Characterizing the Rhinoplasty Outcomes Most Important to Patients, Surgeons, and the General Population.

Understanding rhinoplasty characteristics important to patients, physicians, and society is essential for evaluating outcomes and designing optimal treatment plans. The authors aimed to elucidate specific rhinoplasty-related outcomes that are most important to patients, surgeons, and the general population. A cross-sectional survey comprising 11 rhinoplasty-specific characteristics, was distributed to patients, facial plastic surgeons, and the general population. Adult patients presenting for rhinoplasty consideration or follow-up after undergoing rhinoplasty were recruited. Characteristics rankings were compared between the 3 respondent groups using Spearman's rank correlation coefficient (ρ). Responses from 150 surgeons, 111 patients, and 102 lay individuals from the general population were included for analysis. When ranking rhinoplasty-specific characteristics in order of importance, patients and the general population ranked "ability to breathe through nose while awake" first and "overall appearance of nose" as second. Surgeons ranked "overall appearance of nose" first and "ability to breathe through nose while awake" second. There were strong correlations between patients' and surgeons' rankings (Spearman's ρ=0.836, P =0.002), between patients' and the general population's rankings (Spearman's ρ=0.773, P =0.007), and between surgeons' and the general population's rankings (Spearman's ρ=0.782, P =0.006). Our results highlight a significant correlation between characteristics of the "ideal" nose as determined by patients, surgeons, and the general population.

Facial Rejuvenation in a Patient With Granulomatosis With Polyangiitis-Treatment Protocol for Compromised Skin Flap.

Facial rejuvenation outcomes have not been well studied in patients with granulomatosis with polyangiitis (GP)-formerly Wegener granulomatosis. This report highlights a case of a 49-year-old female with a history of GP, presenting with facial aging and functional nasal concerns. The patient underwent facial rejuvenation and nasal reconstruction procedures, including primary open functional rhinoplasty, septal perforation repair with Alloderm, deep-plane rhytidectomy, platysmaplasty, nanofat grafting, and fractionated erbium laser to the face (sparing the nose and peri-incisional areas). Despite a routine operation, postoperative course was complicated by wound healing and vascular congestion issues related to her underlying autoimmune disease. This case highlights the risks associated with postsurgical healing in patients with GP undergoing esthetic surgery. To the best of our knowledge, this report is the first to discuss management considerations in a patient with GP undergoing facial rejuvenation surgery.

Rhinoplasty for Thick-Skinned Noses: A Systematic Review.

OBJECTIVE: The purpose of this systematic review is to critically examine the literature published on rhinoplasties in thick-skinned patients to determine how to maximize outcomes in these patients. METHODS: The PubMEd and Google Scholar databases were searched for clinical studies related to nasal skin thickness as it relates to rhinoplasty surgery and surgical outcomes. RESULTS: We performed a review of the current body of literature and identified twenty-eight articles that met our inclusion criteria for final analysis. Three articles were level of evidence 1 by CEBM guidelines, while the majority were level 4 (39%) and 5 (32%). Most papers were published in the USA (35%), followed by Saudi Arabia (14%). Here, we outline the current body of literature regarding thick-skinned noses in rhinoplasty surgery and identify optimization strategies. CONCLUSION: We highlight a management scheme subdivided into preoperative, intraoperative and postoperative timepoints for the comprehensive management of this patient population. Optimal results rely on an individualized medical and surgical treatment plan and regimen to achieve desired and realistic results. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Utilization of Leech Therapy after Rhinoplasty.

BACKGROUND: The use of medicinal leeches in modern reconstructive surgery is well-described. Leech therapy after rhinoplasty has not been previously well-characterized. METHODS: The medical records of all patients who underwent open rhinoplasty by a single surgeon over a 4-year period were reviewed. Patient demographics, including age, sex, medical comorbidities, number of previous rhinoplasty surgeries, time to utilization of leech therapy, adjunct therapies used, resolution of skin changes, and smoking status, were recorded. Operative reports were reviewed for pertinent information, including number of tip grafts used, graft materials used, and placement of septal extension grafts or "unicorn" grafts. RESULTS: Between April of 2016 and March of 2020, 545 patients underwent rhinoplasty performed by the senior author (P.S.N.). Of these patients, 39 (7.2 percent) underwent leech therapy postoperatively. The mean age of included patients was 47.4 years. Of the patients who required leech therapy, 34 (87.2 percent) had undergone revision rhinoplasty. The mean number of previous rhinoplasties was 3.4. The mean number of tip grafts used was 2.6. Thirty-three patients (84.6 percent) had either a traditional septal extension graft or unicorn graft placed. Nine patients (23.1 percent) were former smokers. Complete resolution of skin color changes was seen in 38 patients (97.4 percent). There were no major complications after leech therapy. CONCLUSIONS: Leech therapy is a useful tool for the rhinoplasty surgeon, particularly in the setting of complex revision rhinoplasty, in patients who have undergone multiple previous nasal surgical procedures, or in patients who require significant cartilage grafting to reconstruct the nasal tip or lengthen the nose. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

