structure. The phase transition leads to the exchange bias because it results in abrupt changes in magnetocrystalline anisotropy and exchange coupling. Another unique phenomenon identified in this composite system is enhanced magnetic coercivity due to the uniaxial anisotropy of the monoclinic phase. An analysis of the correlations between the observed phenomena is given based on the temperature dependence of the coercivity, the exchange bias field values, and the Verwey transition temperature.

Self-assembly of nanoparticles into ordered patterns is a novel approach to build up new consolidated materials with desired collective physical properties. Herein, nanoparticle assemblies of composition-modulated bimagnetic nanoparticles have been produced via slow evaporation of their colloidal suspension in the absence or presence of magnetic fields. The assemblies obtained in the presence of the magnetic fields exhibit oriented nanoparticle chains in face-centered cubic superlattice structures, compared with the hexagonal closed-packed superlattice obtained without the magnetic field. The oriented structure has an alignment of the easy magnetization axis along the chains. This alignment leads to enhanced intra-superlattice interactions. As a result, the field-induced assembly displays collective magnetic properties with significantly enhanced magnetic anisotropy, remanent magnetization and coercivity. It is also found that the bimagnetic FeCo/CoFe2O4 core/shell nanostructure enhances the intra-particle interaction and thus is beneficial for the growth of oriented assembly of nanoparticles. Furthermore, the collective magnetic behavior is evidenced by the observation of a superferromagnetic-like magnetization relaxation in the ac-susceptibility curves.

ObjectiveWe evaluated the effect of 2 doses of natalizumab on functional outcomes in patients with acute ischemic stroke (AIS).MethodsIn this double-blind phase 2b trial, patients with AIS aged 18–80 years with NIH Stroke Scale scores of 5–23 from 53 US and European sites were randomized 1:1:1 to receive a single dose of 300 or 600 mg IV natalizumab or placebo, with randomization stratified by treatment window (≤9 or >9 to ≤24 hours from patient's last known normal state). The primary endpoint was a composite measure of excellent outcome (modified Rankin Scale score ≤1 and Barthel Index score ≥95) at day 90 assessed in all patients receiving a full dose. Sample size was estimated from a Bayesian model;pvalues were not used for hypothesis testing.ResultsAn excellent outcome was less likely with natalizumab than with placebo (natalizumab 300 or 600 mg odds ratio 0.60; 95% confidence interval 0.39–0.93). There was no effect modification by time to treatment or use of thrombolysis/thrombectomy. For natalizumab 300 mg, 600 mg, or placebo, there were no differences in incidence of adverse events (90.0%, 92.1%, and 92.3%, respectively), serious adverse events (25.6%, 32.6%, and 20.9%, respectively), or deaths (6.7%, 4.5%, and 5.5%, respectively).ConclusionsNatalizumab administered ≤24 hours after AIS did not improve patient outcomes.ClinicalTrials.gov identifierNCT02730455Classification of evidenceThis study provides Class I evidence that for patients with AIS, an excellent outcome was less likely in patients treated with natalizumab than with placebo.

Background We conducted a randomized controlled trial to evaluate the effectiveness of acceptance and commitment therapy (ACT) delivered via a mobile phone messaging robot to patients who had their total hip arthroplasty or total knee arthroplasty procedures postponed due to the COVID-19 pandemic. Methods Ninety patients scheduled for total hip arthroplasty or total knee arthroplasty who experienced surgical delay due to the COVID-19 pandemic were randomized to the ACT group, receiving 14 days of twice daily automated mobile phone messages, or the control group, who received no messages. Minimal clinically important differences (MCIDs) in preintervention and postintervention patient-reported outcome measures were utilized to evaluate the intervention. Results Thirty-eight percent of ACT group participants improved and achieved MCID on the Patient-Reported Outcome Measure Information System Physical Health compared to 17.5% in the control group (P = .038; number needed to treat [NNT] 5). For the joint-specific Hip Disability and Osteoarthritis Outcome Score Joint Replacement and Knee Disability and Osteoarthritis Outcome Score Joint Replacement (KOOS JR), 24% of the ACT group achieved MCID compared to 2.5% in the control group (P = .004; NNT 5). An improvement in the KOOS JR was found in 29% of the ACT group compared to 4.2% in the control group (P = .028; NNT 5). Fourteen percent of the ACT group participants experienced a clinical important decline in the KOOS JR compared to 41.7% in the control group (P = .027; NNT 4). Conclusion A psychological intervention delivered via a text messaging robot improved physical function and prevented decline in patient-reported outcome measures in patients who experienced an unexpected surgical delay during the COVID-19 pandemic. Level of Evidence 1.

Background Walking impairment is a hallmark of multiple sclerosis (MS). It affects > 90% of individuals over time, reducing independence and negatively impacting health-related quality of life, productivity, and daily activities. Walking impairment is consistently reported as one of the most distressing impairments by individuals with MS. Prolonged-release (PR)-fampridine previously has been shown to improve objectively measured walking speed in walking-impaired adults with MS. The impact of PR-fampridine from the perspective of the individual with MS warrants full and detailed examination. Objective The objective of this study was to evaluate whether PR-fampridine has a clinically meaningful effect on self-reported walking ability in walking-impaired participants with MS. Methods ENHANCE was a phase III, randomized, double-blind, placebo-controlled study of PR-fampridine 10 mg twice daily in walking-impaired individuals age 18–70 years with either relapsing or progressive forms of MS and an Expanded Disability Status Scale (EDSS) score of 4.0–7.0 at screening. Participants were stratified by EDSS score (≤ 6.0 or 6.5–7.0) at randomization to ensure a balanced level of disability in the treatment groups. The primary endpoint was the proportion of participants with a mean improvement in the 12-item Multiple Sclerosis Walking Scale (MSWS-12) score exceeding the predefined threshold for clinically meaningful improvement (≥ 8 points) over 24 weeks. Secondary endpoints included the proportion with ≥ 15% improvement in Timed Up and Go (TUG) speed, and mean changes in Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS), Berg Balance Scale (BBS), and ABILHAND scores over 24 weeks. Results In total, 636 participants with MS were randomized (PR-fampridine, n = 317; placebo, n = 319; modified intention-to-treat sample: PR-fampridine, n = 315; placebo, n = 318). At baseline in the PR-fampridine and placebo groups, 46% and 51% had a progressive form of MS, median [range] EDSS scores were 6.0 [4.0–7.0] and 5.5 [4.0–7.0], mean [range] MSWS-12 scores were 63.6 [0–100] and 65.4 [0–100], and mean [range] TUG speed was 0.38 [0.0–1.0] and 0.38 [0.0–1.2] feet/s, respectively. A significantly higher percentage of PR-fampridine-treated participants (136/315 [43.2%]) had clinically meaningful improvement in MSWS-12 score over 24 weeks versus placebo (107/318 [33.6%]; odds ratio 1.61 [95% confidence interval 1.15–2.26]; p = 0.006). For PR-fampridine versus placebo, significantly more participants had a ≥ 15% improvement in TUG speed, and there was significantly greater mean improvement in MSIS-29 PHYS score (p

