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BACKGROUND: Complications of immobilization after quadriceps and patellar tendon repairs include decreased patellar mobility, limited flexion, persistent pain, muscle weakness, and patella baja. In contrast, early motion limits muscle atrophy, accelerates tendon healing, and prevents joint stiffness. HYPOTHESIS: Quadriceps and patellar tendon repairs protected with a 'relaxing suture' are strong enough to safely permit early motion, full weightbearing, and brace-free ambulation. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty quadriceps and 30 patellar tendon ruptures were treated with a primary repair augmented with a single No. 5 Ethibond suture, a postoperative regimen of controlled motion and full weightbearing at 7 to 10 days, and brace-free ambulation at 6 weeks after surgery. At a minimum follow-up of 12 months, results of surgery were assessed with the Lysholm knee rating system. RESULTS: Six weeks after surgery, 120 degrees of flexion and brace-free ambulation were the goals and were achieved at a mean of 7.2 and 7.7 weeks, respectively. By 6 months, all patients reached their preinjury levels of activity (eg, basketball, softball, Rocky Mountain tour guide), 40 had full active extension, and 10 lacked 3 degrees to 10 degrees of active extension. There were no postoperative complications. At a mean follow-up of 4 years (range, 1-12 years), the Lysholm scores averaged 92 points (range, 84-100 points), and there were 35 excellent, 15 good, and no fair or poor results. CONCLUSION: Quadriceps and patellar tendon repairs protected by a relaxing suture were strong enough to safely permit early motion, weightbearing, and brace-free ambulation while producing good and excellent results. [ABSTRACT FROM AUTHOR]

Objective: Reoperative surgery for isolated tricuspid valve (TV) pathology has been associated with high morbidity and mortality rates; however, the current guidelines recommend intervention for severe, symptomatic TV regurgitation or mild to moderate symptoms with progressive right ventricular dysfunction. There are minimal data regarding reoperative intervention for TV disease. Similarly, there are no large series describing robot-assisted reoperative TV surgery., Methods: Institutional Society of Thoracic Surgeons Adult Cardiac Surgery Database data were used to identify patients with previous cardiac surgery undergoing robot-assisted TV surgery from 2017 to 2022 from 2 tertiary referral hospitals. Patient demographics, preoperative characteristics, disease progression, operative details, and outcomes were analyzed. The primary outcome was 30-day mortality. Secondary outcomes were 30-day readmission, length of stay, and adverse events. Descriptive and summative statistics were used to describe clinical data and examine differences in outcomes of patients with primary versus secondary etiology using bivariate analyses., Results: Twenty-four patients were divided into 2 arms, primary TV pathology and secondary dysfunction due to comorbid cardiac conditions. The overall mortality was 8.3%. Major complications, including respiratory failure, renal failure, and reoperation were 12.5%, 8.3%, and 8.3%, respectively. No permanent pacemakers were required, and the 30-day readmission rate was 4.5%., Conclusions: Reoperative robotic TV surgery is a safe and viable alternative to traditional sternotomy for both primary and secondary TV pathology. TV repair and replacement are possible using the minimally invasive technique. The morbidity and mortality rates are acceptable when compared with traditional approaches with decreased need for pacemaker placement in the minimally invasive approach., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Diabetes care within prison walls offers challenges and opportunities for both health care providers and individuals living with diabetes. To meet the challenges, providers and patients work together to manage diabetes within the limitations imposed by imprisonment. Upon release, patients face new challenges, as they transition from incarceration into the community., Competing Interests: No potential conflicts of interest relevant to this article were reported., (© 2024 by the American Diabetes Association.)

Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist and its analogues (fentalogues) are increasingly found in illicit drug samples, both where the primary drug of abuse is an opioid and where it is not. The prevalence of fentalogues in the illicit drug market is thought to be the primary driver of the increased number of opioid-related overdose deaths since 2016. In fact, fentanyl and its analogues are involved in more than 70% of opioid-related overdoses. The standard opioid overdose rescue therapy naloxone is often insufficient to reverse opioid overdoses caused by fentalogue agonists under current treatment paradigms. However, the pharmacology of many fentalogues is unknown. Moreover, within the fentalogue series of compounds, it is possible that antagonists could be identified that might be superior to naloxone as opioid overdose reversal agents. In this report, we explore the pharmacology of 70 fentalogues and identify compounds that behave as MOR antagonists in vitro and demonstrate with one of these reversals of fentanyl-induced respiratory depression in the mouse. Such compounds could provide leads for the development of effective agents for the reversal of opioid overdose.

The ability of cells to sense and respond to mechanical forces is critical in many physiological and pathological processes. However, determining the mechanisms by which forces affect protein function inside cells remains challenging. Motivated by in vitro demonstrations of fluorescent proteins (FPs) undergoing reversible mechanical switching of fluorescence, we investigated whether force-sensitive changes in FP function could be visualized in cells. Guided by a computational model of FP mechanical switching, we develop a formalism for its detection in Förster resonance energy transfer (FRET)-based biosensors and demonstrate its occurrence in cellulo within a synthetic actin crosslinker and the mechanical linker protein vinculin. We find that in cellulo mechanical switching is reversible and altered by manipulation of cell force generation, external stiffness, and force-sensitive bond dynamics of the biosensor. This work describes a framework for assessing FP mechanical stability and provides a means of probing force-sensitive protein function inside cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer-associated fibroblasts (CAF) are a prominent cell type within the tumor microenvironment (TME) where they are known to promote cancer cell growth and survival, angiogenesis, drug resistance, and immunosuppression. The transmembrane prolyl protease fibroblast activation protein (FAP) is expressed on the surface of highly protumorigenic CAFs found in the stroma of nearly every cancer of epithelial origin. The widespread expression of FAP has made it an attractive therapeutic target based on the underlying hypothesis that eliminating protumorigenic CAFs will disrupt the cross-talk between components of TME resulting in cancer cell death and immune infiltration. This hypothesis, however, has never been directly proven. To eliminate FAP-expressing CAFs, we developed an antibody-drug conjugate using our anti-FAP antibody, huB12, coupled to a monomethyl auristatin E (huB12-MMAE) payload. After determining that huB12 was an effective targeting vector, we found that huB12-MMAE potently eliminated FAP-expressing cells as monocultures in vitro and significantly prolonged survival in vivo using a xenograft engineered to overexpress FAP. We investigated the effects of selectively eliminating CAFs using a layered, open microfluidic cell coculture platform, known as the Stacks. Analysis of mRNA and protein expression found that treatment with huB12-MMAE resulted in the increased secretion of the proinflammatory cytokines IL6 and IL8 by CAFs and an associated increase in expression of proinflammatory genes in cancer cells. We also detected increased secretion of CSF1, a cytokine involved in myeloid recruitment and differentiation. Our findings suggest that the mechanism of FAP-targeted therapies is through effects on the immune microenvironment and antitumor immune response., Significance: The direct elimination of FAP-expressing CAFs disrupts the cross-talk with cancer cells leading to a proinflammatory response and alterations in the immune microenvironment and antitumor immune response., (© 2024 The Authors; Published by the American Association for Cancer Research.)

