Composite mesh design for delivery of autologous mesenchymal stem cells influences mesh integration, exposure and biocompatibility in an ovine model of pelvic organ prolapse.

The widespread use of synthetic transvaginal polypropylene mesh for treating Pelvic Organ Prolapse (POP) has been curtailed due to serious adverse effects highlighted in 2008 and 2011 FDA warnings and subsequent legal action. We are developing new synthetic mesh to deliver endometrial mesenchymal stem cells (eMSC) to improve mesh biocompatibility and restore strength to prolapsed vaginal tissue. Here we evaluated knitted polyamide (PA) mesh in an ovine multiparous model using transvaginal implantation and matched for the degree of POP. Polyamide mesh dip-coated in gelatin and stabilised with 0.5% glutaraldehyde (PA/G) were used either alone or seeded with autologous ovine eMSC (eMSC/PA/G), which resulted in substantial mesh folding, poor tissue integration and 42% mesh exposure in the ovine model. In contrast, a two-step insertion protocol, whereby the uncoated PA mesh was inserted transvaginally followed by application of autologous eMSC in a gelatin hydrogel onto the mesh and crosslinked with blue light (PA + eMSC/G), integrated well with little folding and no mesh exposure. The autologous ovine eMSC survived 30 days in vivo but had no effect on mesh integration. The stiff PA/G constructs provoked greater myofibroblast and inflammatory responses in the vaginal wall, disrupted the muscularis layer and reduced elastin fibres compared to PA + eMSC/G constructs. This study identified the superiority of a two-step protocol for implanting synthetic mesh in cellular compatible composite constructs and simpler surgical application, providing additional translational value.

Principal Component Regression on Motor Evoked Potential in Single-Pulse Transcranial Magnetic Stimulation.

Motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) are commonly characterized only by their onset (latency) and size (amplitude) whereas other potentially important information in the MEPs is discarded. Hence, our aim was to examine the morphological information of MEPs using principal component regression (PCR) providing additional perception of MEPs. MEPs were recorded from the first dorsal interosseous muscle following navigated TMS focused at the primary motor cortex. The PCR holding of at least 96% of total variance of the MEP dataset was performed to parameterize MEPs into principal components (PCs), which were used with non-linear least square estimation to reconstruct original MEPs. The comparison between the original and reconstructed MEPs showed that PCs, which accounted for 96% of total variance, were able to characterize the MEP morphology, i.e., the PCR summarizes the repeated information in the MEP dataset into the PC set. In addition, PCR benefited the automated quantification of MEP features as it removed the random noise caused by the environmental interference and the inconsistency of neuronal pathways. Furthermore, we could determine the minimum number of trials required to reliably represent the whole dataset by estimating the partial information of those trials accounted for. Our results showed that this partial information exponentially increased with respect to the number of trials, and saturated within 20 MEPs holding approximately 90% of total variance of the dataset.

Comparison between the STENTYS self-apposing bare metal and paclitaxel-eluting coronary stents for the treatment of saphenous vein grafts (ADEPT trial).

AIMS: To describe the safety and performance of STENTYS self-expandable bare metal stents (BMS) versus paclitaxel-eluting stents (PES) in saphenous vein grafts (SVGs). METHODS AND RESULTS: A randomised controlled trial was performed in four hospitals in three European countries between December 2011 and December 2013. Patients with de novo lesions (>50% stenosis) in an SVG with a diameter between 2.5-6 mm were included. Primary endpoint was late lumen loss at 6 months. Secondary endpoints included procedural success and the occurrence of major adverse cardiac events (MACE) at 12 months. A total of 57 patients were randomised to STENTYS self-apposing BMS (n = 27) or PES (n = 30). Procedural success was obtained in 89.5%. No significant differences in late lumen loss were found between BMS and PES at 6 months (0.53 mm vs 0.47; p = 0.86). MACE rates at 12 months were comparable in both groups (BMS 22.2% vs. PES 26.7%; p = 0.70). CONCLUSIONS: Treatment of SVGs with STENTYS self-expandable stents is safe and effective. No significant differences were found in late lumen loss and MACE between BMS and PES.

Repeatability of knee impulsive loading measurements with skin-mounted accelerometers and lower limb surface electromyographic recordings during gait in knee osteoarthritic and asymptomatic individuals.

