Comparing the Memory Effects of 50-Hz Low-Frequency and 10-kHz High-Frequency Thoracic Spinal Cord Stimulation on Spinal Neural Network in a Myocardial Infarction Porcine Model.

OBJECTIVE: This study evaluated the effects of cessation of both conventional low-frequency (50 Hz) and high-frequency (10 kHz) spinal cord stimulation (SCS) on the cardiospinal neural network activity in pigs with myocardial infarction (MI). The objective is to provide an insight into the memory effect of SCS. MATERIALS AND METHODS: In nine Yorkshire pigs, chronic MI was created by delivering microspheres to the left circumflex coronary artery. Five weeks after MI, anesthetized pigs underwent sternotomy to expose the heart for performing acute ischemia intervention, and laminectomy to expose the T1-T4 spinal regions for extracellular in vivo neural recording and SCS. Cardiac ischemic-sensitive neurons were identified by selective responsiveness to left anterior descending (LAD) coronary artery occlusion. SCS episodes were delivered in a random order between low- (50 Hz) and high- (10 kHz) frequency, for 1 minute, at 90% of the motor threshold current. Neural firing and synchrony of ischemic-sensitive spinal neurons were evaluated before vs after SCS. RESULTS: Using a 64-channel microelectrode array, 2711 spinal neurons were recorded extracellularly. LAD ischemia excited 228 neurons that were labeled as ischemic-responsive neurons. The cessation of 50-Hz SCS caused a higher activation than did inhibition of ischemic-responsive neurons (41 activated vs 19 inhibited), whereas the cessation of 10-kHz SCS caused an opposite response with higher inhibition (11 activated vs 28 inhibited, p < 0.01 vs 50 Hz). Termination of low-frequency SCS caused an increase in ischemic-responsive neuronal firing rate compared with high-frequency SCS (50 Hz: 0.39 Hz ± 0.16 Hz, 10 kHz: -0.11 Hz ± 0.057 Hz, p < 0.01). In addition, SCS delivered at 50 Hz increased the number of synchronized pairs of neurons by 205 pairs, whereas high-frequency SCS decreased the number of synchronized pairs by 345 pairs (p < 0.01). CONCLUSIONS: High-frequency (10 kHz) stimulation provides persistent suppression of the ischemia-sensitive neurons after termination of SCS. In contrast, the spinal neural network reverted to excitatory state after termination of low-frequency (50 Hz) stimulation.

Directing ligament-mimetic bi-directional cell organization in scaffolds through zone-specific microarchitecture for ligament tissue engineering.

Ligament tissues exhibit zone-specific anisotropic cell organization. The cells in ligament-proper are longitudinally oriented, whereas, the cells in epiligament are circumferentially oriented. Therefore, scaffolds developed to regenerate ligament tissues should possess adequate architectural features to govern ligament-mimetic bi-directional cell organization. The scaffold architectural features along with ligament-mimetic cell organization may ultimately yield neo-tissues with ligament-like extracellular matrix (ECM) structure and biomechanical properties. Towards this goal, we fabricated a silk/gelatin-based core-shell scaffold (csSG) with zone-specific anisotropic architectural features, wherein, the core of the scaffold possessed longitudinally aligned pores while the shell of the scaffold possessed parallel microgrooves that are aligned circumferentially around the surface of the scaffold. The ligament-mimetic architectural features significantly improved the mechanical properties of the scaffold. Moreover, architectural features of the csSG scaffold governed zone-specific anisotropic organization of cells. The cells in the core were longitudinally oriented as observed in the ligament-proper and the cells on the shell were circumferentially oriented as observed in epiligament. This bi-directional cell orientation partially mimicked the complex cellular network in native ligament tissue. Additionally, both the core and the shell individually supported fibrogenic differentiation of stem cells which further improved their potential for ligament tissue engineering. Further, the aligned pores of the core could govern unidirectional organization of ECM deposited by cells which is crucial for regenerating anisotropic tissues like ligaments. Finally, when implanted subcutaneously in mice, the scaffolds retained their anisotropic architecture for at least 2 weeks, were biocompatible, supported cell infiltration and governed anisotropic organization of cells and ECM. Taken together, the fabricated biomimetic csSG scaffold, through its zone-specific architectural features, could govern ligament-mimetic cellular and ECM organization which is ultimately expected to achieve regeneration of ligament tissues with native-like hierarchical structure and biomechanical properties. Consequently, this study introduces bi-directional structural parameters as design criteria for developing scaffolds for ligament tissue engineering.

Pharmacologic, Surgical, and Device-Based Cardiac Neuromodulation.