The Mesenchymal Epithelial Transition (MET) receptor tyrosine kinase is upregulated or mutated in 5% of non-small-cell lung cancer (NSCLC) patients and overexpressed in multiple other cancers. We sought to develop a novel single-domain camelid antibody with high affinity for MET that could be used to deliver conjugated payloads to MET expressing cancers. From a naïve camelid variable-heavy-heavy (VHH) domain phage display library, we identified a VHH clone termed 1E7 that displayed high affinity for human MET and was cross-reactive with MET across multiple species. When expressed as a bivalent human Fc fusion protein, 1E7-Fc was found to selectively bind to EBC-1 (MET amplified) and UW-Lung 21 (MET exon 14 mutated) cell lines by flow cytometry and immunofluorescence imaging. Next, we investigated the ability of [ 89 Zr]Zr-1E7-Fc to detect MET expression in vivo by PET/CT imaging. [ 89 Zr]Zr-1E7-Fc demonstrated rapid localization and high tumor uptake in both xenografts with a %ID/g of 6.4 and 5.8 for EBC-1 and UW-Lung 21 at 24 h, respectively. At the 24 h time point, clearance from secondary and nontarget tissues was also observed. Altogether, our data suggest that 1E7-Fc represents a platform technology that can be employed to potentially both image and treat MET-altered NSCLC.

Purpose: Scaffold materials that better support neurogenesis are still needed to improve cell therapy outcomes for neural tissue damage. We have used a modularly tunable, highly compliant, degradable hydrogel to explore the impacts of hydrogel compliance stiffness on neural differentiation. Here we implemented competitive matrix crosslinking mechanics to finely tune synthetic hydrogel moduli within soft tissue stiffnesses, a range much softer than typically achievable in synthetic crosslinked hydrogels, providing a modularly controlled and ultrasoft 3D culture model which supports and enhances neurogenic cell behavior., Methods: Soluble competitive allyl monomers were mixed with proteolytically-degradable poly(ethylene glycol) diacrylate derivatives and crosslinked to form a matrix, and resultant hydrogel stiffness and diffusive properties were evaluated. Neural PC12 cells or primary rat fetal neural stem cells (NSCs) were encapsulated within the hydrogels, and cell morphology and phenotype were investigated to understand cell-matrix interactions and the effects of environmental stiffness on neural cell behavior within this model., Results: Addition of allyl monomers caused a concentration-dependent decrease in hydrogel compressive modulus from 4.40 kPa to 0.26 kPa (natural neural tissue stiffness) without influencing soluble protein diffusion kinetics through the gel matrix. PC12 cells encapsulated in the softest hydrogels showed significantly enhanced neurite extension in comparison to PC12s in all other hydrogel stiffnesses tested. Encapsulated neural stem cells demonstrated significantly greater spreading and elongation in 0.26 kPa alloc hydrogels than in 4.4 kPa hydrogels. When soluble growth factor deprivation (for promotion of neural differentiation) was evaluated within the neural stiffness gels (0.26 kPa), NSCs showed increased neuronal marker expression, indicating early enhancement of neurogenic differentiation., Conclusions: Implementing allyl-acrylate crosslinking competition reduced synthetic hydrogel stiffness to provide a supportive environment for 3D neural tissue culture, resulting in enhanced neurogenic behavior of encapsulated cells. These results indicate the potential suitability of this ultrasoft hydrogel system as a model platform for further investigating environmental factors on neural cell behavior., Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00794-2., Competing Interests: Conflict of interestThe authors state no conflicts of interest or competing interests for this work., (© The Author(s), under exclusive licence to Biomedical Engineering Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: This study sought to investigate the relationship between antibiotic exposure and subsequent risk of psychiatric disorders. Methods: This retrospective cohort study used a national database of 69 million patients from 54 large healthcare organizations. We identified a cohort of 20,214 (42.5% male; 57.9 ± 15.1 years old [mean ± SD]) adults without prior neuropsychiatric diagnoses who received antibiotics during hospitalization. Matched controls included 41,555 (39.6% male; 57.3 ± 15.5 years old) hospitalized adults without antibiotic exposure. The two cohorts were balanced for potential confounders, including demographics and variables with potential to affect: the microbiome, mental health, medical comorbidity, and overall health status. Data were stratified by age and by sex, and outcome measures were assessed starting 6 months after hospital discharge. Results: Antibiotic exposure was consistently associated with a significant decrease in the risk of novel mood disorders and anxiety and stressor-related disorders in: men (mood (OR 0.84, 95% CI 0.77, 0.91), anxiety (OR 0.88, 95% CI 0.82, 0.95), women (mood (OR 0.94, 95% CI 0.89,1.00), anxiety (OR 0.93, 95% CI 0.88, 0.98), those who are 26-49 years old (mood (OR 0.87, 95% CI 0.80, 0.94), anxiety (OR 0.90, 95% CI 0.84, 0.97)), and in those ≥50 years old (mood (OR 0.91, 95% CI 0.86, 0.97), anxiety (OR 0.92, 95% CI 0.87, 0.97). Risk of intentional harm and suicidality was decreased in men (OR 0.73, 95% CI 0.55, 0.98) and in those ≥50 years old (OR 0.67, 95% CI 0.49, 0.92). Risk of psychotic disorders was also decreased in subjects ≥50 years old (OR 0.83, 95 CI: 0.69, 0.99). Conclusion: Use of antibiotics in the inpatient setting is associated with protective effects against multiple psychiatric outcomes in an age- and sex-dependent manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kerman, Glover, Lin, West, Hanlon, Kablinger and Clinton.)

Objective: Using continuous glucose monitoring (CGM) improves diabetes-related outcomes in the community, yet the fingerstick blood glucose monitoring (BGM) method is the norm in prisons. The purpose of this study was to investigate the safety and patient perceptions of CGM in the carceral environment, quantify changes in A1C after initiating CGM, and investigate rates of emergency department (ED) visits for diabetes-related complications comparing CGM users to patients using BGM., Study Design: This pragmatic longitudinal analysis was conducted in two parts. A pilot program was carried out at a single women's prison. A CGM program was initiated at men's facilities within a single U.S. state, where A1C change and ED visit rates were investigated., Methods: Interested patients at an appropriate security level were invited to use CGM. Pre- and post-CGM surveys of glucose monitoring perceptions were administered during the pilot program. Security and perceptions were analyzed descriptively. A1C change was assessed using a t test. Fisher exact test, Barnard exact test, and post hoc power analysis were applied to ED visits., Results: Security was not disrupted. Patient perceptions of glucose monitoring improved with CGM use ( n = 6). A1C declined by 0.60% with a medium effect size (Cohen d -0.45, n = 42). Power to detect a difference in ED visits was low; however, no CGM patients had an ED visit ( n = 758)., Conclusion: It is safe and efficacious to replace BGM with CGM in prisons when patients are engaged in their care and are at a security level allowing CGM devices in their cells., Competing Interests: No potential conflicts of interest relevant to this article were reported., (© 2024 by the American Diabetes Association.)