OBJECTIVES: To determine the repeatability of knee joint impulsive loading measurements with skin-mounted accelerometers (SMAs) and lower limb surface electromyography (EMG) recordings during gait. METHODS: Triaxial SMA and EMG from 4 muscles during level and stair walking in nine healthy and nine knee osteoarthritis (OA) subjects were used. The initial peak acceleration (IPA), root mean square (RMS), maximal acceleration transient rate (ATRmax) and mean EMG activity (EMGact) were calculated. The coefficient of variation (CV) and the intraclass correlation coefficient (ICC) were calculated to measure repeatability. RESULTS: The CV and ICC of RMS accelerations ranged from 4.9% to 10.9% and from 0.69 to 0.96 in both study groups during level walking. The CV and ICC of IPA and ATRmax varied from 7.7% to 14.2% and from 0.85 to 0.99 during level and stairs up walking in healthy subjects. The CV and ICC of EMGact ranged from 8.3% to 31.7% and from 0.16 to 0.97 in both study groups. CONCLUSIONS: RMS accelerations exhibited good repeatability during walking in healthy and knee OA subjects. The repeatability of EMG measurements was acceptable in healthy subjects depending on the measured muscles.

TIDES-ACS Trial: comparison of titanium-nitride-oxide coated bio-active-stent to the drug (everolimus)-eluting stent in acute coronary syndrome. Study design and objectives.

Drug-eluting stents (DES), delivering antiproliferative drugs from a durable polymer, have shown to reduce in-stent restenosis after percutaneous coronary intervention (PCI) compared to bare-metal stents (BMS). However, they have been associated with a hypersensitivity reaction, delayed healing, and incomplete endothelialization, which may contribute to an increased risk of late stent thrombosis. Consequently, a prolonged duration of dual antiplatelet therapy (DAPT) is needed, with an increased risk of bleeding complication. A number of stent technologies are being developed in an attempt to modify late thrombotic events and DAPT duration. The Optimax™ stent is such a novel, next generation bioactive stent (BAS), in which a thicker layer of titanium-nitride-oxide coating is inserted over the stent struts. The rationale of this is to obtain more efficient and rapid vascular healing at the site of the stent implantation. The aim of TIDES-ACS Trial is to compare clinical outcome in patients presenting with ACS, treated with PCI using Optimax-BAS versus Synergy™-EES. Second objective is to explore whether the Optimax™-BAS use is superior compared with Synergy™-EES use with respect of hard end points (cardiac death, myocardial infarction [MI] and major bleeding). A prospective, randomized, multicenter trial (ClinicalTrials.gov Identifier: NCT02049229), will be conducted in interventional centres in Finland (six centres), France (five centres) and Holland (two centres), including a total of 1800 patients.

Electroencephalogram reactivity to verbal command after dexmedetomidine, propofol and sevoflurane-induced unresponsiveness.

Although electroencephalogram reactivity (i.e. transient changes in electrical brain activity following external stimulus) might be useful in depth-of-anaesthesia monitoring, it has not been systematically examined with different anaesthetics at doses titrated to unresponsiveness. Three 10-subject groups of healthy volunteers received dexmedetomidine, propofol or sevoflurane in escalating pseudo-steady-state concentrations at 10-min intervals until they did not open their eyes to command. The electroencephalogram was continuously recorded and spectral variables were calculated with short-time Fourier transform and time-varying autoregressive modelling. Electroencephalogram reactivity was most prominent in the midfrontal derivations (termed F3 and F4). During drug-induced unresponsiveness, electroencephalogram reactivity was still present in all drug groups. Dexmedetomidine, propofol and sevoflurane induced distinct suppression patterns on the electroencephalogram reactivity at the same clinical endpoint (unresponsiveness). Reactivity was best maintained with propofol, while only minimally preserved with dexmedetomidine and sevoflurane. Thus, it may be difficult to harness reactivity for depth-of-anaesthesia monitoring.

[Nonlinear Parameters of the Surface Electromyogram for the Diagnostics of Neuromuscular Disorders and Normal Conditions of the Motor System in Human].

The article presents data on new approaches to the application of the surface electromyogram based on the nonlinear dynamics of complex systems. Special focus is placed on applicability of nonlinear parameters for early and differential diagnostics of Parkinson's disease, various kinds of tremor, schizophrenia, as well as for the estimation of normal processes in the motor system, such as musle development, fatigue and ageing.

EMG signal morphology and kinematic parameters in essential tremor and Parkinson's disease patients.