A Live-Cell Imaging Assay for Nuclear Entry of cAMP-Dependent Protein Kinase Catalytic Subunits Stimulated by Endogenous GPCR Activation.

Nuclear entry of cAMP-dependent protein kinase catalytic subunits is typically inferred from changes in net protein amount or kinase activity in the nucleus. Previous methods to directly assess nuclear entry require kinase subunit overexpression and/or supraphysiological cAMP elevation. We describe a method to detect nuclear entry of catalytic subunits expressed at an endogenous level in living cells, stimulated by cAMP in a physiological range, and in real time.

Endosomal cAMP production broadly impacts the cellular phosphoproteome.

Endosomal signaling downstream of G-protein-coupled receptors (GPCRs) has emerged as a novel paradigm with important pharmacological and physiological implications. However, our knowledge of the functional consequences of intracellular signaling is incomplete. To begin to address this gap, we combined an optogenetic approach for site-specific generation of the prototypical second messenger generated by active GPCRs, cyclic AMP (cAMP), with unbiased mass-spectrometry-based analysis of the phosphoproteome. We identified 218 unique, high-confidence sites whose phosphorylation is either increased or decreased in response to cAMP elevation. We next determined that the same amount of cAMP produced from the endosomal membrane led to more robust changes in phosphorylation than the plasma membrane. Remarkably, this was true for the entire repertoire of 218 identified targets and irrespective of their annotated subcellular localizations (endosome, cell surface, nucleus, cytosol). Furthermore, we identified a particularly strong endosome bias for a subset of proteins that are dephosphorylated in response to cAMP. Through bioinformatics analysis, we established these targets as putative substrates for protein phosphatase 2A (PP2A), and we propose compartmentalized activation of PP2A by cAMP-responsive kinases as the likely underlying mechanism. Altogether, our study extends the concept that endosomal signaling is a significant functional contributor to cellular responsiveness to cAMP by establishing a unique role for localized cAMP production in defining categorically distinct phosphoresponses.

Multiscale modeling meets machine learning: What can we learn?

Machine learning is increasingly recognized as a promising technology in the biological, biomedical, and behavioral sciences. There can be no argument that this technique is incredibly successful in image recognition with immediate applications in diagnostics including electrophysiology, radiology, or pathology, where we have access to massive amounts of annotated data. However, machine learning often performs poorly in prognosis, especially when dealing with sparse data. This is a field where classical physics-based simulation seems to remain irreplaceable. In this review, we identify areas in the biomedical sciences where machine learning and multiscale modeling can mutually benefit from one another: Machine learning can integrate physics-based knowledge in the form of governing equations, boundary conditions, or constraints to manage ill-posted problems and robustly handle sparse and noisy data; multiscale modeling can integrate machine learning to create surrogate models, identify system dynamics and parameters, analyze sensitivities, and quantify uncertainty to bridge the scales and understand the emergence of function. With a view towards applications in the life sciences, we discuss the state of the art of combining machine learning and multiscale modeling, identify applications and opportunities, raise open questions, and address potential challenges and limitations. We anticipate that it will stimulate discussion within the community of computational mechanics and reach out to other disciplines including mathematics, statistics, computer science, artificial intelligence, biomedicine, systems biology, and precision medicine to join forces towards creating robust and efficient models for biological systems.

Spatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network.

G-protein-coupled receptor-regulated cAMP production from endosomes can specify signaling to the nucleus by moving the source of cAMP without changing its overall amount. How this is possible remains unknown because cAMP gradients dissipate over the nanoscale, whereas endosomes typically localize micrometers from the nucleus. We show that the key location-dependent step for endosome-encoded transcriptional control is nuclear entry of cAMP-dependent protein kinase (PKA) catalytic subunits. These are sourced from punctate accumulations of PKA holoenzyme that are densely distributed in the cytoplasm and titrated by global cAMP into a discrete metastable state, in which catalytic subunits are bound but dynamically exchange. Mobile endosomes containing activated receptors collide with the metastable PKA puncta and pause in close contact. We propose that these properties enable cytoplasmic PKA to act collectively like a semiconductor, converting nanoscale cAMP gradients generated from endosomes into microscale elevations of free catalytic subunits to direct downstream signaling.

