Nasal Osteotomies Revisited in Asians: Surface Aesthetics, Anatomical and Technical Considerations.

Background Although osteotomy is commonly performed in rhinoplasty, it is difficult for less experienced surgeon to understand mechanism of the procedure. The primary goal of this study is to improve understanding of nasal osteotomy in Asians by considering the surface aesthetics and anatomy of the nose as well as their relationships with the surgical procedure. Methods Surface aesthetics, anatomic considerations, kinetics of medial and lateral osteotomy, fracture levels of osteotomy were discussed in detail by reviewing the previous publications and 18 years of our experience. Moreover, the technical details of osteotomy were explained and personal tips for performing successful osteotomy were described. Results Dorsal and lateral aesthetic lines, dorsal and basal widths are main characteristics related to the surface aesthetics of nose to perform the osteotomy. In addition, these features are different in Asian population due to the anatomic difference with Caucasians, which makes the procedure difficult and requires more attention to perform osteotomy. Conclusion Because osteotomy is one of the most traumatic and invasive part of the rhinoplasty, it is crucial for the rhinoplasty surgeon to understand the relationship between surface aesthetics and osteotomy techniques to produce consistent and reproducible results.

Surgical anatomy for Asian rhinoplasty: Part III.

This article, which comprises the third part of a series on surgical anatomy for Asian rhinoplasty, addresses the lower one-third of the nose, including the alar cartilage and tip-supporting structures, known as distal mobile framework. As discussed in earlier parts of this series, diversity in surgical anatomy results in different surgical techniques in Asian rhinoplasty compared to rhinoplasty in Caucasian patients. Nasal tip structures are especially important due to their crucial importance for changing the nasal shape in Asians. This article, along with the previous ones, will provide both basic and advanced knowledge of practical surgical anatomy for Asian rhinoplasty.

Swing Door Compressive Fracture Technique for Turbinoplasty: Retrospective Study Based on Computed Tomography and NOSE Scale.

BACKGROUND: Treatment of inferior turbinate hypertrophy is performed using different techniques in rhinoplasty. However, the reported results are not consistent. In this study, we aimed to evaluate the outcomes of Swing door compressive fracture (SDCF) technique for turbinoplasty using computed tomography (CT) and Nasal Obstruction Symptom Evaluation (NOSE) scale. METHODS: This study involved retrospective analysis of 24 patients who underwent inferior turbinoplasty using Swing door compressive fracture (SDCF) technique with or without septoplasty. The angle between the inferior turbinate and lateral nasal wall, total area, inferior turbinate area and the area medial to inferior turbinate were measured preoperatively and postoperatively using coronal section CT images for objective evaluation. Moreover, the NOSE scale was used for subjective evaluation. RESULTS: The angle between inferior turbinate and lateral nasal wall was decreased by 25.3% after the treatment (p <0.0001). Inevitably, postoperative total nasal airway area (area 1) did not face a statistically significant change (p = 0.6878). On the other hand, the area of inferior turbinate (area 2) decreased significantly compared to preoperative value (p = 0.0021), while the area 3, the area medial to inferior turbinate was widened 1.5 times postoperatively. The total preoperative NOSE score was moderate (39.58 ± 22.31%) and it was decreased to mild (5.83 ± 8.81%) after the treatment (p <0.0001). CONCLUSIONS: The Swing door compressive fracture (SDCF) technique for turbinoplasty is an effective and straightforward modality. However, the further study involving more patients and longer follow-up period is mandatory. LEVEL OF EVIDENCE IV: 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 .

SL-Cloud: A Cloud-based resource to support synthetic lethal interaction discovery.

Synthetic lethal interactions (SLIs), genetic interactions in which the simultaneous inactivation of two genes leads to a lethal phenotype, are promising targets for therapeutic intervention in cancer, as exemplified by the recent success of PARP inhibitors in treating BRCA1/2-deficient tumors. We present SL-Cloud, a new component of the Institute for Systems Biology Cancer Gateway in the Cloud (ISB-CGC), that provides an integrated framework of cloud-hosted data resources and curated workflows to enable facile prediction of SLIs. This resource addresses two main challenges related to SLI inference: the need to wrangle and preprocess large multi-omic datasets and the availability of multiple comparable prediction approaches. SL-Cloud enables customizable computational inference of SLIs and testing of prediction approaches across multiple datasets. We anticipate that cancer researchers will find utility in this tool for discovery of SLIs to support further investigation into potential drug targets for anticancer therapies.

