Could it be advantageous to tune the temperature controller during radiofrequency ablation? A feasibility study using theoretical models

Purpose: To assess whether tailoring the Kp and Ki values of a proportional-integral (PI) controller during radiofrequency (RF) cardiac ablation could be advantageous from the point of view of the dynamic behaviour of the controller, in particular, whether control action could be speeded up and larger lesions obtained. Methods: Theoretical models were built and solved by the finite element method. RF cardiac ablations were simulated with temperature controlled at 55 degrees C. Specific PI controllers were implemented with Kp and Ki parameters adapted to cases with different tissue values (specific heat, thermal conductivity and electrical conductivity) electrode-tissue contact characteristics (insertion depth, cooling effect of circulating blood) and electrode characteristics (size, location and arrangement of the temperature sensor in the electrode). Results: The lesion dimensions and T(max) remained almost unchanged when the specific PI controller was used instead of one tuned for the standard case: T(max) varied less than 1.9 degrees C, lesion width less than 0.2 mm, and lesion depth less than 0.3 mm. As expected, we did observe a direct logical relationship between the response time of each controller and the transient value of electrode temperature. Conclusion: The results suggest that a PI controller designed for a standard case (such as that described in this study), could offer benefits under different tissue conditions, electrode-tissue contact, and electrode characteristics.This work received financial support from the Spanish 'Plan Nacional de I+D+I del Ministerio de Ciencia e Innovacion' Grant no. TEC2008-01369/TEC and FEDER Project MTM2010-14909. The translation of this paper was funded by the Universitat Politecnica de Valencia, Spain. The authors alone are responsible for the content and writing of the paperAlba Martínez, J.; Trujillo Guillen, M.; Blasco Giménez, RM.; Berjano Zanón, E. (2011). Could it be advantageous to tune the temperature controller during radiofrequency ablation? A feasibility study using theoretical models. International Journal of Hyperthermia. 27(6):539-548. https://doi.org/10.3109/02656736.2011.586665S539548276Gaita, F., Caponi, D., Pianelli, M., Scaglione, M., Toso, E., Cesarani, F., … Leclercq, J. F. (2010). Radiofrequency Catheter Ablation of Atrial Fibrillation: A Cause of Silent Thromboembolism? Circulation, 122(17), 1667-1673. doi:10.1161/circulationaha.110.937953Anfinsen, O.-G., Aass, H., Kongsgaard, E., Foerster, A., Scott, H., & Amlie, J. P. (1999). Journal of Interventional Cardiac Electrophysiology, 3(4), 343-351. doi:10.1023/a:1009840004782PETERSEN, H. H., CHEN, X., PIETERSEN, A., SVENDSEN, J. H., & HAUNSO, S. (2000). Tissue Temperatures and Lesion Size During Irrigated Tip Catheter Radiofrequency Ablation: An In Vitro Comparison of Temperature-Controlled Irrigated Tip Ablation, Power-Controlled Irrigated Tip Ablation, and Standard Temperature-Controlled Ablation. Pacing and Clinical Electrophysiology, 23(1), 8-17. doi:10.1111/j.1540-8159.2000.tb00644.xTungjitkusolmun, S., Woo, E. J., Cao, H., Tsai, J. Z., Vorperian, V. R., & Webster, J. G. (2000). Thermal—electrical finite element modelling for radio frequency cardiac ablation: Effects of changes in myocardial properties. Medical & Biological Engineering & Computing, 38(5), 562-568. doi:10.1007/bf02345754Lai, Y.