Experiences of fatigued persons with multiple sclerosis with multimodal agility-based exercise training and the ReFEx study protocol: a qualitative extension of a feasibility study.

OBJECTIVES: (1) To explore experiences of fatigued persons with multiple sclerosis (pwMS) with a new multimodal agility-based exercise training (MAT) framework and (2) to investigate the demands of the Rehabilitation, Fatigue, and Exercise (ReFEx) study protocol, which compares high-frequency MAT and 'traditional' strength and endurance training (SET) to identify possible adaptations for a powered randomised controlled trial (RCT). DESIGN: A qualitative interview study nested within a feasibility RCT, comparing MAT and SET. SETTING: Neurological inpatient rehabilitation centre in Germany. PARTICIPANTS: Twenty-two pwMS were recruited for the feasibility study. Six were selected from MAT and SET, respectively, for semistructured face-to-face interviews prior to discharge, following a purposive sampling strategy. Participants had low physical disability but were at least moderately fatigued. INTERVENTIONS: During inpatient rehabilitation (4-6 weeks) MAT participants attended group-based and manual-based MAT sessions in the gym (5×/week, 30 min) and the pool (3×/week, 30 min). SET participants exercised individually on a cycle ergometer (5×/week, 22 min) and on strength training machines (3×/week, 30 min). RESULTS: Three key categories emerged from the interviews: (1) facilitators regarding MAT were variety and playfulness, group setting and challenging exercises. Barriers regarding MAT were feeling overburdened, feeling pressured in the group setting and the wish to perform 'traditional' strength training (not part of MAT). (2) MAT benefits were of physical and psychological nature, with improved balance stated the most. (3) Demands described the perceived exertion during MAT and SET, reflecting that there is no accumulation of fatigue during the intervention. CONCLUSIONS: MAT is appreciated by pwMS and includes facilitators less attainable with 'traditional' SET. Evaluation of MAT in a powered RCT is indicated, if rest breaks postsession, and screening for negative self-evaluation and social comparison are considered. Future (qualitative) research should investigate the important factors of inpatient rehabilitation contributing to fatigue reduction in pwMS. TRIAL REGISTRATION NUMBER: DRKS00023943; German Clinical Trials Register.

Graduated elastic compression stockings in the prevention of post-thrombotic syndrome: A systematic review and meta-analysis.

BACKGROUND: The effect of graduated elastic compression stockings (ECS) in the prevention of post-thrombotic syndrome (PTS) has been questioned since a large randomized trial found no prophylactic effect of ECS. OBJECTIVE: To assess the effect of the wearing time of ECS on the incidence of post-thrombotic syndrome (PTS) after proximal deep venous thrombosis, we performed a meta-analysis of the incidence of PTS across randomized and observational studies. METHOD: PubMed, Embase and Cochrane databases were searched until 12 June 2023 for studies on the effect of ECS on PTS. References of eligible studies were also screened in order to identify other potential studies that might have been missed during the search. RESULTS: Four studies comprising a total of 1467 patients met our inclusion criteria for early initiation and consistent use of ECS in patients with acute proximal DVT. ECS significantly reduced the incidence of mild-moderate PTS (OR: 0.48; 95% CI: 0.36-0.63) as well as severe PTS (OR: 0.44; 95% CI: 0.28-0.58).

Multimodal agility-based exercise training (MAT) versus strength and endurance training (SET) to improve multiple sclerosis-related fatigue and fatigability during inpatient rehabilitation: a randomized controlled pilot and feasibility study [ReFEx].

