Usefulness and description of the intestinal bypass technique in children with short bowel syndrome: report of a Mexican cohort.

BACKGROUND: Short bowel syndrome (SBS) is one of the most frequent causes of intestinal failure, needing parenteral nutrition to maintain an energy-protein and water-electrolyte balance. At the Hospital Infantil de México Federico Gómez (HIMFG), the formation of two stomas is a technique used for intestinal rehabilitation, where the use of residue through the bypass technique (BT) helps to maintain gastrointestinal functionality, water-electrolyte, and nutritional stability. This study aimed to describe the technique of using intestinal residue through BT as a treatment strategy in intestinal rehabilitation and its effect on the biochemical and nutritional status of pediatric patients with SBS. METHODS: An analytical and retrospective cross-sectional study was performed in patients hospitalized at HIMFG with SBS who underwent BT during their hospital stay between 2019 and 2020 and then followed up for 8 weeks. RESULTS: A total of 10 patients were included in this study, with a mean age of 24 months; 50% were female. BT was able to reduce the inflammatory process in the liver caused by the continuous use of parenteral nutrition; enteral caloric intake increased from 25.32 kcal/kg/day to 72.94 kcal/kg/day, but it was insufficient to improve their nutritional status. CONCLUSIONS: BT is a safe and effective alternative in intestinal rehabilitation in patients with SBS to stimulate trophism and intestinal functionality, allowing a progression of enteral feeding and a decrease in the hepatic inflammatory process that occurs in these patients with prolonged parenteral nutrition.

INTRODUCCIÓN: El síndrome de intestino corto (SIC) es una de las causas más frecuentes de insuficiencia intestinal que requiere del uso de nutrición parenteral para mantener un balance energético-proteico e hidroelectrolítico. En el Hospital Infantil de México Federico Gómez (HIMFG) la formación de dos estomas es una técnica empleada para la rehabilitación intestinal, donde con el aprovechamiento de residuo mediante la técnica de puenteo (TP) se ayuda a mantener la funcionalidad gastrointestinal, equilibrio hidro-electrolítico y estabilidad nutricional. El objetivo de este estudio fue describir la técnica del aprovechamiento de residuo intestinal mediante TP como estrategia de tratamiento en la rehabilitación intestinal y su efecto en el estado bioquímico y nutricional de pacientes pediátricos con SIC. MÉTODOS: Se llevó a cabo un estudio transversal analítico y retrospectivo en pacientes hospitalizados en el HIMFG con SIC en quienes se realizó la TP durante su estancia intrahospitalaria entre 2019 y 2020. RESULTADOS: Se incluyeron 10 pacientes en este estudio, con una edad promedio de 24 meses, y el 50% de sexo femenino. La TP logró disminuir el proceso inflamatorio hepático ocasionado por el uso continuo de nutrición parenteral; la ingesta calórica por vía enteral incrementó de 25.32 kcal/kg/día a 72.94 kcal/kg/día, pero fue insuficiente para mejorar el estado nutricional. CONCLUSIONES: La TP es una alternativa segura y efectiva en la rehabilitación intestinal en pacientes con SIC para estimular el trofismo y funcionalidad intestinal, permitiendo una progresión de la alimentación enteral y disminución del proceso inflamatorio hepático que se presentan en estos pacientes con nutrición parenteral prolongada.

The Discovery of inhibitors of the SARS-CoV-2 S protein through computational drug repurposing.

SARS-CoV-2 must bind its principal receptor, ACE2, on the target cell to initiate infection. This interaction is largely driven by the receptor binding domain (RBD) of the viral Spike (S) protein. Accordingly, antiviral compounds that can block RBD/ACE2 interactions can constitute promising antiviral agents. To identify such molecules, we performed a virtual screening of the Selleck FDA approved drugs and the Selleck database of Natural Products using a multistep computational procedure. An initial set of candidates was identified from an ensemble docking process using representative structures determined from the analysis of four 3 µ s molecular dynamics trajectories of the RBD/ACE2 complex. Two procedures were used to construct an initial set of candidates including a standard and a pharmacophore guided docking procedure. The initial set was subsequently subjected to a multistep sieving process to reduce the number of candidates to be tested experimentally, using increasingly demanding computational procedures, including the calculation of the binding free energy computed using the MMPBSA and MMGBSA methods. After the sieving process, a final list of 10 candidates was proposed, compounds which were subsequently purchased and tested ex-vivo. The results identified estradiol cypionate and telmisartan as inhibitors of SARS-CoV-2 entry into cells. Our findings demonstrate that the methodology presented here enables the discovery of inhibitors targeting viruses for which high-resolution structures are available.