BACKGROUND AND PURPOSE A prior study found a link between post-stroke blood-brain barrier disruption and functional outcomes. The current study aimed to replicate this finding in a cohort of patients recruited in the context of a randomized clinical trial. METHODS The ACTION trial was a study of natalizumab in acute stroke patients. Patients with MRI-perfusion weighted imaging (PWI) were included in this post-hoc analysis. Blood-brain permeability images (BBPI) were calculated from the PWI source images. Mean BBPI values from the 24 h time point were compared with modified Rankin scores (mRS) at 5, 30, and 90-day assessments using linear regression. Good functional outcome (mRS< = 1) was compared with mean BBPI using logistic regression. RESULTS One hundred and nineteen patients were included in the analysis (median age = 74, 43% female). Higher mean BBPI was associated with worse mRS at 5 days (p = 0.002; r2 = 0.078) and 30 days (p = 0.036; r2 = 0.039) but did not reach statistical significance at 90 days (p = 0.30; r2 = 0.010). When removing high-value outliers, all outcome measures showed a stronger relationship with mean BBPI. Logistic regression found that with every 1% increase in mean BBPI measured 24 h after the stroke, the likelihood of achieving a good functional outcome at 90 days is decreased by half (OR = 0.53; CI = 0.30:0.95; p = 0.032). CONCLUSIONS With sufficient image quality, elevated BBPI measured in the days after an ischemic event is predictive of worse functional outcome and may serve as a biomarker for post-stroke inflammation.

Fe

Localized heat generation using nanoparticles is a promising supplementary technique to the well-established cancer treatments, such as chemotherapy and radiotherapy. Here, we demonstrate that iron carbide (Fe5C2) nanoparticles with a thin carbon shell have the collective magnetothermal and photothermal effects based on the ferromagnetic and photonic properties. When the Fe5C2 nanoparticle suspension is irradiated with a NIR laser (808 nm), it yields unprecedented heating effects. Further, owing to the observed high magnetization and coercivity, the Fe5C2 nanoparticle suspension on exposure to an alternating magnetic field (ACMF) exhibits an enhanced specific absorption rate (SAR) as compared to Fe3O4 nanoparticles of the same size. This significant improvement in the SAR arises from the cooperative contribution from the hysteresis and susceptibility losses. This work also gives quantitative information about the ACMF effects on heating ability as well as provides some guidelines for obtaining enhanced heating activity in nanoparticle suspensions of a given magnetic material.

In this report, hematene (2D α-Fe2O3 nanosheets) with an exceptionally high coercivity of up to 7.5 kOe has been synthesized via a soft-chemical exfoliation process. The high coercivity correlates with the surface magnetic anisotropy that originates from enhanced uncompensated spin canting as a result of the 2D morphology. This observation is different from the behavior of the bulk counterpart that exhibits collinear antiferromagnetic ordering with no net magnetization at low temperatures. In addition, our study shows a suppression of the Morin transition in 2D nanosheets, which further confirms that the surface spins deviate strongly from the collinear antiferromagnetic ordering. We also observed a spin-glass-like transition with a rapid increase in saturation magnetization and a decrease in anisotropy in the ultra-thin α-Fe2O3 nanosheets at temperatures below 48 K. The spin-glass behavior is correlated with the observed exchange bias and the magnetic field dependence of spin-glass freezing temperature.

Ferromagnetic nanowires (NWs) are novel materials that offer unique magnetic properties, as the geometrical dimensions become comparable to key length scales in magnetism, such as the exchange length or the domain wall width. In this work, compositionally modulated Co1−xNix nanowires (diameter 10–15 nm) with high coercivity have been synthesized via a thermal decomposition method. The structural analysis demonstrates that the hexagonal close-packed (hcp) crystal structure and the wire-shape morphology are maintained up to Ni content of x = 0.3. Based on the shape anisotropy and orientation, the aligned Co1−xNix nanowire assemblies show that the coercivity at room temperature decreases from 11.4 to 5.4 kOe with increasing x from 0 to 0.3. The monotonous decrease in coercivity with Ni content is related to the effective magnetic anisotropy and nanowire diameter which are found to be strongly varied with Ni addition. In addition, it is found that the increase of Ni content in the nanowires brings more resistance to oxidation than the pristine Co nanowires. The exchange bias study indicates that the Ni addition leads to lower blocking temperature of the CoNiO grains and consequently the switch-on temperature for the exchange bias field shifts to low temperatures with the increase of Ni content. Further, the exchange bias behavior that is associated with the existence of antiferromagnetic and spin-glass-like states are confirmed by temperature-dependent magnetization measurements.

Background: Cognitive impairment is common in multiple sclerosis (MS), with cognitive processing speed being the most frequently affected domain. Objective: Examine the effects of daclizumab beta versus intramuscular (IM) interferon (IFN) beta-1a on cognitive processing speed as assessed by Symbol Digit Modalities Test (SDMT). Methods: In DECIDE, patients with relapsing–remitting multiple sclerosis (RRMS) (age: 18–55 years; Expanded Disability Status Scale (EDSS) score 0–5.0) were randomized to daclizumab beta ( n = 919) or IM IFN beta-1a ( n = 922) for 96–144 weeks. SDMT was administered at baseline and at 24-week intervals. Results: At week 96, significantly greater mean improvement from baseline in SDMT was observed with daclizumab beta versus IM IFN beta-1a ( p = 0.0274). Significantly more patients treated with daclizumab beta showed clinically meaningful improvement in SDMT (increase from baseline of ⩾3 points ( p = 0.0153) or ⩾4 points ( p = 0.0366)), and significantly fewer patients showed clinically meaningful worsening (decrease from baseline of ⩾3 points ( p = 0.0103)). Odds representing risk of worsening versus stability or improvement on SDMT were significantly smaller for daclizumab beta ( p = 0.0088 (3-point threshold); p = 0.0267 (4-point threshold)). In patients completing 144 weeks of treatment, the effects of daclizumab beta were generally sustained. Conclusion: These results provide evidence for a benefit of daclizumab beta versus IM IFN beta-1a on cognitive processing speed in RRMS. Trial registration: ClinicalTrials.gov identifier NCT01064401 (Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon β 1a in Participants With Relapsing-Remitting Multiple Sclerosis (DECIDE)): https://clinicaltrials.gov/ct2/show/NCT01064401 .

