Clinical Characteristics, Treatment, and Prognosis of Osteoarticular Brucellosis: A Retrospective Real-World Study in Shenyang, China, 2014-2019.

This study aimed to assess the clinical characteristics, treatment, and prognosis of osteoarticular brucellosis. We conducted a retrospective study enrolling brucellosis patients from the Sixth People's Hospital of Shenyang between September 2014 and June 2019. A total of 1917 participants were admitted during this period. After applying propensity score matching, we retrospectively analyzed 429 patients with osteoarthritis and 429 patients without osteoarthritis. The primary outcome was treatment completion. The secondary outcome was symptom disappearance and seroconversion. Brucellosis patients with osteoarthritis had longer treatment course (160 [134.3-185.7] vs. 120 [102.3-137.7] d, p = 0.008) than those without osteoarthritis. The most common involved site was lumbar vertebrae (290 [67.6%]) in brucellosis patients with osteoarthritis. Longer symptom duration (90 [83.0-97.0] vs. 42 [40.2-43.8], p < 0.001) along with no significant difference in seroconversion (180 [178.8-181.2] vs. 180 [135.1-224.9], p = 0.212) was observed in osteoarthritis patients with treatment course >90 d. Peripheral joint involvement (adjusted hazard ratio [95% confidence interval] 1.485 [1.103-1.999]; p = 0.009) had a shorter symptom duration compared with shaft joint involvement. No significant differences were observed in treatment therapy between doxycycline plus rifampin (DR) or plus cephalosporins (DRC) in treatment course (p = 0.190), symptom persistence (p = 0.294), and seroconversion (p = 0.086). Lumbar vertebra was the most commonly involved site. Even if all symptoms disappeared, Serum agglutination test potentially remained positive in some patients. Compared with peripheral arthritis, shaft arthritis was the high-risk factor for longer symptom duration. The therapeutic effects were similar between DR and DRC. In summary, our study provided important insights into the clinical characteristics, treatment, and outcomes of osteoarticular brucellosis. Clinical Trial Registration number: NCT04020536.

Proteomic and cellular characterization of Omicron breakthrough infections and a third homologous or heterologous boosting vaccination in a longitudinal cohort.

BACKGROUND: The understanding of dynamic plasma proteome features in hybrid immunity and breakthrough infection is limited. A deeper understanding of the immune differences between heterologous and homologous immunization could assist in the future establishment of vaccination strategies. METHODS: In this study, 40 participants who received a third dose of either a homologous BBIBP-CorV or a heterologous ZF2001 protein subunit vaccine following two doses of inactivated coronavirus disease 2019 vaccines and 12 patients with BA.2.2 breakthrough infections were enrolled. Serum samples were collected at Days 0, 28, and 180 following the boosting vaccination and breakthrough and then analyzed using neutralizing antibody tests and mass spectrometer-based proteomics. Mass cytometry of peripheral blood mononuclear cell samples was also performed in this cohort. RESULTS: The chemokine signaling pathway and humoral response markers (IgG2 and IgG3) associated with infection were found to be upregulated in breakthrough infections compared to vaccination-induced immunity. Elevated expression of IGKV, IGHV, IL-17 signaling, and the phagocytosis pathway, along with lower expression of FGL2, were correlated with higher antibody levels in the boosting vaccination groups. The MAPK signaling pathway and Fc gamma R-mediated phagocytosis were more enriched in the heterologous immunization groups than in the homologous immunization groups. CONCLUSION: Breakthrough infections can trigger more intensive inflammatory chemokine responses than vaccination. T-cell and innate immune activation have been shown to be closely related to enhanced antibody levels after vaccination and therefore might be potential targets for vaccine adjuvant design.

Prognostic value of poly-microorganisms detected by droplet digital PCR and pathogen load kinetics in sepsis patients: a multi-center prospective cohort study.

