SARS-CoV-2 antigen-carrying extracellular vesicles activate T cell responses in a human immunogenicity model.

Extracellular vesicles (EVs) are entering the clinical arena as novel biologics for infectious diseases, potentially serving as the immunogenic components of next generation vaccines. However, relevant human assays to evaluate the immunogenicity of EVs carrying viral antigens are lacking, contributing to challenges in translating rodent studies to human clinical trials. Here, we engineered EVs to carry SARS-CoV-2 Spike to evaluate the immunogenicity of antigen-carrying EVs using human peripheral blood mononuclear cells (PBMCs). Delivery of Spike EVs to PBMCs resulted in specific immune cell activation as assessed through T cell activation marker expression. Further, Spike EVs were taken up largely by antigen-presenting cells (monocytes, dendritic cells and B cells). Taken together, this human PBMC-based system models physiologically relevant pathways of antigen delivery, uptake and presentation. In summary, the current study highlights the suitability of using human PBMCs for evaluating the immunogenicity of EVs engineered to carry antigens for infectious disease therapeutics.

Renal Denervation: A Practical Guide for Health Professionals Managing Hypertension.

Growing evidence demonstrates the suitability of renal denervation in a broad population of patients; however, questions remain over its suitability and practical implementation. Given the rapidity of emerging data, this has been a challenging field for potential adopters to navigate. The purpose of this article is twofold: to provide navigation through emerging clinical data and evolving guidance; and to provide physicians with practical, evidence-based advice for identifying eligible patients and providing appropriate management in the pre- and postintervention settings. Although many of these recommendations are based on existing published guidance documents, we reflect equally on our own experiences of using this technology.

Tissue-Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition.

Lymphangioleiomyomatosis (LAM) is a rare disease involving cystic lung destruction by invasive LAM cells. These cells harbor loss-of-function mutations in TSC2, conferring hyperactive mTORC1 signaling. Here, tissue engineering tools are employed to model LAM and identify new therapeutic candidates. Biomimetic hydrogel culture of LAM cells is found to recapitulate the molecular and phenotypic characteristics of human disease more faithfully than culture on plastic. A 3D drug screen is conducted, identifying histone deacetylase (HDAC) inhibitors as anti-invasive agents that are also selectively cytotoxic toward TSC2-/- cells. The anti-invasive effects of HDAC inhibitors are independent of genotype, while selective cell death is mTORC1-dependent and mediated by apoptosis. Genotype-selective cytotoxicity is seen exclusively in hydrogel culture due to potentiated differential mTORC1 signaling, a feature that is abrogated in cell culture on plastic. Importantly, HDAC inhibitors block invasion and selectively eradicate LAM cells in vivo in zebrafish xenografts. These findings demonstrate that tissue-engineered disease modeling exposes a physiologically relevant therapeutic vulnerability that would be otherwise missed by conventional culture on plastic. This work substantiates HDAC inhibitors as possible therapeutic candidates for the treatment of patients with LAM and requires further study.

Techniques for Creating Inconspicuous Facelift Scars: An Update.

Importance: Patients seeking rhytidectomy desire an improved neckline, jawline, and midface, but rarely at the cost of visible incision lines that divulge a facelift. Objective: To describe an update to our facelift incision planning and specific surgical maneuvers to create inconspicuous scars. Design: Surgical pearls-description of novel surgical technique. Setting: A private practice. Participants: Patients who underwent cervicofacial rhytidectomy.

Home-cooked diets cost more than commercially prepared dry kibble diets for dogs with chronic enteropathies.

