Assessing Blood-Based Biomarkers to Define a Therapeutic Window for Natalizumab

Natalizumab is a monoclonal antibody that binds CD49d. Although it is one of the most effective treatments for Relapsing-Remitting Multiple Sclerosis (RRMS), a dosing regimen has not been optimized for safety and efficacy in individual patients. We aimed to identify biomarkers to monitor Natalizumab treatment and to establish a personalized dose utilizing an ongoing longitudinal study in 29 RRMS patients under Natalizumab with standard interval dose (SD) of 300 mg/4wks or extended interval dose (EID) of 300 mg/6wks. Blood samples were analyzed by flow cytometry to determine CD49d saturation and expression in several T and B lymphocytes subpopulations. Each patient was analyzed at two different timepoints separated by 3 Natalizumab administrations. Natalizumab and sVCAM-1 levels in serum were also analyzed using ELISA. To determine the reproducibility of various markers, two different timepoints were compared and no significant differences were observed for CD49d expression nor for saturation; SD patients had higher saturation levels (~80%) than EID patients (~60%). A positive correlation exists between CD49d saturation and Natalizumab serum levels. CD49d expression and saturation are stable parameters that could be used as biomarkers in the immunomonitoring of Natalizumab treatment. Moreover, Natalizumab and sVCAM-1 serum levels could be used to optimize an individual’s dosing schedule.

Split Domination In Interval-valued Fuzzy Graphs

Aims / Objectives: In this paper, we introduced and investigated the concept of split domination in interval-valued fuzzy graph and denoted by γs. We obtained many results related to γs. We investigated and study the relationship of γs with other known parameters in interval-valued fuzzy graph. Finally we calculated γs(G) for some standard interval valued fuzzy graphs.

Similar CNV Neurodynamic Patterns between Sub- and Supra-Second Time Perception

In the field of time psychology, the functional significance of the contingent negative variation (CNV) component in time perception and whether the processing mechanisms of sub- and supra-second are similar or different still remain unclear. In the present study, event-related potential (ERP) technology and classical temporal discrimination tasks were used to explore the neurodynamic patterns of sub- and supra-second time perception. In Experiment 1, the standard interval (SI) was fixed at 500 ms, and the comparison interval (CI) ranged from 200 ms to 800 ms. In Experiment 2, the SI was fixed at 2000 ms, and the CI ranged from 1400 ms to 2600 ms. Participants were required to judge whether the CI was longer or shorter than the SI. The ERP results showed similar CNV activity patterns in the two experiments. Specifically, CNV amplitude would be more negative when the CI was longer or closer to the memorized SI. CNV peak latency increased significantly until the CI reached the memorized SI. We propose that CNV amplitude might reflect the process of temporal comparison, and CNV peak latency might represent the process of temporal decision-making. To our knowledge, it is the first ERP task explicitly testing the two temporal scales, sub- and supra-second timing, in one study. Taken together, the present study reveals a similar functional significance of CNV between sub- and supra-second time perception.

Time changes: Timing contexts support event segmentation in associative memory

We tend to mentally segment a series of events according to perceptual contextual changes, such that items from a shared context are more strongly associated in memory than items from different contexts. It is also known that timing context provides a scaffold to structure experiences in memory, but its role in event segmentation has not been investigated. We adapted a previous paradigm, which was used to investigate event segmentation using visual contexts, to study the effects of changes in timing contexts on event segmentation in associative memory. In two experiments, we presented lists of 36 items in which the interstimulus intervals (ISIs) changed after a series of six items ranging between 0.5 and 4 s in 0.5 s steps. After each list, participants judged which one of two test items were shown first (temporal order judgment) for items that were either drawn from the same context (within an ISI) or from consecutive contexts (across ISIs). Further, participants judged from memory whether the ISI associated to an item lasted longer than a standard interval (2.25 s) that was not previously shown (temporal source memory). Experiment 2 further included a time-item encoding task. Results revealed an effect of timing context changes in temporal order judgments, with faster responses (Experiment 1) or higher accuracy (Experiment 2) when items were drawn from the same context, as opposed to items drawn from across contexts. Further, in both experiments, we found that participants were well able to provide temporal source memory judgments based on recalled durations. Finally, replicated across experiments, we found subjective duration bias, as estimated by psychometric curve fitting parameters of the recalled durations, correlated negatively with within-context temporal order judgments. These findings show that changes in timing context support event segmentation in associative memory.