BACKGROUND: Multimodal agility-based exercise training (MAT) is a group-based exercise training framework for persons with multiple sclerosis (pwMS) with a potential to impact fatigue and fatigability. In a mixed-methods design, this study evaluated the feasibility of implementing MAT in an inpatient rehabilitation setting and the feasibility of a randomized controlled trial (RCT) study protocol with 'traditional' strength and endurance training (SET) as an active control condition. Secondarily, preliminary outcome data was acquired. METHODS: PwMS with low to moderate disability and self-reported fatigue were randomly allocated to either MAT or SET when starting inpatient rehabilitation (4-6 weeks). The MAT-participants exercised in a group following a MAT-manual (sessions were gym- (5x/week) and pool-based (3x/week)). SET-participants exercised individually 5x/week on a cycle ergometer, and 3x/week on strength training machines. Feasibility assessments focused on processes, resources, management, time, and scientific domains. Assessed clinical outcomes at admission and discharge included perceived fatigue, motor and cognitive fatigability, cognitive performance, motor function, and balance confidence. Perceived fatigue was reassessed 1, 4, and 12 weeks after discharge. Feasibility was determined regarding predetermined progression criteria. RESULTS: Twenty-two participants were randomized. Both groups performed the minimum number of sessions (> 18), and retention was adequate (73-91%). SET-participants performed more sessions than MAT-participants (30.8 vs. 22.7) and stayed longer in the facility (34.2 vs. 31.6 days). Non-eligibility of admitted pwMS was high (74% non-eligible), mainly due to high EDSS and inability to attend pool-based sessions. Consequently, recruitment (1.8/month) was slower than the predetermined progression criterium. Baseline assessments took longer than required (only 50% completed within 3 days). Short-term fatigue reduction was similar for both groups. Motor fatigability also improved in both groups, whereas cognitive fatigability deteriorated. In MAT, average improvement in walking endurance (43.9 m) exceeded minimal important change values for individuals (> 26.9 m). CONCLUSIONS: Progressing to a definitive RCT necessitates adaptation of eligibility criteria. In the present design it will also be difficult to attain similar dosing of interventions. A multicenter RCT focused only on gym-based MAT might be another option to assess the effect of MAT. The primary outcome measure should be able to measure change in perceived fatigue more robustly. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00023943, date of registration: 23 September 2021.

Neurogenic Lower Urinary Tract Symptoms, Fatigue, and Depression-Are There Correlations in Persons with Multiple Sclerosis?

The symptoms of multiple sclerosis (MS) frequently include fatigue, depression, and neurogenic lower urinary tract symptoms (LUTS), causing severe burdens on affected individuals. The relationships between these symptoms have not been intensively researched and there are no studies on the detailed influence of the different neurogenic LUTS. We aimed to investigate the relationships between fatigue, depression, and neurogenic LUTS as recorded in bladder diaries by persons with MS. We analyzed the bladder diaries of 274 people and their scores on the Fatigue Scale for Motor and Cognitive Functions and the Centre for Epidemiologic Studies Depression Scale (German version). The neurogenic LUTS were defined as urgency, reduced voided volume, increased standardized voiding frequency, nocturia, and urinary incontinence. Those suffering from incontinence, nocturia, reduced voided volume, or urgency had higher fatigue scores compared to those without these symptoms. Those with nocturia showed significantly higher scores for depression. The severity of urgency and voided volume had the greatest effect on the severity of individuals' fatigue and depression levels. With increasing urgency, the risk of clinically significant fatigue and depression was expected to increase. Urgency and voided volume correlated most with fatigue and depression. A prospective longitudinal study investigating fatigue/depression after the successful treatment of neurogenic LUTS is needed to clarify causality and offer possible treatment options for fatigue and depression.

Physical Exercise as a Potential Treatment for Fatigue in Parkinson's Disease? A Systematic Review and Meta-Analysis of Pharmacological and Non-Pharmacological Interventions.

BACKGROUND: Fatigue is one of the most common and debilitating non-motor symptoms among patients with Parkinson's disease (PD) and significantly impacts quality of life. Therefore, effective treatment options are needed. OBJECTIVE: To provide an update on randomized controlled trials (RCTs) including pharmacological and non-pharmacological (but non-surgical) treatments that examine the effects of fatigue on PD patients. METHODS: We searched the MEDLINE, EMBASE, PsycINFO, CENTRAL, and CINAHL databases for (cross-over) RCTs on pharmacological and non-pharmacological interventions for treating fatigue in PD patients until May 2021. Meta-analyses for random-effects models were calculated when two or more studies on the same treatment option were available using standardized mean differences (SMDs) with 95% confidence intervals (CIs). RESULTS: Fourteen pharmacological and 16 non-pharmacological intervention RCTs were identified. For pharmacological approaches, a meta-analysis could only be performed for modafinil compared to placebo (n = 2) revealing a non-significant effect on fatigue (SMD = - 0.21, 95% CI - 0.74-0.31, p = 0.43). Regarding non-pharmacological approaches, physical exercise (n = 8) following different training approaches versus passive or placebo control groups showed a small significant effect (SMD = - 0.37, 95% CI - 0.69- - 0.05, p = 0.02) which could not be demonstrated for acupuncture vs. sham-acupuncture (SMD = 0.16, 95% CI - 0.19-0.50, p = 0.37). CONCLUSION: Physical exercise may be a promising strategy to treat fatigue in PD patients. Further research is required to examine the efficacy of this treatment strategy and further interventions. Future studies should differentiate treatment effects on physical and mental fatigue as the different underlying mechanisms of these symptoms may lead to different treatment responses. More effort is required to develop, evaluate, and implement holistic fatigue management strategies for PD patients.

