Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation

B-cell depleting anti-CD20 monoclonal antibody therapies are being increasingly used as long-term maintenance therapy for neuroinflammatory disease compared to many non-neurological diseases where they are used as remission-inducing agents. While hypogammaglobulinaemia is known to occur in over half of patients treated with medium to long-term B-cell-depleting therapy (in our cohort IgG 38, IgM 56 and IgA 18%), the risk of infections it poses seems to be under-recognised. Here, we report five cases of serious infections associated with hypogammaglobulinaemia occurring in patients receiving rituximab for neuromyelitis optica spectrum disorders. Sixty-four per cent of the whole cohort of patients studied had hypogammaglobulinemia. We discuss the implications of these cases to the wider use of anti-CD20 therapy in neuroinflammatory disease

Results from the CACTI experiment: Air-Cerenkov and particle measurements of PeV air showers at Los Alamos

An array of six wide angle Cerenkov detectors was constructed amongst the scintillator and muon detectors of the CYGNUS II array at Los Alamos National Laboratory to investigate cosmic ray composition in the PeV region through measurements of the shape of Cerenkov lateral distributions. Data were collected during clear, moonless nights over three observing periods in 1995. Estimates of depths of shower maxima determined from the recorded Cerenkov lateral distributions align well with existing results at higher energies and suggest a mixed to heavy composition in the PeV region with no significant variation observed around the knee. The accuracy of composition determination is limited by uncertainties in the expected levels of depth of maximum predicted using different Monte-Carlo shower simulation models

Wearable sensors can reliably quantify gait alterations associated with disability in people with progressive multiple sclerosis in a clinical setting

Gait disability in people with progressive multiple sclerosis (MS) is difficult to quantify using existing clinical tools. This study aims to identify reliable and objective gait-based biomarkers to monitor progressive multiple sclerosis (MS) in clinical settings. During routine clinical visits, 57 people with secondary progressive MS and 24 healthy controls walked for 6 minutes wearing three inertial motion sensors. Fifteen gait measures were computed from the sensor data and tested for between-session reliability, for differences between controls and people with moderate and severe MS disability, and for correlation with Expanded Disability Status Scale (EDSS) scores. The majority of gait measures showed good to excellent between-session reliability when assessed in a subgroup of 23 healthy controls and 25 people with MS. These measures showed that people with MS walked with significantly longer step and stride durations, reduced step and stride regularity, and experienced difficulties in controlling and maintaining a stable walk when compared to controls. These abnormalities significantly increased in people with a higher level of disability and correlated with their EDSS scores. Reliable and objective gait-based biomarkers using wearable sensors have been identified. These biomarkers may allow clinicians to quantify clinically relevant alterations in gait in people with progressive MS within the context of regular clinical visits

Mechanisms of network changes in cognitive impairment in multiple sclerosis

Background and objectives: Cognitive impairment in multiple sclerosis (MS) is associated with functional connectivity abnormalities. While there have been calls to use functional connectivity measures as biomarkers, there remains to be a full understanding of why they are affected in MS. In this cross-sectional study, we tested the hypothesis that functional network regions may be susceptible to disease-related "wear and tear" and that this can be observable on co-occurring abnormalities on other magnetic resonance metrics. We tested whether functional connectivity abnormalities in cognitively impaired patients with MS co-occur with (1) overlapping, (2) local, or (3) distal changes in anatomic connectivity and cerebral blood flow abnormalities. Methods: Multimodal 3T MRI and assessment with the Brief Repeatable Battery of Neuropsychological tests were performed in 102 patients with relapsing-remitting MS and 27 healthy controls. Patients with MS were classified as cognitively impaired if they scored ≥1.5 SDs below the control mean on ≥2 tests (n = 55) or as cognitively preserved (n = 47). Functional connectivity was assessed with Independent Component Analysis and dual regression of resting-state fMRI images. Cerebral blood flow maps were estimated, and anatomic connectivity was assessed with anatomic connectivity mapping and fractional anisotropy of diffusion-weighted MRI. Changes in cerebral blood flow and anatomic connectivity were assessed within resting-state networks that showed functional connectivity abnormalities in cognitively impaired patients with MS. Results: Functional connectivity was significantly decreased in the anterior and posterior default mode networks and significantly increased in the right and left frontoparietal networks in cognitively impaired relative to cognitively preserved patients with MS (threshold-free cluster enhancement corrected at p ≤ 0.05, 2 sided). Networks showing functional abnormalities showed altered cerebral blood flow and anatomic connectivity locally and distally but not in overlapping locations. Discussion: We provide the first evidence that functional connectivity abnormalities are accompanied by local cerebral blood flow and structural connectivity abnormalities but also demonstrate that these effects do not occur in exactly the same location. Our findings suggest a possibly shared pathologic mechanism for altered functional connectivity in brain networks in MS