This study aimed to investigate the prognostic value of a novel droplet digital polymerase chain reaction (DDPCR) assay in sepsis patients. In this prospective cohort study, univariable and multivariable Cox regressions were used to assess risk factors for 28-day mortality. We also monitored pathogen load together with clinical indicators in a subgroup of the cohort. A total of 107 sepsis patients with positive baseline DDPCR results were included. Detection of poly-microorganisms [adjusted hazard ratio (HR) = 3.19; 95% confidence interval (CI) = 1.34-7.62; P = 0.009], high Charlson Comorbidity Index (CCI) score (adjusted HR = 1.14; 95% CI = 1.01-1.29; P = 0.041), and Sequential Organ Failure Assessment (SOFA) score (adjusted HR = 1.18; 95% CI = 1.05-1.32; P = 0.005) at baseline were independent risk factors for 28-day mortality while initial pathogen load was not associated (adjusted HR = 1.17; 95% CI = 0.82-1.66; P = 0.385). Among 63 patients with serial DDPCR results, an increase in pathogen load at days 6-8 compared to baseline was a risk factor for 28-day mortality (P = 0.008). Also, pathogen load kinetics were significantly different between day-28 survivors and nonsurvivors (P = 0.022), with a decline overtime only in survivors and an increase from days 3 and 4 to days 6-8 in nonsurvivors. Using DDPCR technique, we found that poly-microorganisms detected and increased pathogen load a week after sepsis diagnosis were associated with poor prognosis.IMPORTANCEThis prospective study was initiated to explore the prognostic implications of a novel multiplex PCR assay in sepsis. Notably, our study was the largest cohort of sepsis with droplet digital polymerase chain reaction pathogen monitoring to date, allowing for a comprehensive evaluation of the prognostic significance of both pathogen species and load. We found that detection of poly-microorganisms was an independent risk factors for 28-day mortality. Also, pathogen load increase 1 week after sepsis diagnosis was a risk factor for 28-day mortality, and differential pathogen load kinetics were identified between day-28 survivors and nonsurvivors. Overall, this study demonstrated that pathogen species and load were highly correlated with sepsis prognosis. Patients exhibiting conditions mentioned above face a more adverse prognosis, suggesting the potential need for an escalation of antimicrobial therapy.Registered at ClinicalTrials.gov (NCT05190861).

Risk of reinfection and severity with the predominant BA.5 Omicron subvariant China, from December 2022 to January 2023.

Data on reinfection in large Asian populations are limited. In this study, we aimed to evaluate the reinfection rate, disease severity, and time interval between the infections in the symptomatic and asymptomatic populations which are firstl infected with BA.2 Omicron Variant. We retrospectively included adult patients with COVID-19 discharged from four designated hospitals between 27 April 2021 and 30 November 2022, who were interviewed via telephone from 29 January to 1 March 2023. Univariable and multivariable analyses were used to explore risk factors associated with reinfection. A total of 16,558 patients were followed up, during the telephone survey of an average of 310.0 days, 1610 (9.72%) participants self-reported reinfection. The mean time range of reinfection was 257.9 days. The risks for reinfection were analysed using multivariable logistic regression. Patients with severe first infection were at higher risk for reinfection (aORs, 2.50; P < 0.001). The male (aORs,0.82; P < 0.001), the elderly (aORs, 0.44; P < 0.001), and patients with full vaccination (aORs, 0.67; P < 0.001) or booster (aORs, 0.63; P < 0.001) had the lower risk of reinfection. Patients over 60 years of age (aORs,9.02; P = 0.006) and those with ≥2 comorbidities (aORs,11.51; P = 0.016). were at higher risk for severe reinfection. The number of clinical manifestations of reinfection increases in people with severe first infection (aORs, 2.82; P = 0.023). The overall reinfection rate was 9.72%, and the reinfection rate of Omicron-to-Omicron subvariants was 9.50% at one year. The severity of Omicron-Omicron reinfection decreased. Data from our clinical study may provide clinical evidence and bolster response preparedness for future COVID-19 reinfection waves.

Robust integration of light-driven carbon quantum dots with bacterial cellulose enables excellent mechanical and antibacterial biodegradable yarn.

