Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis.

BACKGROUND: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS. METHODS: Patients with primary/secondary progressive MS from seven AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab, were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise-censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARRs), using Andersen-Gill proportional hazards models and conditional negative binomial model. RESULTS: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (HR 1.49, 95% CI 0.70 to 3.14) and improvement (HR 1.50, 95% CI 0.22 to 10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±SD 0.08±0.28 vs 0.08±0.25; HR 1.05, 95% CI 0.39 to 2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required intensive care unit admission and 36 patients experienced complications after discharge. No treatment-related deaths were reported. CONCLUSION: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity.

Autologous hematopoietic stem cell transplantation for multiple sclerosis: Long-term follow-up data from Norway.

BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) is a potent treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate long-term outcomes of HSCT in MS. METHODS: National retrospective single-center observational study of patients with aggressive RRMS that underwent HSCT in Norway from January 2015 to January 2018. Criteria for receiving HSCT included at least two clinical relapses the last year while on disease modifying treatment (DMT). RESULTS: In total, 29 patients, with a mean follow-up time of 70 months (standard deviation:14.3), were evaluated. Twenty patients (69%) had sustained no evidence of disease activity (NEDA-3) status, 24 (83%) were relapse-free, 23 (79%) free of magnetic resonance imaging (MRI) activity, and 26 (90%) free of progression. Number of patients working full-time increased from 1 (3%), before HSCT, to 10 (33%) after 2 years and 15 (52%) after 5 years. CONCLUSION: HSCT offers long-term disease-free survival with successively increasing work participation in patients with aggressive MS resistant to DMTs.

Healthcare utilization and costs associated with autologous haematopoietic stem cell transplantation in Norwegian patients with relapsing remitting multiple sclerosis.

Multiple sclerosis (MS) patients experience long-term deterioration of neurological function, reduced quality of life, long-lasting treatment cycles, and an increased risk of early workability loss imposing an economic burden to society. Autologous haematopoietic stem cell transplantation (AHSCT) has shown promising treatment effects for relapsing remitting MS (RRMS). This study employs a micro-costing approach to estimate healthcare utilization and costs associated with AHSCT in Norwegian RRMS patients. Patient-level data were extracted from medical journals of 30 RRMS patients receiving AHSCT treatment at Haukeland University Hospital in the period from January 2015 to January 2018. The time horizon for the analysis was from the pretransplant screening until one year after AHSCT. A correlation was found between patient body weight and total healthcare cost. The average total healthcare cost of AHSCT for RRMS patients was estimated to EUR 66 304 (95% CI: EUR 63 598 - EUR 69 010) including costs associated with the pre-AHSCT period, AHSCT treatment phases and one-year follow-up. The majority of the costs, EUR 64 329, occurred during the treatment phase and within the first 100 days after AHSCT. The results indicate that long-term healthcare cost savings may be achieved using AHSCT in selected patients with aggressive RRMS. This is due to the high costs of most used disease modifying treatments. Further research including long-term clinical data is needed to determine the cost-effectiveness of this treatment.

Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis.

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

All-trans Retinoic Acid and Beta-Carotene Increase Sclerostin Production in C2C12 Myotubes.

Sclerostin is a protein secreted by osteocytes whose encoding gene SOST is regulated by mechanical stimuli, cytokines, and all-trans retinoic acid (ATRA) and mediates antianabolic effects on bone formation as an inhibitor of the canonical Wnt/ß-catenin pathway. Interestingly, skeletal muscle has recently been identified as another source of sclerostin, suggesting that the musculature may play an important role in maintaining bone mass. However, regulators of muscular SOST expression are virtually unknown. This study investigates the influence of ATRA and the provitamin A derivative beta-carotene (ß-C) on sclerostin synthesis in muscle cells. The impact of ATRA, its synthetic analog TTNPB, and ß-C on Sost transcription was analyzed by qRT-PCR in C2C12 myotubes and the secreted sclerostin protein by ELISA. ATRA strongly increases the sclerostin synthesis in C2C12 myotubes in a dose-dependent manner. The stimulating effect of ATRA and TTNPB on Sost is largely reduced in the presence of the retinoic acid receptor inhibitor AGN193109. ß-C also increases the Sost expression, but this effect vanishes when ß-C is coincubated with beta-carotene 15,15'-monooxygenase 1 (BCMO1)-specific siRNA. Thus, ATRA is a potent stimulator of sclerostin release in muscle cells. ß-C can also increase Sost mRNA abundance, but this effect depends on the conversion to a retinoid.

