The Berlin Treatment Algorithm: recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue

More than 80% of multiple sclerosis (MS) patients suffer from fatigue. Despite this, there are few therapeutic options and evidence-based pharmacological treatments are lacking. The associated societal burden is substantial (MS fatigue is a major reason for part-time employment or early retirement), and at least one out of four MS patients view fatigue as the most burdensome symptom of their disease. The mechanisms underlying MS-related fatigue are poorly understood, and objective criteria for distinguishing and evaluating levels of fatigue and tiredness have not yet been developed. A further complication is that both symptoms may also be unspecific indicators of many other diseases (including depression, sleep disorders, anemia, renal failure, liver diseases, chronic obstructive pulmonary disease, drug side effects, recent MS relapses, infections, nocturia, cancer, thyroid hypofunction, lack of physical exercise). This paper reviews current treatment options of MS-related fatigue in order to establish an individualized therapeutic strategy that factors in existing comorbid disorders. To ensure that such a strategy can also be easily and widely implemented, a comprehensive approach is needed, which ideally takes into account all other possible causes and which is moreover cost efficient. Using a diagnostic interview, depressive disorders, sleep disorders and side effects of the medication should be identified and addressed. All MS patients suffering from fatigue should fill out the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, the Beck Depression Inventory (or a similar depression scale), and the Pittsburgh Sleep Quality Index (or the Insomnia Severity Index). In some patients, polygraphic or polysomnographic investigations should be performed. The treatment of underlying sleep disorders, drug therapy with alfacalcidol or fampridine, exercise therapy, and cognitive behavioral therapy-based interventions may be effective against MS-related fatigue. The objectives of this article are to identify the reasons for fatigue in patients suffering from multiple sclerosis and to introduce individually tailored treatment approaches. Moreover, this paper focuses on current knowledge about MS-related fatigue in relation to brain atrophy and lesions, cognition, disease course, and other findings in an attempt to identify future research directions

Insufficient treatment of severe depression in neuromyelitis optica spectrum disorder

OBJECTIVE: To investigate depression frequency, severity, current treatment, and interactions with somatic symptoms among patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: In this dual-center observational study, we included 71 patients diagnosed with NMOSD according to the International Panel for NMO Diagnosis 2015 criteria. The Beck Depression Inventory (BDI) was classified into severe, moderate, or minimal/no depressive state category. We used the Fatigue Severity Scale to evaluate fatigue. Scores from the Brief Pain Inventory and the PainDETECT Questionnaire were normalized to estimate neuropathic pain. Psychotropic, pain, and immunosuppressant medications were tabulated by established classes. RESULTS: Twenty-eight percent of patients with NMOSD (n = 20) had BDI scores indicative of moderate or severe depression; 48% of patients (n = 34) endorsed significant levels of neuropathic pain. Severity of depression was moderately associated with neuropathic pain (r = 0.341, p < 0.004) but this relationship was confounded by levels of fatigue. Furthermore, only 40% of patients with moderate or severe depressive symptoms received antidepressant medical treatment. Fifty percent of those treated reported persistent moderate to severe depressive symptoms under treatment. CONCLUSIONS: Moderate and severe depression in patients with NMOSD is associated with neuropathic pain and fatigue and is insufficiently treated. These results are consistent across 2 research centers and continents. Future research needs to address how depression can be effectively managed and treated in NMOSD

Reconstruction of some cosmological models in f(R,T) gravity

In this paper, we reconstruct cosmological models in the framework of $f(R,T)$ gravity, where $R$ is the Ricci scalar and $T$ is the trace of the stress-energy tensor. We show that the dust fluid reproduces $\Lambda$CDM, phantom-non-phantom era and the phantom cosmology. Further, we reconstruct different cosmological models including, Chaplygin gas, scalar field with some specific forms of $f(R,T)$. Our numerical simulation for Hubble parameter shows good agreement with the BAO observational data for low redshifts $z<2$.Comment: 12 pages, 2 figure

First Results from the DRIFT-IIa Dark Matter Detector

Data from the DRIFT-IIa directional dark matter experiment are presented, collected during a near continuous 6 month running period. A detailed calibration analysis comparing data from gamma-ray, x-ray and neutron sources to a GEANT4 Monte Carlo simulations reveals an efficiency for detection of neutron induced recoils of 94+/-2(stat.)+/-5(sys.)%. Software-based cuts, designed to remove non-nuclear recoil events, are shown to reject 60Co gamma-rays with a rejection factor of better than 8x10-6 for all energies above threshold. An unexpected event population has been discovered and is shown here to be due to the alpha-decay of 222Rn daughter nuclei that have attached to the central cathode. A limit on the flux of neutrons in the Boulby Underground Laboratory is derived from analysis of unshielded and shielded data.Comment: 43 pages, 14 figures, submitted to Astroparticle Physic