Correction of the Overly Shortened Nose.

The overly shortened nose can often be the result of previous rhinoplasty. The causes can include weakening or missing cartilage for nasal tip support as well as contraction and scarring of the skin. The purpose of this article was to provide the authors' approach to this deformity.

NIH BRAIN Circuits Programs: An Experiment in Supporting Team Neuroscience.

The NIH BRAIN Initiative is aimed at revolutionizing our understanding of the human brain. Here, we present a discussion of support for team research in investigative neuroscience at different stages and on various scales.

The promise of the BRAIN initiative: NIH strategies for understanding neural circuit function.

New neurotechnologies fueled by the BRAIN Initiative now allow investigators to map, monitor and modulate complex neural circuits, enabling the pursuit of research questions previously considered unapproachable. Yet it is the convergence of molecular neuroscience with the new systems neuroscience that promises the greatest future advances. This is particularly true for our understanding of nervous system disorders, some of which have known molecular drivers or pathology but result in unknown perturbations in circuit function. NIH-supported research on "BRAIN Circuits" programs integrate experimental, analytic, and theoretical capabilities for analysis of specific neural circuits and their contributions to perceptions, motivations, and actions. In this review, we describe the BRAIN priority areas, review our strategy for balancing early feasibility with mature projects, and the balance of individual with team science for this 'BRAIN Circuits' program. We also highlight the diverse portfolio of techniques, species, and neural systems represented in these projects.

Credible practice of modeling and simulation in healthcare: ten rules from a multidisciplinary perspective.

The complexities of modern biomedicine are rapidly increasing. Thus, modeling and simulation have become increasingly important as a strategy to understand and predict the trajectory of pathophysiology, disease genesis, and disease spread in support of clinical and policy decisions. In such cases, inappropriate or ill-placed trust in the model and simulation outcomes may result in negative outcomes, and hence illustrate the need to formalize the execution and communication of modeling and simulation practices. Although verification and validation have been generally accepted as significant components of a model's credibility, they cannot be assumed to equate to a holistic credible practice, which includes activities that can impact comprehension and in-depth examination inherent in the development and reuse of the models. For the past several years, the Committee on Credible Practice of Modeling and Simulation in Healthcare, an interdisciplinary group seeded from a U.S. interagency initiative, has worked to codify best practices. Here, we provide Ten Rules for credible practice of modeling and simulation in healthcare developed from a comparative analysis by the Committee's multidisciplinary membership, followed by a large stakeholder community survey. These rules establish a unified conceptual framework for modeling and simulation design, implementation, evaluation, dissemination and usage across the modeling and simulation life-cycle. While biomedical science and clinical care domains have somewhat different requirements and expectations for credible practice, our study converged on rules that would be useful across a broad swath of model types. In brief, the rules are: (1) Define context clearly. (2) Use contextually appropriate data. (3) Evaluate within context. (4) List limitations explicitly. (5) Use version control. (6) Document appropriately. (7) Disseminate broadly. (8) Get independent reviews. (9) Test competing implementations. (10) Conform to standards. Although some of these are common sense guidelines, we have found that many are often missed or misconstrued, even by seasoned practitioners. Computational models are already widely used in basic science to generate new biomedical knowledge. As they penetrate clinical care and healthcare policy, contributing to personalized and precision medicine, clinical safety will require established guidelines for the credible practice of modeling and simulation in healthcare.

Advanced technologies for intuitive control and sensation of prosthetics.

The Department of Defense, Department of Veterans Affairs and National Institutes of Health have invested significantly in advancing prosthetic technologies over the past 25 years, with the overall intent to improve the function, participation and quality of life of Service Members, Veterans, and all United States Citizens living with limb loss. These investments have contributed to substantial advancements in the control and sensory perception of prosthetic devices over the past decade. While control of motorized prosthetic devices through the use of electromyography has been widely available since the 1980s, this technology is not intuitive. Additionally, these systems do not provide stimulation for sensory perception. Recent research has made significant advancement not only in the intuitive use of electromyography for control but also in the ability to provide relevant meaningful perceptions through various stimulation approaches. While much of this previous work has traditionally focused on those with upper extremity amputation, new developments include advanced bidirectional neuroprostheses that are applicable to both the upper and lower limb amputation. The goal of this review is to examine the state-of-the-science in the areas of intuitive control and sensation of prosthetic devices and to discuss areas of exploration for the future. Current research and development efforts in external systems, implanted systems, surgical approaches, and regenerative approaches will be explored.