Cancer therapies targeting metabolic derangements unique to cancer cells are emerging as a key strategy to address refractory solid tumors such as pancreatic ductal adenocarcinomas (PDAC) that exhibit resistance to extreme nutrient deprivation in the tumor microenvironment. Nicotinamide adenine dinucleotide (NAD) participates in multiple metabolic pathways and nicotinamide phosphoribosyl transferase (NAMPT) is one of the key intracellular enzymes that facilitate the synthesis of NAD. C-terminal binding proteins 1 and 2 (CtBP) are paralogous NAD-dependent oncogenic transcription factors and dehydrogenases that nucleate an epigenetic complex regulating a cohort of genes responsible for cancer proliferation and metastasis. As adequate intracellular NAD is required for CtBP to oligomerize and execute its oncogenic transcriptional coregulatory activities, we hypothesized that NAD depletion would synergize with CtBP inhibition, improving cell inhibitory efficacy. Indeed, depletion of cellular NAD via the NAMPT inhibitor GMX1778 enhanced growth inhibition induced by either RNAi-mediated CtBP1/2 knockdown or the CtBP dehydrogenase inhibitor 4-chlorophenyl-2-hydroxyimino propanoic acid as much as 10-fold in PDAC cells, while untransformed pancreatic ductal cells were unaffected. The growth inhibitory effects of the NAMPT/CtBP inhibitor combination correlated pharmacodynamically with on-target disruption of CtBP1/2 dimerization, CtBP2 interaction with the CoREST epigenetic regulator, and transcriptional activation of the oncogenic target gene TIAM1. Moreover, this same therapeutic combination strongly attenuated growth of PDAC cell line xenografts in immunodeficient mice, with no observable toxicity. Collectively, our data demonstrate that targeting CtBP in combination with NAD depletion represents a promising therapeutic strategy for PDAC., Significance: Effective precision therapies are lacking in PDAC. We demonstrate that simultaneous inhibition of NAD metabolism and the oncoprotein CtBP is potently effective at blocking growth of both PDAC cells in culture and human PDAC-derived tumors in mice and should be explored further as a potential therapy for patients with PDAC., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Major depressive disorder is a highly common disorder, with a lifetime prevalence in the United States of approximately 21%. Traditional antidepressant treatments are limited by a delayed onset of action and minimal efficacy in some patients. Ketamine is effective and fast-acting, but there are concerns over its abuse liability. Thus, there is a need for safe, fast-acting antidepressant drugs. The opioid buprenorphine shows promise but also has abuse liability due to its mu-agonist component. Preclinical evidence indicates that the delta-opioid system contributes to mood disorders, and delta-opioid agonists are effective in preclinical models of depression- and anxiety-like states. In this study, we test the hypothesis that the mu-opioid antagonist diprenorphine by virtue of its partial delta opioid agonist activity may offer a beneficial profile for an antidepressant medication without abuse liability. Diprenorphine was confirmed to bind with high affinity to all three opioid receptors, and functional experiments for G protein activation verified diprenorphine to be a partial agonist at delta- and kappa-opioid receptors and a mu-antagonist. Studies in C57BL/6 mice demonstrated that an acute dose of diprenorphine produced antidepressant-like effects in the tail suspension test and the novelty-induced hypophagia test that were inhibited in the presence of the delta-selective antagonist, naltrindole. Diprenorphine did not produce convulsions, a side effect of many delta agonists but rather inhibited convulsions caused by the full delta agonist SNC80; however, diprenorphine did potentiate pentylenetetrazole-induced convulsions. Diprenorphine, and compounds with a similar pharmacological profile, may provide efficient and safe rapidly acting antidepressants. SIGNIFICANCE STATEMENT: The management of major depressive disorder, particularly treatment-resistant depression, is a significant unmet medical need. Here we show that the opioid diprenorphine, a compound with mu-opioid receptor antagonist activity and delta- and kappa-opioid receptor partial agonist activities, has rapid onset antidepressant-like activity in animal models. Diprenorphine and compounds with a similar pharmacological profile to diprenorphine should be explored as novel antidepressant drugs., (U.S. Government work not protected by U.S. copyright.)

The adrenomedullary chromaffin cell transduces chemical messages into outputs that regulate end organ function throughout the periphery. At least two important neurotransmitters are released by innervating preganglionic neurons to stimulate exocytosis in the chromaffin cell-acetylcholine (ACh) and pituitary adenylate cyclase activating polypeptide (PACAP). Although PACAP is widely acknowledged as an important secretagogue in this system, the pathway coupling PACAP stimulation to chromaffin cell secretion is poorly understood. The goal of this study is to address this knowledge gap. Here, it is shown that PACAP activates a Gαs-coupled pathway that must signal through phospholipase C ε (PLCε) to drive Ca2+ entry and exocytosis. PACAP stimulation causes a complex pattern of Ca2+ signals in chromaffin cells, leading to a sustained secretory response that is kinetically distinct from the form stimulated by ACh. Exocytosis caused by PACAP is associated with slower release of peptide cargo than exocytosis stimulated by ACh. Importantly, only the secretory response to PACAP, not ACh, is eliminated in cells lacking PLCε expression. The data show that ACh and PACAP, acting through distinct signaling pathways, enable nuanced and variable secretory outputs from chromaffin cells., (© 2022 Morales et al.)

The evolution of behavioral and ecological specialization can have marked effects on the tempo and mode of phenotypic evolution. Head-first burrowing has been shown to exert powerful selective pressures on the head and body shapes of many vertebrate and invertebrate taxa. In wrasses, burrowing behaviors have evolved multiple times independently, and are commonly used in foraging and predator avoidance behaviors. While recent studies have examined the kinematics and body shape morphology associated with this behavior, no study to-date has examined the macroevolutionary implications of burrowing on patterns of phenotypic diversification in this clade. Here, we use three-dimensional geometric morphometrics and phylogenetic comparative methods to study the evolution of skull shape in fossorial wrasses and their relatives. We test for skull shape differences between burrowing and non burrowing wrasses and evaluate hypotheses of shape convergence among the burrowing wrasses. We also quantify rates of skull shape evolution between burrowing and non burrowing wrasses to test for whether burrowing constrains or accelerates rates of skull shape evolution in this clade. We find that while burrowing and non burrowing wrasses exhibit similar degrees of morphological disparity, for burrowing wrasses, it took nearly twice as long to amass this disparity. Furthermore, while the disparities between groups are evenly matched, we find that most burrowing species are confined to a particular region of shape space with most species exhibiting narrower heads than many non-burrowing species. These results suggest head-first burrowing constrains patterns of skull shape diversification in wrasses by potentially restricting the range of phenotypes that can perform this behavior., (© 2022 Wiley Periodicals LLC.)