Due to the overuse of antimicrobial drugs, bacterial resistance became an urgent problem to be solved. In this study, carbon quantum dots (CQDs) with high photodynamic antibacterial activity were synthesized by a one-pot hydrothermal method and introduced into bacterial cellulose (BC) dispersion solution. Through a wet-spinning and wet-twisting processing strategy, bionic ordering nanocomposite macrofiber (BC/CQDs-based yarn) based on BC were obtained. The results showed that BC/CQDs-based yarn had excellent tensile strength (226.8 MPa) and elongation (22.2 %). Utilizing the light-driven generation of singlet oxygen (1O2) and hydroxyl radical (·OH), BC/CQDs-based yarn demonstrated remarkable antibacterial efficacy, with 99.9999 % (6 log, P < 0.0001) and 96.54 % (1.46 log, P < 0.0004) effectiveness against E. coli and S. aureus, respectively. At the same time, BC/CQDs-based yarn also displayed the characteristics of photothermal, fluorescent, and biodegradability. In summary, the application potential of BC/CQDs-based yarn is significant, opening up a new strategy for the development of sustainable green weaving and bio-based multi-function yarn.

Highly Stretchable and Fluorescent Visualizable Thermoplastic Polyurethane/Tetraphenylethylene Plied Yarn Strain Sensor with Heterogeneous and Cracked Structure for Human Health Monitoring.

Smart wearable technology has been more and more widely used in monitoring and prewarning of human health and safety, while flexible yarn-based strain sensors have attracted extensive research interest due to their ability to withstand greater external strain and their significant application potential in real-time monitoring of human motion and health signals. Although several strain sensors based on yarn structures have been reported, it remains challenging to strike a balance between high sensitivity and wide strain ranges. At the same time, visual signal sensing is expected to be used in strain sensors thanks to its intuitiveness. In this work, thermoplastic polyurethane (TPU) and tetraphenylethylene (TPE) were wet-spun to fabricate flexible fluorescent fibers used as the substrate of the sensor, followed by the drop addition of polydimethylsiloxane (PDMS) beads and curing to produce a heterogeneous structure, which were further twisted into a plied yarn. Finally, a visualizable flexible yarn strain sensor based on solidified liquid beads and crack structure was obtained by loading polydopamine (PDA) and polypyrrole (PPy) in situ. The sensor exhibited high sensitivity (the GF value was 58.9 at the strain range of 143-184%), a wide working strain range (0-184%), a low monitoring limit (<0.1%), a fast response (58.82 ms), reliable responses at different frequencies, and excellent cycle durability (over 2000 cycles). At the same time, the yarn strain sensor also had excellent photothermal characteristics and a fluorescence crack visualization effect. These attractive advantages enabled yarn strain sensors to accurately monitor various human activities, showing great application potential in health monitoring, personalized medical diagnosis, and other aspects.

Vaccination Shapes Within-Host SARS-CoV-2 Diversity of Omicron BA.2.2 Breakthrough Infection.

BACKGROUND: Low-frequency intrahost single-nucleotide variants of SARS-CoV-2 have been recognized as predictive indicators of selection. However, the impact of vaccination on the intrahost evolution of SARS-CoV-2 remains uncertain at present. METHODS: We investigated the genetic variation of SARS-CoV-2 in individuals who were unvaccinated, partially vaccinated, or fully vaccinated during Shanghai's Omicron BA.2.2 wave. We substantiated the connection between particular amino acid substitutions and immune-mediated selection through a pseudovirus neutralization assay or by cross-verification with the human leukocyte antigen-associated T-cell epitopes. RESULTS: In contrast to those with immunologic naivety or partial vaccination, participants who were fully vaccinated had intrahost variant spectra characterized by reduced diversity. Nevertheless, the distribution of mutations in the fully vaccinated group was enriched in the spike protein. The distribution of intrahost single-nucleotide variants in individuals who were immunocompetent did not demonstrate notable signs of positive selection, in contrast to the observed adaptation in 2 participants who were immunocompromised who had an extended period of viral shedding. CONCLUSIONS: In SARS-CoV-2 infections, vaccine-induced immunity was associated with decreased diversity of within-host variant spectra, with milder inflammatory pathophysiology. The enrichment of mutations in the spike protein gene indicates selection pressure exerted by vaccination on the evolution of SARS-CoV-2.

Pathogen quantitative efficacy of different spike-in internal controls and clinical application in central nervous system infection with metagenomic sequencing.

IMPORTANCE: Metagenomic next-generation sequencing (mNGS) has been used broadly for pathogens detection of infectious diseases. However, there is a lack of method for the absolute quantitation of pathogens by mNGS. We compared the quantitative efficiency of three mNGS internal controls (ICs) Thermus thermophilus, T1 phages, and artificial DNA sequence and developed the most applicable strategies for pathogen quantitation via mNGS in central nervous system infection. The IC application strategy we developed will enable mNGS analysis to assess the pathogen load simultaneously with the detection of pathogens, which should provide critical information for quick decision-making of treatment as well as clinical prognosis.