The Relationship between Diurnal Measures of Tonic Alertness and Self-Reported Fatigue in Persons with Multiple Sclerosis-A Retrospective Data Analysis.

OBJECTIVE: Fatigue in multiple sclerosis (MS) is common, burdensome, and usually assessed by self-report measures. This retrospective data analysis of the twice-daily Alertness test (Test battery of Attentional Performance) examined the extent to which this assessment procedure is associated with MS-related fatigue. METHOD: Two-hundred and thirteen German inpatients (136 women) aged 18-69 years with predominantly relapsing MS (72.8%) were included. Based on reaction time (RT) differences between morning tonic alertness (8:30-11:00 a.m.) and afternoon tonic alertness (3:00-4:30 p.m.), patients were divided into an "improver," "maintainer," or "decliner" group. Multinomial logistic regression (MLR) was calculated to predict the likelihood of belonging to one of these performance groups, taking into account cognitive fatigue (Fatigue Scale of Motor and Cognition, FSMCcog), disease severity (Expanded Disability Status Scale, EDSS), depression (Center for Epidemiologic Studies Depression Scale, CES-D), gender, and tonic alertness (a.m.). RESULTS: The final MLR model (R2 = .30) included tonic alertness (a.m.) (<.001), FSMCcog (.008), EDSS (.038), CES-D (.161), and gender (.057). Using this model, correct assignment to alertness performance groups was 56.8%. Tonic alertness (p.m.) demonstrated the greatest potential for differentiation among the three performance groups (<.001). CONCLUSIONS: These results show a relationship between subjective fatigue and tonic alertness. However, other variables also contribute to this association, suggesting that the RT differences between twice-daily measures of tonic alertness is not related to increased subjective fatigue in a substantial number of pwMS, which diminishes the diagnostic value. Further studies including relevant variables such as sleepiness are urgently needed.

Determinants and clinical outcomes of patients who refused anticoagulation: findings from the global GARFIELD-AF registry.

OBJECTIVE: There is a substantial incidence of stroke in patients with atrial fibrillation (AF) not receiving anticoagulation. The reasons for not receiving anticoagulation are generally attributed to clinician's choice, however, a proportion of AF patients refuse anticoagulation. The aim of our study was to investigate factors associated with patient refusal of anticoagulation and the clinical outcomes in these patients. METHODS: Our study population comprised patients in the Global Anticoagulant Registry in the FIELD (GARFIELD-AF) registry with CHA2DS2-VASc≥2. A logistic regression was developed with predictors of patient anticoagulation refusal identified by least absolute shrinkage and selection operator methodology. Patient demographics, medical and cardiovascular history, lifestyle factors, vital signs (body mass index, pulse, systolic and diastolic blood pressure), type of AF and care setting at diagnosis were considered as potential predictors. We also investigated 2-year outcomes of non-haemorrhagic stroke/systemic embolism (SE), major bleeding and all-cause mortality in patients who refused versus patients who received and patients who did not receive anticoagulation for other reasons. RESULTS: Out of 43 154 AF patients, who were at high risk of stroke, 13 283 (30.8%) did not receive anticoagulation at baseline. The reason for not receiving anticoagulation was unavailable for 38.7% (5146/13 283); of the patients with a known reason for not receiving anticoagulation, 12.5% (1014/8137) refused anticoagulation. Diagnosis in primary care/general practitioner, Asian ethnicity and presence of vascular disease were strongly associated with a higher risk of patient refusal of anticoagulation. Patient refusal of anticoagulation was associated with a higher risk of non-haemorrhagic stroke/SE (adjusted HR (aHR) 1.16 (95% CI 0.77 to 1.76)) but lower all-cause mortality (aHR 0.59 (95% CI 0.43 to 0.80)) compared with patients who received anticoagulation. The GARFIELD-AF mortality score corroborated this result. CONCLUSION: The data suggest patient refusal of anticoagulation is a missed opportunity to prevent AF-related stroke. Further research is required to understand the patient profile and mortality outcome of patients who refuse anticoagulation.

