A systematic review and BMD modeling approach to develop an AOP for humidifier disinfectant-induced pulmonary fibrosis and cell death.

Dosimetry modeling and point of departure (POD) estimation using in vitro data are essential for mechanism-based hazard identification and risk assessment. This study aimed to develop a putative adverse outcome pathway (AOP) for humidifier disinfectant (HD) substances used in South Korea through a systematic review and benchmark dose (BMD) modeling. We collected in vitro toxicological studies on HD substances, including polyhexamethylene guanidine hydrochloride (PHMG-HCl), PHMG phosphate (PHMG-p), a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT), CMIT, and MIT from scientific databases. A total of 193 sets of dose-response data were extracted from 34 articles reporting in vitro experimental results of HD toxicity. The risk of bias (RoB) in each study was assessed following the office of health assessment and translation (OHAT) guideline. The BMD of each HD substance at different toxicity endpoints was estimated using the US Environmental Protection Agency (EPA) BMD software (BMDS). Interspecies- or interorgan differences or most critical effects in the toxicity of the HD substances were analyzed using a 95% lower confidence limit of the BMD (BMDL). We found a critical molecular event and cells susceptible to each HD substance and constructed an AOP of PHMG-p- or CMIT/MIT-induced damage. Notably, PHMG-p induced ATP depletion at the lowest in vitro concentration, endoplasmic reticulum (ER) stress, epithelial-to-mesenchymal transition (EMT), inflammation, leading to fibrosis. CMIT/MIT enhanced mitochondrial reactive oxygen species (ROS) production, oxidative stress, mitochondrial dysfunction, resulting in cell death. Our approach will increase the current understanding of the effects of HD substances on human health and contribute to evidence-based risk assessment of these compounds.

Virtual Reality and Higher Education Sporting Events: Social Anxiety Perception as an Outcome of VR Simulation.

BACKGROUND: This study investigates the relationship between Virtual Reality Exposure Therapy (VRET) and social anxiety in sport environments. Social anxiety is a mental health condition that manifests people's intense fear of being watched and judged by others and worrying about humiliation It is important to research potential tools like VRET that could help to mitigate the impact of social anxiety as people with social anxiety often avoid attending live events due to the venue's sensory stimuli and the social encounters they anticipate. VR simulation could allow socially anxious individuals to fully experience a sporting event simulation minus the anxiety induced by potential social encounters. VR's therapeutic effects on social anxiety should be explored when considering several findings of VR intervention to mental health. AIM: The study aims to assess the impact of exposing socially anxious people to a virtual sporting game by measuring their levels of social anxiety, team identification, and intentions to attend a live sporting event before and after the VR exposure. Due to VR's positive experience, social anxiety is expected to decrease. However, team identification and intentions to attend live sporting events are expected to increase because of VR's ability to develop sport fanship. METHOD: Fourteen students with symptoms of social anxiety participated in the study. To create the VR simulation stimuli, the researchers used six 360° cameras to record an NCAA Division-I women's volleyball game. Participants experienced the sporting event via VR simulation. Data were analyzed via one-group pre- and post-comparison. RESULTS AND CONCLUSIONS: Significant results were found for behavioral intentions of participants after experiencing the simulation. Social anxiety's difference was negative 0.22, t(13) = 3.47, p < 0.01. After watching the game in VR, the respondents' social anxiety decreased significantly. Team identification's difference was 0.53, t(13) = -3.56, p < 0.01. Lastly, event visit intentions' difference was 0.24, t(13) = -2.35, p < 0.05. Team identification and intentions to visit a sporting event rose significantly after viewing the game in VR.

The Ray Method: Aesthetic and Simple Technique for Prosthesis Coverage in Prepectoral Breast Reconstruction.