The cardiac autonomic nervous system plays a key role in maintaining normal cardiac physiology, and once disrupted, it worsens the cardiac disease states. Neuromodulation therapies have been emerging as new treatment options, and various techniques have been introduced to mitigate autonomic nervous imbalances to help cardiac patients with their disease conditions and symptoms. In this review article, we discuss various neuromodulation techniques used in clinical settings to treat cardiac diseases.

Engineering sulfated polysaccharides and silk fibroin based injectable IPN hydrogels with stiffening and growth factor presentation abilities for cartilage tissue engineering.

The extracellular matrix (ECM) presents a framework for various biological cues and regulates homeostasis during both developing and mature stages of tissues. During development of cartilage, the ECM plays a critical role in endowing both biophysical and biochemical cues to the progenitor cells. Hence, designing microenvironments that recapitulate these biological cues as provided by the ECM during development may facilitate the engineering of cartilage tissue. In the present study, we fabricated an injectable interpenetrating hydrogel (IPN) system which serves as an artificial ECM and provides chondro-inductive niches for the differentiation of stem cells to chondrocytes. The hydrogel was designed to replicate the gradual stiffening (as a biophysical cue) and the presentation of growth factors (as a biochemical cue) as provided by the natural ECM of the tissue, thus exemplifying a biomimetic approach. This dynamic stiffening was achieved by incorporating silk fibroin, while the growth factor presentation was accomplished using sulfated-carboxymethyl cellulose. Silk fibroin and sulfated-carboxymethyl cellulose (s-CMC) were combined with tyraminated-carboxymethyl cellulose (t-CMC) and crosslinked using HRP/H2O2 to fabricate s-CMC/t-CMC/silk IPN hydrogels. Initially, the fabricated hydrogel imparted a soft microenvironment to promote chondrogenic differentiation, and with time it gradually stiffened to offer mechanical support to the joint. Additionally, the presence of s-CMC conferred the hydrogel with the property of sequestering cationic growth factors such as TGF-ß and allowing their prolonged presentation to the cells. More importantly, TGF-ß loaded in the developed hydrogel system remained active and induced chondrogenic differentiation of stem cells, resulting in the deposition of cartilage ECM components which was comparable to the hydrogels that were treated with TGF-ß provided through media. Overall, the developed hydrogel system acts as a reservoir of the necessary biological cues for cartilage regeneration and simultaneously provides mechanical support for load-bearing tissues such as cartilage.

Functionally graded hydrogels with opposing biochemical cues for osteochondral tissue engineering.

Osteochondral tissue (OC) repair remains a significant challenge in the field of musculoskeletal tissue engineering. OC tissue displays a gradient structure characterized by variations in both cell types and extracellular matrix components, from cartilage to the subchondral bone. These functional gradients observed in the native tissue have been replicated to engineer OC tissuein vitro. While diverse fabrication methods have been employed to create these microenvironments, emulating the natural gradients and effective regeneration of the tissue continues to present a significant challenge. In this study, we present the design and development of CMC-silk interpenetrating (IPN) hydrogel with opposing dual biochemical gradients similar to native tissue with the aim to regenerate the complete OC unit. The gradients of biochemical cues were generated using an in-house-built extrusion system. Firstly, we fabricated a hydrogel that exhibits a smooth transition of sulfated carboxymethyl cellulose (sCMC) and TGF-ß1 (SCT gradient hydrogel) from the upper to the lower region of the IPN hydrogel to regenerate the cartilage layer. Secondly, a hydrogel with a hydroxyapatite (HAp) gradient (HAp gradient hydrogel) from the lower to the upper region was fabricated to facilitate the regeneration of the subchondral bone layer. Subsequently, we developed a dual biochemical gradient hydrogel with a smooth transition of sCMC + TGF-ß1 and HAp gradients in opposing directions, along with a blend of both biochemical cues in the middle. The results showed that the dual biochemical gradient hydrogels with biochemical cues corresponding to the three zones (i.e. cartilage, interface and bone) of the OC tissue led to differentiation of bone-marrow-derived mesenchymal stem cells to zone-specific lineages, thereby demonstrating their efficacy in directing the fate of progenitor cells. In summary, our study provided a simple and innovative method for incorporating gradients of biochemical cues into hydrogels. The gradients of biochemical cues spatially guided the differentiation of stem cells and facilitated tissue growth, which would eventually lead to the regeneration of the entire OC tissue with a smooth transition from cartilage (soft) to bone (hard) tissues. This promising approach is translatable and has the potential to generate numerous biochemical and biophysical gradients for regeneration of other interface tissues, such as tendon-to-muscle and ligament-to-bone.