Management of Surgical Scars.

An ideal scar is flat, thin, and color matched to the surrounding skin. Incision planning, skin closure, and postoperative care are vital to create an inconspicuous scar. Depressed, hypertrophic, and keloid scars each pose unique challenges to the facial plastic surgeon. Several surgical and nonsurgical options exist in the treatment of scars. Appropriate treatment is based on scar location, quality, and size as well as patient history, preferences, and expectations. This article discusses techniques for prevention and treatment options for unsightly and hypertrophic scars.

Platelet-Rich Plasma for Skin Rejuvenation: Facts, Fiction, and Pearls for Practice.

Platelet-rich plasma (PRP) has gained popularity in facial plastic surgery because of its role in wound healing. PRP, having a higher concentration of platelets, allows for greater release of growth factors and biologically active proteins, which in turn activates the wound-healing cascade stimulating neoangiogenesis and collagen production. One of the most popular uses for PRP is for facial skin rejuvenation in the form of dermal injections and topical application during microneedling. The promising nature of PRP makes using it for injection and/or in conjunction with microneedling a good addition to any practice that deals with skin rejuvenation.

Single-incision sural nerve harvest: Technical considerations for cross-facial nerve grafting.

b.a. is the senior author and performed all of the procedures described, and conceptualized and edited the article. l.e.i. was responsible for data collection and analysis, editing the manuscript, and compiling the figures. d.b.y. performed the first single-incision nerve harvest with b.a. and is responsible for b.a. adopting the practice. b.l. is b.a.'s partner and assisted with the majority of surgeries and proofread the manuscript. g.g.m. was cosurgeon on many of the described cases and is partly responsible for conceptualizing the article. g.l.p. was responsible for data collection and writing of the original manuscript and compiling the illustrations. Laryngoscope, 129:2464-2466, 2019.

Modified Selective Neurectomy for the Treatment of Post-Facial Paralysis Synkinesis.

BACKGROUND: To address functional and smile dysfunction associated with post-facial paralysis synkinesis, the senior author (B.A.) has offered "modified selective neurectomy" of the lower division of the facial nerve as a long-term solution. This article examines technical considerations and outcomes of this procedure. METHODS: A retrospective review was conducted of patients who underwent modified selective neurectomy of buccal and cervical branches of the facial nerve performed by a single surgeon over a 4½-year period. House-Brackmann facial grading scores, electronic clinician-graded facial function scale, and onabotulinumtoxinA (botulinum toxin type A) dosages were examined before and after the procedure. RESULTS: Sixty-three patients underwent modified selective neurectomy between June 20, 2013, and August 12, 2017. There were no serious complications. The revision rate was 17 percent. Temporary oral incompetence was reported in seven patients (11 percent) postoperatively. A statistically significant improvement was achieved in electronic clinician-graded facial function scale analysis of nasolabial fold depth at rest, oral commissure movement with smile, nasolabial fold orientation with smile, nasolabial depth with smile, depressor labii inferioris lower lip movement, midfacial synkinesis, mentalis synkinesis, platysmal synkinesis, static score, dynamic score, synkinesis score, periocular score, lower face and neck score, and midface and smile score. There was a significant decrease in botulinum toxin type A dosage and House-Brackmann score after surgery. CONCLUSION: Modified selective neurectomy of the buccal and cervical divisions of the facial nerve is an effective long-term treatment for smile dysfunction in patients with post-facial paralysis synkinesis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The State of the NIH BRAIN Initiative.

The BRAIN Initiative arose from a grand challenge to "accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought." The BRAIN Initiative is a public-private effort focused on the development and use of powerful tools for acquiring fundamental insights about how information processing occurs in the central nervous system (CNS). As the Initiative enters its fifth year, NIH has supported >500 principal investigators, who have answered the Initiative's challenge via hundreds of publications describing novel tools, methods, and discoveries that address the Initiative's seven scientific priorities. We describe scientific advances produced by individual laboratories, multi-investigator teams, and entire consortia that, over the coming decades, will produce more comprehensive and dynamic maps of the brain, deepen our understanding of how circuit activity can produce a rich tapestry of behaviors, and lay the foundation for understanding how its circuitry is disrupted in brain disorders. Much more work remains to bring this vision to fruition, and the National Institutes of Health continues to look to the diverse scientific community, from mathematics, to physics, chemistry, engineering, neuroethics, and neuroscience, to ensure that the greatest scientific benefit arises from this unique research Initiative.