OBJECTIVE: Nutrition plays a fundamental role in the management of canine chronic enteropathies (CCEs). Dog owners may elect to feed home-cooked diets (HCDs) rather than veterinary commercially prepared diets (CPDs) because of perceived lower costs. There is a paucity of data comparing costs of these options. We hypothesize there will be differences in costs between complete and balanced HCDs and nutritionally comparable CPDs. SAMPLE: 6 Home-cooked diets. PROCEDURES: Six HCD recipes (2 highly digestible, 2 limited antigen, 2 low-fat) were formulated by 2 board-certified veterinary nutritionists to mimic the nutritional and ingredient profiles of veterinary CPDs for management of CCEs. The cost (in US$ on a per 100 kilocalorie [kcal] basis) of each recipe was determined via collection of ingredient prices from 3 grocery stores combined with supplement prices from online retailers. Prices of CPDs were obtained from a national online retailer. Maintenance energy requirements of 1.6 X (70 X BWkg0.75), where BWkg represents body weight in kilograms, were calculated for 3 dog sizes (5, 20, and 40 kg), and costs of feeding maintenance energy requirements with HCDs versus dry and canned CPDs were compared with a Kruskal-Wallis test and post hoc testing. RESULTS: The median costs of all dry and canned CPDs and HCDs were $0.29 (range, $0.18 to $0.46), $1.01 (range, $0.77 to $1.20), and $0.55 (range, $0.35 to $1.14), respectively. Feeding complete and balanced HCDs cost more than feeding dry CPDs (P < .001), but not canned CPDs (P > .99). CLINICAL RELEVANCE: Dry CPDs cost the least for nutritional management of CCEs. There is a wide range of costs for both CPDs and HCDs.

Waitlisted and Transplant Patient Perspectives on Expanding Access to Deceased-Donor Kidney Transplant: A Qualitative Study.

Background: A concerning number of kidneys (eg, expanded donor criteria, extended criteria, or marginal kidneys) are discarded yearly while patients experience significant morbidity and mortality on the transplant waitlist. Novel solutions are needed to solve the shortage of kidneys available for transplant. Patient perceptions regarding the use of these less than ideal kidneys remain unexplored. Objective: To explore the perspectives of patients who have previously received a less than ideal kidney in the past and patients awaiting transplant who could potentially benefit from one. Design: Qualitative description study. Setting: 2 provinces in Canada participated (Saskatchewan and Manitoba). Patients: Patients with end-stage kidney disease who were awaiting kidney transplant and were either (a) aged 65 years and older, or (b) 55 years and older with other medical conditions (eg, diabetes). Methods: Criterion sampling was used to identify participants. Semi-structured, one-on-one interviews were conducted virtually, which explored perceived quality of life, perceptions of less than ideal kidneys, risk tolerance for accepting one, and educational needs to make such a choice. The interviews were transcribed verbatim and thematic analysis was used to analyze the data. Results: 15 interviews were conducted with usable data (n = 10 pretransplant; n = 5 posttransplant). Participants were a mean of 65.5 ± 8.8 years old. Four interrelated themes became prominent including (1) patient awareness and understanding of their situation or context, (2) a desire for information, (3) a desire for freedom from dialysis, and (4) trust. Subthemes of transparency, clarity, standardization, and autonomy were deemed important for participant education. The majority of pretransplant participants (n = 8/10) indicated that between 3 and 5 years off of dialysis would make the risk of accepting a less than ideal kidney feel worthwhile. Limitation: The study setting was limited to 2 Canadian provinces, which limits the generalizability. Furthermore, the participants were homogenous in demographics such as ethnicity. Conclusion: These findings indicate that patients are comfortable to accept a less than ideal kidney for transplant in situations where their autonomy is respected, they are provided clear, standardized, and transparent information, and when they trust their physician. These results will be used to inform the development of a new national registry for expanding access to deceased-donor kidney transplant. Trial Registration: Not registered.

