The effect of guardrail color on driver behavior based on driving style along mountain curves.

OBJECTIVE: Mountain highways are linearly complex, with extensive curves and high accident injury rates, how to improve driving safety is the key to traffic safety management on mountain highways, and it also meets the need for harmonious and sustainable development of the society. Therefore, this study investigates the effects of different guardrail color configurations on the driving behavior of different styles of drivers when driving on mountainous curves from the perspective of improving road aids - guardrails. METHODS: A virtual reality experiment was designed using a driving simulator and VR technology, and 64 subjects were recruited to participate and complete the experiment. RESULTS: Drivers with non-adaptive driving styles (Reckless, Angry, Anxious) traveled at significantly higher speeds than subjects with adaptive driving styles (Cautious) on mountainous roads; drivers with Cautious styles had better lane-keeping ability when passing through different radii of curves as compared to non-adaptive drivers; and the red and yellow guardrails were more effective in decreasing the speeds at which drivers passed and in increasing the stability of lane-keeping. CONCLUSIONS: The results of the study show that the effectiveness of red and yellow guardrails is better, which provides a reference for the traffic management department to propose a standardized color setting of guardrails in mountainous areas, which is conducive to the development of more precise traffic management measures to reduce the occurrence of traffic accidents.

NT-proBNP ratio is a potential predictor for COVID-19 outcomes in adult Chinese patients: a retrospective study.

Despite the progressive decline in the virulence of the novel coronavirus, there has been no corresponding reduction in its associated hospital mortality. Our aim was to redefine an accurate predictor of mortality risk in COVID-19 patients, enabling effective management and resource allocation. We conducted a retrospective analysis of 2917 adult Chinese patients diagnosed with COVID-19 who were admitted to our hospital during two waves of epidemics, involving the Beta and Omicron variants. Upon admission, NT-proBNP levels were measured, and we collected demographic, clinical, and laboratory data. We introduced a new concept called the NT-proBNP ratio, which measures the NT-proBNP level relative to age-specific maximum normal values. The primary outcome was all-cause in-hospital mortality. Our analysis revealed a higher in-hospital mortality rate in 2022, as shown by the Kaplan-Meier Survival Curve. To assess the predictive value of the NT-proBNP ratio, we employed the time-dependent receiver operating characteristic (ROC) curve. Notably, the NT-proBNP ratio emerged as the strongest predictor of mortality in adult Chinese hospitalized COVID-19 patients (area under the curve, AUC = 0.826; adjusted hazard ratio [HR], 3.959; 95% confidence interval [CI] 3.001-5.221; P < 0.001). This finding consistently held true for both the 2020 and 2022 subgroups. The NT-proBNP ratio demonstrates potential predictive capability compared to several established risk factors, including NT-proBNP, hsCRP, and neutrophil-to-lymphocyte ratio, when it comes to forecasting in-hospital mortality among adult Chinese patients with COVID-19.Trial registration Clinical Trial Registration: www.clinicaltrials.gov NCT05615792.

Myocardial injury and related mortality in hospitalized patients with COVID-19 during the Omicron pandemic: new perspectives and insights.

Myocardial injury is one of the most common comorbidity in SARS-CoV-2 infected patients, and has poor prognosis. However, the incidence of myocardial injury in patients with SARS-CoV-2 infection has not been sufficiently investigated during the Omicron wave. We conducted a retrospective study of 2690 patients with confirmed SARS-CoV-2 Omicron infection from Tongji Hospital. The results indicated that the myocardial injury accounted for 30.8% of the total patients with SARS-CoV-2 infection and was associated with higher in-hospital mortality than those without injury before and after propensity score matching (PSM) [adjusted hazard ratio (HR), 10.61; 95% confidence interval (CI), 7.76-14.51; P â€‹< â€‹0.001; adjusted HR, 2.70; 95% CI, 1.86-3.93; P â€‹< â€‹0.001; respectively]. Further, the levels of cytokines (IL-1ß, IL-6, IL-10, and TNF-α) in patients with myocardial injury were higher than those without injury, and the higher levels of cytokines in the myocardial injury group were associated with increased mortality. Administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) could significantly reduce the mortality in patients with myocardial injury (adjusted HR, 0.52; 95% CI, 0.38-0.71; P â€‹< â€‹0.001). Additionally, the level of angiotensin II increased in patients with SARS-CoV-2 infection was even higher in myocardial injury group compared to those without injury. Collectively, the study summarized the clinical characteristic and outcome of SARS-CoV-2 infected patients with myocardial injury during the Omicron wave in China, and validated the protective role of ACEI/ARB in improving the survival of those with myocardial injury.