The aim of this work was to differentiate patients with essential tremor from patients with Parkinson's disease. Electromyographic data from biceps brachii muscles and kinematic data from arms during isometric tension of the arms were measured from 17 patients with essential tremor, 35 patients with Parkinson's disease and 40 healthy controls. The EMG signals were divided to smaller segments from which histograms were calculated. The histogram shape was analysed with a feature dimension reduction method, the principal component analysis, and the shape parameters were used to differentiate between different subject groups. Three parameters, RMS-amplitude, sample entropy and peak frequency were determined from the kinematic measurements of the arms. The height and the side differences of the histogram were the most effective for differentiating between essential tremor and Parkinson's disease groups. The histogram parameters of patients with essential tremor were more similar to patients with Parkinson's disease than healthy controls. With this method it was possible to discriminate 13/17 patients with essential tremor from 26/35 patients with Parkinson's disease and 14/17 patients with essential tremor from 29/40 healthy controls. The kinematic parameters of patients with essential tremor were closer to parameters of patients with Parkinson's disease compared to healthy controls. Combining EMG and kinematic analysis did not increase discrimination efficiency but provided more reliability to the discrimination of subject groups.

Dynamic tension EMG to characterize the effects of DBS treatment of advanced Parkinson's disease.

Deep brain stimulation (DBS) is an effective treatment method for motor symptoms of advanced Parkinson's disease. DBS-electrode is implanted to subthalamic nucleus to give precisely allocated electrical stimuli to brain. The optimal stimulus type has to be adjusted individually. Disease severity, main symptoms and biological factors play a role in correctly setting up the device. Currently there are no objective methods to assess the efficacy of DBS, hence the adjustment is based solely on clinical assessment. In optimal case an objectively measurable feature would point the right settings of DBS. Surface electromyographic and kinematic measurements have been used in Parkinson's disease research. As Parkinson's disease symptoms are known to change the EMG signal properties, these methods could be helpful aid in the clinical adjustment of DBS. In this study, 13 patients with advanced Parkinson's disease who received DBS treatment were measured. The patients were measured with seven different settings of the DBS in clinical range including changes in stimulation amplitude, frequency and pulse width. The EMG analysis was based on parameters that characterize EMG signal morphology. Correlation dimension and recurrence rate made the most significant difference in relation to optimal settings. In conclusion, EMG analysis is able to detect differences between the DBS setups, and can help in finding the correct parameters.

EMG signal morphology in essential tremor and Parkinson's disease.

The aim of this work was to differentiate patients with essential tremor from patients with Parkinson's disease. The electromyographic signal from the biceps brachii muscle was measured during isometric tension from 17 patients with essential tremor, 35 patients with Parkinson's disease, and 40 healthy controls. The EMG signals were high pass filtered and divided to smaller segments from which histograms were calculated using 200 histogram bins. EMG signal histogram shape was analysed with a feature dimension reduction method, the principal component analysis, and the shape parameters were used to differentiate between different patient groups. The height of the histogram and the side difference between left and right hand were the best discriminators between essential tremor and Parkinson's disease groups. With this method, it was possible to discriminate 13/17 patients with essential tremor from 26/35 patients with Parkinson's disease and 14/17 patients with essential tremor from 29/40 healthy controls.

Outcome of ST-elevation myocardial infarction versus non-ST-elevation acute coronary syndrome treated with titanium-nitride-oxide-coated versus everolimus-eluting stents: insights from the BASE-ACS trial.

AIM: The BASE-ACS trial demonstrated an outcome of titanium-nitride-oxide-coated bioactive stents (BAS) that was statistically non-inferior to that of everolimus-eluting stents (EES) at 12-month follow-up, in patients presenting with acute coronary syndrome (ACS) who underwent early percutaneous coronary intervention (PCI). We explored a post-hoc analysis of the 12-month outcome of the BASE-ACS trial in the subgroup of patients with ST-elevation myocardial infarction (STEMI) versus non-ST-elevation ACS (non-STEACS). METHODS: A total of 827 patients with ACS (321 STEMI) were randomly assigned to receive either BAS or EES. The primary endpoint was a composite of cardiac death, non-fatal myocardial infarction (MI) and ischemia-driven target lesion revascularization (TLR) at 12-month follow-up. RESULTS: The 12-month cumulative incidence of the primary endpoint was similar between the two subgroups (9% versus 9.5%, in STEMI versus non-STEACS patients respectively, P=0.90). The 12-month rate of cardiac death was significantly higher in the STEMI subgroup as compared with the non-STEACS subgroup (2.8 versus 0.6%, respectively, P=0.01). However, the rates of non-fatal MI, ischemia-driven TLR, definite stent thrombosis, and non-cardiac death were all statistically matched between the two subgroups (P>0.05 for all). CONCLUSION: In the current post-hoc analysis of the BASE-ACS trial based on the infarction type, the 12-month outcome of patients who underwent early PCI for ACS was slightly worse in the setting of STEMI as compared with non-STEACS, as reflected by a significantly higher rate of cardiac death.

