Clinical variables contributing to the identification of biologically defined subgroups within cognitively unimpaired and mild cognitive impairment individuals.

BACKGROUND: A lack of consensus exists in linking demographic, behavioral, and cognitive characteristics to biological stages of dementia, defined by the ATN (amyloid, tau, neurodegeneration) classification incorporating amyloid, tau, and neuronal injury biomarkers. METHODS: Using a random forest classifier we investigated whether 27 demographic, behavioral, and cognitive characteristics allowed distinction between ATN-defined groups with the same cognitive profile. This was done separately for three cognitively unimpaired (CU) (112 A-T-N-; 46 A+T+N+/-; 65 A-T+/-N+/-) and three mild cognitive impairment (MCI) (128 A-T-N-; 223 A+T+N+/-; 94 A-T+/-N+/-) subgroups. RESULTS: Classification-balanced accuracy reached 39% for the CU and 52% for the MCI subgroups. Logical Delayed Recall (explaining 16% of the variance), followed by the Alzheimer's Disease Assessment Scale 13 (14%) and Everyday Cognition Informant (10%), were the most relevant characteristics for classification of the MCI subgroups. Race and ethnicity, marital status, and Everyday Cognition Patient were not relevant (0%). CONCLUSIONS: The demographic, behavioral, and cognitive measures used in our model were not informative in differentiating ATN-defined CU profiles. Measures of delayed memory, general cognition, and activities of daily living were the most informative in differentiating ATN-defined MCI profiles; however, these measures alone were not sufficient to reach high classification performance.

Objective clinical registration of tremor, bradykinesia, and rigidity during awake stereotactic neurosurgery: a scoping review.

Tremor, bradykinesia, and rigidity are incapacitating motor symptoms that can be suppressed with stereotactic neurosurgical treatment like deep brain stimulation (DBS) and ablative surgery (e.g., thalamotomy, pallidotomy). Traditionally, clinicians rely on clinical rating scales for intraoperative evaluation of these motor symptoms during awake stereotactic neurosurgery. However, these clinical scales have a relatively high inter-rater variability and rely on experienced raters. Therefore, objective registration (e.g., using movement sensors) is a reasonable extension for intraoperative assessment of tremor, bradykinesia, and rigidity. The main goal of this scoping review is to provide an overview of electronic motor measurements during awake stereotactic neurosurgery. The protocol was based on the PRISMA extension for scoping reviews. After a systematic database search (PubMed, Embase, and Web of Science), articles were screened for relevance. Hundred-and-three articles were subject to detailed screening. Key clinical and technical information was extracted. The inclusion criteria encompassed use of electronic motor measurements during stereotactic neurosurgery performed under local anesthesia. Twenty-three articles were included. These studies had various objectives, including correlating sensor-based outcome measures to clinical scores, identifying optimal DBS electrode positions, and translating clinical assessments to objective assessments. The studies were highly heterogeneous in device choice, sensor location, measurement protocol, design, outcome measures, and data analysis. This review shows that intraoperative quantification of motor symptoms is still limited by variable signal analysis techniques and lacking standardized measurement protocols. However, electronic motor measurements can complement visual evaluations and provide objective confirmation of correct placement of the DBS electrode and/or lesioning. On the long term, this might benefit patient outcomes and provide reliable outcome measures in scientific research.

Instrumented Gait Classification Using Meaningful Features in Patients with Impaired Coordination.

Early onset ataxia (EOA) and developmental coordination disorder (DCD) both affect cerebellar functioning in children, making the clinical distinction challenging. We here aim to derive meaningful features from quantitative SARA-gait data (i.e., the gait test of the scale for the assessment and rating of ataxia (SARA)) to classify EOA and DCD patients and typically developing (CTRL) children with better explainability than previous classification approaches. We collected data from 18 EOA, 14 DCD and 29 CTRL children, while executing both SARA gait tests. Inertial measurement units were used to acquire movement data, and a gait model was employed to derive meaningful features. We used a random forest classifier on 36 extracted features, leave-one-out-cross-validation and a synthetic oversampling technique to distinguish between the three groups. Classification accuracy, probabilities of classification and feature relevance were obtained. The mean classification accuracy was 62.9% for EOA, 85.5% for DCD and 94.5% for CTRL participants. Overall, the random forest algorithm correctly classified 82.0% of the participants, which was slightly better than clinical assessment (73.0%). The classification resulted in a mean precision of 0.78, mean recall of 0.70 and mean F1 score of 0.74. The most relevant features were related to the range of the hip flexion-extension angle for gait, and to movement variability for tandem gait. Our results suggest that classification, employing features representing different aspects of movement during gait and tandem gait, may provide an insightful tool for the differential diagnoses of EOA, DCD and typically developing children.