Regulatory perspective for quality evaluation of lipid nanoparticle-based mRNA vaccines in China.

In recent years, urgent unmet medical needs due to the COVID-19 pandemic have accelerated the application of mRNA technology in vaccine development, leading to some of the first approvals of mRNA vaccines in human history by regulatory agencies around the world. For market authorization, comprehensive chemistry, manufacturing and control (CMC) information is required to assure the safety and quality consistency of mRNA vaccines. Evaluating mRNA vaccines for new virus variants poses a challenge for regulators, given the rapid optimization and development based on prior platform knowledge to accelerate the development process, which is traditionally limited for biological products. Here we summarize the current regulatory considerations of CMC evaluation on mRNA vaccines based on the scientific knowledge available, which will be updated with the advance of mRNA biology and pharmaceutical science.

Comparability strategy and demonstration for post-approval production cell line change of a bevacizumab biosimilar IBI305.

High-producing cell line could improve the affordability and availability of biotherapeutic products. A post-approval production cell line change, low-titer CHO-K1S to high-titer CHO-K1SV GS-KO, was performed for a China marketed bevacizumab biosimilar IBI305. Currently, there is no regulatory guideline specifically addressing the requirements for comparability study of post-approval cell line change, which is generally regarded as the most complex process change for biological products. Following the quality by design principle and risk assessment, an extensive analytical characterization and three-way comparison was performed by using a panel of advanced analytical methods. Orthogonal and state-of-the-art techniques including nuclear magnetic resonance and high-resolution mass spectrometry were applied to mitigate the potential uncertainties of higher-order structures and to exclude any new sequence variants, scrambled disulfide bonds, glycan moiety and undesired process-related impurities such as host cell proteins. Nonclinical and clinical pharmacokinetics (PK) studies were conducted subsequently to further confirm the comparability. The results demonstrated that the post-change IBI305 was analytically comparable to the pre-change one and similar to the reference product in physicochemical and biological properties, as well as the degradation behaviors in accelerated stability and forced degradation studies. The comparability was further confirmed by comparable PK, pharmacodynamics, toxicological and immunogenicity profiles of nonclinical and clinical studies. The comparability strategy presented here might extend to cell line changes of other post-approval biological products, and particularly set a precedent in China for post-approval cell line change of commercialized biosimilars.

Beneficial Effects of Angiotensin II Receptor Blockers on Mortality in Patients with COVID-19: A Retrospective Study from 2019 to 2020 in China.

BACKGROUND: The COVID-19 pandemic has become a serious global public health problem. Although the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor type 1 blockers (ARBs) has been recommended in patients with COVID-19 and cardiovascular diseases (CVDs), according to the results of some small-sample retrospective analyses, there remains a lack of sufficient evidence to validate their efficacy. This multicenter retrospective study investigated whether ACEI/ARB administration was beneficial in patients with COVID-19 and CVDs. METHODS: A total of 11,231 patients with confirmed COVID-19 and CVDs, from 138 hospitals in Hubei Province, were included in this multicenter retrospective study. We compared the clinical characteristics and outcomes between the ARB and non-ARB groups and analyzed the risk factors for in-hospital death using univariate and multivariate Cox regression analyses and Kaplan-Meier curves. RESULTS: In the multivariate Cox regression model, after adjusting for age, gender, comorbidities, and in-hospital medications, ARB use was associated with lower all-cause mortality (adjusted HR, 0.53; 95% CI, 0.38-0.73; P < 0.001). After propensity score-matched analysis, the adjusted HR for the use of ARB associated with all-cause mortality was 0.62 (95% CI, 0.40-0.88; P = 0.02). Further subgroup analyses found that the adjusted HRs for the use of ARB associated with all-cause mortality were 0.52 (95% CI, 0.30-0.89; P = 0.016), 0.37 (95% CI, 0.21-0.64; P < 0.001), 0.42 (95% CI, 0.28-0.64; P < 0.001), and 0.55 (95% CI, 0.37-0.84; P = 0.005) in patients with heart failure, diabetes, and hypercholesterolemia, and severe COVID-19, respectively. CONCLUSIONS: ARB administration was significantly associated with a lower risk of all-cause mortality in patients with COVID-19 and CVDs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05615792. https://www. CLINICALTRIALS: gov/ct2/show/NCT05615792.