Impact of previous disease-modifying treatment on safety and efficacy in patients with MS treated with AHSCT.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective treatment for multiple sclerosis (MS). The impact of previous long-lasting disease-modifying treatments (DMT) for safety and efficacy of AHSCT is unknown. OBJECTIVE: To explore whether previous DMTs with long-lasting effects on the immune system (anti-CD20 therapy, alemtuzumab and cladribine) affect treatment-related complications, long-term outcome and risk of new MS disease activity in patients treated with AHSCT. METHODS: Retrospective observational study of 104 relapsing remitting patients with MS treated by AHSCT in Sweden and Norway from 2011 to 2021, grouped according to the last DMT used ≤6 months prior to AHSCT. The primary outcomes were early AHSCT-related complications (mortality, neutropenic fever and hospitalisation length), long-term complications (secondary autoimmunity) and proportion of patients with No Evidence of Disease Activity (NEDA-3 status): no new relapses, no MRI activity and no disease progression during the follow-up. RESULTS: The mean follow-up time was 39.5 months (range 1-95). Neutropenic fever was a common AHSCT-related complication affecting 69 (66%) patients. There was no treatment-related mortality. During the follow-up period, 20 patients (19%) were diagnosed with autoimmunity. Occurrence of neutropenic fever, hospitalisation length or secondary autoimmunity did not vary dependent on the last DMT used prior to AHSCT. A total of 84 patients (81%) achieved NEDA-3 status, including all patients (100%) using rituximab, alemtuzumab or cladribine before AHSCT. CONCLUSION: This study provides level 4 evidence that AHSCT in patients previously treated with alemtuzumab, cladribine or rituximab is safe and efficacious.

Asparaginase encapsulated in erythrocytes as second-line treatment in hypersensitive patients with acute lymphoblastic leukaemia.

Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase-related hypersensitivity causes treatment discontinuation, which is associated with decreased event-free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR-GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1-45 years; median: 6.1 years) with non-high-risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG-asparaginase). Eryaspase (150 u/kg) was scheduled to complete the intended course of asparaginase (1-7 doses) in two Nordic/Baltic treatment protocols. Forty-nine (96.1%) patients had asparaginase enzyme activity (AEA) ≥100 iu/l 14 ± 2 days after the first eryaspase infusion [median AEA 511 iu/l; interquartile range (IQR), 291-780], whereas six of nine (66.7%) patients had AEA ≥100 iu/l 14 ± 2 days after the fourth infusion (median AEA 932 iu/l; IQR, 496-163). The mean terminal half-life of eryaspase following the first infusion was 15.3 ± 15.5 days. Few asparaginase-related adverse events were reported; five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half-life of eryaspase confirmed that a 2-week schedule is appropriate.

From perception to inference: Utilization of probabilities as decision weights in children.

In a probabilistic inference task (three probabilistic cues predict outcomes for two options), we examined decisions from 233 children (5-6 vs. 9-10 years). Contiguity (low vs. high; i.e., position of probabilistic information far vs. close to options) and demand for selectivity (low vs. high; i.e., showing predictions of desired vs. desired and undesired outcomes) were varied as configural aspects of the presentation format. Probability utilization was measured by the frequency of following the predictions of the highest validity cue in choice. High contiguity and low demand for selectivity strongly and moderately increased probability utilization, respectively. Children are influenced by presentation format when using probabilities as decision weights. They benefit from perception-like presentations that present probabilities and options as compounds.

The Interaction of TRAF6 With Neuroplastin Promotes Spinogenesis During Early Neuronal Development.

