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Cocrystals are assemblies of more than one type of molecule stabilized through noncovalent interactions. They are promising materials for improved drug formulation in which the stability, solubility, or biocompatibility of the active pharmaceutical ingredient (API) is improved by including a coformer. In this work, a range of density functional theory (DFT) and density functional tight binding (DFTB) models are systematically compared for their ability to predict the lattice enthalpy of a broad range of existing pharmaceutically relevant cocrystals. These range from cocrystals containing model compounds 4,4'-bipyridine and oxalic acid to those with the well benchmarked APIs of aspirin and paracetamol, all tested with a large set of alternative coformers. For simple cocrystals, there is a general consensus in lattice enthalpy calculated by the different DFT models. For the cocrystals with API coformers the cocrystals, enthalpy predictions depend strongly on the DFT model. The significantly lighter DFTB models predict unrealistic values of lattice enthalpy even for simple cocrystals.
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BACKGROUND: Ibudilast has shown beneficial effects on several imaging outcomes in progressive multiple sclerosis (MS). Slowly enlarging lesions are a proposed imaging biomarker of compartmentalized inflammation within chronic active lesions. OBJECTIVE: To assess the treatment effect of ibudilast on slowly enlarging lesion volumes over 96 weeks from a phase II clinical trial of ibudilast (Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: In total, 255 participants with progressive MS from 28 sites were randomized to oral ibudilast or placebo. Participants with at least four analyzable magnetic resonance imaging (MRI) were included. Slowly enlarging lesions were quantified using Jacobian determinant maps. A linear model was used to assess the effect of ibudilast. Magnetization transfer ratio within slowly enlarging lesions was assessed to determine the effect of ibudilast on tissue integrity. RESULTS: In total, 195 participants were included in this analysis. Ibudilast significantly decreased slowly enlarging lesion volume (23%, p = 0.003). Ibudilast also reduced magnetization transfer ratio change in slowly enlarging lesions: 0.22%/year, p = 0.04. CONCLUSION: Ibudilast showed a significant effect on baseline volume of lesions that were slowly enlarging and magnetization transfer ratio in slowly enlarging lesions. The results support the use of slowly enlarging lesions for assessment of compartmentalized inflammation represented by chronic active lesions and provide further support for the neuroprotective effects of ibudilast in progressive MS.
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Indolizinas , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Pirazóis , Humanos , Encéfalo/patologia , Inflamação/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Piridinas/uso terapêuticoRESUMO
BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). OBJECTIVE: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. METHODS: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. RESULTS: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = -0.113%, 95% confidence interval (CI): -0.204% to -0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. CONCLUSIONS: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect.
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Doenças do Sistema Nervoso Central , Fatores Inibidores da Migração de Macrófagos , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Feminino , Humanos , Masculino , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Fatores Inibidores da Migração de Macrófagos/líquido cefalorraquidiano , Fatores Inibidores da Migração de Macrófagos/uso terapêutico , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/patologiaRESUMO
ABSTRACT: Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease characterized by destruction of mucosal glands resulting in dry eye and dry mouth. Ocular presentations can be heterogenous in SS with corneal nerves abnormalities that are structural, functional, or both. Some individuals present with corneal hyposensitivity, with a phenotype of decreased tear production and epithelial disruption. Others present with corneal hypersensitivity, with a phenotype of neuropathic pain including light sensitivity and pain out of proportion to signs of tear dysfunction. A similar correlate can be found outside the eye, with dry mouth predominating in some individuals while pain conditions predominate in others. Understanding how nerve status affects SS phenotype is an important first step to improving disease management by targeting nerve abnormalities, as well as inflammation.
