Closed-loop optimal and automatic tuning of pulse amplitude and width in EMG-guided controllable transcranial magnetic stimulation.

This paper proposes an efficient algorithm for automatic and optimal tuning of pulse amplitude and width for sequential parameter estimation (SPE) of the neural membrane time constant and input-output (IO) curve parameters in closed-loop electromyography-guided (EMG-guided) controllable transcranial magnetic stimulation (cTMS). The proposed SPE is performed by administering a train of optimally tuned TMS pulses and updating the estimations until a stopping rule is satisfied or the maximum number of pulses is reached. The pulse amplitude is computed by the Fisher information maximization. The pulse width is chosen by maximizing a normalized depolarization factor, which is defined to separate the optimization and tuning of the pulse amplitude and width. The normalized depolarization factor maximization identifies the critical pulse width, which is an important parameter in the identifiability analysis, without any prior neurophysiological or anatomical knowledge of the neural membrane. The effectiveness of the proposed algorithm is evaluated through simulation. The results confirm satisfactory estimation of the membrane time constant and IO curve parameters for the simulation case. By defining the stopping rule based on the satisfaction of the convergence criterion with tolerance of 0.01 for 5 consecutive times for all parameters, the IO curve parameters are estimated with 52 TMS pulses, with absolute relative estimation errors (AREs) of less than 7%. The membrane time constant is estimated with 0.67% ARE, and the pulse width value tends to the critical pulse width with 0.16% ARE with 52 TMS pulses. The results confirm that the pulse width and amplitude can be tuned optimally and automatically to estimate the membrane time constant and IO curve parameters in real-time with closed-loop EMG-guided cTMS.

A formalism for sequential estimation of neural membrane time constant and input-output curve towards selective and closed-loop transcranial magnetic stimulation.

Objective.To obtain a formalism for real-time concurrent sequential estimation of neural membrane time constant and input-output (IO) curve with transcranial magnetic stimulation (TMS).Approach.First, the neural membrane response and depolarization factor, which leads to motor evoked potentials with TMS are analytically computed and discussed. Then, an integrated model is developed which combines the neural membrane time constant and IO curve. Identifiability of the proposed integrated model is discussed. A condition is derived, which assures estimation of the proposed integrated model. Finally, sequential parameter estimation (SPE) of the neural membrane time constant and IO curve is described through closed-loop optimal sampling and open-loop uniform sampling TMS. Without loss of generality, this paper focuses on a specific case of commercialized TMS pulse shapes. The proposed formalism and SPE method are directly applicable to other pulse shapes.Main results.The results confirm satisfactory estimation of the membrane time constant and IO curve parameters. By defining a stopping rule based on five times consecutive convergence of the estimation parameters with a tolerances of 0.01, the membrane time constant and IO curve parameters are estimated with 82 TMS pulses with absolute relative estimation errors (AREs) of less than 4% with the optimal sampling SPE method. At this point, the uniform sampling SPE method leads to AREs up to 16%. The uniform sampling method does not satisfy the stopping rule due to the large estimation variations.Significance.This paper provides a tool for real-time closed-loop SPE of the neural time constant and IO curve, which can contribute novel insights in TMS studies. SPE of the membrane time constant enables selective stimulation, which can be used for advanced brain research, precision medicine and personalized medicine.

A systematic review on regenerative alveolar graft materials in clinical trials: Risk of bias and meta-analysis.

BACKGROUND: Alveolar cleft grafting is a necessary procedure to restore bone defects. Randomized clinical trials (RCTs) are regarded as a golden standard for investigating the efficacy of treatments. Nevertheless, risk of bias (RoB) can still affect the validity of these trials. We aimed to conduct a systemic review of all control trials (CTs) using regenerative materials for alveolar cleft reconstructions to evaluate their RoB and perform a meta-analysis of new bone formation. METHODS: Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), EMBASE AND Google Scholar were searched up to October 2020. Thereafter, the articles underwent quality assessment (according to the Jadad scale and the Delphi list) for the evaluation of the RoB. RESULTS: A total of 15 trials met the inclusion criteria, none of which reached a full score. Of these, 20% didn't randomize the trails, 73,33% failed to describe the way of randomization, and none reported the double-blinded criteria. Furthermore, allocation concealment (99.9%), intention to treat (100%), and patient awareness (100%) were inadequately described. The meta-analysis found no significant difference between regenerative materials and iliac crest graft. CONCLUSION: This review showed high RoB in CTs implying quality improvement of CTs is necessary. Meta-analysis showed no significant difference between the regenerative materials and autogenous grafts.