Utility of clinical metagenomics in diagnosing malignancies in a cohort of patients with Epstein-Barr virus positivity.

Backgrounds: Differentiation between benign and malignant diseases in EBV-positive patients poses a significant challenge due to the lack of efficient diagnostic tools. Metagenomic Next-Generation Sequencing (mNGS) is commonly used to identify pathogens of patients with fevers of unknown-origin (FUO). Recent studies have extended the application of Next-Generation Sequencing (NGS) in identifying tumors in body fluids and cerebrospinal fluids. In light of these, we conducted this study to develop and apply metagenomic methods to validate their role in identifying EBV-associated malignant disease. Methods: We enrolled 29 patients with positive EBV results in the cohort of FUO in the Department of Infectious Diseases of Huashan Hospital affiliated with Fudan University from 2018 to 2019. Upon enrollment, these patients were grouped for benign diseases, CAEBV, and malignant diseases according to their final diagnosis, and CNV analysis was retrospectively performed in 2022 using samples from 2018 to 2019. Results: Among the 29 patients. 16 of them were diagnosed with benign diseases, 3 patients were diagnosed with CAEBV and 10 patients were with malignant diseases. 29 blood samples from 29 patients were tested for mNGS. Among all 10 patients with malignant diagnosis, CNV analysis suggested neoplasms in 9 patients. Of all 19 patients with benign or CAEBV diagnosis, 2 patients showed abnormal CNV results. The sensitivity and specificity of CNV analysis for the identification for tumors were 90% and 89.5%, separately. Conclusions: The application of mNGS could assist in the identification of microbial infection and malignancies in EBV-related diseases. Our results demonstrate that CNV detection through mNGS is faster compared to conventional oncology tests. Moreover, the convenient collection of peripheral blood samples adds to the advantages of this approach.

Neutralization against Omicron subvariants after BA.5/BF.7 breakthrough infection weakened as virus evolution and aging despite repeated prototype-based vaccination1.

BACKGROUND: Omicron had swept the mainland China between December 2022 and January 2023, while SARS-CoV-2 still continued to evolve. To fully prepare for the next wave, it's urgent to evaluate the humoral immune response post BA.5/BF.7 breakthrough infection against predominant sub-lineages among existing vaccination strategies and the elders. METHOD: This study enrolled a longitudinal young-adult cohort from 2/3-dose vaccination to 1 month after breakthrough infection, and an elder cohort at 1 month after breakthrough infection. Seral samples were collected and tested for humoral immune response to SARS-CoV-2 subvariants including WT, BA.2, BA.5, BF.7, BQ.1.1, CH.1.1, XBB.1.5. RESULTS: BA.5/BF.7 breakthrough infection induced higher neutralization activity than solely vaccination in all SARS-CoV-2 strains, while the latest Omicron subvariants, BQ.1.1, CH.1.1, XBB.1.5, exhibited the strongest neutralization evasion ability. There was a negative correlation between age and humoral immune response in WT, BA.5, BQ.1.1, and XBB.1.5. Compared to non-vaccination groups, breakthrough infection in two-dose vaccination groups had significantly higher neutralizing antibody against WT, BA.2, BA.5, BF.7 but not to BQ.1.1, CH.1.1, XBB.1.5 while booster dose against the prototype prior-breakthrough would not further significantly enhance individual's humoral responses against the latest Omicron subvariants. CONCLUSIONS: Newer variants manifest increasing immune evasion from neutralization and repeated prototype-based booster vaccines may not further enhance neutralizing antibody against emerging new variants. Older adults have lower levels of neutralizing antibody. Future vaccination strategies should aim to enhance effective neutralization to contemporary variants.

Experience in the diagnosis and treatment of pneumonia caused by infection with Tropheryma whipplei: A case series.

Tropheryma whipplei (TW) is the root cause of Whipple's disease (WD), a rare infectious illness leading to multi-organ impairment. A prominent feature of WD is acute pneumonia, which can be exceedingly challenging to diagnose clinically due to the pathogen's surreptitious nature. However and significantly, with the advent of metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF), it offers clinicians a potent tool at their disposal to detect TW infections. The present study conducted a retrospective analysis of clinical data gleaned from five patients in Hunan Province in China. Findings in this study demonstrated the potential of BALF-mNGS in diagnosing pneumonia caused by TW infection.