Assessment of the bound conformation of bombesin to the BB1 and BB2 receptors.

Bombesin is an endogenous peptide involved in a wide spectrum of physiological activities ranging from satiety, control of circadian rhythm and thermoregulation in the central nervous system, to stimulation of gastrointestinal hormone release, activation of macrophages and effects on development in peripheral tissues. Actions of the peptide are mediated through the two high affinity G-protein coupled receptors BB1R and BB2R. Under pathophysiological conditions, these receptors are overexpressed in many different types of tumors, such as prostate cancer, breast cancer, small and non-small cell lung cancer and pancreatic cancer. This observation has been used for designing cell markers, but it has not been yet exploited for therapeutical purposes. Despite the enormous biological interest of the peptide, little is known about the stereochemical features that contribute to their activity. On the one hand, mutagenesis studies identified a few receptor residues important for high bombesin affinity and on the other, a few studies focused on the relevance of diverse residues of the peptide for receptor activation. Models of the peptide bound to BB1R and BB2R can be helpful to improve our understanding of the stereochemical features granting bombesin activity. Accordingly, the present study describes the computational process followed to construct such models by means of Steered Molecular Dynamics, using models of the peptide and its receptors. Present results provide new insights into the structure-activity relationships of bombesin and its receptors, as well as render an explanation for the differential binding affinity observed towards BB1R and BB2R. Finally, these models can be further exploited to help for designing novel small molecule peptidomimetics with improved pharmacokinetics profile.

How intramyocardial fat can alter the electric field distribution during Pulsed Field Ablation (PFA): Qualitative findings from computer modeling.

Even though the preliminary experimental data suggests that cardiac Pulsed Field Ablation (PFA) could be superior to radiofrequency ablation (RFA) in terms of being able to ablate the viable myocardium separated from the catheter by collagen and fat, as yet there is no formal physical-based analysis that describes the process by which fat can affect the electric field distribution. Our objective was thus to determine the electrical impact of intramyocardial fat during PFA by means of computer modeling. Computer models were built considering a PFA 3.5-mm blunt-tip catheter in contact with a 7-mm ventricular wall (with and without a scar) and a 2-mm epicardial fat layer. High voltage was set to obtain delivered currents of 19, 22 and 25 A. An electric field value of 1000 V/cm was considered as the lethal threshold. We found that the presence of fibrotic tissue in the scar seems to have a similar impact on the electric field distribution and lesion size to that of healthy myocardium only. However, intramyocardial fat considerably alters the electrical field distribution and the resulting lesion shape. The electric field tends to peak in zones with fat, even away from the ablation electrode, so that 'cold points' (i.e. low electric fields) appear around the fat at the current entry and exit points, while 'hot points' (high electric fields) occur in the lateral areas of the fat zones. The results show that intramyocardial fat can alter the electric field distribution and lesion size during PFA due to its much lower electrical conductivity than that of myocardium and fibrotic tissue.

Cooled Radiofrequency Treatment for Radicular Pain Related to Lumbar Disc Herniation.