Contexte: De nombreux reins sont rejetés chaque année (donneurs à critères élargis, critères étendus ou reins marginaux), alors que les patients qui attendent une greffe présentent une morbidité importante et un taux de mortalité élevé. De nouvelles solutions sont nécessaires pour contrer la pénurie de reins disponibles pour une transplantation. Les perceptions des patients quant à l'utilization de ces reins moins idéaux restent inexplorées. Objectif: Explorer les perceptions des patients ayant reçu un rein moins idéal dans le passé et des patients en attente d'une greffe qui pourraient potentiellement bénéficier d'un tel don. Conception: Étude qualitative et descriptive. Cadre: Deux provinces canadiennes (Saskatchewan et Manitoba). Participants: Des patients atteints d'insuffisance rénale terminale en attente d'une transplantation (a) âgés de 65 ans et plus ou (b) âgés de 55 ans et plus et présentant d'autres problèmes de santé (ex. diabète). Méthodologie: L'échantillonnage avec critères a été utilisé pour identifier les participants. Des entretiens individuels semi-structurés menés virtuellement ont exploré la qualité de vie perçue, la perception quant aux reins moins idéaux, la tolérance à l'égard des risques inhérents à l'acceptation d'un tel rein, et les besoins d'information pour faire ce choix. Les entrevues ont été transcrites intégralement et l'analyze des données a été réalisée par analyze thématique. Résultats: Quinze entrevues avec données utilisables ont été menées (n = 10 avant la greffe; n = 5 après la greffe). Les participants avaient en moyenne 65.5 ± 8.8 ans. Quatre thèmes interreliés ont été dégagés : (1) la sensibilisation et la compréhension des patients quant à leur situation ou au contexte; (2) le besoin d'information; (3) le besoin d'un congé de dialyze; et (4) la confiance envers le médecin. La transparence, la clarté, la normalization et l'autonomie ont été jugées comme des sous-thèmes importants de l'éducation des participants. Pour la majorité des participants en attente d'une greffe (n = 8/10), l'idée d'un congé de 3 à 5 ans de dialyze rendrait acceptables les risques associés à l'acceptation d'un rein moins idéal. Limites: Étude tenue dans deux provinces canadiennes, ce qui limite la généralisabilité des résultats. Homogénéité des participants sur le plan démographique, notamment en ce qui concerne l'origine ethnique. Conclusion: Les résultats indiquent que les patients seraient à l'aise d'accepter un rein moins idéal pour une greffe, pourvu que leur autonomie soit respectée, qu'ils reçoivent des informations claires, standardisées et transparentes, et qu'ils aient confiance en leur médecin. Ces résultats serviront à éclairer l'élaboration d'un nouveau registre national afin d'élargir l'accès à la transplantation de rein provenant de donneurs décédés. Enregistrement de l'essai: Non enregistré.

Results of an international crowdsourcing survey on the treatment of non-ST segment elevation ACS patients at high-bleeding risk undergoing percutaneous intervention.

AIMS: Choosing an antiplatelet strategy in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) at high bleeding risk (HBR), undergoing post-percutaneous coronary intervention (PCI), is complex. We used a unique open-source approach (crowdsourcing) to document if practices varied across a small, global cross-section of antiplatelet prescribers in the post-PCI setting. METHODS AND RESULTS: Five-hundred and fifty-nine professionals from 70 countries (the 'crowd') completed questionnaires containing single- or multi-option and free form questions regarding antiplatelet clinical practice in post-PCI NSTE-ACS patients at HBR. A threshold of 75% defined 'agreement'. There was strong agreement favouring monotherapy with either aspirin or a P2Y12 inhibitor following initial DAPT, within the first year (94%). No agreement was reached on the optimal duration of DAPT or choice of monotherapy: responses were in equipoise for shorter (≤3 months, 51%) or longer (≥6 months, 46%) duration, and monotherapy choice (45% aspirin; 53% P2Y12 inhibitor). Most respondents stated use of guideline-directed tools to assess risk, although clinical judgement was preferred by 32% for assessing bleeding risk and by 46% for thrombotic risk. CONCLUSION: The crowdsourcing methodology showed potential as a tool to assess current practice and variation on a global scale and to achieve a broad demographic representation. These preliminary results indicate a high degree of variation with respect to duration of DAPT, monotherapy drug of choice following DAPT and how thrombotic and bleeding risk are assessed. Further investigations should concentrate on interrogating practice variation between key demographic groups.