Post-operative volumes following endoscopic surgery for non-functioning pituitary macroadenomas are predictive of further intervention, but not endocrine outcomes.

BACKGROUND: Transsphenoidal surgery (TSS) remains the treatment of choice for non-functioning pituitary macroadenomas (NFPMA). The value of measuring tumour volumes before and after surgery, and its influence on endocrine outcomes and further treatment of the residual or recurrent tumour are unknown. METHODS: Data from patients who underwent endoscopic TSS for a NFPMA (2009-2018) in a UK tertiary centre were analysed for pre- and post-operative endocrine and surgical outcomes. RESULTS: Of 173 patients with NFPMA, 159 (61% male) were treatment naïve. At presentation, 76.2% (77/101) had ≥1 pituitary axis deficit. Older age (p = 0.002) was an independent predictor for multiple hormonal deficiencies. Preoperative tumour volume did not correlate with degree of hypopituitarism. Postoperative tumour volume and extent of tumour resection were not predictive of new onset hypopituitarism. Hormonal recovery was observed in 16 patients (20.8%) with impaired pituitary function, with the greatest recovery in the hypothalamic-pituitary-adrenal axis (21.2%, 7/33). A larger residual tumour volume was predictive of adjuvant radiotherapy (3.40 vs. 1.24 cm3, p = 0.005) and likelihood for repeat surgery (5.40 vs. 1.67cm3, p = 0.004). CONCLUSION: Pre- and post-operative NFPMA volumes fail to predict the number of pituitary hormone deficits, however, greater post-operative residual volumes increase the likelihood of further intervention to control tumour growth.

Coulomb Explosion Dynamics of Chlorocarbonylsulfenyl Chloride.

The Coulomb explosion dynamics following strong field ionization of chlorocarbonylsulfenyl chloride was studied using multimass coincidence detection and covariance imaging analysis, supported by density functional theory calculations. These results show evidence of multiple dissociation channels from various charge states. Double ionization to low-lying electronic states leads to a dominant C-S cleavage channel, while higher states can alternatively correlate to the loss of Cl+. Triple ionization leads to a double dissociation channel, the observation of which is confirmed via three-body covariance analysis, while further ionization leads primarily to atomic or diatomic fragments whose relative momenta depend strongly on the starting structure of the molecule.

Author Correction: Towards 5G: A Photonic Based Millimeter Wave Signal Generation for Applying in 5G Access Fronthaul.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Roughened graphite biointerfaced with P450 liver microsomes: Surface and electrochemical characterizations.

Low-cost, voltage-driven biocatalytic designs for rapid drug metabolism assay, chemical toxicity screening, and pollutant biosensing represent considerable significance for pharmaceutical, biomedical, and environmental applications. In this study, we have designed biointerfaces of human liver microsomes with various roughened, high-purity graphite disk electrodes to study electrochemical and electrocatalytic properties. Successful spectral and microscopic characterizations, direct bioelectronic communication, direct electron-transfer rates from the electrode to liver microsomal enzymes, microsomal heme-enzyme specific oxygen reduction currents, and voltage-driven diclofenac hydroxylation (chosen as the probe reaction) are presented.

Prognostic role of chemotherapy-induced nausea and vomiting in recurrent ovarian cancer patients: results of an individual participant data meta-analysis in 1213.