Circulating exosomal microRNA expression patterns distinguish cardiac sarcoidosis from myocardial ischemia.

OBJECTIVE: Cardiac sarcoidosis is difficult to diagnose, often requiring expensive and inconvenient advanced imaging techniques. Circulating exosomes contain genetic material, such as microRNA (miRNA), that are derived from diseased tissues and may serve as potential disease-specific biomarkers. We thus sought to determine whether circulating exosome-derived miRNA expression patterns would distinguish cardiac sarcoidosis (CS) from acute myocardial infarction (AMI). METHODS: Plasma and serum samples conforming to CS, AMI or disease-free controls were procured from the Biologic Specimen and Data Repository Information Coordinating Center repository and National Jewish Health. Next generation sequencing (NGS) was performed on exosome-derived total RNA (n = 10 for each group), and miRNA expression levels were compared after normalization using housekeeping miRNA. Quality assurance measures excluded poor quality RNA samples. Differentially expressed (DE) miRNA patterns, based upon >2-fold change (p < 0.01), were established in CS compared to controls, and in CS compared to AMI. Relative expression of several DE-miRNA were validated by qRT-PCR. RESULTS: Despite the advanced age of the stored samples (~5-30 years), the quality of the exosome-derived miRNA was intact in ~88% of samples. Comparing plasma exosomal miRNA in CS versus controls, NGS yielded 18 DE transcripts (12 up-regulated, 6 down-regulated), including miRNA previously implicated in mechanisms of myocardial injury (miR-92, miR-21) and immune responses (miR-618, miR-27a). NGS further yielded 52 DE miRNA in serum exosomes from CS versus AMI: 5 up-regulated in CS; 47 up-regulated in AMI, including transcripts previously detected in AMI patients (miR-1-1, miR-133a, miR-208b, miR-423, miR-499). Five miRNAs with increased DE in CS included two isoforms of miR-624 and miR-144, previously reported as markers of cardiomyopathy. CONCLUSIONS: MiRNA patterns of exosomes derived from CS and AMI patients are distinct, suggesting that circulating exosomal miRNA patterns could serve as disease biomarkers. Further studies are required to establish their specificity relative to other cardiac disorders.

Radiologic Analysis of Malar Arch Movement in Reduction Malarplasty Without Bony Resection.

BACKGROUND: Reduction malarplasty has been popular among Asians with a wide facial width. In general, malar setback after bony resection is regarded as the standard objective of reduction malarplasty. However, unnecessary bony resection may lead to various postoperative complications. Therefore, we suggest the use of reduction malarplasty without bony resection to achieve a similar narrowing effect of the facial width, based on radiographic analysis of malar arch movement. PATIENTS AND METHODS: This retrospective study analyzed 48 patients with a wide midface who underwent reduction malarplasty between September 2018 and December 2019. We included 40 cases of advancement repositioning malarplasty (AR) without bony resection and 8 cases of setback reduction malarplasty (SR) with bony resection. The three-dimensional position of the malar arch expressed by coordinates (x, y, and z) on three-dimensional computed tomography scans was used to compare the positional change between the surgical methods. The paired t-test, Wilcoxon text, and independent t-test were used in data analysis, and statistical analysis was performed using SPSS 23.0 software. RESULTS: Medial and superior movement of the freed malar arch segment was significantly different between AR and SR (P < 0.05). Although medialization and superiorization were not significantly different between AR and SR, there was a significant difference in anterior-posterior movement between AR and SR (P < 0.05). CONCLUSION: The radiologic analysis based on malar arch movement between AR and SR showed similar narrowing effects on medialization and superiorization of the malar arch regardless of bony resection. Therefore, the AR can be effectively applied in case of arch dominant type or malar asymmetry. In addition, further comprehensive study including analysis on movement of facial soft tissue following malar bony movement is expected based on this study in near future.

