All-optical frequency division on-chip using a single laser.

The generation of spectrally pure microwave signals is a critical functionality in fundamental and applied sciences, including metrology and communications. Optical frequency combs enable the powerful technique of optical frequency division (OFD) to produce microwave oscillations of the highest quality1,2. Current implementations of OFD require multiple lasers, with space- and energy-consuming optical stabilization and electronic feedback components, resulting in device footprints incompatible with integration into a compact and robust photonic platform3-5. Here we demonstrate all-optical OFD on a photonic chip by synchronizing two distinct dynamical states of Kerr microresonators pumped by a single continuous-wave laser. The inherent stability of the terahertz beat frequency between the signal and idler fields of an optical parametric oscillator is transferred to a microwave frequency of a Kerr soliton comb, and synchronization is achieved via a coupling waveguide without the need for electronic locking. OFD factors of N = 34 and 468 are achieved for 227 GHz and 16 GHz soliton combs, respectively. In particular, OFD enables a 46 dB phase-noise reduction for the 16 GHz soliton comb, resulting in the lowest microwave noise observed in an integrated photonics platform. Our work represents a simple, effective approach for performing OFD and provides a pathway towards chip-scale devices that can generate microwave frequencies comparable to the purest tones produced in metrological laboratories.

Field-free switching of perpendicular magnetization by two-dimensional PtTe2/WTe2 van der Waals heterostructures with high spin Hall conductivity.

The key challenge of spin-orbit torque applications lies in exploring an excellent spin source capable of generating out-of-plane spins while exhibiting high spin Hall conductivity. Here we combine PtTe2 for high spin conductivity and WTe2 for low crystal symmetry to satisfy the above requirements. The PtTe2/WTe2 bilayers exhibit a high in-plane spin Hall conductivity σs,y ≈ 2.32 × 105 × h/2e Ω-1 m-1 and out-of-plane spin Hall conductivity σs,z ≈ 0.25 × 105 × h/2e Ω-1 m-1, where h is the reduced Planck's constant and e is the value of the elementary charge. The out-of-plane spins in PtTe2/WTe2 bilayers enable the deterministic switching of perpendicular magnetization at room temperature without magnetic fields, and the power consumption is 67 times smaller than that of the Pt control case. The high out-of-plane spin Hall conductivity is attributed to the conversion from in-plane spin to out-of-plane spin, induced by the crystal asymmetry of WTe2. Our work establishes a low-power perpendicular magnetization manipulation based on wafer-scale two-dimensional van der Waals heterostructures.

Spatially Resolved Functional Group Analysis of OLED Materials Using EELS and ToF-SIMS.

Electron energy-loss spectroscopy (EELS) is widely used in analyzing the electronic structure of inorganic materials at high spatial resolution. In this study, we use a monochromator to improve the energy resolution, allowing us to analyze the electronic structure of organic light-emitting diode (OLED) materials with greater precision. This study demonstrates the use of the energy-loss near-edge structure to map the nitrogen content of organic molecules and identify the distinct bonding characteristics of aromatic carbon and pyridinic nitrogen. Furthermore, we integrate EELS with time-of-flight secondary ion mass spectrometry for molecular mapping of three different bilayers composed of OLED materials. This approach allows us to successfully map functional groups in the by-layer OLED and measure the thickness of two OLED layers. This study introduces spatially resolved functional group analysis using electron beam spectroscopy and contributes to the development of methods for complete nanoscale analysis of organic multilayer architectures.

Tip-based Lithography with a Sacrificial Layer.