BACKGROUND: The aim of this study was to analyze the potential impact of chemotherapy-induced nausea and vomiting (CINV) on dose reductions, discontinuation of chemotherapy, and survival. PATIENTS AND METHODS: This study was designed as individual participant data meta-analysis with the original study data of three phase II/III trials that were conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) including 1213 patients with recurrent ovarian cancer. Logistic and Cox regression analyses were used to estimate odds and hazard ratios after adjusting for age, ECOG, amount of delivered cycles, amount of recurrences, and amount of comedications and study. RESULTS: The majority of patients developed nausea (58.1%) and almost one third experienced vomiting (31.0%). CINV was not associated with FIGO stage, grading, histology, and number of recurrences. The necessity of dose reduction and discontinuation of chemotherapy did not correlate to nausea and vomiting (p = 0.88, p = 0.39 and p = 0.25, p = 0.54 respectively). Progression-free survival was shorter in patients with grade III/IV nausea and vomiting (p = 0.02; hazard ratio (HR) for grade III/IV nausea 1.58, 95% CI 1.14-2.20, and p = 0.02; HR for grade III/IV vomiting 1.67, 95% CI 1.15-2.42 respectively). CINV grade III/IV was also associated with poorer overall survival (p < 0.001; HR for grade III/IV nausea 2.35, 95% CI 1.64-3.37, and p < 0.001; HR for grade III/IV vomiting 1.67, 95% CI 1.15-2.42 respectively). CONCLUSION: CINV is significantly associated with poorer prognosis in recurrent ovarian cancer patients while there was no correlation found with the necessity of dose reduction and prior discontinuation of treatment. This study underlines the importance of prevention and treatment of CINV as part of early best supportive care.

The prognostic and predictive role of pain before systemic chemotherapy in recurrent ovarian cancer: an individual participant data meta-analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO) of 1226 patients.

BACKGROUND: Aim of this study was to analyze the impact of pain on quality of life and survival in recurrent OC patients. METHODS: Raw data including the QLQ-C30 questionnaire from three phase II/III trials ("Topotecan phase III," "Hector," and "TRIAS") conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) were synthesized and analyzed using logistic and Cox regression analyses. RESULTS: Data on pain was available for 952 patients out of 1226. Moderate to severe pain, which was defined as pain ≥ 50 in the QLQ-C30 symptom scale, was experienced by more than one-third of patients (36.6%). A total of 31% were taking non-opioid pain medication and 16% opioids. Median age at randomization was 61 years (range 25-84). Most patients (84.7%) were diagnosed in FIGO III/IV. Pain was independent from age, FIGO stage, grading, amount of recurrences, and chemotherapy-free interval. ECOG was significantly worse in patients with pain (p < 0.001). Fatigue, nausea/vomiting, sleeping disorders, and abdominal symptoms such as loss of appetite, diarrhea, and constipation were more frequently found in patients with pain (all p < 0.001). Quality of life was significantly diminished (p < 0.001). Pain was also an independent marker for overall survival (OS). Median OS was 18.2 months in patients with pain compared with 22.0 months in patients without pain (p = 0.013, HR 1.25, 95% confidence interval 1.05-1.48). OS was shorter in patients with pain and without pain medication compared with those on sufficient pain medication, whereas OS was mostly decreased in patients having pain despite pain medication (18.5, 19.6, and 15.0 months respectively; p = 0.026). Progression-free survival and prior treatment discontinuation were not associated with pain. CONCLUSION: Best supportive care including sufficient pain medication should be delivered as early as possible because effective pain management is crucial for both quality of life and overall survival in patients with recurrent ovarian cancer.

Statistical Model of Motor-Evoked Potentials.

Motor-evoked potentials (MEPs) are widely used for biomarkers and dose individualization in transcranial stimulation. The large variability of MEPs requires sophisticated methods of analysis to extract information fast and correctly. Development and testing of such methods relies on the availability for realistic models of MEP generation, which are presently lacking. This paper presents a statistical model that can simulate long sequences of individualized MEP amplitude data with properties matching experimental observations. The MEP model includes three sources of trial-to-trial variability: excitability fluctuations, variability in the neural and muscular pathways, and physiological and measurement noise. It also generates virtual human subject data from statistics of population variability. All parameters are extracted as statistical distributions from experimental data from the literature. The model exhibits previously described features, such as stimulus-intensity-dependent MEP amplitude distributions, including bimodal ones. The model can generate long sequences of test data for individual subjects with specified parameters or for subjects from a virtual population. The presented MEP model is the most detailed to date and can be used for the development and implementation of dosing and biomarker estimation algorithms for transcranial stimulation.