Highly piezoelectric, biodegradable, and flexible amino acid nanofibers for medical applications.

Amino acid crystals are an attractive piezoelectric material as they have an ultrahigh piezoelectric coefficient and have an appealing safety profile for medical implant applications. Unfortunately, solvent-cast films made from glycine crystals are brittle, quickly dissolve in body fluid, and lack crystal orientation control, reducing the overall piezoelectric effect. Here, we present a material processing strategy to create biodegradable, flexible, and piezoelectric nanofibers of glycine crystals embedded inside polycaprolactone (PCL). The glycine-PCL nanofiber film exhibits stable piezoelectric performance with a high ultrasound output of 334 kPa [under 0.15 voltage root-mean-square (Vrms)], which outperforms the state-of-the-art biodegradable transducers. We use this material to fabricate a biodegradable ultrasound transducer for facilitating the delivery of chemotherapeutic drug to the brain. The device remarkably enhances the animal survival time (twofold) in mice-bearing orthotopic glioblastoma models. The piezoelectric glycine-PCL presented here could offer an excellent platform not only for glioblastoma therapy but also for developing medical implantation fields.

Cellular Uptake Mechanism of Nucleic Acid Nanocapsules and Their DNA-Surfactant Building Blocks.

Nucleic acid nanocapsules (NANs) are enzyme-responsive DNA-functionalized micelles built for the controlled release of DNA-surfactant conjugates (DSCs) that present sequences with demonstrated therapeutic potential. Here, we investigate the mechanisms by which DSCs gain access to intracellular space in vitro and determine the effects of serum on the overall uptake and internalization mechanism of NANs. Using pharmacological inhibitors to selectively block certain pathways, we show, through confocal visualization of cellular distribution and flow cytometry quantification of total cellular association, that scavenger receptor-mediated, caveolae-dependent endocytosis is the major cellular uptake pathway of NANs in the presence and absence of serum. Furthermore, as NANs can be triggered to release DSCs by external stimuli such as enzymes, we sought to examine the uptake profile of particles degraded by enzymes prior to cell-based assays. We found that while scavenger receptor-mediated, caveolae-dependent endocytosis is still at play, energy-independent pathways as well as clathrin-mediated endocytosis are also involved. Overall, this study has helped to elucidate early steps in the cytosolic delivery and therapeutic activity of DSCs packaged into a micellular NAN platform while shedding light on the way in which DNA functionalized nanomaterials in general can be trafficked into cells both as nanostructures and as molecular entities. Importantly, our study also shows that the NAN design in particular is able to stabilize nucleic acids when delivered in the presence of serum, a critical step for effective therapeutic nucleic acid delivery.

Advanced therapy medicinal products in China: Regulation and development.