Extra-Corporeal Membrane Oxygenation in Pregnancy.

Extracorporeal membrane oxygenation (ECMO) is a cardiac or pulmonary function support system that is used in cases of refractory organ failure in addition to conventional treatment. Currently, Level I evidence is not yet available, which reflects improved outcomes with ECMO in pregnant women, the use in pregnancy should be indicated in selected cases and only in specialized centers. We searched articles in the most important scientific databases from 2009 until 31 December 2023 consulting also the site ClinicalTrials.com to find out about studies that have been recently conducted or are currently ongoing. We matched the combination of the following keywords: "ECMO and pregnancy", "H1N1 and pregnancy", "COVID-19 and pregnancy", "ARDS and pregnancy", "ECMO and pregnancy AND (cardiac arrest)". We selected the following number of articles for each keyword combination: "ECMO and pregnancy" (665 articles); "ECMO and influenza H1N1" (384 articles); "pregnancy and influenza H1N1" (1006 articles); "pregnancy and ARDS" (2930 articles); "ECMO and pregnancy and ARDS and influenza H1N1" (24 articles); and "[ECMO and pregnancy AND (cardiac arrest)]" (74 articles). After careful inspection, only 43 papers fitted our scope. There are two types of ECMO: venous-venous (VV-ECMO) and venous-arterial (VA-ECMO). The first-one is necessary to cope with severe hypoxia: oxygen-depleted blood is taken from the venous circulation, oxygenated, and carbon dioxide removed from the extracorporeal circuit and returned to the same venous system. The VA-ECMO is a type of mechanical assistance to the circulatory system that allows to put the failing organ at rest by ensuring adequate oxygenation and systemic de-oxygenation, avoiding multi-organ failure. The main indications for ECMO support in pregnant women are cardiogenic shock, acute respiratory distress syndrome (ARDS), pulmonary embolism, and eclampsia. There are also fetal indications for ECMO, and they are fetal distress, hypoxic-ischemic encephalopathy (HIE), and twin-to-twin transfusion syndrome (TTTS). Until now, based on the outcomes of the numerous clinical studies conducted, ECMO has been shown to be a successful therapeutic strategy in cases where medical treatment has been unsuccessful. In well-selected pregnant patients, it appears to be safe and associated with a low risk of maternal and fetal complications. The aim of this review is to report the main properties of ECMO (VV and VA) and the indications for its use in pregnant women.

Improving Sensitivity and Longevity of In Vivo Glutamate Sensors with Electrodeposited NanoPt.

In vivo glutamate sensing has provided valuable insight into the physiology and pathology of the brain. Electrochemical glutamate biosensors, constructed by cross-linking glutamate oxidase onto an electrode and oxidizing H2O2 as a proxy for glutamate, are the gold standard for in vivo glutamate measurements for many applications. While glutamate sensors have been employed ubiquitously for acute measurements, there are almost no reports of long-term, chronic glutamate sensing in vivo, despite demonstrations of glutamate sensors lasting for weeks in vitro. To address this, we utilized a platinum electrode with nanometer-scale roughness (nanoPt) to improve the glutamate sensors' sensitivity and longevity. NanoPt improved the GLU sensitivity by 67.4% and the sensors were stable in vitro for 3 weeks. In vivo, nanoPt glutamate sensors had a measurable signal above a control electrode on the same array for 7 days. We demonstrate the utility of the nanoPt sensors by studying the effect of traumatic brain injury on glutamate in the rat striatum with a flexible electrode array and report measurements of glutamate taken during the injury itself. We also show the flexibility of the nanoPt platform to be applied to other oxidase enzyme-based biosensors by measuring γ-aminobutyric acid in the porcine spinal cord. NanoPt is a simple, effective way to build high sensitivity, robust biosensors harnessing enzymes to detect neurotransmitters in vivo.

A Novel Digital Health Platform With Health Coaches to Optimize Surgical Patients: Feasibility Study at a Large Academic Health System.