Imaging the infrared multiphoton excitation and dissociation of propargyl chloride.

Infrared multiphoton excitation is combined with UV excitation and state-resolved probes of Cl(2P3/2), Cl*(2P1/2), and HCl to study the photochemistry of propargyl chloride. The results show evidence both of infrared multiphoton dissociation on the ground electronic state and infrared multiphoton excitation followed by UV dissociation. The results are interpreted with the aid of a full characterization of the stationary points on the ground state using ab initio methods, as well as our recent experimental and theoretical characterization of the UV photochemistry of the molecule. The data suggest elimination of HCl on the ground electronic state produces linear propadienylidene as a coproduct over a roaming-like transition state that accesses the Cl-H-C abstraction geometry. This identification is supported by separate chirped-pulse microwave studies in a quasi-uniform flow also reported here.

Effect of vibration frequency and displacement on melt expulsion characteristics and geometric parameters for ultrasonic vibration-assisted laser drilling of steel.

Recently, the applications of ultrasonic vibration assistance to laser-based manufacturing processes are rapidly proliferating. Ultrasonic vibration-assisted laser drilling (UVLD) process involves simultaneous application of high frequency vertical vibrations to the workpiece while being irradiated with a continuous wave laser beam. In UVLD, the ultrasonic vibration assistance causes expulsion of droplets from the laser melted surface, resulting in the formation of deep holes. In this paper, systematic analysis of the effects of ultrasonic vibration frequency (20-40 kHz) and displacement (16-32 µm) on melt expulsion characteristics in early stages of drilling and geometric/quality features of the holes for UVLD of AISI 316 is presented. Based on the analysis of initiation of droplet ejection from the melt pool and particle size of the ejected droplets, mechanisms of droplet ejection based on capillary wave theory are proposed. It was observed that while increasing both ultrasonic vibration frequency and displacement resulted in reduction in droplet ejection initiation time and the formation of deeper holes for the given laser irradiation time (100 ms), the effect of vibration displacement was much more pronounced than the frequency on the variation.

Mixed transitions in the UV photodissociation of propargyl chloride revealed by slice imaging and multireference ab initio calculations.

Resonance-enhanced multiphoton ionization (REMPI) and DC slice imaging were used to detect photoproducts Cl (2P3/2), spin-orbit excited Cl* (2P1/2), and C3H3 in the photodissociation of propargyl chloride at 212 and 236 nm. Cl and Cl* translational energy distributions peak at high recoil energy, suggesting impulsive energy release in the C-Cl coordinate. Near 236 nm, photofragment angular distributions show rapidly changing anisotropy across the main peak for both Cl and Cl*, indicating excitations arising from in-plane or out-of-plane π systems. At 212 nm, the distribution is broader and isotropic for both Cl products. Ionization of C3H3 at 212 nm via 1 + 1 REMPI provides additional insight into these processes. A portion of the C3H3+ distribution is momentum-matched to the Cl, but in addition, there is a component assigned to cyclic C3H3+ formed from dissociative ionization of propargyl chloride. Multireference ab initio calculations show that excitations to three triplet states contribute at the long wavelength region, while predissociation from the first excited singlet state plays a role at the shorter wavelength.

Stability and Antimicrobial Activity of Nisin-Loaded Mesoporous Silica Nanoparticles: A Game-Changer in the War against Maleficent Microbes.