Increased extracellular matrix (ECM) density in the tumor microenvironment has been shown to influence aspects of tumor progression such as proliferation and invasion. Increased matrix density means cells experience not only increased mechanical properties, but also a higher density of bioactive sites. Traditional in vitro ECM models like Matrigel and collagen do not allow these properties to be investigated independently. In this work, a poly(ethylene glycol)-based scaffold is used which modifies with integrin-binding sites for cell attachment and matrix metalloproteinase 2 and 9 sensitive sites for enzyme-mediated degradation. The polymer backbone density and binding site concentration are independently tuned and the effect each of these properties and their interaction have on the proliferation, invasion, and focal complex formation of two different tumor cell lines is evaluated. It is seen that the cell line of epithelial origin (Hs 578T, triple negative breast cancer) proliferates more, invades less, and forms more mature focal complexes in response to an increase in matrix adhesion sites. Conversely, the cell line of mesenchymal origin (HT1080, fibrosarcoma) proliferates more in 2D culture but less in 3D culture, invades less, and forms more mature focal complexes in response to an increase in matrix stiffness., (© 2022 The Authors. Advanced Biology published by Wiley-VCH GmbH.)

Background: The role of extracorporeal membrane oxygenation (ECMO) for patients with refractory respiratory failure due to coronavirus 2019 (COVID-19) is still unclear even now over a year into the pandemic. ECMO is becoming more commonplace even at smaller community hospitals. While the advantages of venovenous (VV) ECMO in acute respiratory distress syndrome (ARDS) from COVID-19 have not been fully determined, we believe the benefits outweighed the risks in our patient population. Here we describe all patients who underwent VV ECMO at our center., Methods: All patients placed on ECMO at our center since the beginning of the pandemic, May 5, 2020, until February 20, 2021 were included in our study. All patients placed on ECMO during the time period described above were followed until discharge or death. The primary endpoint was in-hospital death. Secondary outcomes included discharge disposition, that is, whether patients were sent to a long-term acute care center (LTAC), inpatient rehabilitation, or went directly home., Results: A total of 41 patients were placed on VV ECMO for refractory acute respiratory failure. Survival to discharge, the primary end point, was 63.4% (26/41). Inpatient mortality was 36.6% (15/41)., Conclusions: We show here that a successful high-volume VV ECMO program for ARDS is achievable at even a medium-size community hospital. We think our success can be replicated by most small- and medium-size community hospitals with cardiothoracic surgery programs and intensivist teams., (© 2022 Wiley Periodicals LLC.)

The tumor microenvironment (TME) plays a determining role in everything from disease progression to drug resistance. As such, in vitro models which can recapitulate the cell-cell and cell-matrix interactions that occur in situ are key to the investigation of tumor behavior and selecting effective therapeutic drugs. While naturally derived matrices can retain the dimensionality of the native TME, they lack tunability and batch-to-batch consistency. As such, many synthetic polymer systems have been employed to create physiologically relevant TME cultures. In this review, we discussed the common semi-synthetic and synthetic polymers used as hydrogel matrices for tumor models. We reviewed studies in synthetic hydrogels which investigated tumor cell interactions with vasculature and immune cells. Finally, we reviewed the utility of these models as chemotherapeutic drug-screening platforms, as well as the future directions of the field.

Background: Spinal anesthesia (SA) is routinely used in obstetrics and orthopedic surgery but has not been widely adopted in lumbar spine surgery (LSS). One perceived barrier is the learning curve for the neurosurgical and anesthesia team associated with managing a patient in the prone position under SA., Methods: A retrospective cohort of 34 LSS cases under SA at our institution was examined. Operative time, corrected operative time per level, and complications were analyzed. The learning curve was assessed using a curve-fit regression analysis., Results: Of patients, 62% were female, with mean (SD) age and body mass index of 60.7 (10.8) years and 29.9 (4.6) kg/m 2 , respectively. The mean (SD) for each time segment was operating room arrival to incision 35.7 (8.1) minutes, total surgical time 100.4 (35.8) minutes, and procedure finish to operating room exit 3.4 (2.5) minutes. When the times were normalized to procedure type and analyzed sequentially, the mean (SD) slope of all trendlines was 0.003 (0.005) with correlation coefficients of R 2  = 0.0002-0.01, indicating no appreciable learning curve. Normalized postanesthesia care unit time was significantly shorter for overnight stay versus same-day discharge (0.64 vs. 1.36, P = 0.0005)., Conclusions: Our data demonstrate the lack of a learning curve when SA is implemented in LSS cases by an anesthetic team already familiar with SA techniques for other procedures. Importantly, the surgical team was already familiar with the minimally invasive surgery approaches used in conjunction with SA. This study highlights that the barriers to transitioning to SA for LSS may be fewer than perceived., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sequential biochemical signaling events direct key native tissue processes including disease progression, wound healing and angiogenesis, and tissue regeneration. While in vitro modeling of these processes is critical to understanding endogenous tissue behavior and improving therapeutic outcomes, current models inadequately recapitulate the dynamism of these signaling events. Even the most advanced current synthetic tissue culture constructs are restricted in their capability to sequentially add and remove the same molecule to model transient signaling. Here, we developed a genetically encoded method for reversible biochemical signaling within poly(ethylene glycol) (PEG)-based hydrogels for greater accuracy of modeling tissue regeneration within a reductionist environment. We designed and implemented a recombinant protein with a SpyCatcher domain connected to a cell-adhesive RGDS peptide domain by a light-cleavable domain known as PhoCl. This protein was shown to bind to SpyTag-functionalized PEG-matrices via SpyTag-SpyCatcher isopeptide bonding to present RGDS adhesive ligands to cells. Upon 405 nm light exposure, the PhoCl domain was cleaved to subsequently release the RGDS peptide, which diffused out of the matrix. This system was implemented to confer reversible adhesion of 3T3 fibroblasts to the PEG-based hydrogel surface in 2D culture (73.36 ± 21.47% cell removal upon cell-compatible light exposure) and temporal control over cell spreading over time in 3D culture within cell-degradable PEG-based hydrogels, demonstrating the capability of this system to present dynamic signaling events to cells toward modeling native tissue processes within in a controlled, ECM-mimetic matrix.

Objectives: This article represents a call to action for the mindfulness field to be more diverse and inclusive of Latinx individuals. Building a diverse and inclusive science around mindfulness-based approaches (MBAs) that considers important group-level cultural and contextual information is an important public health challenge in need of innovative solutions., Methods: We describe ways that the Latinx population is poised to benefit from MBAs. We further elucidate challenges, describe potential solutions, and outline a research agenda that may hold promise for building a more inclusive mindfulness movement., Results: Our recommendations center around developing nuanced cultural adaptations to MBAs, engaging Latinx individuals in research, increasing the rigor of scientific studies pertaining to Latinx individuals, relying on implementation science to develop innovative methods for disseminating MBAs to Latinx individuals, developing training and certification mechanisms to increase diversity and representation of Latinx mindfulness teachers, and creating mechanisms for the oversight of MBAs within this group., Conclusions: There has been a lack of inclusivity of Latinx individuals in the field of MBAs with regards to research studies, barriers to access for economically disadvantaged groups, and lack of diversity in its workforce. Considering the recognition of adverse social drivers of health that generate chronic stress and health disparities, the Latinx population is especially poised to benefit greatly from MBAs. A diverse and inclusive mindfulness science holds promise to enhance the effectiveness, acceptability, feasibility, and wide-scale dissemination and implementation of MBAs., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)