Canadian Society of Transplantation White Paper: Ethical and Legal Considerations for Alcohol and Cannabis Use in Solid Organ Listing and Allocation.

Alcohol and cannabis use as a contraindication to organ transplantation is a controversial issue. Until recently, patients in Canada with alcohol-associated liver disease were required to demonstrate abstinence for 6 mo to receive a liver transplant. There is no equivalent rule that is applied consistently for cannabis use. There is some evidence that alcohol and cannabis use disorder pretransplant could be associated with worse outcomes posttransplantation. However, early liver transplantation for patients with alcohol-associated liver disease in France and in the United States has led to challenges of the 6-mo abstinence rule in Canada in the media. It has also resulted in several legal challenges arguing that the rule violates human rights laws regarding discrimination in the provision of medical services and that the rule is also unconstitutional (this challenge is still before the court). Recent legalization of cannabis use for adults in Canada has led to questions about the appropriateness of limiting transplant access based on cannabis use. The ethics committee of the Canadian Society of Transplantation was asked to provide an ethical analysis of cannabis and alcohol abstinence policies. Our conclusions were as follows: neither cannabis use nor the 6-mo abstinence rule for alcohol use should be an absolute contraindication to transplantation, and transplant could be offered to selected patients, further research should be conducted to ensure evidence-based policies; and the transplant community has a duty not to perpetuate stigma associated with alcohol and cannabis use disorders.

Concomitant Rhinoplasty and Septal Perforation Repair.

The rhinoplasty surgeon may encounter nasal septal perforations (NSPs) during the examination of the prospective rhinoplasty candidate, many of whom have had prior septal surgery. While small NSPs may be asymptomatic, larger NSPs may cause nasal obstruction, crusting, bleeding, or external nasal deformities. Septal perforation repair and rhinoplasty can be safely and effectively performed simultaneously for the appropriate surgical candidate. In this article, we review the important considerations when determining the surgical candidacy for concomitant rhinoplasty and septal perforation repair.

Phase Behavior of Amorphous Solid Dispersions of Felodipine: Homogeneity and Drug-Polymer Interactions.

In the current investigation, the role of drug-polymer hydrogen bonding (H-bonding) with respect to the phase behavior of amorphous solid dispersions (ASDs) is studied in depth on a nanometer level. Melt-quenched dispersions of felodipine (FEL) with poly(vinylpyrrolidone), or PVP, poly(vinylpyrrolidone-co-vinylacetate), or PVP/VA, and poly(vinylacetate), or PVAc, were prepared at drug loadings of 50-90% w/w. Modulated differential scanning calorimetry (MDSC) was used to detect microscopic homogeneity for each set of ASDs. A single composition dependent glass transition temperature (Tg) was observed over the entire composition range in MDSC data for each set of ASDs; however some samples within each set of ASDs showed a crystallization exotherm and corresponding melting endotherm in the first heating scan. Solid-state nuclear magnetic resonance spectroscopy (SSNMR) was further employed to understand phase homogeneity in these systems. The proton spin-lattice relaxation times in the laboratory and rotating frame (1H T1 and T1ρ) for the drug and individual polymer for each set of ASDs were measured to evaluate phase homogeneity. On the basis of proton relaxation measurements, it was revealed that FEL:PVP and FEL:PVP/VA ASDs exhibited better compositional homogeneity than FEL:PVAc ASDs. The strength and the extent of H-bonding were studied by using 13C SSNMR spectra. In addition, deconvolution of the carbonyl region of amorphous FEL revealed that 40% of amorphous FEL molecules were hydrogen bonded (H-bonded) through dimers and the remaining 60% were free/non H-bonded. The dimer fraction decreased as the polymer content increased for each set of ASDs, while the free fraction increased. This indicated that the polymers containing hydrogen bond acceptor groups disrupted dimers and formed intermolecular H-bonding interactions with FEL. The strength and extent of FEL:polymer H-bonding was rank ordered as PVP > PVP/VA > PVAc. These findings were also confirmed through DFT calculations on these systems. Our results suggest that drug-polymer H-bonding interaction may impact the phase homogeneity in ASDs formulated by a specific method. The data from the current study further demonstrate that SSNMR is a powerful tool for characterizing phase homogeneity in ASDs with sub-50 nm resolution. In addition, SSNMR can provide insights into drug-polymer interactions and speciation in ASDs.