The possibility of reclamation criteria success in Indonesia: soil condition, vegetation structure and species composition

There are two regulations for mine reclamation success in the forestry area in Indonesia, namely Minister of Forestry Regulation No. P.60/Menhut-II/2009 and Minister of Energy and Mineral Resources Decree No. 1827.K/30/MEM/2018. Both regulations rule vegetation and soil success. This study aims to analyse criteria parameters from both regulations in the mine reclamation and compare them to the surrounding secondary natural forest (SNF). This study was conducted in 6 six types of mine reclamation stand structures: 1, 4, 6, 9, 11-year-old plantation and SNF using 1 hectare of the circular plot each (total 6 ha). Soil samples were collected from 40 cm depth to analyse physical, biological and chemical conditions. Mine reclamation areas had almost similar physical, biological and chemical soil conditions with SNF. Nevertheless, due to the potential acid-forming (PAF) material from overburden, the 1-year-old plantation had pH = 3.23-3.27. The highest diversity index and the number of species and families in all reclamation areas were H’ = 1.82 (11-year-old); 14 species (9-year-old); and 11 families (9-year-old), comparing with SNF were H’ = 3.48; 67 species, and 31 families. Conversely, vegetation structure parameters in mine reclamation areas were higher than SNF (diameter at height breast (DBH; 1.3 m) = 28.42 cm; tree density = 469/ha; basal area = 35.04 m2/ha; and total height = 16.85 m). Compared to the SNF, vegetation structure and soil conditions are mostly possible for mine reclamation success. Still, species composition needs to be considered further as a standard interval to meet the criteria.

Delayed interval BNT162b2 mRNA COVID-19 vaccination provides robust immunity

Shortages of COVID-19 vaccines have results in delayed dosing intervals as a strategy to immunize a greater proportion of the population. The effect of this strategy on vaccine immunogenicity is not well studied. Humoral (anti-RBD levels and neutralization) and cellular immune responses were compared in health care workers receiving two doses of BNT162b2 (Pfizer-BioNTech) vaccines at standard (3-6 week) and delayed (8-12 week) intervals. In the delayed group, anti-RBD antibody titres were significantly enhanced compared to the standard interval group. Neutralizing antibody responses were excellent and comparable in both groups. A slight decrease in Spike-specific polyfunctional CD4+ T-cells expressing interferon-γ and IL-2 as well as monofunctional CD4+ T-cells was seen in the delayed group. Both polyfunctional and monofunctional CD8+ T-cell responses were comparable. Our data suggest that the strategy of delayed second dose mRNA vaccination is not overtly detrimental, and specifically may lead to an enhanced humoral immune response.