Background: Incidental durotomy is a known complication of spinal surgery. Persistent cerebrospinal fluid (CSF) leak after unrecognized durotomy may lead to prolonged hospitalization and significant morbidity. If initial bed rest fails, the surgeon must choose between nontargeted methods such as oversewing the wound and lumbar drain placement or return to the operating room., Objective: To report the novel use of color flow doppler (CFD) in conjunction with ultrasound (US) to localize the point of CSF leak, assist with aspiration of the pseudomeningocele, and direct the application of fibrin sealant or epidural blood patch., Methods: This article includes a description of the technique as a technical note., Results: A 72-year-old man underwent L2-5 laminectomies for spinal stenosis. During the index operation, a durotomy occurred and was repaired primarily. The patient subsequently developed leg weakness, back pain, and bulging of the incision. Using CFD, the site of durotomy was determined. Under direct visualization, 34 mL of CSF was aspirated from the pseudomeningocele and 20 mL of fibrin sealant was placed opposing the durotomy. At 2-month follow-up, CFD confirmed absent flow and MRI demonstrated pseudomeningocele resolution., Conclusion: This article represents the first report highlighting the utility of CFD US to guide epidural patch placement for postsurgical CSF leaks. CFD allows localization of the durotomy and direct application of blood or fibrin sealant, potentially increasing the success rate of epidural blood patch in postoperative patients. This approach is less invasive than revision surgery and does not require the prolonged hospitalization of lumbar drainage or other nontargeted interventions., (Copyright © Congress of Neurological Surgeons 2021. All rights reserved.)

Objective: There has been increasing interest in the use of spinal anesthesia (SA) for spine surgery, especially within Enhanced Recovery After Surgery (ERAS) protocols. Despite the wide adoption of SA by the orthopedic practices, it has not gained wide acceptance in lumbar spine surgery. Studies investigating SA versus general anesthesia (GA) in lumbar laminectomy and discectomy have found that SA reduces perioperative costs and leads to a reduction in analgesic use, as well as to shorter anesthesia and surgery time. The aim of this retrospective, case-control study was to compare the perioperative outcomes of patients who underwent minimally invasive surgery (MIS)-transforaminal lumbar interbody fusion (TLIF) after administration of SA with those who underwent MIS-TLIF under GA., Methods: Overall, 40 consecutive patients who underwent MIS-TLIF by a single surgeon were analyzed; 20 patients received SA and 20 patients received GA. Procedure time, intraoperative adverse events, postoperative adverse events, postoperative length of stay, 3-hour postanesthesia care unit (PACU) numeric rating scale (NRS) pain score, opioid medication, and time to first ambulation were collected for each patient., Results: The two groups were homogeneous for clinical characteristics. A decrease in total operating room (OR) time was found for patients who underwent MIS-TLIF after administration of SA, with a mean OR time of 156.5 ± 18.9 minutes versus 213.6 ± 47.4 minutes for patients who underwent MIS-TLIF under GA (p < 0.0001), a reduction of 27%. A decrease in total procedure time was also observed for SA versus GA (122 ± 16.7 minutes vs 175.2 ± 10 minutes; p < 0.0001). No significant differences were found in intraoperative and postoperative adverse events. There was a difference in the mean maximum NRS pain score during the first 3 hours in the PACU as patients who received SA reported a lower pain score compared with those who received GA (4.8 ± 3.5 vs 7.3 ± 2.7; p = 0.018). No significant difference was observed in morphine equivalents received by the two groups. A difference was also observed in the mean overall NRS pain score, with 2.4 ± 2.1 for the SA group versus 4.9 ± 2.3 for the GA group (p = 0.001). Patients who received SA had a shorter time to first ambulation compared with those who received GA (385.8 ± 353.8 minutes vs 855.9 ± 337.4 minutes; p < 0.0001)., Conclusions: The results of this study have pointed to some important observations in this patient population. SA offers unique advantages in comparison with GA for performing MIS-TLIF, including reduced OR time and postoperative pain, and faster postoperative mobilization.

Background: Incidental durotomy, a known complication of spinal surgery, can lead to persistent cerebrospinal fluid leak and pseudomeningocele if unrecognized or incompletely repaired. We describe the use of ultrasound to visualize the site of durotomy, observe the aspiration of the pseudomeningocele, and guide the precise application of an ultrasound-guided epidural blood patch (US-EBP), under direct visualization in real time., Methods: A retrospective review was performed to determine demographic, procedural, and outcome characteristics for patients who underwent US-EBP for symptomatic postoperative pseudomeningocele., Results: Overall, 48 patients who underwent 49 unique episodes of care were included. The average age and body mass index were 60.5 (±12.6) years and 27.8 (±4.50) kg/m 2 , respectively. The most frequent index operation was laminectomy (24.5%), and 36.7% of surgeries were revision operations. Durotomy was intended or recognized in 73.4% of cases, and the median time from surgery to symptom development was 7 (interquartile range 4-16) days. A total of 61 US-EBPs were performed, with 51.0% of patients experiencing resolution of their symptoms after the first US-EBP. An additional 20.4% were successful with multiple US-EBP attempts. Complications occurred in 14.3% of cases, and the median clinical follow-up was 4.3 (interquartile range 2.4-14.5) months., Conclusions: This manuscript represents the largest series in the literature describing US-EBP for the treatment of postoperative pseudomeningocele. The success rate suggests that routine utilization of US-guided EBP may allow for targeted treatment of pseudomeningoceles, without the prolonged hospitalization associated with lumbar drains or the risks of general anesthesia and impaired wound healing associated with surgical revision., (Copyright © 2021 Elsevier Inc. All rights reserved.)