BACKGROUND: Lower back and radicular pain are leading causes of disability and loss of quality of life, especially due to its high prevalence in the general population. Cooled radiofrequency treatment (CRT) has emerged as a novel non-invasive technique for the management of discogenic pain with safe and effective results. The aim of this study was to evaluate the effectiveness of CRT in the treatment of radicular pain secondary to a lumbar hernia in patients with chronic neuropathic pain after receiving conservative treatment that did not achieve adequate pain management. METHODS: A prospective study of patients undergoing CRT for the management of discogenic low back pain was carried out. When attending the first evaluation and corroborating the lumbar hernias by magnetic resonance imaging (MRI), treatment was offered one month of physiotherapy before CRT. To assess the evolution of the patients, measurements were taken before and after the intervention with the visual analog scale (VAS) and the Oswestry low back pain disability scale (OLBPDS) scores. RESULTS: A total of 74 patients (mean age: 48.42 ± 14.32 years, 66.11% female) were included, who were undergoing a total of 134 herniated intervertebral lumbar discs. When comparing the initial perception of low back pain and after finding a non-significant partial improvement with one month of physiotherapy treatment, it was observed that the patients who were offered CRT showed an average improvement in discogenic pain of 79.92% (p = <0.0001, 95% CI: -7.010 to -6.379) in 98.64% of cases. This was accompanied by an increase in their functionality of daily living activities, as measured by OLBPDS. No patients presented significant adverse events, and in the only case where the desired pain management was not obtained, the patient's discomfort did not worsen. CONCLUSIONS: Intradiscal biacuplasty by CRT is a considerable treatment for lumbar radiculopathy. Postoperative results demonstrated its effectiveness and safety in the management of radicular pain without the presence of significant adverse effects.

Intrathecal Baclofen Infusion Pump for the Treatment of Painful Spastic Hemiplegia: A Case Report.

Painful spastic hemiplegia is a common sequel to a stroke in which patients rarely achieve optimal levels of pain control. Herein, we report the case of a 62-year-old woman with painful spasticity secondary to an ischemic stroke of 15 years' evolution who received multiple pharmacological treatments without reaching motor or pain management goals. After an adequate analgesic response to the intrathecal baclofen test, the placement of an electromechanical pump was decided, reaching an effective maintenance dose of 150 µg per day. Despite achieving partial improvement in spasticity, optimal pain remission was achieved.

Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening.

Mutants of Ras are oncogenic drivers of a large number of human tumors. Despite being recognized as an attractive target for the treatment of cancer, the high affinity for its substrate tagged the protein as undruggable for a few years. The identification of cryptic pockets on the protein surface gave the opportunity to identify molecules capable of acting as allosteric modulators. Several molecules were disclosed in recent years, with sotorasib and adagrasib already approved for clinical use. The present study makes use of computational methods to characterize eight prospective allosteric pockets (P1-P8) in K-Ras, four of which (P1-P4) were previously characterized in the literature. The present study also describes the results of a virtual screening study focused on the discovery of hit compounds, binders of the P4 site that can be considered as peptidomimetics of a fragment of the SOS αI helix, a guanine exchange factor of Ras. After a detailed description of the computational procedure followed, we disclose five hit compounds, prospective binders of the P4 allosteric site that exhibit an inhibitory capability higher than 30% in a cell proliferation assay at 50 µM.

A Case Report on Spinal Neurostimulator Treatment for Painful Postsurgical Neuropathy of the Genitofemoral Nerve.

Painful postsurgical neuropathy is an adverse event inherent to a wide variety of surgical treatments, so its diagnosis and specialized treatment are essential to maintaining the quality of life of the people who suffer from it. We present the case of a 31-year-old male with neuropathy of the genitofemoral nerve diagnosed by electromyography, resulting in intractable left testicular and thigh pain associated with a recent history of ipsilateral inguinal hernioplasty. After assessment by pain medicine and motor and sensory tests, a neurostimulator was placed in T8-T9 with action at the L1-L2 level, as well as a simultaneous electrode in S3, generating optimal pain relief and recovery of functionality.

Is occlusion of the main pancreatic duct by thermal ablation really safe? A surgical innovation assessed according to IDEAL recommendations.