The Relationship between VEGF and AGT Gene Single Nucleotide Polymorphisms and Susceptibility to Renal and Bladder Cancers.

BACKGROUND: We aimed to examine the relationships between the angiotensinogen (AGT) and vascular endothelial growth factor (VEGF) gene single nucleotide polymorphisms and susceptibility to bladder and kidney cancers. METHODS: A 1:1 paired case-control study was conducted, which included 143 newly diagnosed kidney cancer cases, 182 newly diagnosed bladder cancer cases, and healthy subjects in the same period collected from two hospitals. Medical records and a questionnaire were used to obtain relevant information. Genotypes were determined by improved multiple ligase detection reaction (iMLDR) and VEGF serum expression levels were detected by enzyme-linked immunosorbent assays (ELISAs). RESULTS: The VEGF gene/genotype frequencies of rs833061 and rs1570360 were statistically different among various pathological grades of kidney cancer, while the AGT rs699 gene/genotype frequencies were statistically different among various pathological types of bladder cancer. In kidney cancer, rs699 was associated with smoking, drinking, and hair coloring, while in bladder cancer, rs699, rs1570360, rs3025039, and rs833061 were associated with smoking, drinking, hair coloring, exercise, and urine holding. CONCLUSIONS: This work will help identify biomarkers that can predict the early metastasis and recurrence of kidney or bladder cancer, as well as help improve patient survival rates by predicting their susceptibility. SIGNIFICANCE: This work will provide reference for the prevention and treatment of kidney and bladder cancers.

A one-year follow-up study of systematic impact of long COVID symptoms among patients post SARS-CoV-2 omicron variants infection in Shanghai, China.

Long COVID hinders people from normal life and work, posing significant medical and economic challenges. Nevertheless, comprehensive studies assessing its impact on large populations in Asia are still lacking. We tracked over 20,000 patients infected with COVID-19 for the first time during the Omicron BA.2 outbreak in Shanghai from March-June 2022 for one year. Of the 21,799 COVID-19 patients who participated in the 6-month telephone follow-up, 1939 (8.89%) had self-reported long COVID symptoms. 450 long COVID patients participated in the 6-month outpatient follow-up. Participants underwent healthy physical examinations and questionnaires focused on long-COVID-related symptoms and mental health. Mobility problem (P < 0.001), personal care problem (P = 0.003), usual activity problem (P < 0.001), pain/discomfort (P < 0.001), anxiety/depression (P = 0.001) and PTSD (P = 0.001) were more prevalent in long COVID patients than in healthy individuals, but no significant differences were found between the two groups on chest CT and laboratory examinations. Of the 856 long COVID patients who participated in the 12-month follow-up, 587 (68.5%) had their symptoms resolved. In the multivariable logistic analysis, females (P < 0.001), youth (age <40 years) (P < 0.001), ≥ 2 comorbidities (P = 0.009), and severe infection in the acute phase (P = 0.006) were risk factors for developing long COVID. Middle age (40-60 years) was a risk factor for persistent long COVID one year after hospital discharge (P = 0.013). The study found that long COVID mainly manifested as subjective symptoms and impacts partial patients' quality of life and mental status. After one year, most (68.5%) of the patients recovered from long COVID with no impairment of organ function observed.

The Relationship between VEGF and AGT Gene Single Nucleotide Polymorphisms and Susceptibility to Renal and Bladder Cancers