Prolonged-release oxycodone/naloxone in postoperative pain management: from a randomized clinical trial to usual clinical practice.

OBJECTIVE: These studies evaluated the feasibility of using oral prolonged-release oxycodone/naloxone (OXN PR) for the management of acute postoperative pain. METHODS: Three studies were undertaken: (i) the analgesic efficacy of OXN PR was compared with prolonged-release oxycodone (OXY PR) in patients with knee arthroplasty in an immediate postoperative period (IPOP) study; (ii) OXN PR treatment was compared with other opioids during rehabilitation after knee arthroplasty in a noninterventional study (NIS); and (iii) surgical patients on other opioids were switched to OXN PR postoperatively during a quality improvement programme (QIP). RESULTS: In the IPOP study, the pain intensity at rest score decreased by a similar amount in the OXN PR and OXY PR groups, indicating similar analgesic efficacies. In the NIS, patient assessments indicated enhanced efficacy and tolerability for OXN PR compared with other opioids. The QIP indicated significant improvements in bowel function and less difficulty passing urine at the end of OXN PR treatment compared with baseline. No safety concerns were raised. CONCLUSIONS: The analgesic efficacies of OXN PR and OXY PR were similar in postoperative pain settings. OXN PR reduced the degree of restriction in relation to patients carrying out physiotherapy compared with other opioids, and improved bowel and bladder function.

Linear and nonlinear tremor acceleration characteristics in patients with Parkinson's disease.

The purpose of the study was to evaluate linear and nonlinear tremor characteristics of the hand in patients with Parkinson's disease (PD) and to compare the results with those of healthy old and young control subjects. Furthermore, the aim was to study correlation between tremor characteristics and clinical signs. A variety of nonlinear (sample entropy, cross-sample entropy, recurrence rate, determinism and correlation dimension) and linear (amplitude, spectral peak frequency and total power, and coherence) hand tremor parameters were computed from acceleration measurements for PD patients (n = 30, 68.3 ± 7.8 years), and old (n = 20, 64.2 ± 7.0 years) and young (n = 20, 18.4 ± 1.1 years) control subjects. Nonlinear tremor parameters such as determinism, sample entropy and cross-sample entropy were significantly different between the PD patients and healthy controls. These parameters correlated with the Unified Parkinson's disease rating scale (UPDRS), tremor and finger tapping scores, but not with the rigidity scores. Linear tremor parameters such as the amplitude and the maximum power (power corresponding to peak frequency) also correlated with the clinical findings. No major difference was detected in the tremor characteristics between old and young control subjects. The study revealed that tremor in PD patients is more deterministic and regular when compared to old or young healthy controls. The nonlinear tremor parameters can differentiate patients with PD from healthy control subjects and these parameters may have potential in the assessment of the severity of PD (UPDRS).

Cerebral cortex and sub-cortex lateralization in cardiovascular regulation: correlations of BOLD fMRI and heart rate variability.

The role of cerebral cortex in cardiovascular regulation has not yet been mapped in detail. Especially the lateralization of different regions that are connected to cardiovascular modulation is still unknown. In this study we used simultaneously measured electrocardiography (ECG) and blood oxygen level dependent (BOLD) fMRI to examine the correlation of cerebral cortex and sub-cortex activation and heart rate variability parameters. Correlations were calculated for 11 subjects. Regions of interest (ROIs) were predefined from observations made in previous studies. Lateralization was studied by forming ratios of left and right hemisphere activations in ROIs and calculating correlations of these to heart rate variability (HRV) parameters. Statistically significant correlations were found in every ROI.

Titanium-nitride-oxide-coated Titan-2 bioactive coronary stent: a new breakthrough in interventional cardiology.

The introduction of drug-eluting stents (DES) has revolutionized the field of interventional cardiology, since it has reduced the incidence of restenosis by 50% to 70%. However, recent worrisome data from registries and meta-analyses emphasized higher rates of late and very late stent thrombosis associated with DES. The recently introduced titanium-nitride-oxide-coated stent bioactive stent (Titan-2) was manufactured by a proprietary process to coat titanium-nitride-oxide on the surface of the stainless steel stent, based on a plasma technology using the nano-synthesis of gas and metal. This late-breaking stent has demonstrated an excellent biocompatibility, as reflected by lower rates of platelet aggregation and fibrin deposition, and better endothelialization. Preclinical and clinical trials and registries involving real-life unselected populations have shown a low rate of major adverse cardiac events at long-term follow-up. Restenosis rates were comparable with those of DES, with very rare stent thrombosis. Equally favorable results have been obtained in patients at high-risk of in-stent restenosis, such as diabetics and those with small coronary arteries. Results in patients presenting with acute coronary syndrome have been again comparable to those of DES, with tendency to lower rates of myocardial infarction and stent thrombosis. Comparisons with second generation drug-eluting stents have also been promising.

