The Impact of High or Low Doses of Nicotine in a Mouse Model of Vapor Self-Administration.

INTRODUCTION: A wide variety of nicotine concentrations and formulations are available to users of electronic nicotine delivery systems (ENDS). This is increasingly true when considering the many flavors available with ENDS products. To date, there have been few preclinical investigations into the impact of nicotine doses, with and without flavors, on vaping-related behaviors. This present study evaluated how nicotine concentrations relevant to tank-based and pod-based ENDS, with and without flavors, impact reinforcement-related behavior in a mouse model. AIMS AND METHODS: Adult male and female C57/BL6J mice were used in vapor-inhalation self-administration assays. Mice were assigned e-liquids containing 6 mg/mL or 60 mg/mL nicotine. Additional mice were assigned these nicotine doses with green apple or menthol flavorants. Mice were trained on fixed-ratio 1 for 10, 2-hour sessions, then five sessions at FR3, three progressive ratio sessions, and two FR3 sessions. RESULTS: We observed male mice exhibited higher reinforcement-related behavior to menthol-flavored 6 mg/mL nicotine when compared to female mice. Males were only observed to have a menthol-induced enhancement of self-administration at 6 mg/mL nicotine and not 60 mg/mL nicotine. However, female mice exhibited significant menthol-induced increases in reinforcement-related behaviors with 60 mg/mL nicotine. CONCLUSIONS: These data provide evidence that males and females exhibit different dose sensitivities to nicotine. These sex-dependent differences in nicotine sensitivity also indicate that flavor-induced enhancement in nicotine intake is dependent on the different doses for each sex. IMPLICATIONS: There has been much discussion recently regarding the impact of flavors on vaping-related behavior. Our current study may support prior investigations that suggest flavors enhance the palatability of nicotine-containing products. However, this current study provides evidence that males and females exhibit different sensitivities to nicotine.

Chemical Flavorants in Vaping Products Alter Neurobiology in a Sex-Dependent Manner to Promote Vaping-Related Behaviors.

Electronic nicotine delivery systems (ENDS) are distinctly different from combustible cigarettes because of the availability of flavor options. Subjective measures have been used to demonstrate that adults and adolescents prefer flavors for various reasons; (1) they are pleasing and (2) they mask the harshness of nicotine. Despite this, there have been few investigations into the molecular interactions that connect chemical flavorants to smoking or vaping-related behaviors. Here, we investigated the effects of three chemical flavorants (hexyl acetate, ethyl acetate, and methylbutyl acetate) that are found in green apple (GA) ENDS e-liquids but are also found in other flavor categories. We used a translationally relevant vapor self-administration mouse model and observed that adult male and female mice self-administered GA flavorants in the absence of nicotine. Using α4-mCherryα6-GFP nicotinic acetylcholine receptor (nAChR) mice, we observed that mice exposed to GA flavorants exhibited a sex-specific increase (upregulation) of nAChRs that was also brain-region specific. Electrophysiology revealed that mice exposed to GA flavorants exhibited enhanced firing of ventral tegmental area dopamine neurons. Fast-scan cyclic voltammetry revealed that electrically stimulated dopamine release in the nucleus accumbens core is increased in mice that are exposed to GA flavorants. These effects were similarly observed in the medial habenula. Overall, these findings demonstrate that ENDS flavors alone change neurobiology and may promote vaping-dependent behaviors in the absence of nicotine. Furthermore, the flavorant-induced changes in neurobiology parallel those caused by nicotine, which highlights the fact that nonmenthol flavorants may contribute to or enhance nicotine reward and reinforcement.SIGNIFICANCE STATEMENT The impact of flavors on vaping is a hotly debated topic; however, few investigations have examined this in a model that is relevant to vaping. Although a full understanding of the exact mechanism remains undetermined, our observations reveal that chemical flavorants in the absence of nicotine alter brain circuits relevant to vaping-related behavior. The fact that the flavorants investigated here exist in multiple flavor categories of vaping products highlights the fact that a multitude of flavored vaping products may pose a risk toward vaping-dependent behaviors even without the impact of nicotine. Furthermore, as the neurobiological changes have an impact on neurons of the reward system, there exists the possibility that nonmenthol flavorants may enhance nicotine reward and reinforcement.