Is a wearable sensor-based characterisation of gait robust enough to overcome differences between measurement protocols? A multi-centric pragmatic study in patients with multiple sclerosis

Inertial measurement units (IMUs) allow accurate quantification of gait impairment of people with multiple sclerosis (pwMS). Nonetheless, it is not clear how IMU-based metrics might be influenced by pragmatic aspects associated with clinical translation of this approach, such as data collection settings and gait protocols. In this study, we hypothesised that these aspects do not significantly alter those characteristics of gait that are more related to quality and energetic efficiency and are quantifiable via acceleration related metrics, such as intensity, smoothness, stability, symmetry, and regularity. To test this hypothesis, we compared 33 IMU-based metrics extracted from data, retrospectively collected by two independent centres on two matched cohorts of pwMS. As a worst-case scenario, a walking test was performed in the two centres at a different speed along corridors of different lengths, using different IMU systems, which were also positioned differently. The results showed that the majority of the temporal metrics (9 out of 12) exhibited significant between-centre differences. Conversely, the between-centre differences in the gait quality metrics were small and comparable to those associated with a test-retest analysis under equivalent conditions. Therefore, the gait quality metrics are promising candidates for reliable multi-centric studies aiming at assessing rehabilitation interventions within a routine clinical context

First measurement of the Head-Tail directional nuclear recoil signature at energies relevant to WIMP dark matter searches

We present first evidence for the so-called Head-Tail asymmetry signature of neutron-induced nuclear recoil tracks at energies down to 1.5 keV/amu using the 1m^3 DRIFT-IIc dark matter detector. This regime is appropriate for recoils induced by Weakly Interacting Massive Particle (WIMPs) but one where the differential ionization is poorly understood. We show that the distribution of recoil energies and directions induced here by Cf-252 neutrons matches well that expected from massive WIMPs. The results open a powerful new means of searching for a galactic signature from WIMPs.Comment: 4 pages, 6 figures, 1 tabl

Low Energy Electron and Nuclear Recoil Thresholds in the DRIFT-II Negative Ion TPC for Dark Matter Searches

Understanding the ability to measure and discriminate particle events at the lowest possible energy is an essential requirement in developing new experiments to search for weakly interacting massive particle (WIMP) dark matter. In this paper we detail an assessment of the potential sensitivity below 10 keV in the 1 m^3 DRIFT-II directionally sensitive, low pressure, negative ion time projection chamber (NITPC), based on event-by-event track reconstruction and calorimetry in the multiwire proportional chamber (MWPC) readout. By application of a digital smoothing polynomial it is shown that the detector is sensitive to sulfur and carbon recoils down to 2.9 and 1.9 keV respectively, and 1.2 keV for electron induced events. The energy sensitivity is demonstrated through the 5.9 keV gamma spectrum of 55Fe, where the energy resolution is sufficient to identify the escape peak. The effect a lower energy sensitivity on the WIMP exclusion limit is demonstrated. In addition to recoil direction reconstruction for WIMP searches this sensitivity suggests new prospects for applications also in KK axion searches

Quantitative beta autoradiography of a heterogeneous granulite sample and implications for luminescence dating

Beta dose rate heterogeneity is a known source of scatter in OSL measurement and equivalent dose distributions. Without proper methods to describe and account for it, it can contribute significantly to the uncertainties in OSL ages. For this reason, investigating the beta dose rate (β Dr) distribution is necessary to improve the dating of heterogeneous samples. Here we present a method for quantitative and high sensitivity autoradiographic imaging of beta dose rates. It is demonstrated using highly heterogeneous granulite rock samples. The accuracy and sensitivity of this method is improved using pulsed laser stimulation, and by underground exposure of samples in an ultra-low background environment. Results are calibrated using gamma (γ)irradiation and Monte Carlo simulation and have been validated using homogeneous dose rate standards. Combining analysis of autoradiography results and SEM backscattered images of the same samples allows determination of the dose rate distributions in the different mineral phases. A significant difference between the dose rate of K-feldspar grains obtained from the imaging and the dose rates calculated using methods commonly used in OSL dating is noted because of the clustering of grains in the sample. This represents a risk of bias in age determination in coarse grained rock samples which can be analysed using dose rate imaging methods. The beta Dr spatial distributions result in a significant dose scattering received by single grains, even compared to the total dose rate. The effect of such beta dose rate distributions on OSL dating of coarse-grained crystalline materials is discussed