Deviated nose: Physiological and pathological changes of the nasal cavity.

Deviated nose is highly challenging in rhinoplasty since the surgeon should consider both aesthetic and functional aspects of the nose. Deviated nose correction is surgically complex, and a thorough understanding of the mechanical and physiological changes of intranasal structures, including the septum and turbinates, is necessary for functional improvement.

Cadaveric study of deep temporal fascia for autologous rhinoplasty grafts: Dimensions of the temporal compartment in Asians.

BACKGROUND: Due to the anatomical complexity of the deep temporal fascia (DTF), practical guidelines for its safe harvest are lacking. However, since the upper temporal compartment (UTC) contains no vital structures, it may provide safe access for DTF harvest. This study aimed to identify the anatomical structures of the temporal compartment in Asian cadavers and to measure their dimensions to enable safe DTF harvest. METHODS: The anatomical structures surrounding the temporal compartment were identified in 27 hemifaces from 15 Korean cadavers. After dissection, digital images were acquired and craniometric landmarks were placed upon them to identify the boundaries of the temporal compartment. The horizontal and vertical lengths of the temporal compartment were measured and their surface areas were computationally assessed. Subsequently, differences in the results by sex were evaluated. RESULTS: The five-layer anatomical structure of the UTC was clearly visualized. The UTC was bounded by the temporal septa superiorly and inferiorly, the innominate fascia laterally, and the DTF medially. No vital structures were present within the UTC. The vertical and horizontal lengths of the UTC were 6.41±0.67 cm and 10.44±0.83 cm, respectively, and the surface area of the UTC was 48.52±5.65 cm2. No statistically significant differences were observed in any dimensions between male and female patients. CONCLUSIONS: During rhinoplasty, DTF can be harvested as an autologous graft material from the UTC. An anatomical understanding of the UTC will aid in the safe and simple harvest of a sufficient amount of DTF.

In Vitro and in Vivo Biocompatibility and Degradability Evaluation of Modified Polydioxanone Plate.

BACKGROUND: Polydioxanone (PDS) has been widely used in the medical field over the past 30 years. In the 2000s, PDS plate began to be used for rhinoplasty and septoplasty. However, in Asia PDS plates are not widely used due to lack of awareness and high prices. The authors devised a method of producing a modified PDS (m-PDS; Rhinoblock Material & Design Co., Gyeonggi-do, Sothh Korea) at low cost, and compared the biocompatibilities and degradabilities of plates produced with m-PDS and commercial PDS plates (Ethicon, Somerville, NJ) in vivo and in vitro. METHODS: The melting point and decomposition rate of m-PDS were determined by differential scanning calorimetry and thermogravimetric analysis and its tensile strength was also measured. Implants (1 cm × 1 cm × 0.15 mm sized) were inserted subcutaneously into mice and harvested en bloc 2, 5, 10, 15, or 25 weeks later. Tissues were stained with hematoxylin and eosin or Masson's trichrome to evaluate inflammation, extracellular matrix deposition, and vascularization, and plate degradability was also assessed. RESULTS: No significant difference was observed between the thermal analysis and tensile test results of m-PDS and PDS plates. m-PDS started to degrade in vivo from around 10 weeks, and commercial PDS plates from around 15 weeks. After 25 weeks in vivo, both products were completely degraded and not observed in tissue slides. Histologic analysis of excised specimens showed m-PDS and PDS were similar in terms of inflammation, extracellular matrix deposition, and vascularization. CONCLUSION: In vivo and in vitro experiments detected no significant difference between the biocompatibilities and degradabilities of modified and commercial PDS plates. The results of this study suggest that the modified PDS can be used to produce versatile, low cost, absorbable graft materials for rhinoplasty and septoplasty.

Chronic elevation of plasma vascular endothelial growth factor-A (VEGF-A) is associated with a history of blast exposure.

Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [18F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blast-related mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.

Surgical anatomy for Asian rhinoplasty: Part II.