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Córnea , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/fisiopatologia , Síndrome de Sjogren/imunologia , Córnea/inervação , Córnea/patologia , Inflamação/fisiopatologia , Lágrimas/metabolismo , Lágrimas/fisiologia , Síndromes do Olho Seco/fisiopatologia , Síndromes do Olho Seco/etiologiaRESUMO
ICD-11 Complex Posttraumatic Stress Disorder (CPTSD) is a disorder of six symptom clusters including reexperiencing, avoidance, sense of threat, affective dysregulation, negative self-concept, and disturbed relationships. Unlike earlier descriptions of complex PTSD, ICD-11 CPTSD does not list dissociation as a unique symptom cluster. We tested whether the ICD-11 CPTSD symptoms can exist independently of dissociation in a nationally representative sample of adults (N = 1,020) who completed self-report measures. Latent class analysis was used to identify unique subsets of people with distinctive symptom profiles. The best fitting model contained four classes including a "low symptoms" class (48.9%), a "PTSD" class (14.7%), a "CPTSD" class (26.5%), and a "CPTSD + Dissociation" class (10.0%). These classes were related to specific adverse childhood experiences, notably experiences of emotional and physical neglect. The "PTSD," "CPTSD," and "CPTSD + Dissociation" classes were associated with a host of poor health outcomes, however, the "CPTSD + Dissociation" class had the poorest mental health and highest levels of functional impairment. Findings suggest that ICD-11 CPTSD symptoms can occur without corresponding dissociative experiences, however, when CPTSD symptoms and dissociative experiences occur together, health outcomes appear to be more severe.
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Transtornos de Estresse Pós-Traumáticos , Adulto , Humanos , Transtornos de Estresse Pós-Traumáticos/psicologia , Classificação Internacional de Doenças , Autorrelato , Emoções , Transtornos DissociativosRESUMO
BACKGROUND: Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome. METHODS: VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18-75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895. FINDINGS: Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline -1·92 points (95% CI -4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group). INTERPRETATION: The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future. FUNDING: Novartis.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome de Sjogren/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Índice de Gravidade de Doença , Síndrome de Sjogren/diagnóstico , Resultado do TratamentoRESUMO
In situ investigations of electrocatalytic processes of increasing societal interest such as the nitrogen reduction reaction (NRR) require aggressive experimental conditions that are not readily compatible with surface sensitive techniques such as attenuated total reflection surface enhanced infrared absorption spectroscopy (ATR-SEIRAS). A method for performing ATR-SEIRAS studies at very negative potentials where conventional IR-active films delaminate and fail is reported. The method relies on a thin film of very robust boron-doped diamond deposited on a micromachined Si wafer, which provides extended mid-IR transparency at long wavelengths. SEIRAS activity is achieved by electrodepositing gold nanoparticles onto the conductive BDD layer. The Au@BDD layers are shown to sustain prolonged periods of electrolysis at negative potentials, with no degradation of the modifying layer. The efficacy of these substrates for electrocatalysis is demonstrated by studying the reduction of N2 at -1.5 V vs Ag/AgCl in an aqueous-based electrolyte. Under these conditions, direct spectroscopic evidence of both NH3 and hydrazine formed from the nitrogen reduction reaction (NRR) is provided.
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BACKGROUND: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. OBJECTIVE: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. METHODS: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). RESULTS: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). CONCLUSION: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. CLINICALTRIALS.GOV: NCT01982942.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Piridinas/uso terapêutico , Atrofia/tratamento farmacológico , Atrofia/patologiaRESUMO
BACKGROUND: In the OPTIMUM trial in patients with relapsing MS, treatment differences in annualized relapse rate (ARR, 0.088) and change in fatigue at week 108 (3.57 points, measured using the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis, symptom domain (FSIQ-RMS-S)) favored ponesimod over teriflunomide. However, the importance of the fatigue outcome to patients was unclear. OBJECTIVE: To assess the importance of the OPTIMUM FSIQ-RMS-S results using data from an MS discrete choice experiment (DCE). METHODS: The DCE included components to correlate levels of physical and cognitive fatigue with FSIQ-RMS-S scores. Changes in relapses/year and time to MS progression equivalent to the treatment difference in fatigue in OPTIMUM were determined for similar fatigue levels as mean baseline fatigue in OPTIMUM. RESULTS: DCE participants would accept 0.06 more relapses/year or a 0.15-0.17 year decrease in time to MS progression for a 3.57-point difference in physical fatigue on the FSIQ-RMS-S. To improve cognitive fatigue by 3.57-points on the FSIQ-RMS-S, DCE participants would accept 0.09-0.10 more relapses/year or a 0.24-0.28 year decrease in time to MS progression. CONCLUSION: MS patients would accept 0.06 more relapses/year to change their fatigue by a similar magnitude as the between-treatment difference observed in the OPTIMUM trial.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Preferência do Paciente , Doença Crônica , RecidivaRESUMO