Approach to Correction of Septal Perforation.

Iatrogenic septal perforation is a complication of nasal surgery. Small or posterior perforations cause few symptoms, and need only conservative treatment. Larger and anterior perforations contribute to nasal airflow disturbances and external nasal deformities. When considering surgical candidacy, one should consider the severity of symptoms, location and size of the perforation, and need for revsional rhinoplasty. We repair perforations using intranasal mucosal advancement flaps augmented by an interposition connective tissue graft. Septal perforation repairs are tedious and technically challenging. We review key points to minimize unintended perforation formation following nasal surgery.

Enhancing Facelift With Simultaneous Submalar Implant Augmentation.

BACKGROUND: The midface is particularly prone to the senescent changes of soft tissue ptosis and volume loss, which in individuals with aging or low adiposity can manifest as submalar hollowing. Facelift alone in those with submalar hollowing inadequately addresses the volume loss and may result in a gaunt appearance postoperatively. Submalar implant augmentation is a powerful tool for permanent midface volume restoration for a more youthful and natural contour, as opposed to soft tissue fillers that diminish over time. When performed together, submalar augmentation and facelift synergistically enhance facial rejuvenation results. OBJECTIVES: Determine the long-term safety and efficacy of submalar implant augmentation as an adjunct to facelift. METHODS: Retrospective review evaluating results and complications in all consecutive patients who had submalar implant augmentation with SMAS-plication facelift in a single surgeon private practice setting from January 1, 1991, to December 31, 2017. RESULTS: Forty-eight patients underwent submalar augmentation with simultaneous facelift with an overall satisfaction rate of 95.7%. Complications included 2.1%transient infraorbital hypoesthesia, 1.1% prolonged swelling, and 1.1% capsular contraction that required a minor adjustment under local anesthesia. No infection, implant migration, or extrusion or facial nerve injury occurred. CONCLUSIONS: Submalar implant augmentation is a safe and effective means of enhancing facelift results through midface volume restoration, subperiosteal release, and improved soft tissue suspension in a more favorable vector. Submalar implant augmentation performed simultaneously with facelift may be an attractive alternative to repeated soft tissue filler or fat injections for patients with submalar hollowing who are interested in facial rejuvenation surgery.

Contemporary Trends in the Surgical Management of Nasal Septal Perforations: A Community Survey.

There currently exists an overabundance of publications advocating different septal perforation repair methods. The objective of this article was to examine the preponderance of techniques and trends in the surgical management of septal perforations in the practices of otolaryngologists, rhinologists, and facial plastic surgeons. The study was designed as a multicenter cross-sectional survey. The participants were members of the American Academy of Facial Plastic and Reconstructive Surgery and the American Rhinologic Society. Septal perforation closure rates and perforation repair approach, technique, and interposition graft material preferences were the main outcomes. A total of 320 respondents completed the survey, of whom 75% performed perforation repairs. The success rates in closing perforations < 1 cm, 1-2 cm, and > 2 cm were 84%, 64%, and 31%, respectively. The respondents had a similar preference for the endoscopic (52%) and external rhinoplasty (49%) approaches, followed by the endonasal approach (43%). Bilateral intranasal mucosal advancement flaps (79%) and unilateral intranasal mucosal rotational or advancement flaps (60%) were the favored repair techniques. Most respondents (84%) incorporated an interposition graft and intranasal splints (89%) for the repair, and the most popular interposition graft material was acellular dermis (63%). The self-reported perforation closure success rates in this survey were lower than those published in the literature, a phenomenon possibly explained by the premise that surgeons with favorable outcomes are more apt to share their results. The preferred surgical approach was evenly distributed between the external rhinoplasty and endoscopic approaches and influenced by a surgeon's training, perforation size and location, and the need for concomitant rhinoplasty. This study is the first to characterize contemporary community trends in the surgical closure of septal perforations and demonstrates that while preference for perforation repair approach among the respondents varied, surgeons favored septal perforation repair using bilateral intranasal mucosal advancement flaps with an interposition graft.