Correct brain wiring depends on reliable synapse formation. Nevertheless, signaling codes promoting synaptogenesis are not fully understood. Here, we report a spinogenic mechanism that operates during neuronal development and is based on the interaction of tumor necrosis factor receptor-associated factor 6 (TRAF6) with the synaptic cell adhesion molecule neuroplastin. The interaction between these proteins was predicted in silico and verified by co-immunoprecipitation in extracts from rat brain and co-transfected HEK cells. Binding assays show physical interaction between neuroplastin's C-terminus and the TRAF-C domain of TRAF6 with a K d value of 88 µM. As the two proteins co-localize in primordial dendritic protrusions, we used young cultures of rat and mouse as well as neuroplastin-deficient mouse neurons and showed with mutagenesis, knock-down, and pharmacological blockade that TRAF6 is required by neuroplastin to promote early spinogenesis during in vitro days 6-9, but not later. Time-framed TRAF6 blockade during days 6-9 reduced mEPSC amplitude, number of postsynaptic sites, synapse density and neuronal activity as neurons mature. Our data unravel a new molecular liaison that may emerge during a specific window of the neuronal development to determine excitatory synapse density in the rodent brain.

Safety and efficacy of autologous hematopoietic stem cell transplantation for multiple sclerosis in Norway.

BACKGROUND: Hematopoietic stem cell treatment (HSCT) is a promising treatment option for multiple sclerosis (MS), but detailed safety and efficacy measures are still scarce. OBJECTIVE: To evaluate the efficacy and safety of HSCT in MS. METHODS: Retrospective single-center observational study of all MS patients that underwent HSCT in Norway during January 2015 to January 2018. The primary outcome was no evidence of disease activity (NEDA-3) status. RESULTS: A total of 30 patients with a median follow-up time of 26 months (range: 11-48) were evaluated. In total, 25 (83%) achieved NEDA-3 status, and none received disease-modifying treatment after HSCT. For 13 (43%) of the patients, there were sustained improvement in Expanded Disability Status Scale (EDSS) score, and 10 (33%) were working full time after the treatment, compared to only 1 (3%) before treatment. There were no serious treatment-related complications and was no mortality. Five patients (17%) were diagnosed with an autoimmune thyroid disease after the procedure, and 10 (43%) of the women had amenorrhea lasting >12 months and symptoms of ovarian failure. CONCLUSION: HSCT in MS is an effective and relatively safe treatment option, with few serious complications and no mortality in Norway, so far. However, long-term adverse event with amenorrhea is a common problem.

Stereochemical Rules Govern the Soft Self-Assembly of Achiral Compounds: Understanding the Heliconical Liquid-Crystalline Phases of Bent-Core Mesogens.

A series of bent-shaped 4-cyanoresorcinol bisterephthalates is reported. Some of these achiral compounds spontaneously form a short-pitch heliconical lamellar liquid-crystalline phase with incommensurate 3-layer pitch and the helix axis parallel to the layer normal. It is observed at the paraelectric-(anti)ferroelectric transition, if it coincides with the transition from random to uniform tilt and with the transition from anticlinic to synclinic tilt correlation of the molecules in the layers of the developing tilted smectic phase. For compounds with long chains the heliconical phase is only field-induced, but once formed it is stable in a distinct temperature range, even after switching off the field. The presence of the helix changes the phase properties and the switching mechanism from the naturally preferred rotation around the molecular long axis, which reverses the chirality, to a precession on a cone, which retains the chirality. These observations are explained by diastereomeric relations between two coexisting modes of superstructural chirality. One is the layer chirality, resulting from the combination of tilt and polar order, and the other one is the helical twist evolving between the layers. At lower temperature the helical structure is replaced by a non-tilted and ferreoelectric switching lamellar phase, providing an alternative non-chiral way for the transition from anticlinic to synclinic tilt.

Chiral Incommensurate Helical Phase in a Smectic of Achiral Bent-Core Mesogens.