INTRODUCTION: Pre-clinical studies suggest that thermal ablation of the main pancreatic duct (TAMPD) is more recommendable than glue for reducing postoperative pancreatic fistula (POPF). Our aims were (1) to analyze the changes in the pancreas of patients after TAMPD and (2) to correlate the clinical findings with those obtained from a study on an animal model. MATERIALS AND METHODS: A retrospective early feasibility study of a marketed device for a novel clinical application was carried out on a small number of subjects (n = 8) in whom TAMPD was conducted to manage the pancreatic stump after a pancreatectoduodenectomy (PD). Morphological changes in the remaining pancreas were assessed by computed tomography for 365 days after TAMPD. RESULTS: All the patients showed either Grade A or B POPF, which generally resolved within the first 30 days. The duct's maximum diameter significantly increased after TAMPD from 1.5 ± 0.8 mm to 8.6 ± 2.9 mm after 7 days (p = .025) and was then reduced to 2.6 ± 0.8 mm after 365 days PO (p < .0001). The animal model suggests that TAMPD induces dilation of the duct lumen by enzymatic digestion of ablated tissue after a few days and complete exocrine atrophy after a few weeks. CONCLUSIONS: TAMPD leads to long-term exocrine pancreatic atrophy by completely occluding the duct. However, the ductal dilatation that occurred soon after TAMPD could even favor POPF, which suggests that TAMPD should be conducted several weeks before PD, ideally by digestive endoscopy.

A Step Forward toward Selective Activation/Inhibition of Bak, a Pro-Apoptotic Member of the Bcl-2 Protein Family: Discovery of New Prospective Allosteric Sites Using Molecular Dynamics.

Bak is a pro-apoptotic protein and a member of the Bcl-2 family that plays a key role in apoptosis, a programmed cell death mechanism of multicellular organisms. Its activation under death stimuli triggers the permeabilization of the mitochondrial outer membrane that represents a point of no return in the apoptotic pathway. This process is deregulated in many tumors where Bak is inactivated, whereas in other cases like in neurodegeneration, it exhibits an excessive response leading to disorders such as the Alzheimer disease. Members of the Bcl-2 family share a common 3D structure, exhibiting an extremely similar orthosteric binding site, a place where both pro and antiapoptotic proteins bind. This similarity raises a selectivity issue that hampers the identification of new drugs, capable of altering Bak activation in a selective manner. An alternative activation site triggered by antibodies has been recently identified, opening the opportunity to undertake new drug discovery studies. Despite this recent identification, an exhaustive study to identify cryptic pockets as prospective allosteric sites has not been yet performed. Thus, the present study aims to characterize novel hotspots in the Bak structure. For this purpose, we have carried out extensive molecular dynamics simulations using three different Bak systems including Bak in its apo form, Bak in complex with its endogen activator Bim and an intermediate form, set up by removing Bim from the previous complex. The results reported in the present work shed some light on future docking studies on Bak through the identification of new prospective allosteric sites, not previously described in this protein.

Acute Phrenic Neuropathy and Diaphragmatic Dysfunction as a Complication of COVID-19: A Report of Four Cases.

Among the neurological manifestations associated with coronavirus disease 2019 (COVID-19), neuropathies are rare. They have been associated with prolonged prostration and metabolic failure in a seriously ill patient. We present a case series of four Mexican patients diagnosed with diaphragmatic dysfunction due to phrenic neuropathy during acute COVID-19, documented by conduction velocities of the phrenic nerves. Blood tests, chest computed tomography (CT), and nerve conduction velocities of the phrenic nerves were performed. COVID-19 patients with phrenic nerve neuropathy represent a therapeutic challenge since they have high oxygen requirements due to the malfunction of ventilatory mechanics secondary to neuromuscular damage, as well as the damage that pneumonia generates in lung tissue. We confirm and extend the neurological manifestations of COVID-19, the impact on the neuromuscular dysfunction of the diaphragm, and its consequences such as the difficulty of weaning from mechanical ventilation.

How far the zone of heat-induced transient block extends beyond the lesion during RF catheter cardiac ablation.