Machine learning applications in tobacco research: a scoping review.

OBJECTIVE: Identify and review the body of tobacco research literature that self-identified as using machine learning (ML) in the analysis. DATA SOURCES: MEDLINE, EMABSE, PubMed, CINAHL Plus, APA PsycINFO and IEEE Xplore databases were searched up to September 2020. Studies were restricted to peer-reviewed, English-language journal articles, dissertations and conference papers comprising an empirical analysis where ML was identified to be the method used to examine human experience of tobacco. Studies of genomics and diagnostic imaging were excluded. STUDY SELECTION: Two reviewers independently screened the titles and abstracts. The reference list of articles was also searched. In an iterative process, eligible studies were classified into domains based on their objectives and types of data used in the analysis. DATA EXTRACTION: Using data charting forms, two reviewers independently extracted data from all studies. A narrative synthesis method was used to describe findings from each domain such as study design, objective, ML classes/algorithms, knowledge users and the presence of a data sharing statement. Trends of publication were visually depicted. DATA SYNTHESIS: 74 studies were grouped into four domains: ML-powered technology to assist smoking cessation (n=22); content analysis of tobacco on social media (n=32); smoker status classification from narrative clinical texts (n=6) and tobacco-related outcome prediction using administrative, survey or clinical trial data (n=14). Implications of these studies and future directions for ML researchers in tobacco control were discussed. CONCLUSIONS: ML represents a powerful tool that could advance the research and policy decision-making of tobacco control. Further opportunities should be explored.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

OBJECTIVE: To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. PATIENTS AND METHODS: We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. RESULTS: The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. CONCLUSION: This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumours: a guide to immunohistochemistry implementation and interpretation.

Immunotherapy with checkpoint inhibitors is well established as an effective treatment for non-small cell lung cancer and melanoma. The list of approved indications for treatment with PD-1/PD-L1 checkpoint inhibitors is growing rapidly as clinical trials continue to show their efficacy in patients with a wide range of solid tumours. Clinical trials have used a variety of PD-L1 immunohistochemical assays to evaluate PD-L1 expression on tumour cells, immune cells or both as a potential biomarker to predict response to immunotherapy. Requests to pathologists for PD-L1 testing to guide choice of therapy are rapidly becoming commonplace. Thus, pathologists need to be aware of the different PD-L1 assays, methods of evaluation in different tumour types and the impact of the results on therapeutic decisions. This review discusses the key practical issues relating to the implementation of PD-L1 testing for solid tumours in a pathology laboratory, including evidence for PD-L1 testing, different assay types, the potential interchangeability of PD-L1 antibody clones and staining platforms, scoring criteria for PD-L1, validation, quality assurance, and pitfalls in PD-L1 assessment. This review also explores PD-L1 IHC in solid tumours including non-small cell lung carcinoma, head and neck carcinoma, triple negative breast carcinoma, melanoma, renal cell carcinoma, urothelial carcinoma, gastric and gastroesophageal carcinoma, colorectal carcinoma, hepatocellular carcinoma, and endometrial carcinoma. The review aims to provide pathologists with a practical guide to the implementation and interpretation of PD-L1 testing by immunohistochemistry.

Current Trends in Breast Augmentation: Analysis of 2011-2015 Maintenance of Certification (MOC) Tracer Data.

BACKGROUND: Breast augmentation is the most common aesthetic surgery performed in the United States. Despite its popularity, there is no consensus on many aspects of the procedure. OBJECTIVES: The authors assessed current trends and changes in breast augmentation from January 1, 2011 to December 31, 2015. METHODS: A retrospective cross-sectional study of 11,756 women who underwent breast augmentation based on the American Board of Plastic Surgery (ABPS) Maintenance of Certification Tracer Database was performed. RESULTS: There were clearly dominant trends in how ABPS-certified plastic surgeons performed breast augmentations. Most surgeries were performed in freestanding outpatient (47.3%) or office operating room (33.7%). The inframammary fold incision was most popular (75.1%), followed by periareolar (17.8%) and transaxillary approaches (4.1%). Implants were more commonly placed in a submuscular pocket (30.6%) compared with dual plane (26.7%) or subglandular (6.7%). Silicone implants (66.8%) were favored over saline (25.1%), with a statistically significant increase in silicone prostheses from 2011 to 2015. Data were "not applicable" or "other" in the remainder of cases. Administration of both preoperative antibiotics (3.8% in 2011, 98.7% in 2015, P < 0.05) and deep venous thromboembolism (DVT) prophylaxis (3.8% in 2011, 90.6% in 2015, P < 0.05) dramatically increased during the study period. Overall adverse events (7.4%) and reoperation rates (2.2%) were low. CONCLUSIONS: Changes in standard of care for breast augmentation are reflected by the evolving practice patterns of plastic surgeons. This is best evidenced by the dramatic increase in use of antibiotic and DVT prophylaxis from 2011 to 2015.