In prepectoral breast reconstruction, the acellular dermal matrix (ADM) is commonly used to envelop breast implants. Various wrapping methods have been proposed. We present a simple but aesthetic method (ie, the ray method) for wrapping in prepectoral breast reconstruction. Without any complicated design, we folded the four corners of one large ADM and sewed them together to completely envelop the implant. Then, the 6 o'clock corner of the ADM envelope was folded up and sutured to make a pentagonal shape. The other corners of the ADM envelope were quilted to determine the position and movement of the internal implant. Additional sutures were placed on the ADM envelope to separate the implant from the host tissue. The folded 6 o'clock corner was cut to a convex contour and had a diagonal gap to prevent the collection of fluid in the ADM envelope. Finally, the wrapped implant was inserted in the postmastectomy space, and the ADM envelope was spread widely to support soft tissue effectively. This simple design is straightforward for inexperienced surgeons and reduces operation time. The position and movement of the breast implant in the ADM envelope can be easily controlled by using quilted sutures. Subclavian depression and step-off deformities can be minimized by this wide-stretched ADM. By total coverage with a large ADM, the breast implant is separated from the surrounding tissue, and foreign body reactions are reduced. This method is reliable for maximizing the aesthetic advantages of prepectoral direct-to-implant breast reconstruction.

Corrigendum: Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies.

[This corrects the article DOI: 10.3389/fimmu.2023.1272055.].

Toxicological evidence integration to confirm the biological plausibility of the association between humidifier disinfectant exposure and respiratory diseases using the AEP-AOP framework.

Objectives: Exposure to humidifier disinfectants has been linked to respiratory diseases, including interstitial lung disease, asthma, and pneumonia. Consequently, numerous toxicological studies have explored respiratory damage as both a necessary and sufficient condition for these diseases. We systematically reviewed and integrated evidence from toxicological studies by applying the evidence integration method established in previous research to confirm the biological plausibility of the association between exposure and disease. Methods: We conducted a literature search focusing on polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT), the primary ingredients in humidifier disinfectants. We selected relevant studies based on their quality and the population, exposure, comparator, outcome (PECO) statements. These studies were categorized into 3 lines of evidence: hazard information, animal studies, and mechanistic studies. Based on a systematic review, we integrated the evidence to develop an aggregate exposure pathway-adverse outcome pathway (AEP-AOP) model for respiratory damage. The reliability and relevance of our findings were assessed by comparing them with the hypothesized pathogenic mechanisms of respiratory diseases. Results: The integration of each AEP-AOP component for PHMG and CMIT/MIT led to the development of an AEP-AOP model, wherein disinfectants released from humidifiers in aerosol or gaseous form reached target sites, causing respiratory damage through molecular initiating events and key events. The model demonstrated high reliability and relevance to the pathogenesis of respiratory diseases. Conclusion: The AEP-AOP model developed in this study provides strong evidence that exposure to humidifier disinfectants causes respiratory diseases. This model demonstrates the pathways leading to respiratory damage, a hallmark of these conditions.

Utility of Cellular Measurements of Non-Specific Endocytosis to Assess the Target-Independent Clearance of Monoclonal Antibodies.

Past studies have demonstrated higher clearance for monoclonal antibodies possessing increased rates of non-specific endocytosis. However, this metric is oftentimes evaluated indirectly using biophysical techniques or cell surface binding studies that may not provide insight into the specific rates of cellular turnover. Furthermore, few examples evaluating non-specific endocytosis have been reported for a therapeutic antibody that reached clinical assessment. In the current report, we evaluated a therapeutic human immunoglobulin G2 monoclonal antibody targeted against the interleukin-4 receptor alpha chain (IL-4Rα) that exhibited elevated target independent clearance in previous Phase 1 and 2 studies. We confirmed high non-specific clearance of the anti-IL-4Rα antibody as compared to a reference antibody during pharmacokinetic assessments in wild type mice where target-mediated disposition was absent. We then developed a cell-based method capable of measuring cellular protein endocytosis and demonstrated the anti-IL-4Rα antibody exhibited marked non-specific uptake relative to the reference compound. Antibody homology modeling identified the anti-IL-4Rα antibody possessed positive charge patches whose removal via targeted mutations substantially reduced its non-specific endocytosis. We then expanded the scope of the study by evaluating panels of both preclinical and clinically relevant monoclonal antibodies and demonstrate those with the highest rates of non-specific uptake in vitro exhibited elevated target independent clearance, low subcutaneous bioavailability, or both. Our results support the observation that high non-specific endocytosis is a negative attribute in monoclonal antibody development and demonstrate the utility of a generic cell-based screen as a quantitative tool to measure non-specific endocytosis of protein therapeutics at the single-cell level.