PURPOSE: While radiofrequency catheter ablation (RFCA) creates a lesion consisting of the tissue points subjected to lethal heating, the sublethal heating (SH) undergone by the surrounding tissue can cause transient electrophysiological block. The size of the zone of heat-induced transient block (HiTB) has not been quantified to date. Our objective was to use computer modeling to provide an initial estimate. METHODS AND MATERIALS: We used previous experimental data together with the Arrhenius damage index (Ω) to fix the Ω values that delineate this zone: a lower limit of 0.1-0.4 and upper limit of 1.0 (lesion boundary). An RFCA computer model was used with different power-duration settings, catheter positions and electrode insertion depths, together with dispersion of the tissue's electrical and thermal characteristics. RESULTS: The HiTB zone extends in depth to a minimum and maximum distance of 0.5 mm and 2 mm beyond the lesion limit, respectively, while its maximum width varies with the energy delivered, extending to a minimum of 0.6 mm and a maximum of 2.5 mm beyond the lesion, reaching 3.5 mm when high energy settings are used (25 W-20s, 500 J). The dispersion of the tissue's thermal and electrical characteristics affects the size of the HiTB zone by ±0.3 mm in depth and ±0.5 mm in maximum width. CONCLUSIONS: Our results suggest that the size of the zone of heat-induced transient block during RFCA could extend beyond the lesion limit by a maximum of 2 mm in depth and approximately 2.5 mm in width.

Evidence of sea level rise at the Peruvian coast (1942-2019).

The present work aims to analyze the variability of the sea level of the Peruvian coast with time series over a long observation period (Seventy-eight years, from 1942 to 2019). Data came from the Talara, Callao and Matarani tide gauge stations located at the north, center and south of the coast. Variations of sea level as well as air and seawater surface temperature were analyzed. Among the different scenarios studied, a sea level rise of 6.79, 4.21 and 5.16 mm/year for Talara, Callao and Matarani, respectively was found during the 1979-1997 nodal cycle. However, these results decreased significantly during the next cycle (1998-2016) until values of 1.53, 2.16 and 1.0 mm/year for Talara, Callao and Matarani, respectively. Thus, it has been demonstrated that sea level rise are highly dependent on the time interval chosen. Moreover, large interannual changes of up to 200 mm/year are observed, due to recurring phenomena, such as "El Niño". On the other hand, the trends obtained are slightly lower than those shown by the IPCC up until 2006 but significantly higher values have been observed. Finally, the results presented herein show the necessity of a local study of the sea level variability at the coastal areas.

Low-energy (360 J) radiofrequency catheter ablation using moderate power - short duration: proof of concept based on in silico modeling.

BACKGROUND: Pilot clinical studies suggest that very high power-very short duration (vHPvSD, 90 W/4 s, 360 J energy) is a feasible and safe technique for ablation of atrial fibrillation (AF), compared with standard applications using moderate power-moderate duration (30 W/30 s, 900 J energy). However, it is unclear whether alternate power and duration settings for the delivery of the same total energy would result in similar lesion formation. This study compares temperature dynamics and lesion size at different power-duration settings for the delivery of equivalent total energy (360 J). METHODS: An in silico model of radiofrequency (RF) ablation was created using the Arrhenius function to estimate lesion size under different power-duration settings with energy balanced at 360 J: 30 W/12 s (MPSD), 50 W/7.2 s (HPSD), and 90 W/4 s (vHPvSD). Three catheter orientations were considered: parallel, 45°, and perpendicular. RESULTS: In homogenous tissue, vHPvSD and HPSD produced similar size lesions independent of catheter orientation, both of which were slightly larger than MPSD (lesion size 0.1 mm deeper, ~ 0.7 mm wider, and ~ 25 mm3 larger volume). When considering heterogeneous tissue, these differences were smaller. Tissue reached higher absolute temperature with vHPvSD and HPSD (5-8 °C higher), which might increase risk of collateral tissue injury or steam pops. CONCLUSION: Ablation for AF using MPSD or HPSD may be a feasible alternative to vHPvSD ablation given similar size lesions with similar total energy delivery (360 J). Lower absolute tissue temperature and slower heating may reduce risk of collateral tissue injury and steam pops associated with vHPvSD and longer applications using moderate power.

In Silico Modelling to Assess the Electrical and Thermal Disturbance Provoked by a Metal Intracoronary Stent during Epicardial Pulsed Electric Field Ablation.