Randomised controlled pilot and feasibility study of multimodal agility-based exercise training (MAT) versus strength and endurance training (SET) to improve multiple sclerosis-related fatigue and fatigability during inpatient rehabilitation (ReFEx): study protocol.

INTRODUCTION: Subjective fatigue and objectively assessed fatigability are common symptoms in persons with multiple sclerosis (pwMS). Recent work has suggested a positive effect of balance and motor control training (BMCT) in reducing fatigue. It is unclear whether this effect can also be attained during inpatient rehabilitation. Multimodal agility-based exercise training (MAT) has been developed as a framework that incorporates BMCT with added agility components but has not been applied to pwMS. Therefore, this study will evaluate the feasibility of a randomised controlled trial comparing MAT against strength and endurance training (SET) for the improvement of MS-related fatigue and fatigability in a German neurological rehabilitation centre. METHODS AND ANALYSIS: A total of 24 pwMS (Expanded Disability Status Scale ≤5.0, Fatigue Scale for Motor and Cognitive Functions ≥53) will be randomly assigned to either SET or land and water-based MAT for 4-6 weeks during inpatient rehabilitation. Assessments of subjective fatigue, motor and cognitive fatigability, cognitive and cardiorespiratory performance, and balance confidence will be performed at admission and discharge. Subjective fatigue will also be assessed at 1, 4 and 12 weeks after discharge. Feasibility outcomes will include patients' acceptance of study procedures and interventions, recruitment rate, retention rate, time needed to complete baseline assessments, intervention adherence and fidelity. All quantitative outcomes will be reported descriptively. A total of 12 pwMS (6 per group) will be interviewed to gain insights into participants' experiences during study participation. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of the University of Bonn (reference number: 543/20). Dissemination of findings is planned via peer-reviewed journals, conferences and media releases. TRIAL REGISTRATION NUMBER: DRKS00023943.

Fear of Progression is Determined by Anxiety and Self-Efficacy but not Disease-Specific Parameters in Patients with Parkinson's Disease: Preliminary Data from a Multicenter Cross-Sectional Study.

BACKGROUND: Fear of progression (FoP) is a reactive, conscious concern about chronic disease progression and its consequences which may limit quality of life substantially. Only one study has examined FoP in Parkinson's disease (PD), showing the second highest FoP scores among chronic diseases. OBJECTIVE: To examine FoP prevalence and to exploratorily analyze determinants of FoP in PD. METHODS: Within a multicenter cross-sectional study, 120 PD inpatients (age: 64.45±9.20; 60.8% male; UPDRS-III: 28.86±16.12) were examined with the FoP questionnaire (FoP-Q; max. 20 points). Stepwise multiple linear regression analysis examined sociodemographic, clinical, and (neuro-) psychological determinants of FoP. RESULTS: With a mean FoP-Q score of 8.08±2.17, 63.0% of the patients were classified with moderate FoP and 17.6% with dysfunctional (i.e., severe) FoP. The highest scores were shown for the subscale 'loss of autonomy'. Increased levels of anxiety, less self-efficacy, female gender, current employment, and lower health literacy were identified as significant determinants associated with FoP. CONCLUSION: With more than 80% of patients showing moderate to dysfunctional FoP, it must be regarded as a frequent symptom in PD, which needs to be further understood and addressed in clinical practice. Clinical parameters like PD duration and severity were no determinants for FoP, indicating that FoP awareness must be considered by professionals at all disease stages.

Application of Activators Ecarin and Factor Xa in Thrombelastography for Measurement of Anticoagulant Effect of Direct Oral Anticoagulants Using TEG 5000.

There are situations where monitoring direct oral anticoagulants (DOACs) would be useful, including bleedings and trauma. The thromboelastographic technique has proven useful in bleeding situations in trauma and heart surgery. The aim of this study was to examine the effect of DOACs on all currently commercially available conventional TEG®5000 assays as well as novel modified assay using Ecarin and human factor Xa (HFXa). Healthy male volunteers were given single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg. Kaolin, RapidTEG, functional fibrinogen, PlateletMapping assay, and novel modified assays using Ecarin and HFXa were prepared. All TEG parameters were recorded. DOAC concentrations were correlated to the parameters with highest response to the DOAC effect. Sensitivity and negative predictive value of the parameter with highest response to DOAC concentration of 50 ng/mL was calculated. None of the conventional TEG assays demonstrated significant response to the effect on apixaban. Using Ecarin, reaction time R was strongly correlated with dabigatran concentrations. Using HFXa assay, R was strongly correlated with rivaroxaban and apixaban concentrations: r = 0.96, 0.84, and 0.86, respectively; p < 0.0001 for all. The R times obtained with the modified assays demonstrated strong sensitivity and negative predictive values for DOAC levels of ≥50 ng/mL. We have demonstrated that TEG®5000 can monitor the DOAC effect on hemostasis when the appropriate activator is used with significant correlation with DOAC concentrations. Larger clinical studies are warranted for correlation of TEG profile and clinical outcomes.