There are no Food and Drug Administration-approved medications for cocaine use disorder, including relapse. The μ -opioid receptor (MOPr) partial agonist buprenorphine alone or in combination with naltrexone has been shown to reduce cocaine-positive urine tests and cocaine seeking in rodents. However, there are concerns over the abuse liability of buprenorphine. Buprenorphine's partial agonist and antagonist activity at the nociception receptor (NOPr) and κ -opioid receptor (KOPr), respectively, may contribute to its ability to inhibit cocaine seeking. Thus, we hypothesized that a buprenorphine derivative that exhibits antagonist activity at MOPr and KOPr with enhanced agonist activity at the NOPr could provide a more effective treatment. Here we compare the pharmacology of buprenorphine and two analogs, BU10119 and BU12004, in assays for antinociception and for cocaine- and stress-primed reinstatement in the conditioned place preference paradigm. In vitro and in vivo assays showed that BU10119 acts as an antagonist at MOPr, KOPr, and δ -opioid receptor (DOPr) and a partial agonist at NOPr, whereas BU12004 showed MOPr partial agonist activity and DOPr, KOPr, and NOPr antagonism. BU10119 and buprenorphine but not BU12004 lessened cocaine-primed reinstatement. In contrast, BU10119, BU12004, and buprenorphine blocked stress-primed reinstatement. The selective NOPr agonist SCH221510 but not naloxone decreased cocaine-primed reinstatement. Together, these findings are consistent with the concept that NOPr agonism contributes to the ability of BU10119 and buprenorphine to attenuate reinstatement of cocaine-conditioned place preference in mice. The findings support the development of buprenorphine analogs lacking MOPr agonism with increased NOPr agonism for relapse prevention to cocaine addiction. SIGNIFICANCE STATEMENT: There are no Food and Drug Administration-approved medications for cocaine use disorder. Buprenorphine has shown promise as a treatment for cocaine relapse prevention; however, there are concerns over the abuse liability of buprenorphine. Here we show a buprenorphine analogue, BU10119, which lacks μ -opioid receptor agonism and inhibits cocaine-primed and stress-primed reinstatement in a conditioned place-preference paradigm. The results suggest the development of BU10119 for the management of relapse to cocaine seeking., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Acute spinal cord injury is a devastating injury that may lead to loss of independent function. Stem-cell therapies have shown promise; however, a clinically efficacious stem-cell therapy has yet to be developed. Functionally, endothelial progenitor cells induce angiogenesis, and neural stem cells induce neurogenesis. In this study, we explored using a multimodal therapy combining endothelial progenitor cells with neural stem cells encapsulated in a bioactive biomimetic hydrogel matrix to facilitate stem cell-induced neurogenesis and angiogenesis in a rat hemisection spinal cord injury model., Design: Laboratory experimentation., Setting: University laboratory., Subjects: Female Fischer 344 rats., Interventions: Three groups of rats: 1) control, 2) biomimetic hydrogel therapy, and 3) combined neural stem cell, endothelial progenitor cell, biomimetic hydrogel therapy underwent right-sided spinal cord hemisection at T9-T10. The blinded Basso, Beattie, and Bresnahan motor score was obtained weekly; after 4 weeks, observational histologic analysis of the injured spinal cords was completed., Measurements and Main Results: Blinded Basso, Beattie, and Bresnahan motor score of the hind limb revealed significantly improved motor function in rats treated with combined neural stem cell, endothelial progenitor cell, and biomimetic hydrogel therapy ( p < 0.05) compared with the control group. The acellular biomimetic hydrogel group did not demonstrate a significant improvement in motor function compared with the control group. Immunohistochemistry evaluation of the injured spinal cords demonstrated de novo neurogenesis and angiogenesis in the combined neural stem cell, endothelial progenitor cell, and biomimetic hydrogel therapy group, whereas, in the control group, a gap or scar was found in the injured spinal cord., Conclusions: This study demonstrates proof of concept that multimodal therapy with endothelial progenitor cells and neural stem cells combined with a bioactive biomimetic hydrogel can be used to induce de novo CNS tissue in an injured rat spinal cord., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.This work was performed at Duke University, Durham, NC., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objectives: Research has shown that yoga may be an effective adjunctive treatment for persistent depression, the benefits of which may accumulate over time. The objectives of this study were to evaluate the following in a sample of persistently depressed individuals: whether yoga increases mindfulness and whether yoga attenuates rumination. Rumination and mindfulness both represent attentional processes relevant for onset and maintenance of depressive episodes., Methods: One-hundred-ten individuals who were persistently depressed despite ongoing use of pharmacological treatment were recruited into an RCT comparing yoga with a health education class. Mindfulness and rumination were assessed at baseline and across 3 time points during the ten-week intervention., Results: Findings demonstrate that, compared to health education, yoga was associated with higher mean levels of the observe facet of mindfulness relative to the control group during the intervention period ( p =.004, d =0.38), and that yoga was associated with a faster rate of increase in levels of acting with awareness over the intervention period ( p = .03, f 2 =0.027). There were no differences between intervention groups with respect to rumination., Conclusions: Results suggest a small effect of yoga on components of mindfulness during a 10-week intervention period. Previous research suggests that continued assessment after the initial 10 weeks may reveal continued improvement. Future research may also examine moderators of the impact of yoga on mindfulness and rumination, including clinical factors such as depression severity or depression chronicity, or demographic factors such as age.

Objective: From the perspective of percutaneous coronary intervention (PCI) centers, locations of ST-segment elevation myocardial infarction (STEMI) diagnosis can include a referring facility, emergency medical services (EMS) transporting to a PCI center, or the PCI center's emergency department (ED). This challenges the use of door-to-balloon-time as the primary evaluative measure of STEMI treatment pathways. Our objective was to identify opportunities to improve care by quantifying differences in the timeliness of STEMI treatment mobilization based on the location of the diagnostic ECG., Methods: This 3-year, single-center, retrospective cohort study classified patients by diagnostic ECG location: referring facility, EMS, or PCI center ED. We quantified door-to-balloon-time and diagnosis-to-balloon-time with its care subintervals., Results: Of 207 ED STEMI patients, 180 (87%) received PCI. Median diagnosis-to-balloon-times were shortest among the ED-diagnosed (78 minutes [interquartile range (IQR), 61-92]), followed by EMS-identified patients (89 minutes [IQR, 78-122]), and longest among those referred (140 minutes [IQR, 119-160]), reflecting time for transport to the PCI center. Conversely, referred patients had the shortest median door-to-balloon-times (38 minutes [IQR, 34-43]), followed by the EMS-identified (64 minutes [IQR, 47-77]), whereas ED-diagnosed patients had the longest (89 minutes [IQR, 70-114]), reflecting diagnosis and catheterization lab activation frequently occurring before PCI center ED arrival for referred and EMS-identified patients., Conclusions: Diagnosis-to-balloon-time and its care subintervals are complementary to the traditional door-to-balloon-times as measures of the STEMI treatment process. Together, they highlight opportunities to improve timely identification among ED-diagnosed patients, use of out-of-hospital cath lab activation for EMS-identified patients, and encourage pathways for referred patients to bypass PCI center EDs., (© 2021 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Despite advances in biomaterials research, there is no ideal device for replacing weight-bearing soft tissues like menisci or intervertebral discs due to poor integration with tissues and mechanical property mismatch. Designing an implant with a soft and porous tissue-contacting structure using a material conducive to cell attachment and growth could potentially address these limitations. Polycarbonate urethane (PCU) is a soft and tough biocompatible material that can be 3D printed into porous structures with controlled pore sizes. Porous biomaterials of appropriate chemistries can support cell proliferation and tissue ingrowth, but their optimal design parameters remain unclear. To investigate this, porous PCU structures were 3D-printed in a crosshatch pattern with a range of in-plane pore sizes (0 to 800 μm) forming fully interconnected porous networks. Printed porous structures had ultimate tensile strengths ranging from 1.9 to 11.6 MPa, strains to failure ranging from 300 to 486%, Young's moduli ranging from 0.85 to 12.42 MPa, and porosity ranging from 13 to 71%. These porous networks can be loaded with hydrogels, such as collagen gels, to provide additional biological support for cells. Bare PCU structures and collagen-hydrogel-filled porous PCU support robust NIH/3T3 fibroblast cell line proliferation over 14 days for all pore sizes. Results highlight PCU's potential in the development of tissue-integrating medical implants., (© 2020 Wiley Periodicals LLC.)