Instrumented classification of patients with early onset ataxia or developmental coordination disorder and healthy control children combining information from three upper limb SARA tests.

BACKGROUND: Early Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) share several phenotypical characteristics, which can be clinically hard to distinguish. AIM: To combine quantified movement information from three tests obtained from inertial measurements units (IMUs), to improve the classification of EOA and DCD patients and healthy controls compared to using a single test. METHODS: Using IMUs attached to the upper limbs, we collected data from EOA, DCD and healthy control children while they performed the three upper limb tests (finger to nose, finger chasing and fast alternating movements) from the Scale for the Assessment and Rating of Ataxia (SARA) test. The most relevant features for classification were extracted. A random forest classifier with 300 trees was used for classification. The area under the receiver operating curve (ROC-AUC) and precision-recall plots were used for classification performance assessment. RESULTS: The most relevant discerning features concerned smoothness and velocity of movements. Classification accuracy on group level was 85.6% for EOA, 63.5% for DCD and 91.2% for healthy control children. In comparison, using only the finger to nose test for classification 73.7% of EOA and 53.4% of DCD patients and 87.2% of healthy controls were accurately classified. For the ROC/precision recall plots the AUC was 0.96/0.89 for EOA, 0.92/0.81 for DCD and 0.97/0.94 for healthy control children. DISCUSSION: Using quantified movement information from all three SARA-kinetic upper limb tests improved the classification of all diagnostic groups, and in particular of the DCD group compared to using only the finger to nose test.

Three Days of Measurement Provide Reliable Estimates of Daily Tremor Characteristics: A Pilot Study in Organic and Functional Tremor Patients.

Background: Long-term tremor recording is particularly useful for the assessment of overall severity and therapeutic interventions in tremor patients. The purpose of this paper is to investigate the optimal number of days needed to obtain reliable estimates of tremor percentage, tremor frequency variability and tremor intensity in tremor patients using long-term tremor recordings. Methods: Participants were 18 years or older and were diagnosed with tremor by a movement disorders specialist. Participants wore an accelerometer on the wrist of the most affected arm during 30 consecutive days. Tremor presence, frequency variability and intensity were calculated per day. We used reliability analysis to determine the minimum number of days needed to obtain reliable estimates of these tremor characteristics. Results: Data from 36 adult organic (OrgT) and functional tremor (FT) patients (24 males; mean age 63.9 ± 11.9 years; 15 FT) were analyzed. Using five hours per day, one day of measurement is enough, except for tremor frequency variability in the OrgT group, where three days are needed and for tremor intensity where two days are always needed. Discussion: Visual analysis suggested that reliability can be increased considerably by using data from three days instead of one day even when using six hours of data per day. Three days with at least three hours of tremor data provide estimates of tremor percentage, frequency variability and intensity with good to excellent reliability, both for organic and functional tremor.

Similar association between objective and subjective symptoms in functional and organic tremor.

BACKGROUND: A previous study reported a dramatic mismatch in objectively detected and self-reported tremor duration in patients with functional tremor. As these findings have an important and widespread impact in both clinical care and research, we conducted a validation study with a longer study duration and a larger sample of patients. METHODS: Fourteen patients with functional tremor and 19 with organic tremor completed a 30 day study period. Objective tremor duration was recorded using a wrist-worn accelerometer. Simultaneously, participants completed a web-based diary five times a day, each time rating their symptom burden since the previous diary entry. RESULTS: Patients with functional tremor had shorter objective tremor duration compared to patients with organic tremor (21.6% vs 30.7%, P = 0.034). A post-hoc analysis revealed the difference in objective duration was mainly due to patients with essential tremor (37.2%). Subjective symptom burden was not significantly different between functional and organic tremors (38.7 vs 28.7 on a 0-100 VAS scale, P = 0.138). Finally, a mixed model analysis did not reveal significant differences in the association between subjective and objective tremor symptoms (P = 0.168). CONCLUSIONS: patients with functional tremor do have an objectively detectable, persistent tremor during daily life activities. Furthermore, they have a similar symptom burden and a similar association between subjective and objective tremor symptoms as patients with organic tremor.