BACKGROUND: Pip is a novel digital health platform (DHP) that combines human health coaches (HCs) and technology with patient-facing content. This combination has not been studied in perioperative surgical optimization. OBJECTIVE: This study's aim was to test the feasibility of the Pip platform for deploying perioperative, digital, patient-facing optimization guidelines to elective surgical patients, assisted by an HC, at predefined intervals in the perioperative journey. METHODS: We conducted an institutional review board-approved, descriptive, prospective feasibility study of patients scheduled for elective surgery and invited to enroll in Pip from 2.5 to 4 weeks preoperatively through 4 weeks postoperatively at an academic medical center between November 22, 2022, and March 27, 2023. Descriptive primary end points were patient-reported outcomes, including patient satisfaction and engagement, and Pip HC evaluations. Secondary end points included mean or median length of stay (LOS), readmission at 7 and 30 days, and emergency department use within 30 days. Secondary end points were compared between patients who received Pip versus patients who did not receive Pip using stabilized inverse probability of treatment weighting. RESULTS: A total of 283 patients were invited, of whom 172 (60.8%) enrolled in Pip. Of these, 80.2% (138/172) patients had ≥1 HC session and proceeded to surgery, and 70.3% (97/138) of the enrolled patients engaged with Pip postoperatively. The mean engagement began 27 days before surgery. Pip demonstrated an 82% weekly engagement rate with HCs. Patients attended an average of 6.7 HC sessions. Of those patients that completed surveys (95/138, 68.8%), high satisfaction scores were recorded (mean 4.8/5; n=95). Patients strongly agreed that HCs helped them throughout the perioperative process (mean 4.97/5; n=33). The average net promoter score was 9.7 out of 10. A total of 268 patients in the non-Pip group and 128 patients in the Pip group had appropriate overlapping distributions of stabilized inverse probability of treatment weighting for the analytic sample. The Pip cohort was associated with LOS reduction when compared to the non-Pip cohort (mean 2.4 vs 3.1 days; median 1.9, IQR 1.0-3.1 vs median 3.0, IQR 1.1-3.9 days; mean ratio 0.76; 95% CI 0.62-0.93; P=.009). The Pip cohort experienced a 49% lower risk of 7-day readmission (relative risk [RR] 0.51, 95% CI 0.11-2.31; P=.38) and a 17% lower risk of 30-day readmission (RR 0.83, 95% CI 0.30-2.31; P=.73), though these did not reach statistical significance. Both cohorts had similar 30-day emergency department returns (RR 1.06, 95% CI 0.56-2.01, P=.85). CONCLUSIONS: Pip is a novel mobile DHP combining human HCs and perioperative optimization content that is feasible to engage patients in their perioperative journey and is associated with reduced hospital LOS. Further studies assessing the impact on clinical and patient-reported outcomes from the use of Pip or similar DHPs HC combinations during the perioperative journey are required.

Bakuchiol nanoemulsion loaded electrospun nanofibers for the treatment of burn wounds.

The present work aims to develop and evaluate the wound healing potential of bakuchiol nanoemulsion loaded electrospun scaffolds. Since oxidative stress and microbial burden leads the burn wounds to become chronic and fatal to patients, a phytoconstituent, bakuchiol (BAK), was screened on the basis of antioxidant and antimicrobial potential which also defined its dose. Furthermore, BAK was incorporated into a nanoemulsion to enhance its therapeutic efficacy, reduce its dosage frequency, and maximize its stability. The present study is inclined towards the collaborative interaction of natural products and novel drug delivery systems to develop safe and therapeutically efficient systems for burn wound healing. The optimized nanoemulsion showed excellent antioxidant and antimicrobial potential against wound susceptible pathogens, i.e., Candida albicans and Methicillin-resistant Staphylococcus aureus which was further loaded into gelatin based hydrogel and nanofibrous scaffold system. The mesh structure of scaffolds was chosen as a suitable carrier system for wound healing process not only because it offers resemblance to skin's anatomy but is also capable of providing uniform distribution of wound biomarkers across the skin. The prepared nanofibers were assessed for their analgesic, anti-inflammatory, and wound healing potential which was observed to be significantly better than its gel formulation.

Ventricular arrhythmia inducibility in porcine infarct model after stereotactic body radiation therapy.

BACKGROUND: Ventricular arrhythmia (VA) is the primary mechanism of sudden death in patients with structural heart disease. Cardiac stereotactic body radiation therapy (SBRT) delivered to the scar in the left ventricle significantly reduces the burden of VA. OBJECTIVE: The goal of this study was to investigate the impact of SBRT on scar morphology and VA inducibility in a porcine infarct model. METHODS: Myocardial infarction (MI) was created in 10 Yorkshire pigs involving the left anterior descending artery territory. Cardiac positron emission tomography and computed tomography were performed for targeted SBRT. Alternative pigs received SBRT at 25 Gy in a single fraction. The terminal experiment included endocardial mapping, programmed ventricular stimulation, and tissue harvesting. RESULTS: Of the 10 pigs infarcted, 2 died prematurely after MI and 8 (4 MI and 4 MI+SBRT) survived. Mean time from MI to SBRT was 48 ± 12 days, and mean time from SBRT to harvest was 32 ± 12 days. Scar was localized on intracardiac mapping in all pigs, and the scar was denser in the MI+SBRT compared with the MI-only group (33% ± 20% vs 14% ± 11%; P = .07). All 4 MI pigs had inducible VA during programmed stimulation, whereas only 1 of 4 pigs had inducible VA in the MI+SBRT arm (100% vs 25%; P = .07). No myocardial fibrosis was seen in the remote areas in either group. CONCLUSION: SBRT reduced VA inducibility in pigs with scarring after MI. Endocardial mapping revealed denser scar in pigs receiving SBRT compared with those that did not, suggesting that SBRT suppresses VA inducibility through better scar homogenization.