Lung function and self-rated symptoms in healthy volunteers after exposure to hydrotreated vegetable oil (HVO) exhaust with and without particles.

BACKGROUND: Diesel engine exhaust causes adverse health effects. Meanwhile, the impact of renewable diesel exhaust, such as hydrotreated vegetable oil (HVO), on human health is less known. Nineteen healthy volunteers were exposed to HVO exhaust for 3 h in a chamber with a double-blind, randomized setup. Exposure scenarios comprised of HVO exhaust from two modern non-road vehicles with 1) no aftertreatment system ('HVOPM+NOx' PM1: 93 µg m-3, EC: 54 µg m-3, NO: 3.4 ppm, NO2: 0.6 ppm), 2) an aftertreatment system containing a diesel oxidation catalyst and a diesel particulate filter ('HVONOx' PM1: ~ 1 µg m-3, NO: 2.0 ppm, NO2: 0.7 ppm) and 3) filtered air (FA) as control. The exposure concentrations were in line with current EU occupational exposure limits (OELs) of NO, NO2, formaldehyde, polycyclic aromatic hydrocarbons (PAHs), and the future OEL (2023) of elemental carbon (EC). The effect on nasal patency, pulmonary function, and self-rated symptoms were assessed. Calculated predicted lung deposition of HVO exhaust particles was compared to data from an earlier diesel exhaust study. RESULTS: The average total respiratory tract deposition of PM1 during HVOPM+NOx was 27 µg h-1. The estimated deposition fraction of HVO PM1 was 40-50% higher compared to diesel exhaust PM1 from an older vehicle (earlier study), due to smaller particle sizes of the HVOPM+NOx exhaust. Compared to FA, exposure to HVOPM+NOx and HVONOx caused higher incidence of self-reported symptoms (78%, 63%, respectively, vs. 28% for FA, p < 0.03). Especially, exposure to HVOPM+NOx showed 40-50% higher eye and throat irritation symptoms. Compared to FA, a decrement in nasal patency was found for the HVONOx exposures (- 18.1, 95% CI: - 27.3 to - 8.8 L min-1, p < 0.001), and for the HVOPM+NOx (- 7.4 (- 15.6 to 0.8) L min-1, p = 0.08). Overall, no clinically significant change was indicated in the pulmonary function tests (spirometry, peak expiratory flow, forced oscillation technique). CONCLUSION: Short-term exposure to HVO exhaust concentrations corresponding to EU OELs for one workday did not cause adverse pulmonary function changes in healthy subjects. However, an increase in self-rated mild irritation symptoms, and mild decrease in nasal patency after both HVO exposures, may indicate irritative effects from exposure to HVO exhaust from modern non-road vehicles, with and without aftertreatment systems.

[Perioperative heparin bridging is rarely indicated].

Numerous studies have shown that perioperative heparin bridging in patients treated with a vitamin K antagonist leads to an increased incidence of bleeding and so far, there is no evidence that it leads to a significant reduction in postoperative thromboembolism as summarised in this review. Prophylactic dosage of heparin is recommended after major surgery. Heparin bridging is not relevant in patients receiving a direct oral anticoagulant due to the rapid onset and offset of action of DOACs.

Biomarkers after Controlled Inhalation Exposure to Exhaust from Hydrogenated Vegetable Oil (HVO).