Simultaneous Septal Perforation Repair with Septorhinoplasty: A 31-Year Experience.

Septal perforation repair and septorhinoplasty (SRP) each present unique surgical challenges. However, in many instances, these procedures may be performed together successfully. In this study, the authors aim to determine the safety and effectiveness of combining primary or revision SRP and septal perforation repair via an open approach. A retrospective review was carried out of all consecutive patients who had SRP and septal perforation repair via an open approach between 1986 and 2017 in the senior author's practice. Perforation closure in surgery and at the patient's last follow-up, resolution of presenting symptoms, cosmetic results, and complications were analyzed. Records for 141 patients who had simultaneous septal perforation repair and SRP via an open approach, with a mean follow-up of 3.24 years, were reviewed. The mean anterior-posterior perforation dimension was 1.41 ± 0.89 cm, and the mean vertical perforation dimension was 1.16 ± 0.59 cm. The most common etiologies for septal perforation were previous SRP (35.4%) and septoplasty (24.1%). An overall 93.6%, perforation closure, 91.1% symptom relief, and 91.2% patient satisfaction with cosmetic results were achieved. Septal perforations under 1.5 cm in height were closed in 96.7% of patients as opposed to 71.4% of patients with perforations 1.5 cm or taller. Minor revision rhinoplasties were performed in 7.0% of patients. Postoperative infections were rare and noted in only two (1.4%) patients. In the largest study of its kind to date, the authors have shown that in experienced hands septal perforation repair may be performed simultaneously with primary or revision SRP via an open approach without compromising the perforation repair outcome. The vertical dimension of a septal perforation and presence of mucosa above and below a perforation are important considerations for the difficulty of a perforation closure, as septal mucosa is recruited from these locations in our technique of four-quadrant intranasal bipedicled mucosal advancement flap closure.

Clinical practices and attitudes regarding the diagnosis and management of heart failure: findings from the CORE Needs Assessment Survey.

AIMS: CORE is a continuing medical education initiative designed to support the evidence-based management of heart failure (HF) in the primary and secondary care settings. The goal of the CORE Needs Assessment Survey is to describe current clinical practice patterns and attitudes among global stakeholders in HF care. METHODS AND RESULTS: The CORE Steering Committee guided the development of survey questions to assess clinical practice, confidence, and attitudes/perceptions among cardiologists, primary care physicians, and nurses involved in HF management. In total, 346 healthcare professionals from Australia (n = 59), Austria (n = 59), Canada (n = 60), Spain (n = 58), Sweden (n = 52), and the UK (n = 58) contributed survey data. Results revealed multiple gaps over the spectrum of HF care, including diagnosis (low recognition of the signs and symptoms of HF and limited use of diagnostic tests), treatment planning (underuse of recommended agents and subtherapeutic dosing), treatment monitoring and adjustment (lack of adherence to recommendations), and long-term management (low confidence in providing patient education). Although primary care and specialist physicians and nurses shared common unmet needs, healthcare professional-specific clinical gaps were also identified. CONCLUSIONS: The CORE Needs Assessment Survey provides timely data describing current clinical practices and attitudes among physicians and nurses regarding key aspects of HF care. These findings will be useful for guiding the development of interventions tailored to the specific educational needs of different provider types and designed to support the evidence-based care of patients with HF.