Liposuction-Assisted Short-Scar Brachioplasty: Technical Highlights.

Upper arm contouring is based on the location and amount of excess skin and fat. The short-scar brachioplasty addresses minimal to moderate skin laxity and lipodystrophy in the proximal arm in patients with appropriate skin tone and quality. This article highlights technical refinements of the senior author's (R.J.R.) approach to short-scar medial liposuction-assisted brachioplasty to maximize results and minimize incision length. To highlight this simple and safe approach with high patient/surgeon satisfaction, the authors discuss the following in this Video Plus article: patient examination, preoperative assessment, surgical pearls, and postoperative outcomes.

Technical Refinements in Autologous Hand Rejuvenation.

The aging hand is characterized by skin changes and soft-tissue deflation, which leads to rhytides, dermal atrophy, and distinct anatomical structures. Soft-tissue deflation and prominent hand anatomy can be corrected with volume augmentation using dermal fillers or lipofilling. Fat transfer volumizes the hand with prolonged durability and efficacy, autologous tissue replacement, and possible dermal regeneration. The senior author's (R.J.R.) technique for hand rejuvenation is described, which uses minimal access and blunt dissection to effectively augment the soft-tissue compartments of the hand. This approach addresses the prominent aged anatomy of the hand, providing excellent contour and aesthetic outcomes.

The novel use of intraoperative laser-induced fluorescence of indocyanine green tissue angiography for evaluation of the gastric conduit in esophageal reconstructive surgery.

BACKGROUND: Esophagectomy with reconstruction using a gastric conduit is associated with a relatively high rate of anastomotic leakage. We used indocyanine green tissue angiography to evaluate the gastric conduit intraoperatively before gastroesophageal anastomosis to identify ischemia. METHODS: We performed an institutional review board-approved retrospective review of all esophagectomies performed from 2010 to the beginning of 2011. Patient histories and perioperative outcomes were reviewed retrospectively. Postoperative morbidity and 30-day mortality were determined. RESULTS: Eleven patients had an esophagectomy performed using this technology. All had adequate perfusion on gross examination. All but 1 had good perfusion with tissue angiography, and there were 2 anastomotic leakages leaks including this patient. There were no mortalities at 30 days. CONCLUSIONS: We report preliminary results using this imaging system in esophageal reconstructive surgery. Larger randomized controlled studies are needed to determine if surgical outcomes can be improved using this technology.

Closure of meningomyelocele defects using acellular dermal matrix.

Spina bifida is the most common birth defect of the CNS, with meningomyelocele observed in 1 in 800 to 1000 infants. A single reliable method of providing adequate soft-tissue coverage (skin, but also including subcutaneous fat, fascia, and muscle) of the meningomyelocele defect while preventing dehiscence and infection has yet to be defined. This study reviews a case series of 3 patients with large meningomyeloceles treated by a single neurosurgeon /plastic surgeon team at a single institution. Following repair of the neural elements (both dura and neural placode), soft-tissue coverage (skin, but also subcutaneous tissue and fascia) was achieved using acellular dermal matrix over the neural elements, repaired with sutures, and covered with skin flaps. In this series of 3 patients, stable coverage was achieved in all patients. One patient experienced minor wound dehiscence treated with debridement and primary closure with simple relaxing incisions. This series demonstrates that the usage of acellular dermal matrix provides a stable soft-tissue coverage for large meningomyelocele defects in an easily reproducible operation preserving local soft tissue (muscle, fascia) for potential salvage operations or revisions (such as for scoliosis) as well as providing a less demanding operation on the fragile physiology of the neonate.