Advanced therapy medicinal products (ATMPs) have shown dramatic efficacy in addressing serious diseases over the past decade. With the acceleration and deepening of China's drug regulatory reforms, the country sees a continuous introduction of policies that encourage drug innovation. The capacity and efficiency of the Center for Drug Evaluation (CDE), National Medical Products Administration have significantly improved, where substantial resources have been allocated to ATMPs with major innovations and outstanding clinical values that satisfy urgent clinical needs. These changes have greatly stimulated the research and development of biological products in China, ushering in a period of explosive growth in the number of investigational new drug (IND) applications of ATMPs. Here, we described China's ATMP regulatory framework and analyzed data on IND applications for ATMPs submitted to CDE. The data show that China's ATMP industry is expanding dramatically, but lagging behind in terms of the innovative targets and the coverage of indications. However, in recent years, the diversity of product types, targets, and indications is growing. We discussed challenges and opportunities in ATMP regulation. Risk-based regulation and cross-discipline collaborations are encouraged to promote more ATMPs toward market authorization in China.

Wuhan 3 years after the outbreak of the pandemic-cardiological insights and perspectives.

In November 2019, Wuhan, a city in Central China, became the center of an outbreak of pneumonia of unknown cause, which was later named "coronavirus disease 2019" (COVID-19). COVID-19 is caused by the novel severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection. The emergence of novel SARS-CoV­2 strains and mutations exerted a serious global public health threat. Although various vaccines have been developed, specific anti-SARS-CoV­2 drugs are limited. As cardiologists, we believe that because SARS-CoV­2 can bind to the angiotensin 2 receptor on the surface of cardiomyocytes, it may also lead to cardiac injury. COVID-19-associated cardiac injury is not rare in clinical practice, and most of these cases are mild, while a few might progress to fulminant myocarditis (FM). Overactivated immune response and inflammatory storm represent the core pathogenesis of COVID-19-associated FM. Early identification and diagnosis of COVID-19-associated FM are critical for its treatment. Recently, Wuhan was hit by the Omicron variant again. We proposed managing COVID-19-associated cardiac injury according to the severity, which has had a significant effect on outcome.

Immunopathogenesis and immunomodulatory therapy for myocarditis.

Myocarditis is an inflammatory cardiac disease characterized by the destruction of myocardial cells, infiltration of interstitial inflammatory cells, and fibrosis, and is becoming a major public health concern. The aetiology of myocarditis continues to broaden as new pathogens and drugs emerge. The relationship between immune checkpoint inhibitors, severe acute respiratory syndrome coronavirus 2, vaccines against coronavirus disease-2019, and myocarditis has attracted increased attention. Immunopathological processes play an important role in the different phases of myocarditis, affecting disease occurrence, development, and prognosis. Excessive immune activation can induce severe myocardial injury and lead to fulminant myocarditis, whereas chronic inflammation can lead to cardiac remodelling and inflammatory dilated cardiomyopathy. The use of immunosuppressive treatments, particularly cytotoxic agents, for myocarditis, remains controversial. While reasonable and effective immunomodulatory therapy is the general trend. This review focuses on the current understanding of the aetiology and immunopathogenesis of myocarditis and offers new perspectives on immunomodulatory therapies.

Biosimilars: navigating the regulatory maze across two worlds.

The impending loss of market exclusivity for established biologic products creates a lucrative market opportunity for biosimilars. However, complex and variable regulatory requirements between regions present challenges to developers. Understanding the regulatory differences between two major markets, Europe and China, will expedite entry into these key markets.

Positive and negative affect facilitate creativity motivation: Findings on the effects of habitual mood and experimentally induced emotion.

This research involved two investigations that examined the effects of two types of affect (i.e., mood and emotion) on creativity motivation. Study 1 examined the degree to which noninduced habitual mood impacted creativity motivation in the context of a group of junior secondary school students in Hong Kong (n = 588), while Study 2 examined the effect of the experimental manipulation of emotion induction on creativity motivation in the context of a group of undergraduate students in Hong Kong (n = 653). The Chinese version of the Creativity Motivation Scale, the International Positive and Negative Affect Schedule-Short Form, and the Affect Grid were employed to assess creativity motivation, mood, and emotional states, respectively. Interesting findings were obtained. First, both studies consistently demonstrated a facilitating role of positive and negative affect in creativity motivation. Second, both studies consistently showed that the impact of positive affect on creativity motivation was stronger than that of negative affect. While previous affect-creativity research has focused predominantly on the role of affect in the cognitive components of creativity and yielded mixed results, this research adds to the literature by showing that students' motivation to engage in creativity-related behaviors can be influenced by a broad spectrum of affective experiences (i.e., positive and negative affect, stable and enduring moods, and momentary and mutable emotions). The theoretical and educational implications of the findings are highlighted.