Next generation risk assessment of biocides (PHMG-p and CMIT/MIT)-induced pulmonary fibrosis using adverse outcome pathway-based transcriptome analysis.

Next-generation risk assessment (NGRA) has emerged as a promising alternative to non-animal studies owing to the increasing demand for the risk assessment of inhaled toxicants. In this study, NGRA was used to assess the inhalation risks of two biocides commonly used as humidifier disinfectants: polyhexamethylene guanidine phosphate (PHMG-p) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT). Human bronchial epithelial cell transcriptomic data were processed based on adverse outcome pathways and used to establish transcriptome-based points of departure (tPODs) for each biocide. tPOD values were 0.00500-0.0510 µg/cm2 and 0.0342-0.0544 µg/cm2 for PHMG-p and CMIT/MIT, respectively. tPODs may provide predictive power comparable to that of traditional animal-based PODs (aPODs). The tPOD-based NGRA determined that both PHMG-p and CMIT/MIT present a high inhalation risk. Moreover, the identified PHMG-p posed a higher risk than CMIT/MIT, and children were identified as more susceptible population compared to adults. This finding is consistent with observations from actual exposure events. Our findings suggest that NGRA with transcriptomics offers a reliable approach for risk assessment of specific humidifier disinfectant biocides, while acknowledging the limitations of current models and in vitro systems, particularly regarding uncertainties in pharmacokinetics (PK) and pharmacodynamics (PD).

Incidence and Characteristics of Cerebral Infarction After Microsurgical Clipping of Unruptured Anterior Circulation Cerebral Aneurysms: Diffusion-Weighted Imaging-Based Analysis of 600 Patients.

BACKGROUND AND OBJECTIVES: Postclipping cerebral infarction (PCI) remains a major concern after treatment for unruptured intracranial aneurysms (UIAs). However, studies of microsurgical clipping based on diffusion-weighted imaging are limited. We aimed to present the incidence, risk factors, and types of PCI and its radiological and clinical characteristics. METHODS: This was a retrospective single-center study in which patients were scheduled to undergo microsurgical clipping for anterior circulation UIAs. The overall incidence and risk factors were calculated. Based on the operation and relevant artery, we categorized PCI on diffusion-weighted imaging into 4 types and presented their radiological and clinical characteristics. RESULTS: We reviewed the radiological and clinical data of 605 patients. The overall incidence of PCI was 16.7% (101/605), of which asymptomatic infarction was 14.9% (90/605) and symptomatic infarction was 1.8% (11/605). Hypertension (adjusted odds ratio [aOR], 2.258; 95% confidence interval [CI]: 1.330-3.833), temporary clipping (aOR, 1.690; 95% CI: 1.034-2.760), multiple aneurysm locations (aOR, 1.832; 95% CI: 1.084-3.095), and aneurysm dome size (aOR, 1.094; 95% CI: 1.006-1.190) were independent risk factors for PCI. Type II (perianeurysmal perforator) infarction was the most common type of PCI (48.6%) and the most common cause of symptomatic infarction (72.7%). Types II and III (distal embolic) infarctions correlated with atherosclerotic changes in the aneurysm wall and temporary clipping (62.4% and 70.6%, respectively). The type IV (unrelated) infarction group had a higher incidence of systemic atherosclerosis (55%). CONCLUSION: Microsurgical clipping is a safe and viable option for the treatment of anterior circulation UIAs. However, modification of the surgical technique, preoperative radiological assessment, and patient selection are required to reduce the incidence of PCI.

Influence of strength and balance ability on functional performance in the involved and uninvolved sides after anterior cruciate ligament reconstruction.