Antimicrobial agents, such as nisin, are used extensively in the food industry. Here, we investigated various approaches to load nisin onto mesoporous silica nanoparticles (MSNs, 92 ± 10 nm in diameter), to enhance its stability and sustained release. The morphology, size, and surface charge of the as-prepared nanoparticles were analyzed using scanning transmission electron microscopy, dynamic light scattering, and ζ potential measurement. Nisin was either physically adsorbed or covalently attached to the variously functionalized MSNs, with high loading capacities (>600 mg of nisin g-1 of nanoparticles). The results of antibacterial activity analysis of nisin against Staphylococcus aureus showed that, despite the very low antibacterial activity of nisin covalently conjugated onto MSNs, the physical adsorption of nisin onto the unfunctionalized nanoparticles enhances its antimicrobial activities under various conditions, with no significant cytotoxicity effects on mouse fibroblast L929 cells. In conclusion, MSNs can be recommended as suitable carriers for nisin under various conditions.

Expression III: patients' expectations and preferences regarding physician-patient relationship and clinical management-results of the international NOGGO/ENGOT-ov4-GCIG study in 1830 ovarian cancer patients from European countries.

Backround: The primary aim of this study was to investigate information needs and treatment preferences of patients with ovarian cancer, focusing especially on physician-patient relationship and treatment. Patients and methods: A questionnaire was developed based on the experiences of the national German survey 'Expression II', and was provided to patients with ovarian cancer either at initial diagnosis or with recurrent disease via Internet (online-version) or as print-out-version. Results: From December 2009 to October 2012, a total of 1830 patients with ovarian cancer from eight European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain) participated, 902 (49.3%) after initial diagnosis and 731 (39.9%) with recurrent ovarian cancer. The median age was 58 years (range 17-89). Nearly all patients (96.2%) had experienced upfront surgery followed by first-line chemotherapy (91.8%). The majority of patients were satisfied with the completeness and comprehensibility of the explanation about the diagnosis and treatment options. The three most important aspects, identified by patients to improve the treatment for ovarian cancer included: 'the therapy should not induce alopecia' (42%), 'there must be more done to counter fatigue' (34.5%) and 'the therapy should be more effective' (29.7%). Out of 659 (36%) patients, who were offered participation in a clinical trial, 476 (26%) were included. Conclusion: This study underlines the high need of patients with ovarian cancer for all details concerning treatment options irrespective of their cultural background, the stage of disease and the patient's age. Increased information requirements regarding potential side effects and treatment alternatives were recorded. Besides the need for more effective therapy, alopecia and fatigue are the most important side effects of concern to patients.

Making Graphene Nanoribbons Photoluminescent.

We demonstrate the alignment-preserving transfer of parallel graphene nanoribbons (GNRs) onto insulating substrates. The photophysics of such samples is characterized by polarized Raman and photoluminescence (PL) spectroscopies. The Raman scattered light and the PL are polarized along the GNR axis. The Raman cross section as a function of excitation energy has distinct excitonic peaks associated with transitions between the one-dimensional parabolic subbands. We find that the PL of GNRs is intrinsically low but can be strongly enhanced by blue laser irradiation in ambient conditions or hydrogenation in ultrahigh vacuum. These functionalization routes cause the formation of sp3 defects in GNRs. We demonstrate the laser writing of luminescent patterns in GNR films for maskless lithography by the controlled generation of defects. Our findings set the stage for further exploration of the optical properties of GNRs on insulating substrates and in device geometries.

Valve exchange towards an adjustable differential pressure valve with gravitational unit, clinical outcome of a single-center study.