Background: Pulsed Electric Field (PEF) ablation has been recently proposed to ablate cardiac ganglionic plexi (GP) aimed to treat atrial fibrillation. The effect of metal intracoronary stents in the vicinity of the ablation electrode has not been yet assessed. Methods: A 2D numerical model was developed accounting for the different tissues involved in PEF ablation with an irrigated ablation device. A coronary artery (with and without a metal intracoronary stent) was considered near the ablation source (0.25 and 1 mm separation). The 1000 V/cm threshold was used to estimate the 'PEF-zone'. Results: The presence of the coronary artery (with or without stent) distorts the E-field distribution, creating hot spots (higher E-field values) in the front and rear of the artery, and cold spots (lower E-field values) on the sides of the artery. The value of the E-field inside the coronary artery is very low (~200 V/cm), and almost zero with a metal stent. Despite this distortion, the PEF-zone contour is almost identical with and without artery/stent, remaining almost completely confined within the fat layer in any case. The mentioned hot spots of E-field translate into a moderate temperature increase (<48 °C) in the area between the artery and electrode. These thermal side effects are similar for pulse intervals of 10 and 100 µs. Conclusions: The presence of a metal intracoronary stent near the ablation device during PEF ablation simply 'amplifies' the E-field distortion already caused by the presence of the vessel. This distortion may involve moderate heating (<48 °C) in the tissue between the artery and ablation electrode without associated thermal damage.

Actinomycete Potential as Biocontrol Agent of Phytopathogenic Fungi: Mechanisms, Source, and Applications.

Synthetic fungicides have been the main control of phytopathogenic fungi. However, they cause harm to humans, animals, and the environment, as well as generating resistance in phytopathogenic fungi. In the last few decades, the use of microorganisms as biocontrol agents of phytopathogenic fungi has been an alternative to synthetic fungicide application. Actinomycetes isolated from terrestrial, marine, wetland, saline, and endophyte environments have been used for phytopathogenic fungus biocontrol. At present, there is a need for searching new secondary compounds and metabolites of different isolation sources of actinomycetes; however, little information is available on those isolated from other environments as biocontrol agents in agriculture. Therefore, the objective of this review is to compare the antifungal activity and the main mechanisms of action in actinomycetes isolated from different environments and to describe recent achievements of their application in agriculture. Although actinomycetes have potential as biocontrol agents of phytopathogenic fungi, few studies of actinomycetes are available of those from marine, saline, and wetland environments, which have equal or greater potential as biocontrol agents than isolates of actinomycetes from terrestrial environments.

Effects of solvents on the conformational profile of Balaram's peptide: a computational study.

The present work reports the results of a computational study aimed at characterizing the conformational profile of Balaram's peptide (Ace-Leu-Val-Val-Aib-Gly-Leu-Val-Val-NHMe) in different solvents, including chloroform, dimethyl sulfoxide, methanol and water. For this purpose, 10 µs molecular dynamics trajectories were computed in explicit solvents for each system, starting from an extended conformation. The results of the present study confirm the former NMR and CD findings and provide further insights that permit fine-tuning of the conclusions previously derived. The present results show that the peptide exhibits a helical conformation in chloroform, but a mixture of ß-hairpin and Ω-shape conformations, as the predominant structures in DMSO and MeOH. Finally, the peptide does not exhibit a preferred conformation in water, although significant populations of helical and ß-hairpin conformations are available. The present results underline the role of solvents in the conformational profile of a peptide and it is an example of the complementarity between computational methods and spectroscopy studies.

Limitations of Baseline Impedance, Impedance Drop and Current for Radiofrequency Catheter Ablation Monitoring: Insights from In silico Modeling.