Hydrogenated vegetable oil (HVO) is a renewable diesel fuel used to replace petroleum diesel. The organic compounds in HVO are poorly characterized; therefore, toxicological properties could be different from petroleum diesel exhaust. The aim of this study was to evaluate the exposure and effective biomarkers in 18 individuals after short-term (3 h) exposure to HVO exhaust and petroleum diesel exhaust fumes. Liquid chromatography tandem mass spectrometry was used to analyze urinary biomarkers. A proximity extension assay was used for the measurement of inflammatory proteins in plasma samples. Short-term (3 h) exposure to HVO exhaust (PM1 ~1 µg/m3 and ~90 µg/m3 for vehicles with and without exhaust aftertreatment systems, respectively) did not increase any exposure biomarker, whereas petroleum diesel exhaust (PM1 ~300 µg/m3) increased urinary 4-MHA, a biomarker for p-xylene. HVO exhaust from the vehicle without exhaust aftertreatment system increased urinary 4-HNE-MA, a biomarker for lipid peroxidation, from 64 ng/mL urine (before exposure) to 141 ng/mL (24 h after exposure, p < 0.001). There was no differential expression of plasma inflammatory proteins between the HVO exhaust and control exposure group. In conclusion, short-term exposure to low concentrations of HVO exhaust did not increase urinary exposure biomarkers, but caused a slight increase in lipid peroxidation associated with the particle fraction.

Risk profile, antithrombotic treatment and clinical outcomes of patients in Nordic countries with atrial fibrillation - results from the GARFIELD-AF registry.

AIMS: The objective was to evaluate the clinical characteristics, management and two-year outcomes of patients with newly diagnosed non-valvular atrial fibrillation at risk for stroke in Nordic countries. METHODS: We examined the baseline characteristics, antithrombotic treatment, and two-year clinical outcomes of patients from four Nordic countries. RESULTS: A total of 52,080 patients were enrolled in the GARFIELD-AF. Out of 29,908 European patients, 2,396 were recruited from Nordic countries. The use of oral anticoagulants, alone or in combination with antiplatelet (AP), was higher in Nordic patients in all CHA2DS2-VASc categories: 0-1 (72.8% vs 60.3%), 2-3 (78.7% vs 72.9%) and ≥4 (79.2% vs 74.1%). In Nordic patients, NOAC ± AP was more frequently prescribed (32.0% vs 27.7%) and AP monotherapy was less often prescribed (10.4% vs 18.2%) when compared with Non-Nordic European patients. The rates (per 100 patient years) of all-cause mortality and non-haemorrhagic stroke/systemic embolism (SE) were similar in Nordic and Non-Nordic European patients [3.63 (3.11-4.23) vs 4.08 (3.91-4.26), p value = .147] and [0.98 (0.73-1.32) vs 1.02 (0.93-1.11), p value = .819], while major bleeding was significantly higher [1.66 (1.32-2.09) vs 1.01 (0.93-1.10), p value < .001]. CONCLUSION: Nordic patients had significantly higher major bleeding than Non-Nordic-European patients. In contrast, rates of all-cause mortality and non-haemorrhagic stroke/SE were comparable. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT01090362. URL: http://www.clinicaltrials.gov. KEY MESSAGE: Nordic countries had significantly higher major bleeding than Non-Nordic-European countries. Rates of mortality and non-haemorrhagic stroke/SE were similar .

Repeated application of the covert shift of attention task improves endogenous but not exogenous attention in patients with unilateral visuospatial inattention.

BACKGROUND: Most neglect treatment studies focus on automatic re-orientation procedures, assuming a deficit in automatic processes. We compare an automatic- and a controlled procedure, using the endogenous and exogenous variants of Posner's covert shift of attention task. METHOD: In two experiments, neglect patients and patients with a right hemispherical stroke without neglect performed three blocks of Posner's covert shift of attention task (Posner Task) on two days. In Study 1 we used endogenous cues, in Study 2, exogenous cues. RESULTS: In the endogenous task, neglect patients improved significantly with valid left-sided cues between block 1 and 2 on Day 1, subsequently showing a plateauing. They also showed a gradual improvement on invalid trials on both days. In the exogenous condition, all participants responded only increasingly faster on trials with a long stimulus onset asynchrony. Practicing on both tasks led to fewer omissions for left-sided targets, minimally in the exogenous and clearly in the endogenous condition. CONCLUSION: In line with prior neuroanatomical studies, our study shows that practicing an endogenous, but not an exogenous, visuospatial attention task leads to significant improvements in neglect patients, especially for invalid trials, suggesting that neglect treatments based on top-down strategies should be given more attention.

Cognitive Fatigue Predicts Cognitive Failure in Multiple Sclerosis Patients and Healthy Controls: A Case-Control Study.