Transdiagnostic hippocampal damage patterns in neuroimmunological disorders

Hippocampal damage and associated cognitive deficits are frequently observed in neuroimmunological disorders, but comparative analyses to identify shared hippocampal damage patterns are missing. Here, we adopted a transdiagnostic analytical approach and investigated hippocampal shape deformations and associated cognitive deficits in four neuroimmunological diseases. We studied 120 patients (n = 30 in each group), including patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), anti-NMDAR and anti-LGI1 encephalitis. A control group was matched to each patient sample from a pool of 79 healthy participants. We performed an MRI-based vertex-wise hippocampal shape analysis, extracted hippocampal volume estimates and scalar projection values as a measure of surface displacement. Cognitive testing included assessment of verbal memory and semantic fluency performance. Our cross-sectional analyses revealed characteristic patterns of bilateral inward deformations covering up to 32% of the hippocampal surface in MS, anti-NMDAR encephalitis, and anti-LGI1 encephalitis, whereas NMOSD patients showed no deformations compared to controls. Significant inversions were noted mainly on the hippocampal head, were accompanied by volume loss, and correlated with semantic fluency scores and verbal episodic memory in autoimmune encephalitis and MS. A deformation overlap analysis across disorders revealed a convergence zone on the left anterior hippocampus that corresponds to the CA1 subfield. This convergence zone indicates a shared downstream substrate of immune-mediated damage that appears to be particularly vulnerable to neuroinflammatory processes. Our transdiagnostic morphological view sheds light on mutual pathophysiologic pathways of cognitive deficits in neuroimmunological diseases and stimulates further research into the mechanisms of increased susceptibility of the hippocampus to autoimmunity

Track Reconstruction and Performance of DRIFT Directional Dark Matter Detectors using Alpha Particles

First results are presented from an analysis of data from the DRIFT-IIa and DRIFT-IIb directional dark matter detectors at Boulby Mine in which alpha particle tracks were reconstructed and used to characterise detector performance--an important step towards optimising directional technology. The drift velocity in DRIFT-IIa was [59.3 +/- 0.2 (stat) +/- 7.5 (sys)] m/s based on an analysis of naturally-occurring alpha-emitting background. The drift velocity in DRIFT-IIb was [57 +/- 1 (stat) +/- 3 (sys)] m/s determined by the analysis of alpha particle tracks from a Po-210 source. 3D range reconstruction and energy spectra were used to identify alpha particles from the decay of Rn-222, Po-218, Rn-220 and Po-216. This study found that (22 +/- 2)% of Po-218 progeny (from Rn-222 decay) are produced with no net charge in 40 Torr CS2. For Po-216 progeny (from Rn-220 decay) the uncharged fraction is (100 +0 -35)%.Comment: 27 pages, 12 figures, 5 tables. Submitted to Nuclear Instruments and Methods in Physics Research, Section A. Subj-class: Instrumentation and Detector

Prefrontal-amygdala emotion regulation and depression in multiple sclerosis

Depression is among the most common comorbidities in multiple sclerosis and has severe psychosocial consequences. Alterations in neural emotion regulation in amygdala and prefrontal cortex have been recognized as key mechanism of depression but never been investigated in multiple sclerosis depression. In this cross-sectional observational study, we employed a functional MRI task investigating neural emotion regulation by contrasting regulated versus unregulated negative stimulus perception in 16 persons with multiple sclerosis and depression (47.9 ± 11.8 years; 14 female) and 26 persons with multiple sclerosis but without depression (47.3 ± 11.7 years; 14 female). We tested the impact of depression and its interaction with lesions in amygdala-prefrontal fibre tracts on brain activity reflecting emotion regulation. A potential impact of sex, age, information processing speed, disease duration, overall lesion load, grey matter fraction, and treatment was taken into account in these analyses. Patients with depression were less able (i) to downregulate negative emotions than those without (t = -2.25, P = 0.012, β = -0.33) on a behavioural level according to self-report data and (ii) to downregulate activity in a left amygdala coordinate (t = 3.03, P(Family-wise error [FWE]-corrected) = 0.017, β = 0.39). Moreover, (iii) an interdependent effect of depression and lesions in amygdala-prefrontal tracts on activity was found in two left amygdala coordinates (t = 3.53, p(FWE9 = 0.007, β = 0.48; t = 3.21, p(FWE) = 0.0158, β = 0.49) and one right amygdala coordinate (t = 3.41, p(FWE) = 0.009, β = 0.51). Compatible with key elements of the cognitive depression theory formulated for idiopathic depression, our study demonstrates that depression in multiple sclerosis is characterized by impaired neurobehavioural emotion regulation. Complementing these findings, it shows that the relation between neural emotion regulation and depression is affected by lesion load, a key pathological feature of multiple sclerosis, located in amygdala-prefrontal tracts

Stability analysis of agegraphic dark energy in Brans-Dicke cosmology

Stability analysis of agegraphic dark energy in Brans-Dicke theory is presented in this paper. We constrain the model parameters with the observational data and thus the results become broadly consistent with those expected from experiment. Stability analysis of the model without best fitting shows that universe may begin from an unstable state passing a saddle point and finally become stable in future. However, with the best fitted model, There is no saddle intermediate state. The agegraphic dark energy in the model by itself exhibits a phantom behavior. However, contribution of cold dark matter on the effective energy density modifies the state of teh universe from phantom phase to quintessence one. The statefinder diagnosis also indicates that the universe leaves an unstable state in the past, passes the LCDM state and finally approaches the sable state in future.Comment: 15 pages, 12 figure

T2 relaxation times of knee cartilage in 109 patients with knee pain and its association with disease characteristics

Background and purpose — Quantitative T2 mapping MRI of cartilage has proven value for the assessment of early osteoarthritis changes in research. We evaluated knee cartilage T2 relaxation times in a clinical population with knee complaints and its association with patients and disease characteristics and clinical symptoms. Patients and methods — In this cross-sectional study, T2 mapping knee scans of 109 patients with knee pain who were referred for an MRI by an orthopedic surgeon were collected. T2 relaxation times were calculated in 6 femoral and tibial regions of interest of full-thickness tibiofemoral cartilage. Its associations with age, sex, BMI, duration of complaints, disease onset (acute/chronic), and clinical symptoms were assessed with multivariate regression analysis. Subgroups were created of patients with abnormalities expected to cause predominantly medial or lateral tibiofemoral cartilage ch