Effects of Age and Sex on Aerobic Fitness, Sprint Performance, and Change of Direction Speed in High School Athletes.

ABSTRACT: Hackett, DA, He, W, Fleeton, JRM, Orr, R, and Sanders, RH. Effects of age and sex on aerobic fitness, sprint performance, and change of direction speed in high school athletes. J Strength Cond Res 37(5): 325-331, 2023-The purpose of this study was to examine the effects of sex and age on aerobic fitness, sprinting performance, and change of direction speed (CODS) in high school athletes, with consideration for maturity. This cross-sectional study involved 2,132 adolescents (1,415 male and 717 female athletes) aged 12.0-15.9 years. Assessment of aerobic fitness using the 20-m multistage fitness test (20MSFT) and 20-m sprint and CODS using the 505 test was performed. For the analysis of data, subjects were separated into 4 age groups: U/13 years, U/14 years, U/15 years, and U/16 years. Estimated age at peak height velocity was a covariate in the data analysis to control for maturity status. Compared with female athletes, male athletes had superior performances at all age groups in 10-m sprint ( p < 0.001, effect size [ES] = >-0.44), 20-m sprint ( p < 0.001, ES = >-0.55), and 505 test ( p < 0.001, ES = >-0.41). Female athletes performed better than male athletes in 20MSFT at U/13 ( p < 0.01, ES = -0.22); however, male athletes had better performances at U/15 ( p < 0.01, ES = 0.27) and U/16 ( p < 0.001, ES = 0.67). At each consecutive age group, male athletes improve their performances in 20MSFT and sprints and at U/14 and U/16 in the 505 test ( p < 0.001, ES > -0.37). Female athletes showed no improvement in the 20MSFT and 505 test between U/13-U/16 but showed improved sprint performance at U/15 compared with U/13 and at U/16 compared with U/14 ( p < 0.05). This study shows that adolescent male athletes perform consistently better than female athletes in running-related field-based tests and display continuous improvements across age groups.

Research progress of microglia regulating phagocytosis of apoptotic neurons after intracerebral hemorrhage / 中华神经科杂志

Intracerebral hemorrhage is the bleeding caused by spontaneous non-traumatic rupture of blood vessels in brain parenchyma. It has high disability rate and mortality. A series of injuries after intracerebral hemorrhage will lead to neuronal apoptosis. If apoptotic neurons are not cleared in time, intracellular toxic substances will be released, thereby further aggravating the inflammatory reaction. Therefore, the timely clearance of apoptotic cells is of great significance to the brain homeostasis after intracerebral hemorrhage. At the same time, a large number of phagocytic "eat me" signal phosphatidylserine (PS) will appear on the surface of apoptotic neurons. Microglia, as resident macrophages in the brain, have a variety of PS receptors on their surface, which promote the phagocytosis of apoptotic neurons by microglia and reduce the occurrence of local inflammatory responses.

A study on repair method of type Ⅱc injury in lateral meniscus popliteal tendon area of porcine knee / 中国修复重建外科杂志