The twin, chemically orthogonal protein ligation domains, SpyCatcher and SnoopCatcher, were used to link two engineered proteins into poly(ethylene glycol) (PEG) hydrogels in order to control both endothelial cell adhesion and material-mediated pro-mitotic stimulation. SpyCatcher was appended with an N-terminal adhesion ligand RGDS to form RGDS-SC, and SnoopCatcher was appended with the vascular endothelial growth factor (VEGF)-mimetic peptide QK to form QK-SnpC. QK-SnpC formed a spontaneous covalent bond with SnoopTag peptide with 40% reaction efficiency, both in solution, in a PEG gel containing SnoopTag peptide, and in a PEG gel with both SnoopTag and SpyTag sites. QK-SnpC added to cell culture media enhanced endothelial cell proliferation compared to a negative control, and was statistically indistinguishable from the positive control of 130 pM VEGF 165 . Endothelial cells seeded onto PEG gels presenting both RGDS-SC and QK-SnpC showed ∼50% of cells actively proliferating (defined as Ki67+), compared to ∼31% of cells seeded on gels presenting RGDS-SC alone. These results show that complementary nondiffusing biochemical signals can be linked into PEG-DA hydrogels simultaneously using 'Catcher-based ligation strategies, thereby inducing more nuanced cell-material interactions.

The specific microenvironment that cells reside in fundamentally impacts their broader function in tissues and organs. At its core, this microenvironment is composed of precise arrangements of cells that encourage homotypic and heterotypic cell-cell interactions, biochemical signaling through soluble factors like cytokines, hormones, and autocrine, endocrine, or paracrine secretions, and the local extracellular matrix (ECM) that provides physical support and mechanobiological stimuli, and further regulates biochemical signaling through cell-ECM interactions like adhesions and growth factor sequestering. Each cue provided in the microenvironment dictates cellular behavior and, thus, overall potential to perform tissue and organ specific function. It follows that in order to recapitulate physiological cell responses and develop constructs capable of replacing damaged tissue, we must engineer the cellular microenvironment very carefully. Many great strides have been made toward this goal using various three-dimensional (3D) tissue culture scaffolds and specific media conditions. Among the various 3D biomimetic scaffolds, synthetic hydrogels have emerged as a highly tunable and tissue-like biomaterial well-suited for implantable tissue-engineered constructs. Because many synthetic hydrogel materials are inherently bioinert, they minimize unintentional cell responses and thus are good candidates for long-term implantable grafts, patches, and organs. This review will provide an overview of commonly used biomaterials for forming synthetic hydrogels for tissue engineering applications and techniques for modifying them to with bioactive properties to elicit the desired cell responses.

Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.

Hydrogel materials have become a versatile platform for in vitro cell culture due to their ability to simulate many aspects of native tissues. However, precise spatiotemporal presentation of peptides and other biomolecules has remained challenging. Here we report the use of light-sensing proteins (LSPs), more commonly used in optogenetics research, as light-activated reversible binding sites within synthetic poly(ethylene glycol) (PEG) hydrogels. We used LOVTRAP, a two component LSP system consisting of LOV2, a protein domain that can cycle reversibly between "light" and "dark" conformations in response to blue light, and a z-affibody, Zdark (Zdk), that binds the dark state of LOV2, to spatiotemporally control the presentation of a recombinant protein within PEG hydrogels. By immobilizing LOV2 within PEG gels, we were able to capture a recombinant fluorescent protein (used as a model biomolecule) containing a Zdk domain, and then release the Zdk fusion protein using blue light. Zdk was removed from LOV2-containing PEG gels using focused blue light, resulting in a 30% reduction of fluorescence compared to unexposed regions of the gel. Additionally, the reversible binding capability of LOVTRAP was observed in our system, enabling our LOV2 gels to capture and release Zdk at least three times. By adding a Zdk domain to a recombinant peptide or protein, dynamic, spatially constrained displays of non-diffusing ligands within a PEG gel could feasibly be achieved using LOV2.

A new system of yolk-shell microcapsules containing two types of dye-doped liquid crystals was prepared via seed emulsion polymerization in which the synthetic process was mimicking plant respiration. The resulting system demonstrated reversible low voltage-driven switching between multispectral colored and transparent states. Moreover, wearable multicolor electrochromic fibers based on calcium alginate were produced via wet spinning to expand the application of yolk-shell dye-doped liquid crystal microcapsules. In addition to its long-term optical stability, the proposed cells and fibers also have satisfactory driving voltage values of color change (4.8 and 9.0 V), which are far lower than the human body safety voltage (12 V). We believe that the prepared microcapsules and fibers are potentially widely applicable in smart windows, electronic paper, and military camouflage clothing.

Background: In regard to scientific information, are we effectively reaching the universe of physicians in the 21st century, all of whom have different backgrounds, practice environments, educational experiences, and varying degrees of research knowledge?, Methods: A comparison of the top nine neurosurgery journals based on various popular citation indices and also on the digital metric, Readers (Users)/month, was compiled from available metrics and from internet sources., Results: Major differences in the ranking of the Readers (Users)/month metrics compared to ranking of the various citation indices were found. It is obvious that the citation indices do not measure the number of readers of a publication. Which metric should be used in judging the value of a scientific paper? The answer to that question relates to what the interest of the reader has in the scientific information. It appears that the academic scientist may have a different reason for reading a scientific publication than a physician caring for a patient., Conclusions: There needs to be more than one type of metric that measures the value and "Impact" of a scientific paper based on how physicians learn., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Surgical Neurology International.)

De novo vascularization of implantable tissue and whole organ constructs has been a significant challenge in the field of tissue engineering; the use of endothelial cell populations for this task is constrained by the cell population's limited regeneration capacity and potential for loss of function. Thus, there is a need for a stem-cell population that may be induced into an endothelial cell phenotype reliably. Adipose derived stem cells (ADSCs) are multipotent cells that can be readily isolated from donor fat and may have the potential to be readily induced into endothelial cells. The ability to stimulate endothelial differentiation of these cells has been limited in standard 2D culture. We hypothesized that 3D culture would yield better differentiation. To study the influence of cell density and culture conditions on the potential of ADSCs to differentiate into an endothelial-like state, we seeded these cells types within a 3D cell-adhesive, proteolytically degradable, peptide-modified poly(ethylene-glycol) (PEG) hydrogel. ADSCs were either cultured in basal media or pro-angiogenic media supplemented with 20 ng/mL of VEGF in 2D and then encapsulated at low or high densities within the PEG-based hydrogel. These encapsulated cells were maintained in either basal media or pro-angiogenic media. Cells were then isolated from the hydrogels and cultured in Matrigel to assess the potential for tubule formation. Our work shows that maintenance of ADSCs in a pro-angiogenic medium in 2D monoculture alone does not result in any CD31 expression. Furthermore, the level of CD31 expression was affected by the density of the cells encapsulated within the PEG-based hydrogel. Upon isolation of these cells, we found that these induced ADSCs were able to form tubules within Matrigel, indicative of endothelial function, while ADSCs cultured in basal medium could not. This finding points to the potential for this stem-cell population to serve as a safe and reliable source of endothelial cells for tissue engineering and regenerative medicine purposes.

