Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P)

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)

Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes

Aims/hypothesis Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31–72 years), followed up for 18–32 years. Methods Peripheral blood samples were obtained from slow progressors (n = 8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes. Results Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells. Conclusions/interpretations We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes. Graphical abstract

Plasma and CSF Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Cross-Sectional and Longitudinal Study

Background: Neurofilament light chain (NfL) is a validated biofluid marker of neuroaxonal damage with great potential for monitoring patients with neurodegenerative diseases. We aimed to further validate the clinical utility of plasma (p) vs. CSF (c) NfL for distinguishing patients with Amyotrophic Lateral Sclerosis (ALS) from ALS mimics. We also assessed the association of biomarker values with clinical variables and survival and established the longitudinal changes of pNfL during the disease course.Methods: We studied 231 prospectively enrolled patients with suspected ALS who underwent a standardized protocol including neurological examination, electromyography, brain MRI, and lumbar puncture. Patients who received an alternative clinical diagnosis were considered ALS mimics. We classified the patients based on the disease progression rate (DPR) into fast (DPR &gt; 1), intermediate (DPR 0.5–1), and slow progressors (DPR &lt; 0.5). All patients were screened for the most frequent ALS-associated genes. Plasma and CSF samples were retrospectively analyzed; NfL concentrations were measured with the SIMOA platform using a commercial kit.Results: ALS patients (n = 171) showed significantly higher pNfL (p &lt; 0.0001) and cNfL (p &lt; 0.0001) values compared to ALS mimics (n = 60). Both cNfL and pNfL demonstrated a good diagnostic value in discriminating the two groups, although cNfL performed slightly better (cNfL: AUC 0.924 ± 0.022, sensitivity 86.8%, specificity 92.4; pNfL: AUC 0.873 ± 0.036, sensitivity 84.7%, specificity 83.3%). Fast progressors showed higher cNfL and pNfL as compared to intermediate (p = 0.026 and p = 0.001) and slow progressors (both p &lt; 0.001). Accordingly, ALS patients with higher baseline cNfL and pNfL levels had a shorter survival (highest tertile of cNfL vs. lowest tertile, HR 4.58, p = 0.005; highest tertile of pNfL vs. lowest tertile, HR 2.59, p = 0.015). Moreover, there were positive associations between cNfL and pNfL levels and the number of body regions displaying UMN signs (rho = 0.325, p &lt; 0.0001; rho = 0.308, p = 0.001). Finally, longitudinal analyses in 57 patients showed stable levels of pNfL during the disease course.Conclusion: Both cNfL and pNfL have excellent diagnostic and prognostic performance for symptomatic patients with ALS. The stable longitudinal trajectory of pNfL supports its use as a marker of drug effect in clinical trials.

Association of CT-Based Hypoperfusion Index With Ischemic Core Enlargement in Patients With Medium and Large Vessel Stroke

Objective:The rate of infarct core progression in patients with acute ischemic stroke is variable and affects outcome of reperfusion therapy. We evaluated hypoperfusion index (HI) to estimate the initial rate of core progression in patients with medium-vessel-occlusion (MeVO) compared to large-vessel-occlusion (LVO) stroke and within a larger time frame since stroke onset.Methods:Core progression was assessed in 106 patients with acute stroke and CT perfusion. Using reperfusion trial core-time criteria, fast progressors had core>70-mL within 6-hours of stroke onset and slow progressors had core ≤70mL, mismatch ≥15mL and mismatch-to-core-ratio ≥1.8 within 6-24-hours. The relationship between HI and infarct core progression (core/time) was examined using receiver-operating-characteristics to determine optimal HI cut-off. The HI cut-off was then tested in overall cohort, compared between MeVO and LVO, and evaluated in patients up to 24-hours from stroke onset to differentiate fast from slow rate of core progression. HI threshold was assessed in a second independent cohort of 110 acute ischemic stroke patients.Results:In 106 patients with acute stroke, 6.6% were fast progressors, 27.4% were slow progressors, and 66% were not classified as fast or slow progressor by reperfusion trial core-time criteria. HI>0.5 was associated with fast progression and able to distinguish fast from slow progressors (AUC=0.94;95%CI=0.80-0.99). In MeVO patients (n=26) HI>0.5 had a core progression of 0.30-mL/min compared to 0.03-mL/min with HI≤0.5 (p<0.001). In LVO patients (n=80), HI>0.5 had a core progression of 0.26-mL/min compared to 0.02-mL/min with HI≤0.5 (p<0.001). In patients not classified as fast or slow progressor by reperfusion trial criteria, those with HI>0.5 had progression rate of 0.21-mL/min compared to 0.03-mL/min with HI≤0.5 (p<0.001). Validation in a second cohort of patients with acute ischemic stroke (n=110; MeVO n=42, LVO n=68) yielded similar results for HI>0.5 to distinguish fast and slow core progression with an AUC of 0.84(95%CI=0.72-0.97).Conclusions:HI can differentiate fast from slow core progression in MeVO and LVO patients within the first 24-hours of acute ischemic stroke. Consideration of core progression rate at time of stroke evaluation may have implications in the selection of MeVO and LVO stroke patients for reperfusion therapy that warrant further study.