-C., Choy, Y. B., Haemmerich, D., Vorperian, V. R., & Webster, J. G. (2004). Lesion Size Estimator of Cardiac Radiofrequency Ablation at Different Common Locations With Different Tip Temperatures. IEEE Transactions on Biomedical Engineering, 51(10), 1859-1864. doi:10.1109/tbme.2004.831529Jain, M. K., & Wolf, P. D. (1999). Temperature-controlled and constant-power radio-frequency ablation: what affects lesion growth? IEEE Transactions on Biomedical Engineering, 46(12), 1405-1412. doi:10.1109/10.804568Panescu, D., Whayne, J. G., Fleischman, S. D., Mirotznik, M. S., Swanson, D. K., & Webster, J. G. (1995). Three-dimensional finite element analysis of current density and temperature distributions during radio-frequency ablation. IEEE Transactions on Biomedical Engineering, 42(9), 879-890. doi:10.1109/10.412649Hong Cao, Vorperian, V. R., Tungjitkusolmun, S., Jan-Zern Tsai, Haemmerich, D., Young Bin Choy, & Webster, J. G. (2001). Flow effect on lesion formation in RF cardiac catheter ablation. IEEE Transactions on Biomedical Engineering, 48(4), 425-433. doi:10.1109/10.915708Tungjitkusolmun, S., Vorperian, V. R., Bhavaraju, N., Cao, H., Tsai, J.-Z., & Webster, J. G. (2001). Guidelines for predicting lesion size at common endocardial locations during radio-frequency ablation. IEEE Transactions on Biomedical Engineering, 48(2), 194-201. doi:10.1109/10.909640Schutt, D., Berjano, E. J., & Haemmerich, D. (2009). Effect of electrode thermal conductivity in cardiac radiofrequency catheter ablation: A computational modeling study. International Journal of Hyperthermia, 25(2), 99-107. doi:10.1080/02656730802563051Langberg, J. J., Calkins, H., el-Atassi, R., Borganelli, M., Leon, A., Kalbfleisch, S. J., & Morady, F. (1992). Temperature monitoring during radiofrequency catheter ablation of accessory pathways. Circulation, 86(5), 1469-1474. doi:10.1161/01.cir.86.5.1469Calkins, H., Prystowsky, E., Carlson, M., Klein, L. S., Saul, J. P., & Gillette, P. (1994). Temperature monitoring during radiofrequency catheter ablation procedures using closed loop control. Atakr Multicenter Investigators Group. Circulation, 90(3), 1279-1286. doi:10.1161/01.cir.90.3.1279Lennox CD, Temperature controlled RF coagulation. Patent number: 5.122.137 Hudson NHEdwards SD, Stern RA, Electrode and associated system using thermally insulated temperature sensing elements. Patent number: US Patent 5,456,682Panescu D, Fleischman SD, Whayne JG, Swanson DK, (EP Technology. Effects of temperature sensor placement on performance of temperature-controlled ablation. IEEE 17th Annual Conference, Engineering in Medicine and Biology Society, Montreal, Canada (1995)BLOUIN, L. T., MARCUS, F. I., & LAMPE, L. (1991). Assessment of Effects of a Radiofrequency Energy Field and Thermistor Location in an Electrode Catheter on the Accuracy of Temperature Measurement. Pacing and Clinical Electrophysiology, 14(5), 807-813. doi:10.1111/j.1540-8159.1991.tb04111.xBerjano, E. J. (2006). BioMedical Engineering OnLine, 5(1), 24. doi:10.1186/1475-925x-5-24Bhavaraju, N. C., Cao, H., Yuan, D. Y., Valvano, J. W., & Webster, J. G. (2001). Measurement of directional thermal properties of biomaterials. IEEE Transactions on Biomedical Engineering, 48(2), 261-267. doi:10.1109/10.909647Hong Cao, Tungjitkusolmun, S., Young Bin Choy, Jang-Zern Tsai, Vorperian, V. R., & Webster, J. G. (2002). Using electrical impedance to predict catheter-endocardial contact during RF cardiac ablation. IEEE Transactions on Biomedical Engineering, 49(3), 247-253. doi:10.1109/10.983459PETERSEN, H. H., & SVENDSEN, J. H. (2003). Can Lesion Size During Radiofrequency Ablation Be Predicted By the Temperature Rise to a Low Power Test Pulse in Vitro? Pacing and Clinical Electrophysiology, 26(8), 1653-1659. doi:10.1046/j.1460-9592.2003.t01-1-00248.xLANGBERG, J. J., LEE, M. A., CHIN, M. C., & ROSENQVIST, M. (1990). Radiofrequency Catheter Ablation: The Effect of Electrode Size on Lesion Volume In Vivo. Pacing and Clinical Electrophysiology, 13(10), 1242-1248. doi:10.1111/j.1540-8159.1990.tb02022.