An achiral, bent-core mesogen forms several tilted smectic liquid crystal phases, including a nonpolar, achiral de Vries smectic A which transitions to a chiral, ferroelectric state in applied electric fields above a threshold. At lower temperature, a chiral, ferrielectric phase with a periodic, supermolecular modulation of the tilt azimuth, indicated by a Bragg peak in carbon-edge resonant soft x-ray scattering, is observed. The absence of a corresponding resonant umklapp peak identifies the superlayer structure as a twist-bend-like helix that is only weakly modulated by the smectic layering.

A Self-Assembled Bicontinuous Cubic Phase with a Single-Diamond Network.

The first single-diamond cubic phase in a liquid crystal is reported. This skeletal structure with the F d 3 ‾ m space group is formed by self-assembly of bolaamphiphiles with swallow-tailed lateral chains. It consists of bundles of π-conjugated p-terphenyl rods fused into an infinite network by hydrogen-bonded spheres at tetrahedral four-way junctions. We also present a quantitative model relating molecular architecture to the space-filling requirements of six possible bicontinuous cubic phases, that is, the single- and double-network versions of gyroid, diamond, and "plumber's nightmare".

Transition between tangential and co-axial liquid crystalline honeycombs in the self-assembly of Y-shaped bolapolyphiles.

p-Terphenyl based Y-shaped bolapolyphiles self-assemble into liquid crystalline honeycombs with co-axial organization of the π-conjugated rods around columns filled by alkyl sidechains. In this new hexagonal honeycomb with P6/mmm symmetry the orientation of the π-conjugated rods is perpendicular to the tangential honeycombs formed at lower temperature or with longer chain length.

Formation and development of nanometer-sized cybotactic clusters in bent-core nematic liquid crystalline compounds.

Two homologue achiral bent-core liquid crystals (LCs), BCN66 and BCN84, in their nematic phases are studied by dielectric spectroscopy in the frequency range 10 Hz-10 MHz. In each of these compounds, two relaxation processes are identified and assigned to (i) collective dynamics of molecules in nanometer-sized cybotactic clusters and (ii) individual molecular relaxations, in the ascending order of frequency of the probe field. The temperature and the bias electric field dependence of the dielectric strength and relaxation frequency for these processes are shown to give rise to sharpness in cluster boundaries, increased size and volume fraction in the LC nematic phase. The effect of the bias field on the LC cell is similar to reducing its temperature; both variables increase the cluster size and volume fraction and give rise to sharp cluster boundaries. The findings confirm that dielectric spectroscopy is a powerful and an extremely useful technique to provide a deeper understanding of the mechanism of cybotactic cluster formation in the isotropic liquid and the nematic phase of LCs as a function of temperature and the bias field.

A complex of Neuroplastin and Plasma Membrane Ca2+ ATPase controls T cell activation.

The outcome of T cell activation is determined by mechanisms that balance Ca2+ influx and clearance. Here we report that murine CD4 T cells lacking Neuroplastin (Nptn -/-), an immunoglobulin superfamily protein, display elevated cytosolic Ca2+ and impaired post-stimulation Ca2+ clearance, along with increased nuclear levels of NFAT transcription factor and enhanced T cell receptor-induced cytokine production. On the molecular level, we identified plasma membrane Ca2+ ATPases (PMCAs) as the main interaction partners of Neuroplastin. PMCA levels were reduced by over 70% in Nptn -/- T cells, suggesting an explanation for altered Ca2+ handling. Supporting this, Ca2+ extrusion was impaired while Ca2+ levels in internal stores were increased. T cells heterozygous for PMCA1 mimicked the phenotype of Nptn -/- T cells. Consistent with sustained Ca2+ levels, differentiation of Nptn -/- T helper cells was biased towards the Th1 versus Th2 subset. Our study thus establishes Neuroplastin-PMCA modules as important regulators of T cell activation.

The conserved macrodomains of the non-structural proteins of Chikungunya virus and other pathogenic positive strand RNA viruses function as mono-ADP-ribosylhydrolases.