Surgical anatomy for Asian rhinoplasty Part I reviewed layered anatomy with neurovascular system of the nose. Part II discusses upper two-thirds of nose which consists of nasal bony and cartilaginous structures. Nasal physiology is mentioned briefly since there are several key structures that are important in nasal function. Following Part III will cover lower one-third of nose including in-depth anatomic structures which are important for advanced Asian rhinoplasty.

Composition of Caenorhabditis elegans extracellular vesicles suggests roles in metabolism, immunity, and aging.

The nematode Caenorhabditis elegans has been instrumental in the identification of evolutionarily conserved mechanisms of aging. C. elegans also has recently been found to have evolutionarily conserved extracellular vesicle (EV) signaling pathways. We have been developing tools that allow for the detailed study of EV biology in C. elegans. Here we apply our recently published method for high specificity purification of EVs from C. elegans to carry out target-independent proteomic and RNA analysis of nematode EVs. We identify diverse coding and non-coding RNA and protein cargo types commonly found in human EVs. The EV cargo spectrum is distinct from whole worms, suggesting that protein and RNA cargos are actively recruited to EVs. Gene ontology analysis revealed C. elegans EVs are enriched for extracellular-associated and signaling proteins, and network analysis indicates enrichment for metabolic, immune, and basement membrane associated proteins. Tissue enrichment and gene expression analysis suggests the secreted EV proteins are likely to be derived from intestine, muscle, and excretory tissue. An unbiased comparison of the EV proteins with a large database of C. elegans genome-wide microarray data showed significant overlap with gene sets that are associated with aging and immunity. Taken together our data suggest C. elegans could be a promising in vivo model for studying the genetics and physiology of EVs in a variety of contexts including aging, metabolism, and immune response.

Circulating MicroRNAs and Extracellular Vesicle-Containing MicroRNAs as Response Biomarkers of Anti-programmed Cell Death Protein 1 or Programmed Death-Ligand 1 Therapy in NSCLC.

INTRODUCTION: Anti-programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) antibody therapy is a standard treatment for advanced NSCLC, and PD-L1 immunohistochemistry is used as a predictive biomarker for therapeutic response. However, because not all patients with NSCLC with high PD-L1 respond, and some patients with low PD-L1 expression exhibit durable benefit, more accurate predictive biomarkers are needed. Circulating microRNA (miRNA) and miRNA packaged in extracellular vesicles (EVs) are believed to play a role in intercellular communication among immune cells and between immune cells and tumor cells and may represent a good source of mechanism-related biomarkers. METHODS: Pretreatment plasma of patients with advanced NSCLC treated with single-agent anti-PD-1 or anti-PD-L1 antibody was used in this study. Plasma EVs were isolated using size-exclusion chromatography. Whole plasma and EV-containing RNAs were extracted. The miRNA profile was analyzed with a next-generation sequencing platform. RESULTS: Samples from 14 responders (patients who exhibited partial response or stable disease ≥6 mo) and 15 nonresponders (patients who exhibited progressive disease as per Response Evaluation Criteria in Solid Tumors) were analyzed. In total, 32 miRNAs (p = 0.0030-0.0495) from whole plasma and seven EV-associated miRNAs (p = 0.041-0.0457) exhibited significant concentration differences between responders and nonresponders. The results of some of these circulating miRNAs were validated in a separate cohort with eight responders and 13 nonresponders. The tumor PD-L1 level was also assessed using immunohistochemistry for patients involved in both cohorts. CONCLUSIONS: Specific circulating miRNAs in whole plasma and plasma EVs are differentially expressed between responders and nonresponders and have potential as predictive biomarkers for anti-PD-1/PD-L1 treatment response.

Author Correction: New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Alterations in Plasma microRNA and Protein Levels in War Veterans with Chronic Mild Traumatic Brain Injury.