Background: For patients with relapsing-remitting multiple sclerosis (RRMS) undergoing continuous immunomodulatory therapy, understanding whether vaccinations can be performed safely and effectively is important. We tested the immune response to inactivated seasonal influenza vaccine during long-term daclizumab beta treatment. Methods: In this prospective, open-label, single-arm extension SELECTED study, an optional vaccine substudy was performed on patients with RRMS who had already received daclizumab beta for 1 to 2 years in previous studies. Patients were administered the seasonal vaccine as a single intramuscular dose containing three inactivated influenza virus strains: A/California/7/2009 (A/H1N1), A/Texas/50/2012 (A/H3N2), and B/Massachusetts/2/2012 (B). Endpoints included proportion of patients achieving seroprotection, proportion of patients who seroconverted, geometric mean titer ratio before and after vaccination, and adverse events reported during 28-day follow-up. Results: Ninety patients received the influenza vaccine (mean previous daclizumab beta exposure, 49.6 doses). Seroprotection (anti–hemagglutination immunoglobulin G titer ≥40) was detected in 92% (95% confidence interval [CI], 85%–97%) of patients for A/H1N1, 91% (83%–96%) for A/H3N2, and 67% (56%–76%) for B. The proportion of patients who seroconverted was 69% (95% CI, 58%–78%) for A/H1N1, 69% (58%–78%) for A/H3N2, and 44% (34%–55%) for B. The anti–hemagglutination immunoglobulin geometric mean titer ratio was 7.7 for A/H1N1, 9.0 for A/H3N2, and 4.3 for B. There were no significant adverse events considered related to vaccination during 28-day follow-up. Conclusions: Patients with RRMS receiving long-term daclizumab beta treatment mounted an immune response to the seasonal influenza vaccine at levels considered to confer protection. No major or new safety issues were identified.

Natalizumab, a human immunoglobulin monoclonal antibody that targets α4β1/α4β7 integrin, is an effective therapy approved for the treatment of multiple sclerosis (MS). The objective of this analysis was to develop a population exposure–response model utilizing gadolinium-enhancing (Gd) lesion count data from four clinical studies and annualized relapse rate (ARR) data from three clinical studies. The natalizumab exposures were derived for the individuals using a population pharmacokinetic model. A log-linear exposure effect on Gd lesion count and ARR adequately characterized the relationship between exposure and disease response. In the case of the Gd lesion count model, a bimodal model that distributed subjects into two subpopulations based on low or high baseline Gd lesion count provided a superior goodness of fit. The mean (95% confidence interval) slopes from the exposure–Gd lesion count model and exposure-ARR model are −0.0903 (−0.100, −0.081) and −0.0222 (−0.026, −0.015) (mg/L)−1, respectively. From these slopes, it can be inferred that both Gd lesion count and ARR decrease with increasing exposure to natalizumab in MS subjects. Model-based simulations demonstrated that although reductions in Gd lesion count and ARR were observed with lower doses (75, 150, or 200 mg), only the dose of 300 mg every 4 weeks (q4w) was associated with an ARR ≤0.25 and was considered clinically effective. The results from the exposure-Gd lesion count and exposure-ARR models thus support the appropriateness of the approved natalizumab dose (300 mg q4w) in MS subjects.

Summary Background In animal models of acute ischaemic stroke, blocking of the leukocyte-endothelium adhesion by antagonism of α4 integrin reduces infarct volumes and improves outcomes. We assessed the effect of one dose of natalizumab, an antibody against the leukocyte adhesion molecule α4 integrin, in patients with acute ischaemic stroke. Methods In this double-blind, phase 2 study, patients with acute ischaemic stroke (aged 18–85 years) from 30 US and European clinical sites were randomly assigned (1:1) to 300 mg intravenous natalizumab or placebo with stratification by treatment window and baseline infarct size. Patients, investigators, and study staff were masked to treatment assignments. The primary endpoint was the change in infarct volume from baseline to day 5 and was assessed in the modified intention-to-treat population. Secondary endpoints were the change in infarct volume from baseline to day 30, and from 24 h to days 5 and 30; the National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at days 5 (or discharge), 30, and 90; and modified Rankin Scale (mRS) and Barthel Index (BI) at days 5 (or discharge), 30, and 90. This trial is registered with ClinicalTrials.gov, number NCT01955707. Findings Between Dec 16, 2013, and April 9, 2015, 161 patients were randomly assigned to natalizumab (n=79) or placebo (n=82). Natalizumab did not reduce infarct volume growth from baseline to day 5 compared with placebo (median absolute growth 28 mL [range −8 to 303] vs 22 mL [−11 to 328]; relative growth ratio 1·09 [90% CI 0·91–1·30], p=0·78) or to day 30 (4 mL [−43 to 121] vs 4 mL [−28 to 180]; 1·05 [0·88–1·27], p=0·68), from 24 h to day 5 (8 mL [−30 to 177] vs 7 mL [−13 to 204]; 1·00 [0·89–1·12], p=0·49), and from 24 h to day 30 (−5 mL [−93 to 81] vs −5 mL [−48 to 48]; 0·98 [0·87–1·11], p=0·40). No difference was noted between the natalizumab and placebo groups in the NIHSS (score ≤1 or ≥8 point improvement) from baseline at 24 h, day 5 (or discharge), day 30 (27 [35%] vs 36 [44%]; odds ratio 0·69 [90% CI 0·39–1·21], p=0·86), and day 90 (36 [47%] vs 37 [46%]; 1·10 [0·63–1·93], p=0·39). More patients in the natalizumab group than in the placebo group had mRS scores of 0 or 1 at day 30 (13 [18%] vs seven [9%]; odds ratio 2·88 [90% CI 1·20–6·93], p=0·024) and day 90 (18 [25%] vs 16 [21%]; 1·48 [0·74–2·98], p=0·18); and BI (score ≥95) at day 90 (34 [44%] vs 26 [33%]; 1·91 [1·07–3·41], p=0·033) but not significantly at day 5 or day 30 (26 [34%] vs 26 [32%]; 1·13 [0·63–2·00], p=0·37). Natalizumab and placebo groups had similar incidences of adverse events (77 [99%] of 78 patients vs 81 [99%] of 82 patients), serious adverse events (36 [46%] vs 38 [46%]), and deaths (14 [18%] vs 13 [16%]). Two patients in the natalizumab group died because of adverse events assessed as related to treatment by the investigator (pneumonia, and septic shock and multiorgan failure). Interpretation Natalizumab administered up to 9 h after stroke onset did not reduce infarct growth. Treatment-associated benefits on functional outcomes might warrant further investigation. Funding Biogen.