OBJECTIVE: Fatigue and cognitive deficits are frequent symptoms of multiple sclerosis (MS). However, the exact nature of their co-occurrence is not fully understood. We sought to determine the impact of cognitive and physical fatigue on subjective cognitive deficits in MS patients and healthy controls. METHODS: Self-reports of fatigue (FSMC), depression (CES-D), cognitive deficits (CFQ), and personality traits (NEO-FFI, ANPS) among 30 MS inpatients and 30 healthy controls were analyzed using hierarchical regression models. The frequency of cognitive mistakes was used as the dependent variable and the extent of cognitive and physical fatigue as the independent variable. RESULTS: Cognitive fatigue was the only unique and significant predictor of cognitive mistakes in both groups, explaining 13.3% of additional variance in the MS group after correcting for age, mood, and physical fatigue. Physical fatigue had no significant impact on cognitive mistakes. While age had an impact on cognitive mistakes and depression in healthy controls, this association was not significant in MS patients. Depression was significantly correlated with cognitive mistakes and cognitive fatigue in MS patients. CONCLUSIONS: The interplay of cognitive fatigue and subjective cognitive impairment can be generalized, with the exception of the variables of age and depression, which were shown to have differing impacts on cognitive mistakes in MS patients and healthy controls, respectively. Cognitive fatigue was linked to cognitive mistakes even after correcting for overlapping items in MS patients only. Future research should further investigate the link between cognitive fatigue and attention lapses in daily life by using various objective assessments.

Measurement of Anticoagulation in Patients on Dabigatran, Rivaroxaban, and Apixaban Therapy by Novel Automated Thrombelastography.

Background Direct-acting oral anticoagulants (DOACs) do not require monitoring. Measurement of DOAC effect would be useful in the event of bleeding, trauma, and thromboembolism while on anticoagulation. We evaluated the effectiveness of the investigational DOAC assays on the TEG®6s Hemostasis Analyzer to assess the anticoagulant effect of DOACs in patients treated for atrial fibrillation or deep vein thrombosis (DVT). Methods Patients on treatment for a minimum of 7 days with standard doses of dabigatran, rivaroxaban, and apixaban were included. DOAC plasma concentrations and TEG®6s Reaction (R)-time were measured and correlated. The sensitivity, specificity, and negative predictive value (NPV) of R-time to detect DOAC concentrations of ≥30, ≥50, and ≥100 ng/mL were calculated. Results A total of 189 patients were included, ( n = 50) on apixaban, ( n = 62) on rivaroxaban, ( n = 53) on dabigatran, and ( n = 24) on no DOAC were studied. Using the direct thrombin inhibitor (DTI) channel, R-time demonstrated strong linear correlation with dabigatran levels (r = 0.93, p < 0.0001). Using the antifactor Xa (AFXa) channel, R-time demonstrated strong nonlinear correlation with rivaroxaban and apixaban levels ( r s = 0.92 and 0.84, respectively, p < 0.0001 for both). R-time revealed strong sensitivity and NPV in detecting low DOAC levels for the predefined concentrations. Conclusion R-time measured by TEG®6s DOAC-specific cartridge has a strong correlation with concentrations of the most commonly used DOACs with high sensitivity and NPV for detecting lower drug levels that are considered clinically relevant for patients in need of antidote, or prior to urgent surgery. Further studies to determine the relation of R-time to clinical outcomes are warranted.

Feasibility of Music-Assisted Treadmill Training in Parkinson's Disease Patients With and Without Deep Brain Stimulation: Insights From an Ongoing Pilot Randomized Controlled Trial.

Background: Music-assisted treadmill training (MATT) is a new therapeutic approach for Parkinson's disease (PD) patients, combining treadmill training with rhythmic auditory cueing and visual feedback. PD studies have shown larger positive effects on motor outcomes than usual treadmill training. However, effects on cognition, in contrast, are less clear. Existing studies provided intensive training protocols and included only stable medicated patients. Thus, a pilot randomized controlled trial was designed to analyze the feasibility of a shorter training protocol as well as preliminary effects on cognition, motor function, and patient-centered outcomes in a rehabilitation setting where PD patients with and without deep brain stimulation (DBS) undergo adaptation of medication and DBS settings. Here, we present the results from the feasibility analysis of the still ongoing trial. Methods: Non-demented PD patients with and without DBS were recruited during their inpatient rehabilitation and randomized to an experimental group (EG; 20 min MATT) or an active control group (CG; 20 min bike ergometer training). The trainings took place for 8 consecutive days and were added to the usual rehabilitation. Feasibility was assessed with the following parameters: patients' study protocol acceptance, study protocol transferability into clinical routine, training-induced adverse events, and patients' training perception. Results: Thirty-two patients (EG: n = 15; CG: n = 17; 72% DBS) were included. The study protocol was well-accepted (inclusion rate: 84%). It was transferable into clinical routines; dropout rates of 40% (EG) and 18% (CG) were observed. However, an in-depth analysis of the dropout cohort did not reveal intervention-related dropout reasons. The MATT and the standard ergometer training showed no adverse events and were positively perceived by PD patients with and without DBS. Conclusion: MATT was shown to be a feasible, safe, and enjoyable treatment option in PD patients with and without DBS. Furthermore, the dropout cohort analysis revealed some exciting first insights into possible dropout reasons that go beyond the form of intervention. Therefore, research would benefit from a common practice of dropout analyses, as this would enhance our understanding of patients' therapy adherence and expectations.