BACKGROUND: Smoking is associated with an increased risk of multiple sclerosis (MS) and disability worsening. The relationship between smoking, cognitive processing speed, and brain atrophy remains uncertain. OBJECTIVE: To quantify the impact of smoking on processing speed and brain volume in MS and to explore the longitudinal relationship between smoking and changes in processing speed. METHODS: A retrospective study of MS patients who completed the processing speed test (PST) between September 2015 and March 2020. Demographics, disease characteristics, smoking history, and quantitative magnetic resonance imaging (MRI) were collected. Cross-sectional associations between smoking, PST performance, whole-brain fraction (WBF), gray matter fraction (GMF), and thalamic fraction (TF) were assessed using multivariable linear regression. The longitudinal relationship between smoking and PST performance was assessed by linear mixed modeling. RESULTS: The analysis included 5536 subjects of whom 1314 had quantitative MRI within 90 days of PST assessment. Current smokers had lower PST scores than never smokers at baseline, and this difference persisted over time. Smoking was associated with reduced GMF but not with WBF or TF. CONCLUSION: Smoking has an adverse relationship with cognition and GMF. Although causality is not demonstrated, these observations support the importance of smoking cessation counseling in MS management.
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Doenças do Sistema Nervoso Central , Fumar Cigarros , Esclerose Múltipla , Humanos , Esclerose Múltipla/patologia , Velocidade de Processamento , Estudos Retrospectivos , Estudos Transversais , Fator de Maturação da Glia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Atrofia/patologiaRESUMO
INTRODUCTION: Sjögren's Disease, SjD, is a systemic autoimmune disorder characterized by reduced function of the salivary and lacrimal glands. Patients suffer from dryness, fatigue, and pain and may present with or without extra-glandular organ involvement. Symptoms limit SjD patients' quality of life and are the most difficult to improve with therapy. SjD patients are heterogeneous and clustering them into biologically similar subgroups might improve the efficacy of therapies. The need for therapies that address both the symptoms and extra glandular organ involvement of SjD presents an unmet opportunity that has recently attracted a growing interest in the pharmaceutical industry. AREAS COVERED: The goal of this report is to review recent phase II/III studies in SjD. To accomplish our goal, we performed a literature search for phase II/III studies and abstracts recently presented at conferences. EXPERT OPINION: This review allows updates the reader on the multitude of recent phase II/III clinical trials. We speculate on how subtypes of SjD will drive future therapeutic targeting and inform pathogenesis.
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Qualidade de Vida , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
Chromium ions can make their way into the primary coolant of nuclear power reactors from the corrosion of stainless-steel reactor components, decreasing the material's corrosion resistance and resulting in increased transport of further corrosion products. Despite these potential effects, the radiation-induced redox speciation of chromium ions in aqueous solution is not well understood, especially at the elevated temperatures experienced by reactor coolants. In the present work, we report new experimental results demonstrating that in aerated aqueous solution, the radiolytic oxidation of Cr(III) to Cr(VI) occurs at pH 4, while the reduction of Cr(VI) to Cr(III) occurs at pH 2. The oxidation of Cr(III) is primarily attributed to the reaction of the hydroxyl radical (ËOH) with the Cr(OH)2+ species, while the reduction of Cr(VI) is attributed to reactions involving the hydrated electron (eaq-) and hydrogen atom (HË). Additionally, the steady-state equilibrium yield of Cr(VI) from the gamma irradiation of pH 4 Cr(III) solutions decreased with increasing temperature (over a range of 37-195 °C). This observation indicates that the activation energy of the Cr(VI) reduction reactions is higher than that for the Cr(III) oxidation reactions, such that it becomes relatively more favorable at higher temperatures. Overall, these data are important for the development of complementary multiscale models for the prediction of metal ion speciation in high temperature radiation environments.