Background Daclizumab has been evaluated in multicentre, randomised, double-blind studies for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). Safety and tolerability are key considerations in MS treatment selection, as they influence adherence to medication. Objective Evaluate the safety of daclizumab in patients with RRMS from an integrated analysis of six clinical studies. Methods Patients treated with at least one dose of subcutaneous daclizumab 150 mg or 300 mg monthly in three completed and three ongoing clinical studies were included in this integrated analysis. Cumulative incidence of treatment-emergent adverse events (AEs) was the primary endpoint. Results This analysis included 2236 patients with 5214 patient-years of exposure to daclizumab. The cumulative incidence of any AE was 84% and of any serious AE excluding MS relapse was 16%. The incidences of AEs when evaluated by 6-month intervals remained stable over the 6.5 years of maximum follow-up. Most AEs were mild or moderate in severity. An important safety concern associated with daclizumab therapy involved hepatic AEs (16%) and serum transaminase elevations at least three times the upper limit of normal (10%), most of which were asymptomatic, self-limiting, and non-recurring. Cumulative incidences of cutaneous, infectious, and gastrointestinal AEs were 33%, 59%, and 25%, respectively; most events either resolved spontaneously or were treated successfully with standard medical interventions and did not result in discontinuation of treatment. Conclusion This integrated analysis demonstrates that treatment of RRMS with daclizumab for periods of up to 6.5 years is associated with an acceptable safety profile with no evidence of cumulative toxicity over time.

Introduction Cutaneous adverse events (AEs) have been observed in clinical studies of daclizumab high-yield process (HYP) in relapsing-remitting multiple sclerosis (RRMS). Here, we report cutaneous AEs observed in the randomized, double-blind, active-comparator DECIDE study (ClinicalTrials.gov identifier, NCT01064401). Methods DECIDE was a randomized, double-blind, active-controlled phase 3 study of daclizumab HYP 150 mg subcutaneous every 4 weeks versus interferon (IFN) beta-1a 30 mcg intramuscular (IM) once weekly in RRMS. Treatment-emergent AEs were classified and recorded by investigators. Investigators also assessed the severity of each AE, and whether it met the criteria for a serious AE. Cutaneous AEs were defined as AEs coded to the Medical Dictionary for Regulatory Activities System Organ Class of skin and subcutaneous tissue disorders. The incidence, severity, onset, resolution, and management of AEs were analyzed by treatment group. Results Cutaneous AEs were reported in 37% of daclizumab HYP-treated patients and 19% of IFN beta-1a-treated patients. The most common investigator-reported cutaneous AEs with daclizumab HYP were rash (7%) and eczema (4%). Most patients with cutaneous AEs remained on treatment (daclizumab HYP, 81%; IM IFN beta-1a, 90%) and had events that were mild or moderate (94% and 98%) and subsequently resolved (78% and 82%). Most patients with cutaneous AEs did not require treatment with corticosteroids or were treated with topical corticosteroids (daclizumab HYP, 73%; IM IFN beta-1a, 81%). Serious cutaneous AEs were reported in 14 (2%) daclizumab HYP patients and one (

Aims To characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the high-affinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes. Methods Twenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixed-effects model. Results The 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0–12 h (0.93–1.15), S-warfarin AUC from 0 to infinity (AUC[0–inf]) (0.95–1.06), omeprazole AUC(0–inf) (0.88–1.13) and midazolam AUC(0–inf) (0.89–1.15) were within the no-effect boundary of 0.80–1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76–1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity. Conclusions DAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity.

Background and purpose In the SELECT study, treatment with daclizumab high-yield process (DAC HYP) versus placebo reduced the frequency of gadolinium-enhancing (Gd+) lesions in patients with relapsing−remitting multiple sclerosis (RRMS). The objective of this post hoc analysis of SELECT was to evaluate the effect of DAC HYP on the evolution of new Gd+ lesions to T1 hypointense lesions (T1 black holes). Methods SELECT was a randomized double-blind study of subcutaneous DAC HYP 150 or 300 mg or placebo every 4 weeks. Magnetic resonance imaging (MRI) scans were performed at baseline and weeks 24, 36 and 52 in all patients and monthly between weeks 4 and 20 in a subset of patients. MRI scans were evaluated for new Gd+ lesions that evolved to T1 black holes at week 52. Data for the DAC HYP groups were pooled for analysis. Results Daclizumab high-yield process reduced the number of new Gd+ lesions present at week 24 (P = 0.005) or between weeks 4 and 20 (P = 0.014) that evolved into T1 black holes at week 52 versus placebo. DAC HYP treatment also reduced the percentage of patients with Gd+ lesions evolving to T1 black holes versus placebo. Conclusions Treatment with DAC HYP reduced the evolution of Gd+ lesions to T1 black holes versus placebo, suggesting that inflammatory lesions that evolved during DAC HYP treatment are less destructive than those evolving during placebo treatment.