BACKGROUND: The restoration and management of the uninvolved side have been emphasized to prevent a second anterior cruciate ligament (ACL) injury and to ensure that athletes return to sports after ACL reconstruction. OBJECTIVE: To determine the factors influencing the single leg hop test (SLHT) and single leg vertical jump test (SLVJT) at 1 year postoperatively after ACL reconstruction in both the involved and uninvolved sides. METHODS: Ninety-four patients who underwent ACL reconstruction were assessed at 1 year postoperatively. Multiple regression models included eight independent variables with two dependent variables (SLHT and SLVJT.), each on the involved and uninvolved side. RESULTS: On the involved side, the Y balance test (YBT), extensor peak torque per body weight (PT/BW), Biodex balance system anteroposterior index (BBS-API), and sex accounted for 53.9% of the variance in SLHT (P= 0.002), and extensor PT/BW and YBT accounted for 26.3% of the variance in SLVJT (P= 0.027). On the uninvolved side, YBT, sex, age, BBS-API, and flexor PT/BW accounted for 47.0% of the variance in SLHT (P= 0.046), and flexor PT/BW, YBT, and age accounted for 44.9% of the variance in SLVJT (P= 0.002). CONCLUSION: Knee extensor strength on the involved side and flexor strength on the uninvolved side influence the two functional performance tests. The YBT was an important factor in the two functional performance tests in both sides. Anteroposterior stability was the only factor that influenced the SLHT bilaterally.

Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies.

Conventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows only modest results in the clinic given the short half-life and high toxicity of current type I IFN therapies, which limit IFN exposure in the tumor. CD8+ T cell immunity is dependent on IFN signaling in cDC1s and preclinical studies suggest targeting IFN directly to cDC1s may be sufficient to drive anti-tumor immunity. Here, we engineered an anti-XCR1 antibody (Ab) and IFN mutein (IFNmut) fusion protein (XCR1Ab-IFNmut) to determine whether systemic delivery could drive selective and sustained type I IFN signaling in cDC1s leading to anti-tumor activity and, in parallel, reduced systemic toxicity. We found that the XCR1Ab-IFNmut fusion specifically enhanced cDC1 activation in the tumor and spleen compared to an untargeted control IFN. However, multiple treatments with the XCR1Ab-IFNmut fusion resulted in robust anti-drug antibodies (ADA) and loss of drug exposure. Using other cDC1-targeting Ab-IFNmut fusions, we found that localizing IFN directly to cDC1s activates their ability to promote ADA responses, regardless of the cDC1 targeting antigen. The development of ADA remains a major hurdle in immunotherapy drug development and the cellular and molecular mechanisms governing the development of ADA responses in humans is not well understood. Our results reveal a role of cDC1s in ADA generation and highlight the potential ADA challenges with targeting immunostimulatory agents to this cellular compartment.

Rehabilitation after Repair of Medial Meniscus Posterior Root Tears: A Systematic Review of the Literature.

Background: There is no consensus established on postoperative rehabilitation after medial meniscus posterior root tear (MMPRT) repair, including when and how physicians can apply range of motion (ROM) exercise, weight-bearing (WB), brace use, and return to sports (RTS). The purpose of this study was to systematically review the literature on postoperative rehabilitation characteristics of MMPRT repair regarding ROM, WB, brace use, and RTS. Methods: A literature search was performed using the Medline/PubMed, Cochrane Central Register of Controlled Trials, and Embase databases. The inclusion criteria were English language, human clinical studies, and studies describing rehabilitation protocols after MMPRT repair such as ROM, WB, brace use, and RTS. Abstracts, case reports, cohort studies, controlled laboratory studies, human cadaveric or animal studies, systematic reviews, and meta-analyses were excluded. Results: Thirteen studies were included. Of the 12 ROM studies, ROM was started immediately within 1 or 2 days after operation in 6 studies and after 2 to 3 weeks of knee immobilization in the rest. Of the 13 WB studies, partial weight-bearing was initiated 1 to 4 weeks after operation in 8 studies and 6 weeks in the rest. Of the 9 brace studies, patients were immobilized by a splint for 2 weeks in 3 studies, and in the rest, a brace with full extension was applied for 3 to 6 weeks after several days of splint application. Of the 7 RTS studies, RTS was allowed at 6 months in 6 studies and 5 to 7 months in 1 study. Conclusions: This systematic review revealed conservative rehabilitation protocols were more widely adapted as ROM and WB were restricted at certain degrees during postoperative periods in most protocols analyzed. However, it is impossible to identify a consensus on rehabilitation protocols as the protocols analyzed in this review were distinct each other and heterogeneous. In the future, a well-designed comparative study among different rehabilitation protocols is essential to establish a consensus.