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BACKGROUND: COVID-19 has challenged health services throughout the world in terms of hospital capacity and put staff and vulnerable populations at risk of infection. In the face of these challenges, many health providers have implemented remote patient monitoring (RPM) of COVID-19 patients in their own homes. However systematic reviews of the literature on these implementations have revealed wide variations in how RPM is implemented; along with variations in particulars of RPM reported on, making comparison and evaluation difficult. A review of reported items is warranted to develop a framework of key items to enhance reporting consistency. The aims of this review of remote monitoring for COVID-19 patients are twofold: (1) to facilitate comparison between RPM implementations by tabulating information and values under common domains. (2) to develop a reporting framework to enhance reporting consistency. METHOD: A review of the literature for RPM for COVID-19 patients was conducted following PRISMA guidelines. The Medline database was searched for articles published between 2020 to February 2023 and studies reporting on items with sufficient detail to compare one with another were included. Relevant data was extracted and synthesized by the lead author. Quality appraisal was not conducted as the the articles considered were evaluated as informational reports of clinical implementations rather than as studies designed to answer a research question. RESULTS: From 305 studies retrieved, 23 studies were included in the review: fourteen from the US, two from the UK and one each from Africa, Ireland, China, the Netherlands, Belgium, Australia and Italy. Sixteen generally reported items were identified, shown with the percentage of studies reporting in brackets: Reporting Period (82%), Rationale (100%), Patients (100%), Medical Team (91%) Provider / Infrastructure (91%), Communications Platform (100%), Patient Equipment (100%), Training (48%), Markers (96%), Frequency of prompt / Input (96%),Thresholds (82%), Discharge (61%), Enrolled (96%), Alerts/Escalated (78%), Patient acceptance (43%), and Patient Adherence (52%). Whilst some studies reported on patient training and acceptance, just one reported on staff training and none on staff acceptance. CONCLUSIONS: Variations in reported items were found. Pending the establishment of a robust set of reporting guidelines, we propose a reporting framework consisting of eighteen reporting items under the following four domains: Context, Technology, Process and Metrics.
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COVID-19 , Humanos , COVID-19/epidemiologia , Cooperação do Paciente , África , Austrália , BélgicaRESUMO
Most cues to speech intelligibility are within a narrow frequency range, with its upper limit not exceeding 4 kHz. It is still unclear whether speaker-related (indexical) information is available past this limit or how speaker characteristics are distributed at frequencies within and outside the intelligibility range. Using low-pass and high-pass filtering, we examined the perceptual salience of dialect and gender cues in both intelligible and unintelligible speech. Setting the upper frequency limit at 11 kHz, spontaneously produced unique utterances (n = 400) from 40 speakers were high-pass filtered with frequency cutoffs from 0.7 to 5.56 kHz and presented to listeners for dialect and gender identification and intelligibility evaluation. The same material and experimental procedures were used to probe perception of low-pass filtered and unmodified speech with cutoffs from 0.5 to 1.1 kHz. Applying statistical signal detection theory analyses, we found that cues to gender were well preserved at low and high frequencies and did not depend on intelligibility, and the redundancy of gender cues at higher frequencies reduced response bias. Cues to dialect were relatively strong at low and high frequencies; however, most were in intelligible speech, modulated by a differential intelligibility advantage of male and female speakers at low and high frequencies.
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Cognição , Inteligibilidade da Fala , Feminino , Humanos , Masculino , Sinais (Psicologia) , Idioma , PercepçãoRESUMO
The frequency range audible to humans can extend from 20 Hz to 20 kHz, but only a portion of this range-the lower end up to 8 kHz-has been systematically explored because extended high-frequency (EHF) information above this low range has been considered unnecessary for speech comprehension. This special issue presents a collection of research studies exploring the presence of EHF information in the acoustic signal and its perceptual utility. The papers address the role of EHF hearing in auditory perception, the impact of EHF hearing loss on speech perception in specific populations and occupational settings, the importance of EHF in speech recognition and in providing speaker-related information, the utility of acoustic EHF energy in fricative sounds, and ultrasonic vocalizations in mice in relation to human hearing. Collectively, the research findings offer new insights and converge in showing that not only is EHF energy present in the speech spectrum, but listeners can utilize EHF cues in speech processing and recognition, and EHF hearing loss has detrimental effects on perception of speech and non-speech sounds. Together, this collection challenges the conventional notion that EHF information has minimal functional significance.