Magnetic cobalt ferrite CoFe2O4 is rich with physical phenomena, owing to its crystalline and magnetic structures. When such a ferrite is produced in a modulated nanoscale size, the increased specific surface area gives rise to even more complex behavior in its magnetism, particularly in relation to magnetic hardening. By correlating nanoparticle size (from 3.5 nm to 80 nm) with crystallite size and magnetic properties, we can observe interesting relations between particle size and magnetic coercivity. On exceeding the superparamagnetic limit of about 10 nm, room-temperature coercivity and remanence values are found to increase with increasing nanoparticle size, up to a maximum value of 4.1 kOe and 52 emu g−1, respectively, at a size of approximately 45 nm. Above this critical size, the nanoparticles are comprised of multiple crystallites, and demonstrate the existence of a cooperative phenomenon, the so-called interaction domains, which leads to a decrease in coercivity and remanence values. More interestingly, the ultrasmall-sized CoFe2O4 nanoparticles (3.5–16 nm) show an anomalous coercivity enhancement and irreversible behavior at low temperatures, as compared to the large-sized nanoparticles, which may be ascribed to enhanced effective magnetic anisotropy due to the surface spin-canting effect. Furthermore, training behavior in the exchange bias field, together with field-dependent blocking behavior, indicate that ultrasmall CoFe2O4 nanoparticles possess highly frustrated surface spins, which rearrange much more slowly than their interior spins, resulting in magnetic hardening at low temperatures.

Cobalt (Co) is one of the most important 3d transition metal elements used in the development of magnetic materials, especially in hard magnetic materials, from the early Co-based steel magnets to the rare-earth permanent magnets based on the 3d-4f compounds. Like iron (Fe), Co possesses a high saturation magnetization (MS) and a high Curie temperature (TC). Unlike Fe, Co has high magnetocrystalline anisotropy due to its spin-orbit coupling. As a result, it can be used to achieve a high degree of magnetic hardening in its elemental, alloy or compound materials. For instance, Co-based magnetic recording media is based on its elemental material. On the other hand, nano-structuring of Co-based alloys gives important hard magnetic materials including Alnico magnets and Fe–Cr–Co magnets, which are probably the earliest nanostructured hard magnetic materials. Recent progress in the development of Co-containing nanoscale hard magnetic materials has been very encouraging and promising based on the outstanding magnetic properties we have seen in L10 CoPt, tetragonally distorted FeCo and Co-based intermetallics. Particularly, the morphology of the nanoparticles has also been modulated to develop high coercivity via utilizing shape anisotropy, leading to extraordinarily high coercivity in Co nanowire assemblies. This review presents an overview of the development of Co-based hard and semi-hard magnetic materials and their intrinsic and extrinsic magnetic properties in view of fundamental understanding and technological applications.

To examine the impact of missing data when evaluating the confirmed disability worsening (CDW) endpoint in multiple sclerosis clinical trials and explore analytical methods for handling censored participants (those with missing confirmation data).CDW risk factors were assessed among participants with an initial disability worsening (≥ 1.0-point increase in Expanded Disability Status Scale [EDSS] score from a baseline score of ≥ 1.0; ≥ 1.5-point increase from a baseline of 0) using data from the DECIDE trial of daclizumab beta. A post-hoc simulation study was performed to evaluate three strategies for imputing confirmation status in censored participants: assume all were confirmed; assume none were confirmed (standard analytical approach); or use an observed rate multiple imputation (ORMI) approach based on treatment group and similar participant risk factors. Simulation study results were used to evaluate pre-specified analyses in DECIDE.In DECIDE, larger change from baseline to initial disability worsening in EDSS score (p = 0.0003), higher baseline EDSS score (p = 0.0013), age (p = 0.004), and preceding relapse (p 0.0001) were associated with 12-week CDW. In the simulation study, relative to the full dataset (no missing data), the strategy of assuming no censored participants were confirmed underestimated the treatment effect, and the strategy of assuming all censored participants were confirmed overestimated the treatment effect (hazard ratio 0.749 and 0.713 vs 0.733). ORMI correctly estimated treatment effect and increased study power by ~5-10% compared with the standard analytical approach.The ORMI approach based on CDW risk factors minimizes bias and is expected to provide the most accurate treatment effect estimate for the CDW endpoint.

Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders.We conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing-remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate.The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P=0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs.1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%).Among patients with relapsing-remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a. (Funded by Biogen and AbbVie Biotherapeutics; DECIDE ClinicalTrials.gov number, NCT01064401.).

Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor α subunit (IL-2Rα or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ∼50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN-γ, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2Rβγ signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

For patients with relapsing-remitting multiple sclerosis (RRMS) undergoing continuous immunomodulatory therapy, understanding whether vaccinations can be performed safely and effectively is important. We tested the immune response to inactivated seasonal influenza vaccine during long-term daclizumab beta treatment.In this prospective, open-label, single-arm extension SELECTED study, an optional vaccine substudy was performed on patients with RRMS who had already received daclizumab beta for 1 to 2 years in previous studies. Patients were administered the seasonal vaccine as a single intramuscular dose containing three inactivated influenza virus strains: A/California/7/2009 (A/H1N1), A/Texas/50/2012 (A/H3N2), and B/Massachusetts/2/2012 (B). Endpoints included proportion of patients achieving seroprotection, proportion of patients who seroconverted, geometric mean titer ratio before and after vaccination, and adverse events reported during 28-day follow-up.Ninety patients received the influenza vaccine (mean previous daclizumab beta exposure, 49.6 doses). Seroprotection (anti-hemagglutination immunoglobulin G titer ≥40) was detected in 92% (95% confidence interval [CI], 85%-97%) of patients for A/H1N1, 91% (83%-96%) for A/H3N2, and 67% (56%-76%) for B. The proportion of patients who seroconverted was 69% (95% CI, 58%-78%) for A/H1N1, 69% (58%-78%) for A/H3N2, and 44% (34%-55%) for B. The anti-hemagglutination immunoglobulin geometric mean titer ratio was 7.7 for A/H1N1, 9.0 for A/H3N2, and 4.3 for B. There were no significant adverse events considered related to vaccination during 28-day follow-up.Patients with RRMS receiving long-term daclizumab beta treatment mounted an immune response to the seasonal influenza vaccine at levels considered to confer protection. No major or new safety issues were identified.