Role of T2 mapping in left ventricular reverse remodeling after TAVR.

BACKGROUND: Patients with severe aortic stenosis (AS) are subjected to left ventricular hypertrophy (LVH) with increasing morbidity and mortality. Transcatheter aortic valve replacement (TAVR) induces reverse left ventricular remodeling which can be monitored by cardiovascular magnetic resonance (CMR). CMR is able to analyze myocardial tissue properties by magnetic relaxation times (parametric CMR). The objective of this study was to study myocardial T2 relaxation in reverse ventricular remodeling after TAVR. METHODS: Forty-three patients with severe AS (19 males, 81.9 ±â€¯4.9 years) underwent CMR with T2 mapping before and 6 months after TAVR. A cohort of age- and gender-matched volunteers served as controls. Analyzed parameters included left ventricular ejection fraction (LV-EF), mass indexed to body surface area (LVMi), interventricular septum thickness (IVS), end-diastolic volume (LVEDV), global longitudinal strain (GLS), peak diastolic strain rate (SRe) and myocardial T2 values. RESULTS: CMR characteristics for patients with AS displayed LVH concomitant to elevated myocardial T2 values, reduced GLS and SRe. Patients with T2 values above 70.2 ms at baseline were characterized by eccentric hypertrophy with reduced LV-EF. T2 values decreased after TAVR (67.4 ±â€¯3.4 to 63.3 ±â€¯4.2 ms, p < 0.01) during left ventricular remodeling. Patients with T2 values above 70.2 ms at baseline exhibited pronounced reverse remodeling which proved to be a significant predictor of LV-EF improvement and LVEDV reduction in uni- and multivariate analyses. CONCLUSIONS: Multiparametric CMR can be used to characterize myocardial hypertrophy due to severe AS and to monitor myocardial adaptations after TAVR. It may provide additional information in the prediction of left ventricular remodeling after TAVR.

Platelet function testing: dead or alive.

Essentials Pharmacodynamic response to antiplatelet medication is heterogeneous. Platelet reactivity to dual antiplatelet therapy was analyzed by three platelet function assays. The prevalence of high and low platelet reactivity differed significantly between assays. Future trials are needed to determine the best assay to analyze platelet function. SUMMARY: Background High on-treatment platelet reactivity (HTPR) to antiplatelet medication leads to ischemic events, whereas low on-treatment platelet reactivity (LTPR) increases bleeding risk. However, various trials have failed to demonstrate superiority of tailored antiplatelet regimens (ARCTIC, ANTARCTIC, Trigger-PCI, and GRAVITAS). TROPICAL-ACS was the first study that demonstrated the benefit of tailoring antiplatelet medication according to platelet function analysis. A potential reason may be that different platelet function assays were used in these trials. Objectives To evaluate whether the results of platelet function tests are comparable. Patients/Methods We tested three commonly used assays - light transmission aggregometry (LTA), (Multiplate impedance aggregometry [MP]), and vasodilator-stimulated phosphoprotein phosphorylation assay (VASP) - in 23 patients receiving dual antiplatelet therapy with aspirin and clopidogrel. Results With LTA, HTPR occurred in 57% of patients; with VASP, it occurred in 43% of patients; and with MP, it occurred in 13% of patients. According to LTA, only 35% of patients were in the therapeutic window; according to VASP, 57% of patients were in the therapeutic window; and according to MP, 48% of patients were in the therapeutic window. With LTA, LTPR occurred in 9% of patients; with VASP, it occurred in 0% of patients; and with MP, it occurred in 39% of patients. Therefore, the prevalences of HTPR and LTPR differed significantly between assays. Remarkably, in 17% of patients, one assay showed HTPR whereas another showed LTPR. Conclusions The results of different platelet function assays differ substantially. Up to now, only TROPICAL-ACS had demonstrated a benefit of tailoring antiplatelet medication according to platelet function analysis. Future trials are needed to evaluate whether the platelet function assay used in TROPICAL-ACS is the 'correct' one and revives platelet function testing.