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Perda Auditiva Neurossensorial , Percepção da Fala , Humanos , Animais , Camundongos , Audição , Percepção Auditiva , Ruído , Som , Limiar AuditivoRESUMO
Artificial metallo-nucleases (AMNs) are promising DNA damaging drug candidates. Here, we demonstrate how the 1,2,3-triazole linker produced by the Cu-catalysed azide-alkyne cycloaddition (CuAAC) reaction can be directed to build Cu-binding AMN scaffolds. We selected biologically inert reaction partners tris(azidomethyl)mesitylene and ethynyl-thiophene to develop TC-Thio, a bioactive C3 -symmetric ligand in which three thiophene-triazole moieties are positioned around a central mesitylene core. The ligand was characterised by X-ray crystallography and forms multinuclear CuII and CuI complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, CuII -TC-Thio becomes a potent DNA binding and cleaving agent. Mechanistic studies reveal DNA recognition occurs exclusively at the minor groove with subsequent oxidative damage promoted through a superoxide- and peroxide-dependent pathway. Single molecule imaging of DNA isolated from peripheral blood mononuclear cells shows that the complex has comparable activity to the clinical drug temozolomide, causing DNA damage that is recognised by a combination of base excision repair (BER) enzymes.
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Química Click , Cobre , Cobre/química , Leucócitos Mononucleares/metabolismo , Ligantes , DNA/química , Azidas/químicaRESUMO
BACKGROUND: Detecting cortical demyelination using magnetic resonance imaging (MRI) in multiple sclerosis (MS) remains a challenge. Magnetization transfer ratio (MTR), T1-weighted/T2-weighted ratio (T1T2R), and T2-weighted (T2w) signal are sensitive to cortical demyelination, but their accuracy is unknown. OBJECTIVES: To quantify the sensitivity, specificity, and accuracy of postmortem T1T2R, MTR, and T2w in detecting cortical demyelination. METHODS: In situ postmortem MRIs from 9 patients were used to measure T1T2R, MTR, and T2w along the midline of cortical gray matter and classified as normal or abnormal. MRIs were co-registered and compared to hemispheric myelin staining. The sensitivity, specificity, and accuracy of T1T2R, MTR, and T2w in detecting cortical demyelination were measured. RESULTS: The mean age (standard deviation) at death was 64.7 (+/-13.7) years with a disease duration of 23.8 (+/-10.5) years. The sensitivity was 78% for MTR, 75% for T1T2R, and 63% for T2w. The specificity was 46% (T2w), 13% (T1T2R), and 29% (MTR). The accuracy was 71% (T2w), 39% (MTR), and 42% (T1T2R). There were no significant differences between different MRI measures in cortical demyelination or intracortical/subpial lesion detection. CONCLUSIONS: Although somewhat sensitive, the modest specificity of conventional MRI modalities for cortical demyelination indicates that they are influenced by cortical changes other than demyelination. Improved acquisition and post-processing are needed to reliably measure cortical lesion load.
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Imageamento por Ressonância Magnética , Esclerose Múltipla , Idoso , Autopsia , Encéfalo/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Bainha de Mielina/patologiaRESUMO
BACKGROUND: Dimethyl fumarate (DMF) demonstrated favorable benefit-risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. OBJECTIVE: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. METHODS: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0-2), then DMF (Years 3-10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. RESULTS: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04-10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF (n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120-0.169)), while for PBO/DMF (n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0-2 years, 0.330 (95% CI, 0.266-0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118-0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. CONCLUSION: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Fumarato de Dimetilo/efeitos adversos , Fumarato de Dimetilo/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study. OBJECTIVE: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years. METHODS: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group). RESULTS: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term. CONCLUSION: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation. TRIAL REGISTRATION NUMBER: NCT01665144.
Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Atrofia , Azetidinas , Compostos de Benzil , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , RecidivaRESUMO
BACKGROUND: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). OBJECTIVE: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). METHODS: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. RESULTS: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. CONCLUSION: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.