Ocrelizumab Extended Interval Dosing in Multiple Sclerosis in Times of COVID-19

ObjectiveTo evaluate the clinical consequences of extended interval dosing (EID) of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) during the coronavirus disease 2019 (COVID-19) pandemic.MethodsIn our retrospective, multicenter cohort study, we compared patients with RRMS on EID (defined as ≥4-week delay of dose interval) with a control group on standard interval dosing (SID) at the same period (January to December 2020).ResultsThree hundred eighteen patients with RRMS were longitudinally evaluated in 5 German centers. One hundred sixteen patients received ocrelizumab on EID (median delay [interquartile range 8.68 [5.09–13.07] weeks). Three months after the last ocrelizumab infusion, 182 (90.1%) patients following SID and 105 (90.5%) EID patients remained relapse free (p = 0.903). Three-month confirmed progression of disability was observed in 18 SID patients (8.9%) and 11 EID patients (9.5%, p = 0.433). MRI progression was documented in 9 SID patients (4.5%) and 8 EID patients (6.9%) at 3-month follow-up (p = 0.232). Multivariate logistic regression showed no association between treatment regimen and no evidence of disease activity status at follow-up (OR: 1.266 [95% CI: 0.695–2.305]; p = 0.441). Clinical stability was accompanied by persistent peripheral CD19+ B-cell depletion in both groups (SID vs EID: 82.6% vs 83.3%, p = 0.463). Disease activity in our cohort was not associated with CD19+ B-cell repopulation.ConclusionOur data support EID of ocrelizumab as potential risk mitigation strategy in times of the COVID-19 pandemic.Classification of EvidenceThis study provides Class IV evidence that for patients with RRMS, an EID of at least 4 weeks does not diminish effectiveness of ocrelizumab.

Impact of dose-dense neoadjuvant chemotherapy on pathologic response and survival for HER2-positive breast cancer patients who receive trastuzumab

To compare outcomes in patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer who received either dose-dense neoadjuvant chemotherapy (NAC) with trastuzumab or standard-interval chemotherapy with trastuzumab. Patients with HER2-positive breast cancer who received NAC, including epirubicin and cyclophosphamide followed by paclitaxel with trastuzumab were included. Patients were divided into either the dose-dense or standard-interval group. We compared pathologic complete remission (pCR), distant disease-free survival (DDFS), event-free survival (EFS), and breast cancer-specific survival (BCSS) between the two groups. Two hundred (49.6%) patients received dose-dense NAC, and 203 (50.4%) received standard-interval NAC. The pCR rate was 38.4% in the dose-dense group and 29.2% in the standard-interval group (P = 0.052). In patients with lymph node (LN) metastases, the LN pCR rate was 70.9% in the dose-dense group and 56.5% in the standard-interval group (P = 0.037). After a median follow-up of 54.6 months, dose-dense chemotherapy presented an improvement on DDFS (hazard ratio [HR] = 0.49, 95% confidence interval [CI]: 0.19–1.28, EFS (HR = 0.54, 95% CI: 0.24–1.21), and BCSS (HR = 0.41, 95% CI: 0.11–1.51), but the difference was not significant. Compared with standard-interval chemotherapy, dose-dense chemotherapy resulted in a superior 5-year DDFS (100% vs. 75.3%, P = 0.017) and 5-year EFS (96.9% vs. 78.3%, P = 0.022) in patients younger than 40 years. HER2-positive patients can achieve a higher LN pCR rate with dose-dense NAC than with standard-interval NAC with trastuzumab. Better survival may also be achieved with dose-dense chemotherapy with trastuzumab than with standard-interval chemotherapy with trastuzumab among young patients (age ≤ 40 years).

The utility of daily mood ratings in clinical trials of patients with bipolar II disorder

Objective: To demonstrate that there can be distinctive differences in information generated by standard interval measures as against using daily monitoring for evaluating progress in those with a bipolar disorder. Method: We undertook a 20-week study of individuals with a bipolar II disorder randomly assigned to receive either lamotrigine or lithium. Patients were rated on standard measures of depression and hypomania at monthly intervals, and they also completed a daily rating measure of their mood swings. We sought to demonstrate the potential for differing interpretations that emerge from these measurement strategies. Results: We graphed data for one subject who showed distinct improvement but demonstrated distinctly differing trajectories provided by monthly and daily data. In a second analysis, we considered sets of those who were judged as improving distinctly with lithium or lamotrigine to determine whether the drugs differed in speed of action, and again observed differing patterns between monthly and daily rating measures. Conclusions: A daily rating strategy appeared to provide additional and differing data compared to standard monthly measures. We therefore argue for the inclusion of daily mood ratings in clinical trials evaluating mood stabilisers and their use by clinicians in managing those with a bipolar II disorder.