Evidence integration on health damage for humidifier disinfectant exposure and legal presumption of causation.

OBJECTIVES: Inhalation exposure to humidifier disinfectants has resulted to various types of health damages in Korea. To determine the epidemiological correlation necessary for presuming the legal causation, we aimed to develop a method to synthesize the entire evidence. METHODS: Epidemiological and toxicological studies are systematically reviewed. Target health problems are selected by criteria such as frequent complaints of claimants. Relevant epidemiologic studies are reviewed and the risk of bias and confidence level of the total evidence are evaluated. Toxicological literature reviews are conducted on three lines of evidence including hazard information, animal studies, and mechanistic studies, considering the source-to-exposure-to-outcome continuum. The confidence level of the body of evidence is then translated into the toxicological evidence levels for the causality between humidifier disinfectant exposure and health effects. Finally, the levels of epidemiological and toxicological evidence are synthesized. RESULTS: Under the Special Act revised in 2020, if the history of exposure and the disease occurred/worsened after exposure were approved, and the epidemiological correlation between the exposure and disease was verified, the legal causation is presumed unless the company proves the evidence against it. The epidemiological correlation can be verified through epidemiological investigations, health monitoring, cohort investigations and/or toxicological studies. It is not simply as statistical association as understood in judicial precedents, but a general causation established by the evidence as a whole, i.e., through weight-of-the-evidence approach. CONCLUSIONS: The weight-of-the-evidence approach differs from the conclusive single study approach and this systematic evidence integration can be used in presumption of causation.

Miniscrews position for a tissue bone borne palatal C-expander affects the displacement pattern of nasomaxillary complex: a finite element study.

This study aimed to evaluate the difference in expansion patterns based on the position of miniscrews for a tissue-bone-borne palatal C-expander using a finite element method. Ten expansion models were examined, each representing a different position of miniscrews on the palate. Models A and B had miniscrews symmetrically placed 7 mm and 15 mm below the cementoenamel junction (CEJ), respectively. Models C to J had miniscrews positioned in a triangular manner at 7 mm and 15 mm below CEJ. Stress, displacement, angular changes of the bone and teeth, and changes in the nasomaxillary complex were measured using elastoplastic behavior models through static-nonlinear simulation employing an implicit method. The anterior and posterior parts of paramidpalatal suture area were identified as ANT, TPS-M, and TPS-L, and their ratio was assessed. Model A, which featured three miniscrews located 7 mm below the CEJ, exhibited the least molar inclination and the smallest amount of skeletal expansion. Model I, with two miniscrews placed between the first and second molars, demonstrated the greatest lateral displacement at point N on the nasal cavity wall, along with the smallest ratio of ANT to TPS-M or TPS-L. This finding suggests that the posterior expansion of the palate in relation to the anterior expansion was maximized. The results of this study indicate that strategic positioning of miniscrews is effective in achieving various expansion patterns based on the targeted correction areas within the nasomaxillary complex.

Does a Lower Limb Balance Test after Anterior Cruciate Ligament Reconstruction Have a Significant Correlation with Postoperative Clinical Score, Stability, and Functional Performance Test?