Summary Background In the SELECT trial, disease activity was reduced in patients with multiple sclerosis who received daclizumab high-yield process (HYP) for 52 weeks. The primary aim of the SELECTION extension study was to assess the safety and immunogenicity of extended treatment with daclizumab HYP. Methods A multicentre, randomised, double-blind, 52-week extension trial was done in 74 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, and the UK between Feb 13, 2009, and Oct 3, 2012. Eligible patients were aged 18–55 years, had relapsing-remitting multiple sclerosis, and had completed the SELECT study. Patients who received placebo in SELECT were randomly assigned (1:1) to receive 150 mg or 300 mg subcutaneous daclizumab HYP every 4 weeks for 52 weeks (treatment initiation group); those who had received daclizumab HYP were randomly assigned (1:1) to continue their present dose with (washout and re-initiation group) or without (continuous treatment group) a washout period of 20 weeks. All randomisation was done with a centralised, interactive voice-response system. Patients and personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug but had no interaction with patients. The primary endpoints were the safety and immunogenicity of daclizumab HYP. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00870740. Findings 517 (91%) of 567 patients who completed the SELECT trial entered SELECTION, of whom 170 were in the treatment initiation group, 173 in the continuous treatment group, and 174 in the washout and re-initiation group. 11 patients in the treatment initiation group (6%), 13 in the continuous treatment group (8%), and ten in the washout and re-initiation group (6%) had any serious adverse event other than relapse of multiple sclerosis. One patient in the washout and re-initiation group (300 mg daclizumab HYP) died because of autoimmune hepatitis; a contributory role of daclizumab HYP could not be excluded. Seven patients tested positive for neutralising antidrug antibodies: one (1%) of 128 for whom data were available in the continuous treatment group (this patient also tested positive at SELECTION baseline), four (2%) in the treatment initiation group, and two (2%) of 129 in the washout and re-initiation group. Interpretation Adverse events and immunogenicity were not increased in the second year of continuous treatment with daclizumab HYP or during treatment washout and re-initiation. These results support further assessment of daclizumab HYP for relapsing-remitting multiple sclerosis. Funding Biogen Idec and AbbVie Biotherapeutics.

The magnetic properties of single crystalline hcp Co nanowire (NW) assemblies with different packing densities are investigated. The compacted assemblies exhibit an unusual increase in coercivity (HC) from 5.5 kOe to 6.1 kOe with the increase of the packing density from 2.1 to 4.5 g/cm3. While Hc decreases with further increase in packing density. A similar trend in Hc value variation with density has also been noticed at different temperatures. The initial increase in HC values is ascribed to magnetostatic interaction between the nanowires, which became stronger with the increased packing density. However, above the density of 4.5 g/cm3, the Hc decreases due to the proximity effect as shown in the δM plot. The δM plot shows a negative peak at high field and it becomes prominent with the increased density. Moreover, it has been found that the variation of HC with the packing density is also related to diameter of Co NWs. A larger diameter of the nanowires gives a negative dependence of the Hc value with the density in the whole investigated region.The magnetic properties of single crystalline hcp Co nanowire (NW) assemblies with different packing densities are investigated. The compacted assemblies exhibit an unusual increase in coercivity (HC) from 5.5 kOe to 6.1 kOe with the increase of the packing density from 2.1 to 4.5 g/cm3. While Hc decreases with further increase in packing density. A similar trend in Hc value variation with density has also been noticed at different temperatures. The initial increase in HC values is ascribed to magnetostatic interaction between the nanowires, which became stronger with the increased packing density. However, above the density of 4.5 g/cm3, the Hc decreases due to the proximity effect as shown in the δM plot. The δM plot shows a negative peak at high field and it becomes prominent with the increased density. Moreover, it has been found that the variation of HC with the packing density is also related to diameter of Co NWs. A larger diameter of the nanowires gives a negative dependence of the Hc value with t...

Patients with highly active relapsing-remitting multiple sclerosis (RRMS) are at greater risk for disease progression and may respond differently to MS therapeutics than those with less active disease. The current post hoc analysis evaluated the effects of daclizumab high-yield process (DAC HYP) vs. placebo in patients with highly active RRMS in the SELECT study. Highly active RRMS was defined as patients with ≥2 relapses in the year before randomization and ≥1 gadolinium-enhancing (Gd+) lesion at baseline. Because results were similar in the DAC HYP dose groups, data from the DAC HYP arms were pooled for analysis. Treatment with DAC HYP resulted in similar effects in highly active (n = 88) and less active (n = 506) RRMS patients. DAC HYP reduced the annualized relapse rate by 50 % and 51 % in the highly active (p = 0.0394) and less active (p

Daclizumab, a humanised monoclonal antibody, modulates interleukin-2 signalling by blocking the α subunit (CD25) of the interleukin-2 receptor. We assessed whether daclizumab high-yield process (HYP) would be effective when given as monotherapy for a 1 year treatment period in patients with relapsing-remitting multiple sclerosis.We did a randomised, double-blind, placebo-controlled trial at 76 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, Turkey, and the UK between Feb 15, 2008, and May 14, 2010. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1), via a central interactive voice response system, to subcutaneous injections of daclizumab HYP 150 mg or 300 mg, or placebo, every 4 weeks for 52 weeks. Patients and study personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug for injection, but had no interaction with the patient. The primary endpoint was annualised relapse rate. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00390221.204 patients were assigned to receive placebo, 208 to daclizumab HYP 150 mg, and 209 to daclizumab HYP 300 mg, of whom 188 (92%), 192 (92%), and 197 (94%), respectively, completed follow-up to week 52. The annualised relapse rate was lower for patients given daclizumab HYP 150 mg (0·21, 95% CI 0·16-0·29; 54% reduction, 95% CI 33-68%; p0·0001) or 300 mg (0·23, 0·17-0·31, 50% reduction, 28-65%; p=0·00015) than for those given placebo (0·46, 0·37-0·57). More patients were relapse free in the daclizumab HYP 150 mg (81%) and 300 mg (80%) groups than in the placebo group (64%; p0·0001 in the 150 mg group and p=0·0003 in the 300 mg group). 12 (6%) patients in the placebo group, 15 (7%) of those in the daclizumab 150 mg group, and 19 (9%) in the 300 mg group had serious adverse events excluding multiple sclerosis relapse. One patient given daclizumab HYP 150 mg who was recovering from a serious rash died because of local complication of a psoas abscess.Subcutaneous daclizumab HYP administered every 4 weeks led to clinically important effects on multiple sclerosis disease activity during 1 year of treatment. Our findings support the potential for daclizumab HYP to offer an additional treatment option for relapsing-remitting disease.Biogen Idec and AbbVie Biotherapeutics Inc.