OBJECTIVE@#To investigate the repair method of type Ⅱc injury in the lateral meniscus popliteal tendon area based on the porcine knee joint.@*METHODS@#Eighteen commercially available fresh porcine knee joints were randomly divided into 3 groups ( n=6). After preparing a type Ⅱc injury in the lateral meniscus popliteal tendon area, and the anterior (group A), posterior (group B), or anterior and posterior (group C) of the popliteal hiatus (PH) was sutured by vertical mattress. The tension meter was used to apply gradient tensions of 2, 4, 6, 8, and 10 N along the tibial plateau horizontally, respectively, to pull the midpoint of the lateral meniscus popliteal tendon area. The displacement values before modeling, after modeling, and after suture were recorded. The reduction value of lateral meniscus displacement and reduction rate after suture were calculated and compared between groups.@*RESULTS@#There was no significant difference between groups ( P>0.05) in the displacement values before modeling, after modeling, and after suture under different tensions. There was no significant difference between groups A and C ( P>0.05) in the reduction value of lateral meniscus displacement and reduction rate after suture under different tensions. The reduction value of lateral meniscus displacement and reduction rate after suture in group B were lower than those in groups A and C. The reduction value of lateral meniscus displacement under tension of 2 N and the reduction rates under tensions of 2, 4, and 6 N between groups A and B showed significant differences ( P<0.05). The reduction value of lateral meniscus displacement and the reduction rate under tensions of 2, 4, and 6 N between groups B and C showed significant differences ( P<0.05).@*CONCLUSION@#Suturing the anterior area of PH is the key to repairing type Ⅱc injury of lateral meniscus popliteal tendon area.

Glimepiride Use is Associated with Reduced Cardiovascular Mortality in Patients with Type 2 Diabetes and Chronic Heart Failure: A Prospective Cohort Study.

BACKGROUND: Glimepiride has good cardiovascular safety. However, whether glimepiride benefits clinical cardiovascular outcomes is unclear. METHODS: A total of 21,451 inpatients with type 2 diabetes (T2D) and chronic heart failure (CHF) were analyzed, including 638 who received glimepiride treatment and 20,813 who did not. Propensity score matching yielded 509 pairs (glimepiride and non-glimepiride groups), and both groups were followed up. Kaplan-Meier and Cox regression analyses were used to compare all-cause mortality, cardiovascular mortality, hospitalizations and emergency visits for heart failure, and hospitalizations for acute myocardial infarction or stroke. RESULTS: During follow-up, the all-cause mortality (adjusted hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.35-0.63; P < 0.001), cardiovascular mortality (adjusted HR, 0.34; 95% CI, 0.24-0.48; P < 0.001), and number of hospitalizations and emergency visits for heart failure (adjusted HR, 0.42; 95% CI, 0.36-0.50; P < 0.001) and hospitalizations for acute myocardial infarction or stroke (adjusted HR, 0.53; 95% CI, 0.38-0.73; P < 0.001) were significantly lower in the glimepiride group; the conclusion remained similar in all subgroups. Furthermore, high-dose glimepiride use (2-4 mg/day) was associated with lower cardiovascular mortality than low-dose (1 mg/day) (adjusted HR, 0.55; 95% CI, 0.31-0.99; P = 0.047). Glimepiride exhibited good molecular docking with soluble epoxide hydrolase (sEH) and increased the level epoxyeicosatrienoic acid (EET). CONCLUSIONS: Long-term continuous glimepiride use is associated with better survival, fewer hospitalizations and emergency visits for heart failure, and fewer hospitalizations for acute myocardial infarction or stroke in patients with T2D and CHF. High-dose glimepiride has greater cardiovascular protective advantages than low-dose glimepiride. The cardiovascular protective effect of glimepiride may be related to the EET level increase through sEH inhibition.

Long-term continuous glimepiride use is associated with better survival, fewer hospitalizations and emergency visits for heart failure. High-dose glimepiride has greater cardiovascular protective advantages than low-dose glimepiride. Trial registration: ClinicalTrials.gov NCT05538819. https://www.clinicaltrials.gov/ct2/show/NCT05538819.