OBJECTIVE: Overdrainage in children is a long-term problem for shunted patients which might lead to chronic anatomical changes. In order to prevent these problems, valve exchange is performed on a regular basis in patients without hydrostatic units towards a valve with both an adjustable and a gravitational unit. The clinical outcome of these patients is reported in a retrospective study. METHODS: Between 2009 and 2014, the in-house database was analyzed for patients who received a valve exchange towards an adjustable differential pressure valve with gravitational unit. The study protocol included the patients shunt history, image analysis for ventricular width, and necessity of revision surgery after valve exchange. A questionnaire was sent to the patients in order to ask for their subjective experience for symptom changes and treatment experience. RESULTS: Forty-six patients were identified (26 girls, mean age 11.8 ± 6.1 years) with a mean follow-up of 36.3 ± 15 months. The ventricular width did increase after valve exchange as measured in frontal and occipital horn ratio (0.364 ± 0.032 vs. 0.402 ± 0.09, p = 0.0017). Of the patients suffering from acute symptoms, 89% improved after treatment. The shunt and valve survival rates were 88 and 95%, respectively, after 12 months. Comparing the total amount of revisions before and after valve exchange, a significant reduction was seen in total but a no significant difference was analyzed in amount of revisions to time ratio. CONCLUSION: Valve exchange might be cautiously decided if patients seem to perform clinically well. In our study, we were able to show that the strategy of valve exchange to prevent chronic overdrainage is well tolerated and seem to improve patient's clinical outcome in terms of ventricular width, symptom relieve, and revision rate.

Enhancing Effects of Curcumin on Cytotoxicity of Paclitaxel, Methotrexate and Vincristine in Gastric Cancer Cells

Curcumin (Diferuloylmethane), a polyphenolic compound with antioxidant, anti-inflammatory and anticancer properties, has been found to increase chemotherapeutic agents-induced cytotoxicity in some resistant cancer cell lines. This investigation aimed to study the effects of curcumin on efficacy of some common anticancer agents in gastric cancer cells. AGS cells were cultured in RPMI-1640 medium under standard culture conditions (5% CO2 and 95% humidified air at 37°C). Curcumin was used at concentrations of 5, 15, 30 and 50 µM. Cells were treated with a combination of curcumin and paclitaxel (300 nm) or methotrexate (100 µm) or vincristine (5 nm). Cell viability, the percentage of live cells in the whole population, was evaluated by MTT assay after 48 hours. The results showed that cell viability was significantly decreased after incubation of AGS cells with curcumin. Combination with curcumin (15-50 µm) significantly increased cytotoxicity of all three agents (P<0.001). Regarding high anticancer potential and enhancement of chemotherapeutic agent-induced cytotoxicity, the combined use of curcumin with standard chemotherapy of gastric cancer is suggested as a strategy for better management of this fatal cancer.

Job satisfaction and its relationship to Radiation Protection Knowledge, Attitude and Practice (RPKAP) of Iranian radiation workers.

This study aimed to find the association between job satisfaction and radiation protection knowledge, attitude and practice of medical radiation workers occupationally exposed to ionizing radiation. In this crosssectional study, 530 radiation workers affiliated to Tehran University of Medical Sciences completed a knowledge, attitude and practice questionnaire on protecting themselves against radiation and Job Descriptive Index as a job satisfaction measure during May to November 2014. Opportunities for promotion (84.2%) and payment (91.5%) were the most important factors for dissatisfaction. Radiation workers who were married, had more positive attitudes toward protecting themselves against radiation, and had higher level of education accounted for 15.8% of the total variance in predicting job satisfaction. In conclusion, medical radiation workers with a more positive attitude toward self-protection against radiation were more satisfied with their jobs. In radiation environments, improving staff attitudes toward their safety may be considered as a key strategy to increase job satisfaction.

A Tri-Leaflet Nitinol Mesh Scaffold for Engineering Heart Valves.

The epidemiology of valvular heart disease has significantly changed in the past few decades with aging as one of the main contributing factors. The available options for replacement of diseased valves are currently limited to mechanical and bioprosthetic valves, while the tissue engineered ones that are under study are currently far from clinical approval. The main problem with the tissue engineered heart valves is their progressive deterioration that leads to regurgitation and/or leaflet thickening a few months after implantation. The use of bioresorbable scaffolds is speculated to be one factor affecting these valves' failure. We have previously developed a non-degradable superelastic nitinol mesh scaffold concept that can be used for heart valve tissue engineering applications. It is hypothesized that the use of a non-degradable superelastic nitinol mesh may increase the durability of tissue engineered heart valves, avoid their shrinkage, and accordingly prevent regurgitation. The current work aims to study the effects of the design features on mechanical characteristics of this valve scaffold to attain proper function prior to in vivo implantation.