Dynamic estimation of cardiac repolarization characteristics during hypoglycemia in healthy and diabetic subjects.

Hypoglycemia is known to affect the repolarization characteristics of the heart, but the mechanisms behind these changes are not completely understood. We analyzed repolarization characteristics continuously from 22 subjects during normoglycemic period, transition period (blood glucose concentration decreasing) and hypoglycemic period from nine healthy controls (Healthy), six otherwise healthy type 1 diabetics (T1DM) and seven type 1 diabetics with disease complications (T1DMc). An advanced principal component regression (PCR)-based method was used for estimating ECG parameters beat-by-beat, and thus, continuous comparison between the repolarization characteristics and blood glucose values was made. We observed that hypoglycemia related ECG changes in the T1DMc group were smaller than changes in the Healthy and T1DM groups. We also noticed that when glucose concentration remained at a low level, the heart rate corrected QT interval prolonged progressively. Finally, a few minutes time lag was observed between the start of hypoglycemia and cardiac repolarization changes. One explanation for these observations could be that hypoglycemia related hormonal changes have a significant role behind the repolarization changes. This could explain at least the observed time lag (hormonal changes are slow) and the lower repolarization changes in the T1DMc group (hormonal secretion lowered in long duration diabetics).

Hypoglycemia detection based on cardiac repolarization features.

Hypoglycemia is known to affect repolarization characteristics of the heart. These changes are shown from ECG by prolonged QT-time and T-wave flattening. In this study we constructed a classifier based on these ECG parameters. By using the classifier we tried to detect hypoglycemic events from measurements of 22 test subjects. Hypoglycemic state was achieved using glucose clamp technique. Used test protocol consisted of three stages: normoglycemic period, transition period (blood glucose concentration decreasing) and hypoglycemic period. Subjects were divided into three groups: 9 healthy controls (Healthy), 6 otherwise healthy type 1 diabetics (T1DM) and 7 type 1 diabetics with disease complications (T1DMc). Detection of hypoglycemic event could be made passably from 15/22 measurements. In addition, we found that detection process is easier for healthy and T1DM groups than T1DMc group diabetics because in T1DMc group subjects' have lower autonomic response to hypoglycemic events. Also we noticed that changes in ECG occurs few minutes after blood glucose is decreased below 3.5 mmol/1.

Analysis of heart rate variability dynamics during propofol and dexmedetomidine anesthesia.

It has been observed that heart rate variability (HRV) diminishes during anesthesia, but the exact mechanisms causing it are not completely understood. The aim of this paper was to study the dynamics of HRV during low dose propofol (N=9) and dexmedetomidine (N=8) anesthesia by using state-of-the-art time-varying methods, and thereby ultimately try to improve the safety of anesthesia. The time-varying spectrum is estimated by using a Kalman smoother approach. The results show that there is an overall increase in HRV and decrease in heart rate prior to loss of consciousness. For dexmedetomidine these changes are more considerable than for propofol. For dexmedetomidine the variability also seems to start decreasing right after loss of consciousness, whereas for propofol HRV continues increasing.

Time-varying spectrum estimation of heart rate variability signals with Kalman smoother algorithm.

A time-varying parametric spectrum estimation method for analyzing dynamics of heart rate variability (HRV) signals is presented. In the method, HRV signal is first modeled with a time-varying autoregressive model and the model parameters are solved recursively with a Kalman smoother algorithm. Time-varying spectrum estimates are then obtained from the estimated model parameters. The obtained spectrum can be further decomposed into separate components, which is especially advantageous in HRV applications where low frequency (LF) and high frequency (HF) components are generally aimed to be distinguished. As case studies, the dynamics of HRV signals recorded during 1) orthostatic test, 2) exercise test and 3) simulated driving task are analyzed.

Kalman smoother based time-varying spectrum estimation of EEG during single agent propofol anesthesia.

A time-varying parametric spectrum estimation method for analyzing EEG dynamics is presented. EEG signals are first modeled as a time-varying auto-regressive stochastic process and the model parameters are estimated recursively with a Kalman smoother algorithm. Time-varying spectrum estimates are then obtained from the estimated parameters. The proposed method was applied to measurements collected during low dose propofol anesthesia. The method was able to detect changes of event related (de)synchronization type elicited by verbal command.