Background: Baseline impedance, radiofrequency current, and impedance drop during radiofrequency catheter ablation are thought to predict effective lesion formation. However, quantifying the contributions of local versus remote impedances provides insights into the limitations of indices using those parameters. Methods: An in silico model of left atrial radiofrequency catheter ablation was used based on human thoracic measurements and solved for (1) initial impedance (Z), (2) percentage of radiofrequency power delivered to the myocardium and blood (3) total radiofrequency current, (4) impedance drop during heating, and (5) lesion size after a 25 W−30 s ablation. Remote impedance was modeled by varying the mixing ratio between skeletal muscle and fat. Local impedance was modeled by varying insertion depth of the electrode (ID). Results: Increasing the remote impedance led to increased baseline impedance, lower system current delivery, and reduced lesion size. For ID = 0.5 mm, Z ranged from 115 to 132 Ω when fat percentage varied from 20 to 80%, resulting in a decrease in the RF current from 472 to 347 mA and a slight decrease in lesion size from 5.6 to 5.1 mm in depth, and from 9.2 to 8.0 mm in maximum width. In contrast, increasing the local impedance led to lower system current but larger lesions. For a 50% fat−muscle mixture, Z ranged from 118 to 138 Ω when ID varied from 0.3 to 1.9 mm, resulting in a decrease in the RF current from 463 to 443 mA and an increase in lesion size, from 5.2 up to 7.5 mm in depth, and from 8.4 up to 11.6 mm in maximum width. In cases of nearly identical Z but different contributions of local and remote impedance, markedly different lesions sizes were observed despite only small differences in RF current. Impedance drop better predicted lesion size (R2 > 0.93) than RF current (R2 < 0.1). Conclusions: Identical baseline impedances and observed RF currents can lead to markedly different lesion sizes with different relative contributions of local and remote impedances to the electrical circuit. These results provide mechanistic insights into the advantage of measuring local impedance and identifies potential limitations of indices incorporating baseline impedance or current to predict lesion quality.

In-Silico Modeling to Compare Radiofrequency-Induced Thermal Lesions Created on Myocardium and Thigh Muscle.

Beating heart (BH) and thigh muscle (TM) are two pre-clinical models aimed at studying the lesion sizes created by radiofrequency (RF) catheters in cardiac ablation. Previous experimental results have shown that thermal lesions created in the TM are slightly bigger than in the BH. Our objective was to use in-silico modeling to elucidate some of the causes of this difference. In-silico RF ablation models were created using the Arrhenius function to estimate lesion size under different energy settings (25 W/20 s, 50 W/6 s and 90 W/4 s) and parallel, 45° and perpendicular catheter positions. The models consisted of homogeneous tissue: myocardium in the BH model and striated muscle in the TM model. The computer results showed that the lesion sizes were generally bigger in the TM model and the differences depended on the energy setting, with hardly any differences at 90 W/4 s but with differences of 1 mm in depth and 1.5 m in width at 25 W/20 s. The higher electrical conductivity of striated muscle (0.446 S/m) than that of the myocardium (0.281 S/m) is possibly one of the causes of the higher percentage of RF energy delivered to the tissue in the TM model, with differences between models of 2-5% at 90 W/4 s, ~9% at 50 W/6 s and ~10% at 25 W/20 s. Proximity to the air-blood interface (just 2 cm from the tissue surface) artificially created in the TM model to emulate the cardiac cavity had little effect on lesion size. In conclusion, the TM-based experimental model creates fairly similar-sized lesions to the BH model, especially in high-power short-duration ablations (50 W/6 s and 90 W/4 s). Our computer results suggest that the higher electrical conductivity of striated muscle could be one of the causes of the slightly larger lesions in the TM model.

Peptidic Scaffolds Enable Rapid and Multivariate Secondary Sphere Evolution for an Abiotic Metallocatalyst.

Metalloenzymes have benefited from the iterative process of evolution to achieve the precise arrangements of secondary sphere non-covalent interactions that enhance metal-centered catalysis. Iterative synthesis of scaffolds that display complex secondary sphere elements in abiotic systems can be highly challenging and time-intensive. To overcome this synthetic bottleneck, we developed a highly modular and rapid synthetic strategy, leveraging the efficiency of solid-phase peptide synthesis and conformational control afforded by non-canonical residues to construct a ligand platform displaying up to four unique residues of varying electronics and sterics in the secondary coordination sphere. As a proof-of-concept that peptidic secondary sphere can cooperate with the metal complex, we applied this scaffold to a well-known, modestly active C-H oxidizing Fe catalyst to evolve specific non-covalent interactions that is more than double its catalytic activity. Solution-state NMR structures of several catalyst variants suggest that higher activity is correlated with a hydrophobic pocket above the Fe center that may enhance the formation of a catalyst-substrate complex. Above all, we show that peptides are a convenient, highly modular, and structurally defined ligand platform for creating secondary coordination spheres that comprise multiple, diverse functional groups.