Jonathan Q Tran,1 Ahmed A Othman,2,3 Alvydas Mikulskis,4 Paul Wolstencroft,5 Jacob Elkins6 1Clinical Pharmacology, Biogen, Cambridge, MA, USA; 2Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA; 3Faculty of Pharmacy, Cairo University, Cairo, Egypt; 4Global Biomarker Discovery and Development, Cambridge, MA, USA; 5Global Clinical Operation, Biogen, Maidenhead, Berkshire, UK; 6Global Clinical Development, Biogen, Cambridge, MA, USA Background: Daclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the a subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials. Objective: To characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Twenty-six patients with RRMS received DAC HYP 150 mg SC q4wk for a total of six doses. Serial PK blood samples were collected over the first and last dosing intervals and trough PK samples were collected between these doses. Blood samples for immunogenicity assessment were collected throughout the study. Serum DAC HYP levels and anti-DAC HYP antibodies were characterized using validated immunoassays. PK parameters were estimated using noncompartmental analysis. Results: DAC HYP showed slow SC absorption with a median time to reach maximum observed concentration (Cmax) value of ~1 week. Steady state was reached by the fourth injection. At steady state, DAC HYP mean serum Cmax, minimum observed concentration (Cmin), and area under the concentration–time curve within a dosing interval (AUCtau) values were 29.1 µg/mL, 14.9 µg/mL, and 638 µg · day/mL, respectively, with intersubject variability of 35%–40%. The AUC accumulation ratio was ~2.5 at steady state. DAC HYP had a long elimination half-life of ~22 days and low apparent clearance (0.274 L/day). Nine patients tested positive for anti-DAC HYP antibodies, with no impact on DAC HYP clearance in this limited data set. Conclusion: The PK of DAC HYP in patients with RRMS are consistent with those previously reported in healthy volunteers. The half-life of ~3 weeks and the low fluctuations in peak and trough concentrations of serum DAC HYP support the once-monthly SC dosing regimen. Keywords: pharmacokinetics, daclizumab high-yield process, multiple sclerosis

To characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the high-affinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes.Twenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixed-effects model.The 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0-12 h (0.93-1.15), S-warfarin AUC from 0 to infinity (AUC[0-inf]) (0.95-1.06), omeprazole AUC(0-inf) (0.88-1.13) and midazolam AUC(0-inf) (0.89-1.15) were within the no-effect boundary of 0.80-1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76-1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity.DAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity.

Objective: The objective of this study was to evaluate whether interleukin-2 (IL-2) receptor expression on CD56bright natural killer (NK) cells predicted CD56bright NK cell expansion and therapeutic response to daclizumab (DAC) in multiple sclerosis (MS). Methods: DAC exposure, CD56bright NK cell counts, IL-2 receptor alpha (CD25) and beta (CD122) subunits, and new or enlarged lesions on brain MRI were measured in 64 subjects in a pharmacokinetic/pharmacodynamic substudy of the phase 2 CHOICE trial at multiple time points. Peripheral blood mononuclear cell (PBMC) samples were obtained from healthy subjects to assess the relationship among DAC treatment, intermediate affinity IL-2 signaling, and CD56bright NK cell expansion. Results: Increased CD56bright NK cell counts in DAC/interferon beta (IFNβ)-treated subjects were observed by day 14, the first post-dosing time point (mean [SD] ln{CD56bright NK cell count}: DAC high/IFNβ, 2.01 [1.25]; DAC low/IFNβ, 2.29 [1.06]; placebo/IFNβ, 1.01 [1.03]; adjusted p = 0.003), and persisted throughout the treatment period. Higher DAC dose predicted a faster rate of CD56bright NK cell expansion ( p bright NK cells from baseline levels were only weakly correlated with DAC exposure ( r2 = 0.167). Higher expression of the intermediate-affinity IL-2 receptor subunit (CD122) on CD56bright NK cells at baseline predicted fewer new gadolinium-enhanced (Gd+) lesions during the treatment period (1.77 vs. 0.62 adjusted mean new Gd+ lesions during weeks 8–24, lowest vs. highest quartile of percentage CD122+ CD56bright NK cells; p = 0.033) and a greater increase in CD56bright NK cell counts at the end of DAC dosing ( p = 0.029). Conclusion: CD56bright NK cell expansion after DAC treatment appears to reflect individual differences in the capacity for intermediate-affinity IL-2 signaling and could provide a basis for predicting clinical response to DAC in MS.

Background The 12-question Multiple Sclerosis Walking Scale (MSWS-12v1) is a widely-used patient-reported outcome (PRO) measure of walking ability in multiple sclerosis (MS). Objective To estimate the magnitude of an important change in MSWS-12v1 scores for the interpretation of meaningful subject-level improvements across a 6-month trial of MS patients with walking disability. Methods MOBILE was a 6-month exploratory study assessing fampridine’s effect on walking ability in 132 people with MS. Three PRO measures assessed walking ability: MSWS-12v1, EuroQol 5-Dimension-5 Level (EQ-5D-5L) mobility question, and a patient global impression of change (PGIC) in overall walking ability. Pre-specified anchor- and distribution-based analyses estimated the MSWS-12v1 change scores representing an important change for participants. Results were triangulated to propose a single best value indicating meaningful improvement. Results Using baseline to week 2 through week 24 change scores, anchor-based analyses demonstrated mean and median improvements of 5.2–6.6 (PGIC) and 9.7–13.4 (EQ-5D-5L mobility) points on the MSWS-12v1, indicating meaningful improvements. The distribution-based estimate was 6.8 points. Triangulation across the results suggested an 8-point reduction in MSWS-12v1 score represents an important subject-level change in these participants. Conclusion In similar MS clinical trials, an 8-point improvement on the MSWS-12v1 is a reasonable estimate of meaningful improvement in walking ability.