Amyotrophic Lateral Sclerosis-Associated Persistent Organic Pollutant cis-Chlordane Causes GABAA-Independent Toxicity to Motor Neurons, Providing Evidence toward an Environmental Component of Sporadic Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the death of upper and lower motor neurons. While causative genes have been identified, 90% of ALS cases are not inherited and are hypothesized to result from the accumulation of genetic and environmental risk factors. While no specific causative environmental toxin has been identified, previous work has indicated that the presence of the organochlorine pesticide cis-chlordane in the blood is highly correlated with ALS incidence. Never before tested on the motor system, here, we show that cis-chlordane is especially toxic to motor neurons in vitro- and in vivo-independent of its known antagonism of the GABAA receptor. We find that human stem-cell-derived motor neurons are more sensitive to cis-chlordane than other cell types and their action potential dynamics are altered. Utilizing zebrafish larvae, we show that cis-chlordane induces motor neuron and neuromuscular junction degeneration and subsequent motor deficits in a touch-evoked escape response. Together, our work points to cis-chlordane as a potential sporadic ALS exacerbating environmental pollutant.

Application of digital positioning guide plates for the surgical extraction of multiple impacted supernumerary teeth: A case report and review of literature.

BACKGROUND: An extra tooth in the normal tooth sequence in any region of the dental arch is regarded as a supernumerary tooth (SNT). Due to the large variation in location and morphology, the extraction of impacted SNTs is an extensive and complex procedure with high risks of several complications. This report presents a rare case of seven impacted SNTs in the bilateral upper and lower arch that were successfully extracted with the use of digital positioning guide plates. CASE SUMMARY: In January 2022, a 21-year-old male was referred to our department with a chief complaint of pain in relation to tooth #36. Clinical examination showed a deep carious lesion with pulpal involvement in tooth #36 and lingual swelling of the bilateral mandibular posterior area. Radiographic examination revealed seven deeply impacted SNTs in the bilateral posterior area and bilateral impacted mandibular third molars. Based on these findings, the patient was diagnosed with bilateral, multiple impacted SNTs and tooth #36 chronic pulpitis. A root canal treatment and an all-ceramic crown restoration for tooth #36 were performed. An individualized digital positioning guide plate was designed by computer-aided design/computer-aided manufacturing technology and cone-beam computed tomography for extraction of the impacted SNTs. During the operation, the digital positioning guide plate allowed rapid positioning and exposure of the SNTs while avoiding adjacent important anatomical structures. At 3-month follow-up, regeneration of bone and soft tissues was visible. CONCLUSION: The application of digital positioning guide plates is useful for the individualized and minimalized extraction of impacted supernumerary teeth.

Vaccination with Mycoplasma pneumoniae membrane lipoproteins induces IL-17A driven neutrophilia that mediates Vaccine-Enhanced Disease.

Bacterial lipoproteins are an often-underappreciated class of microbe-associated molecular patterns with potent immunomodulatory activity. We previously reported that vaccination of BALB/c mice with Mycoplasma pneumoniae (Mp) lipid-associated membrane proteins (LAMPs) resulted in lipoprotein-dependent vaccine enhanced disease after challenge with virulent Mp, though the immune responses underpinning this phenomenon remain poorly understood. Herein, we report that lipoprotein-induced VED in a mouse model is associated with elevated inflammatory cytokines TNF-α, IL-1ß, IL-6, IL-17A, and KC in lung lavage fluid and with suppurative pneumonia marked by exuberant neutrophilia in the pulmonary parenchyma. Whole-lung-digest flow cytometry and RNAScope analysis identified multiple cellular sources for IL-17A, and the numbers of IL-17A producing cells were increased in LAMPs-vaccinated/Mp-challenged animals compared to controls. Specific IL-17A or neutrophil depletion reduced disease severity in our VED model-indicating that Mp lipoproteins induce VED in an IL-17A-dependent manner and through exuberant neutrophil recruitment. IL-17A neutralization reduced levels of TNF-α, IL-1ß, IL-6, and KC, indicating that IL-17A preceded other inflammatory cytokines. Surprisingly, we found that IL-17A neutralization impaired bacterial clearance, while neutrophil depletion improved it-indicating that, while IL-17A appears to confer both maladaptive and protective responses, neutrophils play an entirely maladaptive role in VED. Given that lipoproteins are found in virtually all bacteria, the potential for lipoprotein-mediated maladaptive inflammatory responses should be taken into consideration when developing vaccines against bacterial pathogens.