Human pathogenic positive single strand RNA ((+)ssRNA) viruses, including Chikungunya virus, pose severe health problems as for many neither efficient vaccines nor therapeutic strategies exist. To interfere with propagation, viral enzymatic activities are considered potential targets. Here we addressed the function of the viral macrodomains, conserved folds of non-structural proteins of many (+)ssRNA viruses. Macrodomains are closely associated with ADP-ribose function and metabolism. ADP-ribosylation is a post-translational modification controlling various cellular processes, including DNA repair, transcription and stress response. We found that the viral macrodomains possess broad hydrolase activity towards mono-ADP-ribosylated substrates of the mono-ADP-ribosyltransferases ARTD7, ARTD8 and ARTD10 (aka PARP15, PARP14 and PARP10, respectively), reverting this post-translational modification both in vitro and in cells. In contrast, the viral macrodomains possess only weak activity towards poly-ADP-ribose chains synthesized by ARTD1 (aka PARP1). Unlike poly-ADP-ribosylglycohydrolase, which hydrolyzes poly-ADP-ribose chains to individual ADP-ribose units but cannot cleave the amino acid side chain - ADP-ribose bond, the different viral macrodomains release poly-ADP-ribose chains with distinct efficiency. Mutational and structural analyses identified key amino acids for hydrolase activity of the Chikungunya viral macrodomain. Moreover, ARTD8 and ARTD10 are induced by innate immune mechanisms, suggesting that the control of mono-ADP-ribosylation is part of a host-pathogen conflict.

Differential effects of glucagon-like peptide-1 receptor agonists on heart rate.

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1-12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1-3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6-10 bpm compared with dulaglutide and exenatide LAR at 3-4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure.

Similar pharmacokinetics and pharmacodynamics of rapid-acting insulin lispro products SAR342434 and US- and EU-approved Humalog in subjects with type 1 diabetes.

AIM: To compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 rapid-acting insulin lispro products: SAR342434 solution, United States (US)-approved Humalog and European Union (EU)-approved Humalog. METHODS: In a single-centre, randomized, double-blind, 3-treatment, 3-period, 6-sequence, crossover, euglycaemic clamp study (NCT02273258), adult male subjects with type 1 diabetes were randomized to receive 0.3 U/kg of SAR342434 solution, US-approved and EU-approved Humalog under fasted conditions. PK and PD (glucose infusion rate [GIR]) were assessed up to 12 hours. RESULTS: Of the 30 subjects randomized, 28 completed all 3 treatment periods. Mean concentration and GIR vs time profiles were similar for all 3 products. Exposure (INS-Cmax , INS-AUClast and INS-AUC) and activity (GIRmax and GIR-AUC0-12h ) of SAR342434, US-approved and EU-approved Humalog were similar in all comparisons (point estimates of treatment ratios, 0.95-1.03 for PK parameters and 1.00-1.07 for PD parameters), with 90% confidence intervals for the ratios of geometric least squares means within the pre-specified bioequivalence limit (0.80-1.25) and no significant differences in time-related parameters. Within-subject variability of exposure and activity was low across the 3 clamps, indicating high day-to-day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for all 3 products. No safety concerns were noted in vital signs or in laboratory and electrocardiogram data. CONCLUSIONS: The results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US- and EU-approved Humalog, and between both US- and EU-approved Humalog, supporting the use of SAR342434 solution for injection as a follow-on product.

Spontaneous helix formation in non-chiral bent-core liquid crystals with fast linear electro-optic effect.

Liquid crystals (LCs) represent one of the foundations of modern communication and photonic technologies. Present display technologies are based mainly on nematic LCs, which suffer from limited response time for use in active colour sequential displays and limited image grey scale. Herein we report the first observation of a spontaneously formed helix in a polar tilted smectic LC phase (SmC phase) of achiral bent-core (BC) molecules with the axis of helix lying parallel to the layer normal and a pitch much shorter than the optical wavelength. This new phase shows fast (∼30 µs) grey-scale switching due to the deformation of the helix by the electric field. Even more importantly, defect-free alignment is easily achieved for the first time for a BC mesogen, thus providing potential use in large-scale devices with fast linear and thresholdless electro-optical response.