A Global Health Survey of People Who Vape but Never Smoked: Protocol for the VERITAS (Vaping Effects: Real-World International Surveillance) Study.

BACKGROUND: There is only limited information about the health effects of regular vaping. Research on the health status of people who used to smoke faces the challenge that previous smoking may have caused unknown health effects. Only studies of people who vape but have never smoked combustible cigarettes can enable the detection of harms attributable to vaping. Large prospective studies of well-characterized electronic cigarette users with and without a history of combustible cigarette smoking are warranted to establish the long-term effects of regular vaping on respiratory health. OBJECTIVE: We will conduct a global cross-sectional survey of individuals from 6 world regions. Respiratory symptoms will be assessed using a validated questionnaire-the Respiratory Symptom Experience Scale (RSES). Current vapers who are nonusers of other tobacco or nicotine products will be compared with matched controls who are nonusers of vapes and other tobacco or nicotine products. METHODS: This will be a multicountry, cross-sectional internet-based survey of 750 adults aged ≥18 years who satisfy the criteria for inclusion in either a cohort of people who exclusively vape and who are nonusers of other tobacco or nicotine products ("vapers cohort"; target N=500) or a cohort of nonvapers who are also nonusers of other tobacco or nicotine products ("controls cohort"; target N=250). The primary end point of the study is the RSES score. RSES scores of people in the "vapers cohort" will be compared with those of people in the "controls cohort." Additionally, the study will collect data to characterize patterns of vaping product use among the vapers cohort. Data collection will include information about the age initiation of using vape products, reasons for starting and continuing the use of vape products, specific types of products used, flavors and nicotine strengths of recently used products, as well as the frequency and intensity of product use in the past 30 days. RESULTS: Participant recruitment started in April 2023, and enrollment was completed by November 2023 with 748 participants. Results will be reported in 2024. CONCLUSIONS: This will be the first study providing key insights into respiratory health effects associated with using electronic cigarettes in people who vape with no established use of combustible cigarettes or other tobacco or nicotine products. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54236.

REMAP Periop: a randomised, embedded, multifactorial adaptive platform trial protocol for perioperative medicine to determine the optimal enhanced recovery pathway components in complex abdominal surgery patients within a US healthcare system.

INTRODUCTION: Implementation of enhanced recovery pathways (ERPs) has resulted in improved patient-centred outcomes and decreased costs. However, there is a lack of high-level evidence for many ERP elements. We have designed a randomised, embedded, multifactorial, adaptive platform perioperative medicine (REMAP Periop) trial to evaluate the effectiveness of several perioperative therapies for patients undergoing complex abdominal surgery as part of an ERP. This trial will begin with two domains: postoperative nausea/vomiting (PONV) prophylaxis and regional/neuraxial analgesia. Patients enrolled in the trial will be randomised to arms within both domains, with the possibility of adding additional domains in the future. METHODS AND ANALYSIS: In the PONV domain, patients are randomised to optimal versus supraoptimal prophylactic regimens. In the regional/neuraxial domain, patients are randomised to one of five different single-injection techniques/combination of techniques. The primary study endpoint is hospital-free days at 30 days, with additional domain-specific secondary endpoints of PONV incidence and postoperative opioid consumption. The efficacy of an intervention arm within a given domain will be evaluated at regular interim analyses using Bayesian statistical analysis. At the beginning of the trial, participants will have an equal probability of being allocated to any given intervention within a domain (ie, simple 1:1 randomisation), with response adaptive randomisation guiding changes to allocation ratios after interim analyses when applicable based on prespecified statistical triggers. Triggers met at interim analysis may also result in intervention dropping. ETHICS AND DISSEMINATION: The core protocol and domain-specific appendices were approved by the University of Pittsburgh Institutional Review Board. A waiver of informed consent was obtained for this trial. Trial results will be announced to the public and healthcare providers once prespecified statistical triggers of interest are reached as described in the core protocol, and the most favourable interventions will then be implemented as a standardised institutional protocol. TRIAL REGISTRATION NUMBER: NCT04606264.