Biocompatible gold nanoparticles designed to absorb light at wavelengths of high tissue transparency have been of particular interest for biomedical applications. The ability of such nanoparticles to convert absorbed near-infrared light to heat and induce highly localized hyperthermia has been shown to be highly effective for photothermal cancer therapy, resulting in cell death and tumor remission in a multitude of preclinical animal models. Here we report the initial results of a clinical trial in which laser-excited gold-silica nanoshells (GSNs) were used in combination with magnetic resonance-ultrasound fusion imaging to focally ablate low-intermediate-grade tumors within the prostate. The overall goal is to provide highly localized regional control of prostate cancer that also results in greatly reduced patient morbidity and improved functional outcomes. This pilot device study reports feasibility and safety data from 16 cases of patients diagnosed with low- or intermediate-risk localized prostate cancer. After GSN infusion and high-precision laser ablation, patients underwent multiparametric MRI of the prostate at 48 to 72 h, followed by postprocedure mpMRI/ultrasound targeted fusion biopsies at 3 and 12 mo, as well as a standard 12-core systematic biopsy at 12 mo. GSN-mediated focal laser ablation was successfully achieved in 94% (15/16) of patients, with no significant difference in International Prostate Symptom Score or Sexual Health Inventory for Men observed after treatment. This treatment protocol appears to be feasible and safe in men with low- or intermediate-risk localized prostate cancer without serious complications or deleterious changes in genitourinary function., Competing Interests: Conflict of interest statement: A.R.R. is the national principal investigator for the multiinstitutional trial of GSN-directed ablation, funded by Nanospectra Biosciences. He is also a consultant for Nanospectra Biosciences. J.L.W. and N.J.H. cofounded Nanospectra Biosciences in 2001 to transfer the photothermal therapeutics process from their labs into the clinic. They both have a small equity stake in this company but are not involved in any way with the company’s business or strategic decisions., (Copyright © 2019 the Author(s). Published by PNAS.)

SpyCatcher, a 15 kDa protein domain that spontaneously forms a site-specific covalent bond with the 13 amino acid peptide SpyTag, was used to covalently link a model recombinant protein containing a SpyCatcher domain and the adhesive ligand Arg-Gly-Asp-Ser (RGDS) (RGDS-SC) into SpyTag-containing poly(ethylene glycol) (PEG) hydrogels. This new strategy for covalent immobilization of proteins or peptides provides an easy and gentle mechanism for biochemical modification of hydrogels. Labeling efficiency was approximately 100% when soluble RGDS-SC was applied to SpyTag-containing hydrogels at a 1:1 molar ratio. RGDS-SC remained stably bound throughout the 5 days of rinsing, and 3T3 fibroblasts were able to adhere to PEG gels presenting RGDS-SC, but did not adhere when the scrambled amino acid sequence RDGS was presented instead. Fibroblasts encapsulated within 3D cell-degradable PEG hydrogels containing SpyTag did not spread until RGDS-SC was added to the gels, at which point cell spreading was induced. This cell-friendly site-specific ligation strategy could have great utility in driving specific cellular outcomes using biochemically dynamic hydrogels.

A simple process to clad conventional monofilament fibers with low-molecular-weight liquid crystals (LCs) stabilized by an outer polymer sheath is demonstrated. The fibers retain the responsive properties of the LCs but in a highly flexible/drapable format. The monofilament core makes these fibers much more rugged with a magnified response to external stimuli when compared to previously reported LC-core fibers produced by electrospinning or airbrushing. The microscopic structure and the optical properties of round and flattened fibers are reported. The sensitivity of the response of individual fibers can be tuned over a broad range by varying the composition of the LCs. Complex fabrics can be easily woven from fibers that respond to different external stimuli, such as temperature variation, chemical concentrations, and pressure. The fabrics can be fashioned into garments that can sense and report the state of health of the wearer or the status of their environment., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Radiation therapy for malignant head and neck cancers includes a risk for off-target effects to bony structures, posing a risk for osteoradionecrosis (ORN). Patients in whom ORN develops can also harbor concomitant osteomyelitis and reduced healing capacity, making for a particularly challenging entity to treat. Hyperbaric oxygen therapy (HBO) has been shown to be effective in the treatment of mandibular ORN in the otolaryngology literature; yet, few reports exist detailing its utility when treating ORN of the craniocervical junction. Herein, we report 2 cases of ORN of the craniocervical junction who received both neoadjuvant and adjuvant HBO in combination with posterior spinal fusion., Case Description: Two patients with craniocervical junction ORN were treated with HBO delivered over 20 sessions before and after surgery in 90-minute treatments to 2.5 atmospheres of pressure. The patients underwent posterior occipital-cervical fusions with an average operative time of 301 (±21.5) minutes with 250 (±150) mL of blood loss. Both patients stayed in the hospital for 5 days, with no periprocedural complications. Outcomes included a 30% improvement of global assessment of function on follow-up EuroQol 5-Dimension Questionnaire. Postoperative imaging demonstrated solid bony fusion, and both patients returned to full work duty., Conclusions: ORN is a difficult-to-treat radiation complication in head and neck cancers. Few reports exist detailing treatment options for ORN of the craniocervical junction in conjunction with surgical stabilization. We report 2 successful cases of HBO-assisted treatment of ORN and highlight the important role HBO can play in promoting bony fusion in these at-risk patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Once the accepted norm during Harvey Cushing's time, the mantra of work to the exclusion of family and lifestyle is now recognized as deleterious to overall well-being. A number of neurosurgical residency training programs have implemented wellness programs to enhance the physical, mental, and emotional well-being of trainees and faculty. This manuscript highlights existing organized wellness education within neurosurgery residency programs in order to describe the motivations behind development, structure, and potential implementation strategies, cost of implementation, and identify successes and barriers in the integration process. This manuscript is designed to serve as a "how-to" guide for other programs who may identify a need in their own trainees and begins the discussion of how to develop wellness, leadership, grit, and resiliency within our future generation of neurosurgeons., (Copyright © 2018 by the Congress of Neurological Surgeons.)

In this review, we explore the roles of macrophages both in vessel development and in vascularization of tissue engineered constructs. Upon the implantation of tissue engineered constructs into the body, macrophages respond, invade and orchestrate the host's immune response. By altering their phenotype, macrophages can adopt a variety of roles. They can promote inflammation at the site of the implanted construct; they can also promote tissue repair. Macrophages support tissue repair by promoting angiogenesis through the secretion of pro-angiogenic cytokines and by behaving as support cells for nascent vasculature. Thus, the ability to manipulate the macrophage phenotype may yield macrophages capable of supporting vessel development. Moreover, macrophages are an easily isolated autologous cell source. For the generation of vascularized constructs outside of the body, these isolated macrophages can also be skewed to adopt a pro-angiogenic phenotype and enhance blood vessel development in the presence of endothelial cells. To assess the influence of macrophages on vessel development, both in vivo and in vitro models have been developed. Additionally, several groups have demonstrated the pro-angiogenic roles of macrophages in vascularization of tissue engineered constructs through the manipulation of macrophage phenotypes. This review comments on the roles of macrophages in promoting vascularization within these contexts.