Background: Lower limb balance ability is reduced after anterior cruciate ligament reconstruction (ACLR). However, the recovery of balance based on functional test scores after ACLR is not known because the correlation between balance and clinical scores remains unclear. We aimed to analyze the correlation between lower limb balance assessed by functional test and clinical knee test scores after ACLR. Methods: We evaluated lower limb balance using the anterior-posterior stability index (APSI) of the Biodex Balance System (BBS). Patients underwent clinical tests to evaluate the knee, including the Tegner activity score, International Knee Documentation Committee (IKDC) subjective score, Lysholm score, and KT-2000 arthrometer measurement, hamstring per quadriceps muscle strength ratio at 60°/sec (HQ ratio), and functional performance tests (single-leg hop and single-leg vertical jump tests) 1 year after ACLR. We used a paired t-test to compare continuous preoperative and postoperative variables and Pearson's correlation coefficient to determine the relationship between BBS-APSI and clinical scores. Results: Forty-eight patients (35 men and 13 women; mean age, 28.9 ± 8.3 years) were included. The follow-up period and BBS-APSI were 12.4 ± 2.0 months and 0.9 ± 0.4, respectively. Tegner activity score, IKDC subjective score, Lysholm score, and KT-2000 arthrometer measurement improved significantly postoperatively (p < 0.001). BBS-APSI was correlated with the Tegner activity score (r = -0.335, p = 0.020), IKDC subjective score (r = -0.301, p = 0.037), Lysholm score (r = -0.323, p = 0.025), single-leg hop test results (r = -0.300, p = 0.038), and single-leg vertical jump test results (r = -0.336, p = 0.019). There was no correlation between KT-2000 arthrometer measurement and HQ ratio. Conclusions: BBS-APSI was correlated with functional performance test scores after ACLR, rendering the BBS-APSI as a useful assessment tool to evaluate postoperative functional recovery. Continuously improving balance after ACLR could be useful for functional recovery after surgery.

Modified deep-plane facelift and lower midface lifting using deep fat compartment mobilization and zygomaticus major muscle plication.

BACKGROUND: Most facelift techniques greatly improve the lower face; however, techniques for lifting the midface are limited and difficult. Original deep plane face lift is a way to lift the SMAS and skin as a compound unit. Though it minimizes SMAS tear during dissection, damage to the vascular system and incidence of skin necrosis and can be easily used in secondary cases, it does not adequately improve nasolabial fold. We perform a modified and enhanced deep plane facelift to improve the midface. Herein, we explain the effects and procedures of the method. METHODS: This retrospective study included patients (n=632) on whom deep-plane facelift (DPF group, n=299) and modified deep-plane facelift (M-DPF group, n=333) was performed by a single surgeon from January 2014 to January 2017 and February 2017 to December 2020, respectively, at a local clinic. The degree of improvement in wrinkles in the patients' nasolabial fold was assessed using a 5-grade wrinkle severity rating scale (WSRS). RESULTS: Preoperative WSRS was 2.95 ± 0.89 in the DPF group and 2.89 ± 0.92 in the M-DPF group. There was no significant difference in preoperative WSRS between the two groups (p=0.058). Postoperative WSRS was 1.81 ± 0.68 in the DPF group, which was significantly greater than the 1.65 ± 0.66 found in the M-DPF group. CONCLUSIONS: This method developed by us that combines deep-plane facelift with deep fat compartment mobilization and zygomaticus major muscle plication is safe and directly improves the nasolabial fold and promotes a smiling expression for rejuvenation effects.

Post-traumatic Telecanthus Induced by a Missed Diagnosis of Avulsion Fracture of the Medial Canthal Tendon.

Telecanthus is commonly accompanied by severe naso-orbito-ethmoid fractures. If there is only an avulsion fracture of the medial canthal tendon (MCT), the initial diagnosis may be missed, and post-traumatic telecanthus may follow. To avoid misdiagnosis of post-traumatic telecanthus, the following should be considered: avulsion fracture of the MCT should be suspected in the presence of an injury or edema of the medial canthal area; the facial computed tomography images should be carefully analyzed to confirm the presence of bone segment caused by the avulsion fracture of the MCT; physical examinations, such as the bowstring test and bimanual palpation, also provide essential data for early diagnosis. And even if early diagnosis is delayed, post-traumatic telecanthus can be improved through aggressive surgical correction.

Cosmetic Open Rhinoplasty in Acute Nasal Bone Fracture With Pre-Existing Deformity.