Objective: To assess the relationship between CD56 bright natural killer (NK) cells and multiple sclerosis (MS) disease activity in patients with relapsing-remitting MS treated with daclizumab high-yield process (DAC HYP). Methods: Data were from patients enrolled in a 52-week randomized, double-blind, placebo-controlled study of DAC HYP and its extension study. Assessments included relationships of CD56 bright NK cell numbers (identified using fluorescence-activated cell sorting) at weeks 4 and 8 with the numbers of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 and the annualized relapse rate. Results: In DAC HYP–treated patients but not placebo-treated patients, the numbers of CD56 bright NK cells increased over 52 weeks of treatment, and their numbers at weeks 4 and 8 predicted the number of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 of treatment ( p ≤ 0.005 for each comparison). Similar but nonsignificant trends were observed between CD56 bright NK cell counts and the annualized relapse rate in DAC HYP–treated patients. DAC HYP–treated patients who showed lower levels of expansion of CD56 bright NK cells still developed fewer new or newly enlarging T2-hyperintense lesions than placebo-treated patients during the first year of treatment. Conclusions: CD56 bright NK cells appear to mediate some of the treatment-related effects of DAC HYP, but their numbers do not account for the full effect of DAC HYP on MS-related outcomes.

We read with interest the article by Langhauser et al1 that reported no benefit of blocking α4 integrin in a mouse model of acute ischemic stroke. The authors identified several reasons that might account for the discrepancies between their results and those of 3 prior studies2–4 that did observe a benefit of blocking α4 integrin in stroke models. The authors and accompanying editorialists then went on to suggest that more animal studies should be performed before human trials of blocking α4 integrin are undertaken. Although we agree with the need to bring greater standardization to preclinical stroke studies, we do not agree that the ongoing phase II biomarker-driven clinical trial to assess the effect of natalizumab on infarct volume in acute ischemic stroke (NCT01955707) should be halted or delayed pending …

Background: The 29-item Multiple Sclerosis Impact Scale (MSIS-29) was developed to examine the impact of multiple sclerosis (MS) on physical and psychological functioning from a patient’s perspective. Objective: To determine the responder definition (RD) of the MSIS-29 physical impact subscale (PHYS) in a group of patients with relapsing–remitting MS (RRMS) participating in a clinical trial. Methods: Data from the SELECT trial comparing daclizumab high-yield process with placebo in patients with RRMS were used. Physical function was evaluated in SELECT using three patient-reported outcomes measures and the Expanded Disability Status Scale (EDSS). Anchor- and distribution-based methods were used to identify an RD for the MSIS-29. Results: Results across the anchor-based approach suggested MSIS-29 PHYS RD values of 6.91 (mean), 7.14 (median) and 7.50 (mode). Distribution-based RD estimates ranged from 6.24 to 10.40. An RD of 7.50 was selected as the most appropriate threshold for physical worsening based on corresponding changes in the EDSS (primary anchor of interest). Conclusion: These findings indicate that a ≥7.50 point worsening on the MSIS-29 PHYS is a reasonable and practical threshold for identifying patients with RRMS who have experienced a clinically significant change in the physical impact of MS.

Background As disease-activity-free status is now a viable treatment goal in relapsing multiple sclerosis (RMS), no evidence of disease activity (NEDA) is gaining increasing acceptance as an outcome measure. Objective To determine the percentage of RMS patients who achieved NEDA in the DECIDE study. Methods DECIDE was a phase 3 study of 150 mg subcutaneous daclizumab high-yield process (DAC HYP) every 4 weeks versus weekly 30 mcg intramuscular (IM) interferon (IFN) beta-1a over 96–144 weeks. NEDA was defined as no relapses, no 12-week confirmed disability progression, no new/enlarging T2 (NET2) lesions, and no gadolinium-enhancing (Gd+) lesions. Results A greater percentage of patients receiving DAC HYP than IFN beta-1a achieved NEDA by week 96 (24.3% [198/816] vs 13.9% [116/834]; odds ratio [OR]: 1.983 [95% confidence interval (CI): 1.540–2.554]; P Conclusions A significantly greater percentage of patients treated with DAC HYP than with IM IFN beta-1a achieved NEDA. Sponsors: Biogen, AbbVie Biotherapeutics.

Background: Daclizumab high-yield process (DAC HYP) is a humanized anti-CD25 monoclonal antibody that inhibits high-affinity interleukin-2 receptor signaling. Objective: The objective of this paper is to assess the proportion of DAC HYP- versus placebo-treated patients who were free from disease activity. Methods: SELECT was a randomized, double-blind, multicenter study of DAC HYP 150 mg or 300 mg, or placebo, administered subcutaneously every four weeks for 52 weeks. In this post-hoc analysis of the SELECT trial, ‘disease-activity free’ was defined as completion through week 52 without relapses or confirmed three-month disability progression (clinical), with no new/newly enlarging T2-hyperintense lesions and no new gadolinium-enhancing lesions at the week 52 scan (radiological). Primary analyses were based on logistic regression controlling for baseline characteristics. Results: More DAC HYP-treated (39%, n = 156) versus placebo-treated patients (11%, n = 22) were disease-activity free (odds ratio (95% confidence interval), 6.18 (3.71–10.32); p < 0.0001). Furthermore, 77% and 48% of DAC HYP-treated patients were free from clinical or radiological disease activity, respectively, compared with 60% and 18% of placebo-treated patients. Conclusion: At one year, DAC HYP resulted in a meaningful increase in the proportion of relapsing–remitting MS patients who were disease-activity free versus placebo.

Regulatory T cells (Treg) mediate immune tolerance and depend on IL-2 for homeostasis and function. The biology of IL-2 is pleiotropic and complex. As a growth factor for both regulatory and conventional T cells, IL-2 is able to both potentiate and limit adaptive immune responses. Adding to this complexity, IL-2 can signal through a high-affinity (IL-2Rαβγ) and intermediate-affinity (IL-2Rβγ) receptor. Thus, the response to IL-2 at the single cell level is dependent on both receptor expression and local IL-2 concentration. Treg dysfunction is implicated in the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Daclizumab, a humanized monoclonal antibody that binds the IL-2 receptor alpha chain and prevents its association with IL-2, has demonstrated efficacy in patients with RRMS, despite causing a reduction in Tregs. These seemingly contradictory observations led us to investigate Treg dynamics in placebo- and daclizumab-treated RRMS patients in the SELECT clinical trial. We report that CD25 blockade reduces Treg numbers, yet Tregs that remain preserve IL-2 signaling capabilities through the intermediate affinity IL-2Rβγ and maintain epigenetic marks characteristic of a phenotypically stable and functional Treg population. Furthermore, Treg dynamics did not associate with treatment efficacy or development of cutaneous adverse events, indicating that the effect of daclizumab on Treg dynamics may be independent of the therapeutic mechanism of action.