Blast-related mild traumatic brain injury (mTBI) is considered the "signature" injury of the wars in Iraq and Afghanistan. Identifying biomarkers that could aid in diagnosis and assessment of chronic mTBI are urgently needed, as little progress has been made toward identifying blood-based biomarkers of repetitive mTBI in the chronic state. Addressing this knowledge gap is especially important in the population of military veterans who are receiving assessment and care often years after their last exposure. Circulating microRNAs (miRNAs), especially those encapsulated in extracellular vesicles (EVs), have gained interest as a source of biomarkers for neurological conditions. To identify biomarkers for chronic mTBI, we used next generation sequencing (NGS) to analyze miRNAs in plasma and plasma-derived EVs from 27 Iraq and Afghanistan war veterans with blast-related chronic mTBI, 11 deployed veteran non-TBI controls, and 31 civilian controls. We identified 32 miRNAs in plasma and 45 miRNAs in EVs that significantly changed in the chronic mTBI cohort compared with control groups. These miRNAs were predominantly associated with pathways involved in neuronal function, vascular remodeling, blood-brain barrier integrity, and neuroinflammation. In addition, the plasma proteome was analyzed and showed that the concentrations of C-reactive protein (CRP) and membrane metalloendopeptidase (MME) were elevated in chronic mTBI samples. These plasma miRNAs and proteins could potentially be used as biomarkers and provide insights into the molecular processes associated with the long-term health outcomes associated with blast-related chronic mTBI.

Core transcriptional regulatory circuits in prion diseases.

Complex diseases involve dynamic perturbations of pathophysiological processes during disease progression. Transcriptional programs underlying such perturbations are unknown in many diseases. Here, we present core transcriptional regulatory circuits underlying early and late perturbations in prion disease. We first identified cellular processes perturbed early and late using time-course gene expression data from three prion-infected mouse strains. We then built a transcriptional regulatory network (TRN) describing regulation of early and late processes. We found over-represented feed-forward loops (FFLs) comprising transcription factor (TF) pairs and target genes in the TRN. Using gene expression data of brain cell types, we further selected active FFLs where TF pairs and target genes were expressed in the same cell type and showed correlated temporal expression changes in the brain. We finally determined core transcriptional regulatory circuits by combining these active FFLs. These circuits provide insights into transcriptional programs for early and late pathophysiological processes in prion disease.

Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease.

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that (1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or (2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2, and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin, or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.

Distinct Profiles of Cell-Free MicroRNAs in Plasma of Veterans with Post-Traumatic Stress Disorder.

Dysregulation of circulating microRNAs (miRNAs) in body fluids has been reported in psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, and post-traumatic stress disorder (PTSD). Recent studies of various diseases showed that extracellular vesicles (EV) in body fluids can provide different spectra of circulating miRNAs and disease-associated signatures from whole fluid or EV-depleted fraction. However, the association of miRNAs in EVs to PTSD has not been studied. In this study, we performed a comprehensive profiling of miRNAs in whole plasma, extracellular vesicles (EV) and EV-depleted plasma (EVD) samples collected from combat veterans with PTSD and matched controls by utilizing a next-generation sequencing (NGS) platform. In total, 520 circulating miRNAs were quantified from 24 male Iraq and Afghanistan combat veterans with (n = 12) and without (n = 12) PTSD. The overall miRNA profiles in whole plasma, EV and EVD fractions were different and miRNAs affected by PTSD were also distinct in each sample type. The concentration changes of miR-203a-3p in EV and miR-339-5p in EVD were confirmed in an independent validation cohort that consisted of 20 veterans (10 with and 10 without PTSD) using qPCR. The target genes of these two miRNAs were involved in signaling pathways and comorbid conditions associated with PTSD (e.g., neurotransmitter systems such as dopaminergic and serotonergic signaling, inflammatory response, and cardiovascular diseases). Our findings suggest that PTSD may have different impacts on miRNAs encapsulated in vesicles and outside of vesicles. Further studies using larger samples are needed to evaluate the utility of these miRNAs as diagnostic biomarkers for PTSD.

Surgical anatomy for Asian rhinoplasty.

Surgical anatomy is an important and fundamental aspect for all surgical procedures. Anatomy provides a surgeon with the basic and in-depth knowledge that is required and mandatory when performing an operation. Although this subject might be tedious and routine, it is compulsory and should not be overlooked or neglected to avoid any possible postoperative complications. An aggressive and hasty operation without anatomic considerations might cause adverse effects that are irreversible even though a surgical anatomy of the nose is quite simple.