Cancer associated thrombosis in everyday practice: perspectives from GARFIELD-VTE.

Venous thromboembolism (VTE) is common in cancer patients and is an important cause of morbidity and mortality. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE (ClinicalTrials.gov: NCT02155491) is a prospective, observational study of 10,684 patients with objectively diagnosed VTE from 415 sites in 28 countries. We compared baseline characteristics, VTE treatment patterns, and 1-year outcomes (mortality, recurrent VTE and major bleeding) in 1075 patients with active cancer, 674 patients with a history of cancer, and 8935 patients without cancer. Patients with active cancer and history of cancer were older than cancer-free patients, with median ages of 64.8, 68.9, and 58.4 years, respectively. The most common sites of active cancer were lung (14.5%), colorectal (11.0%), breast (10.6%), and gynaecological (10.3%). Active cancer patients had a higher incidence of upper limb and vena cava thrombosis than cancer-free patients (9.0% vs 4.8% and 5.1% vs 1.4%, respectively), and were more likely to receive parenteral anticoagulation as monotherapy than cancer-free patients (57.8% vs 12.1%), and less likely to receive DOACs (14.2% vs 50.6%). Rates of death, recurrent VTE, and major bleeding were higher in active cancer patients than in cancer-free patients, with hazard ratios (95% confidence intervals) of 14.2 (12.1-16.6), 1.6 (1.2-2.0) and 3.8 (2.9-5.0), respectively. VTE was the second most common cause of death in patients with active cancer or history of cancer. In patients with VTE, those with active cancer are at higher risk of death, recurrence, and major bleeding than those without cancer.

Fully automated thromboelastograph TEG 6s to measure anticoagulant effects of direct oral anticoagulants in healthy male volunteers.

BACKGROUND: The ability to assess the hemostatic effect of the direct oral anticoagulant (DOACs) may be valuable in clinical situations such as bleeding or thrombosis, before urgent surgery, or reversal of anticoagulation. We sought to assess the anticoagulant effect of DOACs with the new-generation fully automated thrombelastograph TEG 6s using resonance-frequency viscoelasticity measurements and disposable multichannel microfluidic cartridges. METHODS: A single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg was given to 9 healthy males. Phlebotomy was performed at 0, 1, and 3 hours after administration of DOAC. TEG parameters were measured using TEG _6s. Concentrations of DOACs were measured using chromogenic assays. The TEG parameters were correlated to the DOAC concentrations. RESULTS: The reaction time (R) demonstrated the strongest response to DOAC intake. There were no correlations between other TEG parameters and DOAC concentrations. Using the direct thrombin inhibitor (DTI) channel, R was significantly correlated with dabigatran levels (r = 0.94, P < 0.0001). Using the anti-factor Xa (AFXa) channel, R was significantly correlated with rivaroxaban and apixaban levels (r = 0.93 and r = 0.83, respectively; P < 0.0001 for both). R >2.5 minutes for dabigatran (DTI channel), >2.5 minutes for apixaban, and >1.8 minutes for rivaroxaban (AFXa channel) were associated with 100% sensitivity and ≥ 90% specificity to detect DOAC levels of ≥ 50 ng/mL. CONCLUSION: We have demonstrated that TEG _6s R has significant correlation with DOAC blood concentrations and has potential for monitoring the DOAC's effect on hemostasis with reasonable sensitivity in the small sample analyzed. This novel technology is easy to use on a small volume of whole blood without requiring a specialized laboratory. Further study is warranted to correlate R with clinical outcomes.