Background: We aimed to examine the relationships between the angiotensinogen (AGT) and vascular endothelial growth factor (VEGF) gene single nucleotide polymorphisms and susceptibility to bladder and kidney cancers. Methods: A 1:1 paired case-control study was conducted, which included 143 newly diagnosed kidney cancer cases, 182 newly diagnosed bladder cancer cases, and healthy subjects in the same period collected from two hospitals. Medical records and a questionnaire were used to obtain relevant information. Genotypes were determined by improved multiple ligase detection reaction (iMLDR) and VEGF serum expression levels were detected by enzyme-linked immunosorbent assays (ELISAs). Results: The VEGF gene/genotype frequencies of rs833061 and rs1570360 were statistically different among various pathological grades of kidney cancer, while the AGT rs699 gene/genotype frequencies were statistically different among various pathological types of bladder cancer. In kidney cancer, rs699 was associated with smoking, drinking, and hair coloring, while in bladder cancer, rs699, rs1570360, rs3025039, and rs833061 were associated with smoking, drinking, hair coloring, exercise, and urine holding. Conclusions: This work will help identify biomarkers that can predict the early metastasis and recurrence of kidney or bladder cancer, as well as help improve patient survival rates by predicting their susceptibility. Significance: This work will provide reference for the prevention and treatment of kidney and bladder cancers (AU)

Clinical application and drug-use-guidance value of metagenomic next-generation sequencing in central nervous system infection.

OBJECTIVE: Timely and precise etiology diagnosis is crucial for optimized medication regimens and better prognosis in central nervous system infections (CNS infections). We aimed to analyze the impact of mNGS tests on the management of patients with CNS infections. METHODS: We conducted a single-center retrospective cohort study to analyze the value of mNGS in clinical applications. Three hundred sixty-nine patients with a CNS infection diagnosis were enrolled, and their clinical data were collected. CDI and DDI were defined in our study to describe the intensity of drug use in different groups. We used LOH and mRS to evaluate if the application of mNGS can benefit CNS infected patients. RESULTS: mNGS reported a 91.67% sensitivity in culture-positive patients and an 88.24% specificity compared with the final diagnoses. Patients who participated with the mNGS test had less drug use, both total (58.77 vs. 81.18) and daily (22.6 vs. 28.12, P < 0.1, McNemar) intensity of drug use, and length of hospitalization (23.14 vs. 24.29). Patients with a consciousness grading 1 and 3 had a decrease in CDI (Grade 1, 86.49 vs. 173.37; Grade 3, 48.18 vs. 68.21), DDI (Grade 1, 1.52 vs. 2.72; Grade 3, 2.3 vs. 2.45), and LOH (Grade 1, 32 vs. 40; Grade 3, 21 vs. 23) with the application of mNGS. Patients infected with bacteria in the CNS had a reduced CDI, DDI, and LOH in the mNGS group. This was compared with the TraE group that had 49% of patients altered medication plans, and 24.7% of patients reduced drug intensity four days after mNGS reports. This was because of the reduction of drug types. CONCLUSION: mNGS showed its high sensitivity and specificity characteristics. mNGS may assist clinicians with more rational medication regimens and reduce the drug intensity for patients. The primary way of achieving this is to reduce the variety of drugs, especially for severe patients and bacterial infections. mNGS has the ability of improving the prognosis of CNS infected patients.

Photodynamic activity enhanced by in situ biosynthetic BC/CQDs@PCN-224 membranes through FRET strategy.

Porphyrin-based metal organic frameworks (MOFs) with efficient bactericidal performance have increasingly attracted attention in photodynamic inactivation materials. However, low reactive oxygen species (ROS) yield and drug residue hazards of current porphyrin-MOFs materials lead to unsatisfactory clinical therapeutic effects. In this paper, carbon quantum dots (CQDs) were encapsulated into PCN-224, which enhanced the photodynamic activity of the MOFs through fluorescence resonance energy transfer (FRET) process. Singlet oxygen (1O2) detection confirmed that the photodynamic activity of CQDs-doped PCN-224 (CQDs@PCN-224) was enhanced than that of pristine PCN-224 under illumination. Furthermore, the CQDs@PCN-224 were firmly embedded into bacterial cellulose (BC) nanofibrous membranes by using an eco-friendly biosynthetic approach, efficiently preventing MOFs leakage during use. The results of bactericidal assays demonstrated that BC/CQDs@PCN-224 membrane with higher photodynamic activity causes more severe disruption to bacterial structure and possesses better antibacterial efficiency (>99.99 % reduction of both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli O157:H7 within 30 min) than BC/PCN-224 membrane under visible light illumination (500 W, 15 cm height, λ ≥ 420 nm). In addition, the biosynthesized BC/CQDs@PCN-224 membrane showed good hemocompatibility and low cytotoxicity, revealing that the BC- and MOFs-based material with enhanced PDI efficiency and satisfying safety has great potential in medical fields.