Safety and efficacy of transseptal puncture guided by real-time fusion of echocardiography and fluoroscopy.

AIMS: Visual guidance through echocardiography and fluoroscopy is crucial for a successful transseptal puncture (TSP) in a prespecified region of the fossa ovalis. The novel EchoNavigator system Release II (EchoNav II, Philips Healthcare, Andover, Massachusetts, USA) enables the real-time fusion of fluoroscopic and echocardiographic images. We evaluated this new imaging method in respect to safety and efficacy of TSP during MitraClip implantation and left atrial appendage closure. METHODS: Forty-four patients before (-EchoNav) and 44 patients after (+EchoNav) the introduction of real-time fusion were included in our retrospective, single-centre study. The primary endpoint was the occurrence of adverse events due to TSP. Secondary endpoints were successful puncture at the prespecified region and time until TSP (min). RESULTS: In both groups TSP was performed successfully in the prespecified region and no adverse events occurred during or due to the accomplishment of TSP. Time until TSP was significantly reduced in the +EchoNav group in comparison with the EchoNav group (18.48 ± 5.62 min vs. 23.20 ± 9.61 min, p = 0.006). CONCLUSIONS: Real-time fusion of echocardiography and fluoroscopy proved to be as safe and successful as standard best practice for TSP. Moreover, efficacy was improved through significant reduction of time until TSP.

Percutaneous closure of a left atrial appendage with relevant suture dehiscence.

Atrial fibrillation is a widespread disease and highly relevant as it carries an extended risk for ischaemic stroke. Surgical closure of the left atrial appendage is routinely performed during open heart surgery in patients with atrial fibrillation with the aim of thromboembolic protection. In this report we present a successful percutaneous closure of a left atrial appendage, which showed clinically relevant suture dehiscence several years after surgical closure.

Dabigatran enhances platelet reactivity and platelet thrombin receptor expression in patients with atrial fibrillation.

Essentials Whether or not dabigatran enhances the risk of myocardial infarction is under discussion. We measured platelet reactivity and thrombin receptor expression in dabigatran patients. Platelet reactivity and thrombin receptor expression is enhanced during dabigatran treatment. This should be considered when choosing the optimal direct oral anticoagulant for individuals. SUMMARY: Background The direct oral anticoagulant (DOAC) dabigatran is a direct thrombin inhibitor. Its landmark trial, the RE-LY study, observed a trend towards a higher incidence of myocardial infarctions (MIs) in dabigatran-treated patients. Since then, there have been discussions on whether dabigatran increases the risk of MI. Objective In this study, we aimed to assess platelet reactivity and platelet thrombin receptor expression in dabigatran-treated patients. Methods We conducted a cross-sectional study in 13 hospitalized patients with planned initiation of dabigatran medication. Platelet reactivity was measured by light-transmission aggregometry and platelet thrombin receptor expression was measured by flow cytometry analysis. Results Platelet reactivity was higher after initiation of dabigatran medication as compared with baseline (baseline 44 ± 24% vs. dabigatran 70 ± 25%). Accordingly, the density of both platelet thrombin receptors (protease activated receptor [PAR]-1 and PAR-4) on platelets increased during dabigatran treatment (PAR1, baseline 63 ± 11% vs. dabigatran 70 ± 10%; PAR4, baseline 1.1 ± 0.5% vs. dabigatran 1.6 ± 0.9%). Conclusions Dabigatran increases platelet reactivity by enhancing the thrombin receptor density on platelets. This finding should be considered while choosing the optimal DOAC in individualized medicine.

Antiplatelet effects of aspirin in chronic kidney disease patients.