Pediatric lower extremity mower injuries.

Lawn mower injuries in children represent an unfortunate common problem to the plastic reconstructive surgeon. There are approximately 68,000 per year reported in the United States. Compounding this problem is the fact that a standard treatment algorithm does not exist. This study follows a series of 7 pediatric patients treated for lower extremity mower injuries by a single plastic surgeon. The extent of soft tissue injury varied. All patients were treated with negative pressure wound therapy as a bridge to definitive closure. Of the 7 patients, 4 required skin grafts, 1 required primary closure, 1 underwent a lower extremity amputation secondary to wounds, and 1 was repaired using a cross-leg flap. Function limitations were minimal for all of our patients after reconstruction. Our basic treatment algorithm is presented with initial debridement followed by the simplest method possible for wound closure using negative pressure wound therapy, if necessary.

Contribution of breast density to the volume of the augmented breast: A preliminary study.

BACKGROUND: Prediction of soft tissue contribution to the shape, volume and texture of the augmented breast proves to be an ever-challenging, uncontrollable variable. Similarly, the understanding of the contribution of breast density in breast augmentation has been elusive and, generally, not well studied. OBJECTIVE: With the aid of three-dimensional photographic analysis, the present preliminary study examined the contribution of differing breast densities to the overall volume of the augmented breast. METHODS: All patients undergoing primary augmentation over a six-month period were included in the study. To standardize technique and implant type, all patients received saline-filled moderate-profile implants, which were placed partially underneath the pectoralis muscle through a lower pole approach. Photographic analysis of the breast volume was completed preoperatively and, subsequently, at a minimum of six months postoperatively. Preoperatively, each breast was also assigned to one of four classes of increasing mammographic density, as judged by the mammographic radiologist (fatty, moderately dense, heterogeneously dense and extremely dense). Postoperative breast volumes were, subsequently, correlated to mammographic densities. RESULTS: Thirty-eight augmented breasts in 21 patients were examined. The average volume gain based on the implant size used was 92.7%. Heterogeneously dense breasts comprised 68% of the total breasts and showed an average volume gain of 100.67%, extremely dense breasts comprised 26% of the total breasts and showed an average volume gain of 97.3%, and moderately dense breasts comprised 5% of the total breasts with an average gain of 100.04%. There was no significant difference between the augmented breast volumes and the respective expected volumes (combined preaugmented breast volumes and implant volumes; P=0.3483). Additionally, no statistical difference was found between the density classes and the expected augmented volumes. CONCLUSION: No statistical difference was found between expected and actual augmented breast volumes among or between four different breast density classes. Thus, one would expect that the soft tissue compression or the response of the impression of the implant on the parenchyma, would not be statistically different among classes. Additionally, compressive atrophy, as seen with atrophy of the breasts over time, would be expected to be multifactorial and not uniquely independent to breast density. However, longitudinal analysis is needed to study the durability of breast shape relative to breast density.

Channelpedia: an integrative and interactive database for ion channels.

Ion channels are membrane proteins that selectively conduct ions across the cell membrane. The flux of ions through ion channels drives electrical and biochemical processes in cells and plays a critical role in shaping the electrical properties of neurons. During the past three decades, extensive research has been carried out to characterize the molecular, structural, and biophysical properties of ion channels. This research has begun to elucidate the role of ion channels in neuronal function and has subsequently led to the development of computational models of ion channel function. Although there have been substantial efforts to consolidate these findings into easily accessible and coherent online resources, a single comprehensive resource is still lacking. The success of these initiatives has been hindered by the sheer diversity of approaches and the variety in data formats. Here, we present "Channelpedia" (http://channelpedia.net), which is designed to store information related to ion channels and models and is characterized by an efficient information management framework. Composed of a combination of a database and a wiki-like discussion platform Channelpedia allows researchers to collaborate and synthesize ion channel information from literature. Equipped to automatically update references, Channelpedia integrates and highlights recent publications with relevant information in the database. It is web based, freely accessible and currently contains 187 annotated ion channels with 45 Hodgkin-Huxley models.