The simultaneous reduction of nasal bone fracture and cosmetic rhinoplasty is a challenging procedure, because of fracture severity and skeletal instability. Our aim was to investigate the surgical strategy and outcomes of cosmetic rhinoplasty according to the pre-existing nasal deformity when performing simultaneous reduction of nasal bone fracture and cosmetic rhinoplasty. In total, 71 patients who underwent cosmetic rhinoplasty were included. All patients were categorized according to pre-existing deformity, dorsal hump and irregularities, and deviation of the nose, wide nose, and flat nasal dorsum. The authors performed individual maneuvers to correct each deformity. Autologous tissue was used in all maneuvers for graft. Photoanalysis was performed to measure the deviation, nasal length, radix height, dorsal height, tip projection, nasofrontal angle, and nasolabial angle. Subjective evaluation of the functional and esthetic problems was confirmed through rhinoplasty outcome evaluation. In the analysis of the photographs, most patients presented improved scores ( P <0.05). The scores of satisfaction were significantly higher in the postoperative state ( P <0.05). As a postoperative complication, 2 cases of deviated tip occurred due to septal instability and were successfully revised with septoplasty and columellar strut graft. The authors created a harmonious face by evaluating, categorizing, and treating each deformity of the nose in patients with nasal fractures according to our algorithm.

Fibrinogen on extracellular vesicles derived from polyhexamethylene guanidine phosphate-exposed mice induces inflammatory effects via integrin ß.

Polyhexamethylene guanidine phosphate (PHMG-p), used as a humidifier disinfectant, causes interstitial lung disease, obliterative bronchiolitis, and lung fibrosis; however, little is known about its effect on intercellular interactions. Extracellular vesicles (EVs), which carry diverse compounds including proteins, RNA, and DNA to mediate cell-to-cell communication through their paracrine effects, have been highlighted as novel factors in lung fibrogenesis. This study aimed to identify the effect of proteins on small EVs (sEVs) from bronchoalveolar lavage fluid (BALF) of the recipient cells after PHMG-p exposure. A week after intratracheal administration of PHMG-p, sEVs were isolated from BALF of tissue showing overexpressed inflammatory and fibrosis markers. To investigate the role of sEVs in inflammation, naïve macrophages were cultured with sEVs, which induced their activation. To identify sEV proteins that are associated with these responses, proteomics analysis was performed. In the gene ontology analysis, coagulation, fibrinolysis, and hemostasis were associated with the upregulated proteins in sEVs. The highest increase was observed in fibrinogen levels, which was also related to those gene ontologies. We validated role of exosomal fibrinogen in inflammation using recombinant fibrinogen and an inhibitor of the integrin, which is the binding receptor for fibrinogen. Overall, we elucidated that increased fibrinogen levels in the early sEVs-PHMG activated inflammatory response during early fibrosis. These results suggest that sEVs from the BALF of PHMG-p-exposed mice could aggravate fibrogenesis by activating naïve macrophages via various proteins in the sEVs, Furthermore, this finding will be broadening the spectrum of communicating mediators.

Preventive effect of empagliflozin and ezetimibe on hepatic steatosis in adults and murine models.

BACKGROUND: Even though many oral glucose-lowering or lipid-lowering agents have already been reported to improve hepatic steatosis to some degree, which drug had a more beneficial effect on hepatic steatosis among those drugs has not been precisely explored. We analysed the effect of empagliflozi, a selective sodium-glucose cotransporter 2 inhibitor, and ezetimibe on developing hepatic steatosis. METHODS AND RESULTS: Using 4005,779 patients with type 2 diabetes mellitus (T2DM) or dyslipidemia provided by the Korean National Health Insurance Service (NHIS) between January 2015 and December 2015, we analyzed the odds ratio (OR) of fatty liver development (fatty liver index [FLI] >60). Additionally, we examined the metabolic effects of ezetimibe and empagliflozin in mice fed with a choline-deficient high-fat diet, mimicking the features of human NAFLD. The experiment for agents was performed for the non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) mouse models independently. In the NHIS data, ORs for the development of fatty liver were significantly lower in all treatment groups than in the reference group, which did not receive ezetimibe or empagliflozin. (Ezetimibe therapy; OR=0.962, empagliflozin therapy; OR=0.527, ezetimibe plus empagliflozin; OR=0.509 compared to reference therapy). Unlike non-alcoholic steatohepatitis mouse model, ezetimibe, empagliflozin, and combination therapy also reduced liver steatosis in the non-alcoholic fatty liver mouse model. CONCLUSIONS: Compared with other agents, empagliflozin and/or ezetimibe treatment reduced the risk of developing hepatic steatosis. Our data suggest that empagliflozin or ezetimibe can be primarily considered in type 2 DM or dyslipidemia patients to prevent hepatic steatosis.