Association of circulating cell-free double-stranded DNA and metabolic derangements in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with unclear aetiology and poorly understood pathophysiology. Although plasma levels of circulating cell-free DNA (ccf-DNA) and metabolomic changes have been reported in IPF, the associations between ccf-DNA levels and metabolic derangements in lung fibrosis are unclear. Here, we demonstrate that ccf-double-stranded DNA (dsDNA) is increased in patients with IPF with rapid progression of disease compared with slow progressors and healthy controls and that ccf-dsDNA associates with amino acid metabolism, energy metabolism and lipid metabolism pathways in patients with IPF.

Use baseline axial length measurements in myopic patients to predict the control of myopia with and without atropine 0.01%

Purpose Identifying axial length growth rate as an indicator of fast progression before initiating atropine 0.01% for myopia progression in children. Method From baseline, axial length growth over six months was measured prospectively. Subjects were then initiated on atropine 0.01% if axial length growth was greater than 0.1mm per 6 months (fast progressors), axial length and spherical equivalent change measurements recorded every six months. The rate of change was compared to the baseline pre-treatment rate. If axial length change was below the threshold, subjects received monitoring only. Results 73 subjects were identified as fast progressors and commenced atropine 0.01%, (mean baseline refraction of OD -2.9±1.6, OS -2.9±1.8 and a mean baseline axial length OD 24.62 ± 1.00 mm, OS 24.53 ± 0.99 mm). At six months, the mean paired difference of axial length growth rate was significantly reduced by 50% of baseline (all 73 subjects, p<0.05). 53 subjects followed to 12 months, and 12 to 24 months maintained a reduced growth rate. Change in mean spherical equivalent was significantly reduced compared to pre-treatment refractive error (mean paired difference p<0.05) and at each subsequent visit. 91 children were slow progressors and remained untreated. Their axial length growth rate did not change significantly out to 24 months. Spherical equivalent changed less than -0.5D annually in this group. Conclusion Identifying fast progressors before treatment initiation demonstrated a strong treatment effect with atropine 0.01% reducing their individual rate of myopia progression by 50%. Another large group of myopic children, slow progressors, continued without medical intervention. A baseline axial length growth rate is proposed as a guideline to identify fast progressors who are more likely to benefit from atropine 0.01%.

Clinical characteristics of fast and slow progressors of infarct growth in anterior circulation large vessel occlusion stroke

Fast and slow progressor phenotypes of infarct growth due to anterior circulation large vessel occlusion (ACLVO) remain poorly understood. We aimed to define clinical predictors of fast and slow progressors in a retrospective study of patients with ACLVO who underwent baseline advanced imaging within 24 hours of stroke onset. Fast progressors (ischemic core > 70 ml, < 6 hours after onset) and slow progressors (ischemic core ≤ 30 ml, 6 to 24 hours after onset) were identified amongst 185 patients. Clinical and laboratory variables were tested for association with fast or slow progressor status. In the early epoch, no significant differences were found between fast progressors and controls. In the delayed epoch, slow progressors had a median NIHSS of 14 versus 20 (p < 0.01) and MCA occlusion in 80% versus 63% (p < 0.05) relative to controls. In multivariate analyses, NIHSS (OR 0.83, 95% CI 0.73-0.95), hyperlipidemia (OR 4.24, 95% CI 1.01 – 19.3) and hemoglobin concentration (OR 0.75, 95% CI 0.57 – 0.99) were independently associated with slow progressor status. This study indicates that lower initial stroke symptom severity, a history of hyperlipidemia and mild anemia are associated with individual tolerance to ACLVO stroke.

Continuous HIV-1 Escape from Autologous Neutralization and Development of Cross-Reactive Antibody Responses Characterizes Slow Disease Progression of Children

The antibodies with different effector functions evoked by Human Immunodeficiency Virus type 1 (HIV-1) transmitted from mother to child, and their role in the pathogenesis of infected children remain unresolved. So, too, the kinetics and breadth of these responses remain to be clearly defined, compared to those developing in adults. Here, we studied the kinetics of the autologous and heterologous neutralizing antibody (Nab) responses, in addition to antibody-dependent cellular cytotoxicity (ADCC), in HIV-1 infected children with different disease progression rates followed from close after birth and five years on. Autologous and heterologous neutralization were determined by Peripheral blood mononuclear cells (PBMC)- and TZMbl-based assays, and ADCC was assessed with the GranToxiLux assay. The reactivity to an immunodominant HIV-1 gp41 epitope, and childhood vaccine antigens, was assessed by ELISA. Newborns displayed antibodies directed towards the HIV-1 gp41 epitope. However, antibodies neutralizing the transmitted virus were undetectable. Nabs directed against the transmitted virus developed usually within 12 months of age in children with slow progression, but rarely in rapid progressors. Thereafter, autologous Nabs persisted throughout the follow-up of the slow progressors and induced a continuous emergence of escape variants. Heterologous cross-Nabs were detected within two years, but their subsequent increase in potency and breadth was mainly a trait of slow progressors. Analogously, titers of antibodies mediating ADCC to gp120 BaL pulsed target cells increased in slow progressors during follow-up. The kinetics of antibody responses to the immunodominant viral antigen and the vaccine antigens were sustained and independent of disease progression. Persistent autologous Nabs triggering viral escape and an increase in the breadth and potency of cross-Nabs are exclusive to HIV-1 infected slowly progressing children.

