Energy storage with high energy density and low cost has been the subject of a decades-long pursuit. Sodium-ion batteries are well expected because they utilize abundant resources. However, the lack ...of competent cathodes with both large capacities and long cycle lives prevents the commercialization of sodium-ion batteries. Conventional cathodes with hexagonal-P2-type structures suffer from structural degradations when the sodium content falls below 33%, or when the integral anions participate in gas evolution reactions. Here, we show a "pillar-beam" structure for sodium-ion battery cathodes where a few inert potassium ions uphold the layer-structured framework, while the working sodium ions could diffuse freely. The thus-created unorthodox orthogonal-P2 K
Ni
Mn
O
cathode delivers a capacity of 194 mAh/g at 0.1 C, a rate capacity of 84% at 1 C, and an 86% capacity retention after 500 cycles at 1 C. The addition of the potassium ions boosts simultaneously the energy density and the cycle life.
High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy ...therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset.
In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0–2 years (early) or 4–6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0–10, with higher scores indicating increased disability), at 6–10 years after disease onset, assessed with a linear mixed-effects model.
We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7–8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 SD 1·8 vs 3·5 SD 2·1; p<0·0001), with a difference between groups of −0·98 (95% CI −1·51 to −0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6–10 year follow-up period.
High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6–10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.
National Health and Medical Research Council Australia and MS Society UK.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract In March and early April 2009 a new swine-origin influenza virus (S-OIV), A (H1N1), emerged in Mexico and the USA. The virus quickly spread worldwide through human-to-human transmission. In ...view of the number of countries and communities which were reporting human cases, the World Health Organization raised the influenza pandemic alert to the highest level (level 6) on June 11, 2009. The propensity of the virus to primarily affect children, young adults and pregnant women, especially those with an underlying lung or cardiac disease condition, and the substantial increase in rate of hospitalizations, prompted the efforts of the pharmaceutical industry, including new manufacturers from China, Thailand, India and South America, to develop pandemic H1N1 influenza vaccines. All currently registered vaccines were tested for safety and immunogenicity in clinical trials on human volunteers. All were found to be safe and to elicit potentially protective antibody responses after the administration of a single dose of vaccine, including split inactivated vaccines with or without adjuvant, whole-virion vaccines and live-attenuated vaccines. The need for an increased surveillance of influenza virus circulation in swine is outlined.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of ...individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
The development of a safe, effective and globally affordable HIV vaccine offers the best hope for the future control of the HIV-1 pandemic. Since 1987, scores of candidate HIV-1 vaccines have been ...developed which elicited varying degrees of protective responses in nonhuman primate models, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost combinations. Four of these candidate vaccines have been tested for efficacy in human volunteers, but, to the exception of the recent RV144 Phase III trial in Thailand, which elicited a modest but statistically significant level of protection against infection, none has shown efficacy in preventing HIV-1 infection or in controlling virus replication and delaying progression of disease in humans. Protection against infection was observed in the RV144 trial, but intensive research is needed to try to understand the protective immune mechanisms at stake. Building-up on the results of the RV144 trial and deciphering what possibly are the immune correlates of protection are the top research priorities of the moment, which will certainly accelerate the development of an highly effective vaccine that could be used in conjunction with other HIV prevention and treatment strategies. This article reviews the state of the art of HIV vaccine development and discusses the formidable scientific challenges met in this endeavor, in the context of a better understanding of the immunopathogenesis of the disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
OBJECTIVETo determine the safety and efficacy of balloon vs sham venoplasty of narrowing of the extracranial jugular and azygos veins in multiple sclerosis (MS).
METHODSPatients with relapsing or ...progressive MS were screened using clinical and ultrasound criteria. After confirmation of >50% narrowing by venography, participants were randomized 1:1 to receive balloon or sham venoplasty of all stenoses and were followed for 48 weeks. Participants and research staff were blinded to intervention allocation. The primary safety outcome was the number of adverse events (AEs) during 48 weeks. The primary efficacy outcome was the change from baseline to week 48 in the patient-reported outcome MS Quality of Life–54 (MSQOL-54) questionnaire. Standardized clinical and MRI outcomes were also evaluated.
RESULTSOne hundred four participants were randomized (55 sham; 49 venoplasty) and 103 completed 48 weeks of follow-up. Twenty-three sham and 21 venoplasty participants reported at least 1 AE; one sham (2%) and 5 (10%) venoplasty participants had a serious AE. The mean improvement in MSQOL-54 physical score was +1.3 (sham) and +1.4 (venoplasty) (p = 0.95); MSQOL-54 mental score was +1.2 (sham) and −0.8 (venoplasty) (p = 0.55).
CONCLUSIONSOur data do not support the continued use of venoplasty of extracranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS.
CLINICALTRIALS.GOV IDENTIFIERNCT01864941.
CLASSIFICATION OF EVIDENCEThis study provides Class I evidence that for patients with MS, balloon venoplasty of extracranial jugular and azygous veins is not beneficial in improving patient-reported, standardized clinical, or MRI outcomes.
Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions ...with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary Background Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative ...to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. Methods In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. Findings Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 95% CI 0·14–0·23 vs 0·53 0·46–0·61, p<0·0001) and fingolimod (0·15 0·10–0·20 vs 0·34 0·26–0·41, p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 0·14–0·26 vs 0·19 0·15–0·23, p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio HR 0·66 95% CI 0·36–1·22, p=0·37), fingolimod (1·27 0·60–2·70, p=0·67), and natalizumab (0·81 0·47–1·39, p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 0·65–1·49, p=0·93) and fingolimod (0·50 0·25–1·01, p=0·18), and a lower probability of disability improvement than natalizumab (0·35 0·20–0·59, p=0·0006). Interpretation Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles. Funding National Health and Medical Research Council, and the University of Melbourne.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objective
In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no ...studies have directly compared the outcomes of switching to either of these agents.
Methods
Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing–remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi‐randomization with propensity score–based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise‐censored analyses.
Results
Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on‐study follow‐up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability–time curve) differed between natalizumab and fingolimod (−0.12 vs 0.04 per year, respectively, p < 0.001).
Interpretation
This study suggests that in active multiple sclerosis during treatment with injectable disease‐modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short‐term disability burden. Ann Neurol 2015;77:425–435
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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