UNLABELLED: ESSENTIALS: Chronic kidney disease (CKD) patients have a high risk of cardiovascular events. A pharmacodynamic evaluation of the effects of aspirin in 116 patients was carried out. The antiplatelet effects of aspirin are associated with impaired renal function. The optimal antithrombotic regimen in CKD patients must be investigated on a larger scale. BACKGROUND: The pharmacodynamic response to aspirin varies significantly between individuals. Insufficient antiplatelet effects of aspirin are associated with increased risk of ischemic events. Chronic kidney disease (CKD) is suggested to affect the pharmacodynamic response to antiplatelet medication. High on-treatment platelet reactivity (HTPR) to clopidogrel has been reported to partially account for the enhanced risk of death and cardiovascular events in CKD patients. Objective To investigate the antiplatelet effects of aspirin in patients with CKD. METHODS: We conducted a cross-sectional study in 116 patients on permanent aspirin medication. The pharmacodynamic response to aspirin was determined by arachidonic acid-induced thromboxane formation. RESULTS: HTPR to aspirin was more frequent in patients with impaired renal function (47% vs. 22%; odds ratio, 3.16; 95% confidence interval [CI], 1.34-7.41; P = 0.008). The pharmacodynamic response to aspirin was impaired in patients with moderate/severe CKD (92; interquartile range [IQR], 282 ng mL(-1) ) as compared to patients with normal/mildly reduced renal function (36; IQR, 100 ng mL(-1) ; difference in medians, 57; CI, 5-110 ng mL(-1) ; P = 0.013). Bivariate Pearson analysis showed residual thromboxane formation to be correlated with glomerular filtration rate (R = -0.303; R(2) = 0.092; P = 0.001). Patients with CKD were older and more frequently female. Multivariate linear regression analysis revealed that the correlation was independent of age (R = -0.314; R(2) = 0.082; P = 0.002) and gender (R = -0.305; R(2) = 0.077; P = 0.006). CONCLUSION: Renal function is correlated with pharmacodynamic response to aspirin. Patients with CKD have an increased risk of impaired antiplatelet effects of aspirin. Larger trials are needed to assess the clinical impact of this finding and investigate the optimal antithrombotic regimen in CKD patients.

An unusual presentation of a common infection.

A 40-year-old Ghanaian woman presented with fever and exanthema. She had anemia, leukopenia, increased erythrocyte sedimentation rate (ESR), creatinin kinase, lactate dehydrogenase (LDH), and liver enzymes. She was diagnosed with schistosomiasis and was cured with praziquantel. During the following years, she developed polymyositis, chronic nephritis, and life-threatening perimyocarditis. High numbers of Epstein-Barr virus (EBV)-encoded RNA copies were demonstrated in CD8+ T-lymphocytes from endomyocardial biopsies. There was no evidence of any underlying immunosuppression or an EBV-related malignancy. Chronic active EBV infection was diagnosed, a clinical picture not described in an adult African previously. Interestingly, among all therapy attempts, only rituximab was effective at stabilizing the disease.

Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study).

OBJECTIVES: For patients with severe, chronic limb ischemia in many cases interventional or surgical treatment is not possible anymore. In the past, both intramuscular and intraarterial transplantation of autologous BMCs had been proved therapeutically beneficial. The TAM-PAD study is the first one to analyze combined intraarterial and intramuscular BMC transplantation in its acute and long-term effects. METHODS: 13 patients with chronically ischemic limbs due to peripheral arterial disease (Fontaine stage IIb) were recruited and underwent follow-up examinations after 2 and 13 months. Mononuclear cells from bone marrow were injected intramuscular and intraarterial into the ischemic limb. RESULTS: In contrast to the control group, after 2 months the pain-free walking distance of the transplanted patients significantly increased (from 147 +/- 90 to 500 +/- 614 m, p = 0.001). Furthermore the ankle-brachial index was significantly improved (at rest from 0.66+/-0.18 to 0.80+/-0.15, p = 0.003, after stress from 0.64 +/- 0.19 to 0.76 +/- 0.16, p = 0.006). Similar improvement was documented in capillary-venous oxygen-saturation (thigh from 59 +/- 9 to 66 +/- 5, p = 0.005, lower leg from 56 +/- 14 to 63 +/- 5, p = 0.021) and venous occlusion plethysmography (rest from 2.1 +/- 0.7 to 2.5 +/- 0.7, p = 0.009, mean reactive hyperemia from 5.3 +/- 1.8 to 7.2 +/- 1.8, p = 0.003, and peak flow from 7.2 +/- 3.2 to 10.8 +/- 2.8, p = 0.002). After 13 months these positive effects persisted at their improved level. No side effects or complications were monitored. CONCLUSIONS: Combined intraarterial and intramuscular transplantation of autologous mononuclear bone marrow stem cells is a clinically feasible and minimally invasive therapeutic option for patients with severe chronic peripheral occlusive arterial disease.