Unsupervised clustering reveals a unique Treg profile in slow progressors to type 1 diabetes

ObjectiveTo profile CD4+ regulatory T cells (Tregs) in a well-characterised cohort of slow progressors to type 1 diabetes, individuals positive for multiple islet autoantibodies who remain diabetes-free for at least 10 years.Research Design and MethodsPeripheral blood samples were obtained from extreme slow progressor individuals (n=8), with up to 32 years follow-up, and age and gender-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment, and was individually evaluated in the data analysis. PBMCs were isolated, from donors, and to assess frequency, phenotype and function of Tregs, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, FlowSOM and CITRUS, was used to evaluate Treg phenotypes.ResultsTreg mediated suppression of CD4+ effector T cells, from slow progressors was significantly impaired, compared to healthy donors (P<0.05). Effector CD4 T cells, from slow progressors, were more responsive to Treg suppression, compared to healthy donors, demonstrated by increased suppression of CD25 expression on effector CD4 T cells (P<0.05). Unsupervised clustering on memory CD4 T cells, from slow progressors, showed an increased frequency of activated-memory CD4 Tregs associated with increased expression of GITR, compared to healthy donors (P<0.05). The participant with a raised HbA1c had a different Treg profile, compared to slow progressors and the matched controls.ConclusionsCD4+ Tregs from slow progressor individuals have a unique Treg signature. This report highlights the need for further study of Treg heterogeneity in individuals at-risk of developing type 1 diabetes.

Early Infarct Growth Rate Correlation With Endovascular Thrombectomy Clinical Outcomes

Background and Purpose: Time elapsed from last-known well (LKW) and baseline imaging results are influential on endovascular thrombectomy (EVT) outcomes. Methods: In a prospective multicenter cohort study of imaging selection for endovascular thrombectomy (SELECT [Optimizing Patient’s Selection for Endovascular Treatment in Acute Ischemic Stroke], the early infarct growth rate (EIGR) was defined as ischemic core volume on perfusion imaging (relative cerebral blood flow<30%) divided by the time from LKW to imaging. The optimal EIGR cutoff was identified by maximizing the sum of the sensitivity and specificity to correlate best with favorable outcome and to improve its the predictability. Patients were stratified into slow progressors if EIGR<cutoff and fast progressors if EIGR≥the optimal cutoff. Good collaterals were defined on computed tomography perfusion as a hypoperfusion intensity ratio <0.4 and on computed tomography angiography as collateral score >2. The primary outcome was 90-day functional independence (modified Rankin Scale score =0–2). Results: Of 445 consented, 361 (285 EVT, 76 medical management only) patients met the study inclusion criteria. The optimal EIGR was <10 mL/h; 200 EVT patients were slow and 85 fast progressors. Fast progressors had a higher median National Institutes of Health Stroke Scale (19 versus 15, P <0.001), shorter time from LKW to groin puncture (180 versus 266 minutes, P <0.001). Slow progressors had better collaterals on computed tomography perfusion: hypoperfusion intensity ratio (adjusted odds ratio [aOR]: 5.11 [2.43–10.76], P <0.001) and computed tomography angiography: collaterals-score (aOR: 4.43 [1.83–10.73], P =0.001). EIGR independently correlated with functional independence after EVT, adjusting for age, National Institutes of Health Stroke Scale, time LKW to groin puncture, reperfusion (modified Thrombolysis in Cerebral Infarction score of ≥2b), IV-tPA (intravenous tissue-type plasminogen activator), and transfer status (aOR: 0.78 [0.65–0.94], P =0.01). Slow progressors had higher functional independence rates (121 [61%] versus 30 [35%], P <0.001) and had 3.5 times the likelihood of achieving modified Rankin Scale score =0–2 with EVT (aOR=2.94 [95% CI, 1.53–5.61], P =0.001) as compared to fast progressors, who had substantially worse clinical outcomes both in early and late time window. The odds of good outcome decreased by 14% for each 5 mL/h increase in EIGR (aOR, 0.87 [0.80–0.94], P <0.001) and declined more rapidly in fast progressors. Conclusions: The EIGR strongly correlates with both collateral status and clinical outcomes after EVT. Fast progressors demonstrated worse outcomes when receiving EVT beyond 6 hours of stroke onset as compared to those who received EVT within 6 hours. Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT02446587.