G12/13 Signaling Pathways Substitute for Integrin αIIbβ3-Signaling for Thromboxane Generation in Platelets

We have previously shown that ADP-induced TXA(2) generation requires signaling from αIIbβ3 integrin in platelets. Here we observed that, unlike ADP, protease-activated receptor (PAR)-mediated TXA(2) generation occurs independently of αIIbβ3. PAR agonists, but not ADP, activate G(12/13) signaling pathways. Hence, we evaluated the role of these pathways in TXA(2) generation.Inhibition of ADP-induced thromboxane generation by fibrinogen receptor antagonist SC57101 was rescued by co-stimulation of G(12/13) pathways with YFLLRNP. This observation suggested an existence of a common signaling effector downstream of integrins and G(12/13) pathways. Hence, we evaluated role of three potential tyrosine kinases; c-Src, Syk and FAK (Focal Adhesion Kinase) that are known to be activated by integrins. c-Src and Syk kinase did not play a role in ADP-induced functional responses in platelets. Selective activation of G(12/13) pathways resulted in the activation of FAK, in the absence of integrin signaling. Interestingly, αIIbβ3-mediated FAK activation occurred in a Src family kinase (SFK)-independent manner whereas G(12/13) pathway caused FAK activation in a SFK and RhoA-dependent manner. A FAK selective inhibitor TAE-226, blocked TXA(2) generation. However, in comparison to WT mice, Pf4-Cre/Fak-Floxed mice did not show any difference in platelet TXA(2) generation.Therefore, we conclude that differential activation of FAK occurs downstream of Integrins and G(12/13) pathways. However, the common effector molecule, possibly a tyrosine kinase downstream of integrins and G(12/13) pathways contributing to TXA(2) generation in platelets remains elusive

Defining the research agenda to measure and reduce tuberculosis stigmas

This is an Open Access article, © 2017 International Union Against Tuberculosis and Lung Disease. Content in the UH Research Archive is made available for personal research, educational, and non-commercial purposes only. Unless otherwise stated, all content is protected by copyright, and in the absence of an open license, permissions for further re-use should be sought from the publisher, the author, or other copyright holder.Crucial to finding and treating the 4 million tuberculosis (TB) patients currently missed by National TB Programs, TB stigma is receiving well-deserved and long-delayed attention at the global level. However, the ability to measure and evaluate the success of TB stigma reduction efforts is limited by the need for additional tools. At a 2016 TB stigma measurement meeting held in The Hague, stigma experts discussed and proposed a research agenda around four themes: (1) Drivers: What are the main drivers and domains of TB stigma(s)?; (2) Consequences: How consequential are TB stigmas? How are negative impacts most felt?; (3) Burden: What is the global prevalence and distribution of TB stigma(s)? What explains any variation? (4): Intervention: What can be done to reduce the extent and impact of TB stigma(s)? Each theme was further subdivided into research topics to be addressed to move the agenda forward. These include more clarity on what causes TB stigmas to emerge and thrive, the difficulty of measuring the complexity of stigma, and the improbability of a universal stigma ‘cure’. Notwithstanding, these challenges should not hinder investments in TB stigma measurement and reduction. We believe it is time to focus on how and not whether the global community should measure and reduce TB stigma.Peer reviewedFinal Published versio

Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified

Mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov-2 infection: An international cohort study

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (740%) had emergency surgery and 280 (248%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (261%) patients. 30-day mortality was 238% (268 of 1128). Pulmonary complications occurred in 577 (512%) of 1128 patients; 30-day mortality in these patients was 380% (219 of 577), accounting for 817% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 175 [95% CI 128-240], p<00001), age 70 years or older versus younger than 70 years (230 [165-322], p<00001), American Society of Anesthesiologists grades 3-5 versus grades 1-2 (235 [157-353], p<00001), malignant versus benign or obstetric diagnosis (155 [101-239], p=0046), emergency versus elective surgery (167 [106-263], p=0026), and major versus minor surgery (152 [101-231], p=0047). Interpretation Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research