The fabrication of a highly controlled gold (Au) nanohole (NH) array via tip-based lithography is improved by incorporating a sacrificial layer-a tip-crash buffer layer. This inclusion mitigates scratches during the nano-indentation process by employing a 300 nm thick poly(methyl methacrylate) layer as a sacrificial layer on top of the Au film. Such a precaution ensures minimal scratches on the Au film, facilitating the creation of sub-50 nm Au NHs with a 15 nm gap between the Au NHs. The precision of this method exceeds that of fabricating Au NHs without a sacrificial layer. Demonstrating its versatility, this Au NH array is utilized in two distinct applications: as a dry etching mask to form a molybdenum disulfide hole array and as a catalyst in metal-assisted chemical etching, resulting in conical-shaped silicon nanostructures. Additionally, a significant electric field is generated when Au nanoparticles (NPs) are placed within the Au NHs. This effect arises from coupling electromagnetic waves, concentrated by the Au NHs and amplified by the Au NPs. A notable result of this configuration is the enhancement factor of surface-enhanced Raman scattering, which is an order of magnitude greater than that observed with just Au NHs and Au NPs alone.

Machine learning-based quantification for disease uncertainty increases the statistical power of genetic association studies.

MOTIVATION: Allowance for increasingly large samples is a key to identify the association of genetic variants with Alzheimer's disease (AD) in genome-wide association studies (GWAS). Accordingly, we aimed to develop a method that incorporates patients with mild cognitive impairment and unknown cognitive status in GWAS using a machine learning-based AD prediction model. RESULTS: Simulation analyses showed that weighting imputed phenotypes method increased the statistical power compared to ordinary logistic regression using only AD cases and controls. Applied to real-world data, the penalized logistic method had the highest AUC (0.96) for AD prediction and weighting imputed phenotypes method performed well in terms of power. We identified an association (P<5.0×10-8) of AD with several variants in the APOE region and rs143625563 in LMX1A. Our method, which allows the inclusion of individuals with mild cognitive impairment, improves the statistical power of GWAS for AD. We discovered a novel association with LMX1A. AVAILABILITY AND IMPLEMENTATION: Simulation codes can be accessed at https://github.com/Junkkkk/wGEE_GWAS.

Mining biosynthetic gene clusters in Paenibacillus genomes to discover novel antibiotics.

BACKGROUND: Bacterial antimicrobial resistance poses a severe threat to humanity, necessitating the urgent development of new antibiotics. Recent advances in genome sequencing offer new avenues for antibiotic discovery. Paenibacillus genomes encompass a considerable array of antibiotic biosynthetic gene clusters (BGCs), rendering these species as good candidates for genome-driven novel antibiotic exploration. Nevertheless, BGCs within Paenibacillus genomes have not been extensively studied. RESULTS: We conducted an analysis of 554 Paenibacillus genome sequences, sourced from the National Center for Biotechnology Information database, with a focused investigation involving 89 of these genomes via antiSMASH. Our analysis unearthed a total of 848 BGCs, of which 716 (84.4%) were classified as unknown. From the initial pool of 554 Paenibacillus strains, we selected 26 available in culture collections for an in-depth evaluation. Genomic scrutiny of these selected strains unveiled 255 BGCs, encoding non-ribosomal peptide synthetases, polyketide synthases, and bacteriocins, with 221 (86.7%) classified as unknown. Among these strains, 20 exhibited antimicrobial activity against the gram-positive bacterium Micrococcus luteus, yet only six strains displayed activity against the gram-negative bacterium Escherichia coli. We proceeded to focus on Paenibacillus brasilensis, which featured five new BGCs for further investigation. To facilitate detailed characterization, we constructed a mutant in which a single BGC encoding a novel antibiotic was activated while simultaneously inactivating multiple BGCs using a cytosine base editor (CBE). The novel antibiotic was found to be localized to the cell wall and demonstrated activity against both gram-positive bacteria and fungi. The chemical structure of the new antibiotic was elucidated on the basis of ESIMS, 1D and 2D NMR spectroscopic data. The novel compound, with a molecular weight of 926, was named bracidin. CONCLUSIONS: This study outcome highlights the potential of Paenibacillus species as valuable sources for novel antibiotics. In addition, CBE-mediated dereplication of antibiotics proved to be a rapid and efficient method for characterizing novel antibiotics from Paenibacillus species, suggesting that it will greatly accelerate the genome-based development of new antibiotics.

Efficacy and safety of MC-003 solution for endoscopic mucosal or submucosal resection: a prospective, multicenter, randomized, triple-blinded, parallel-group, phase III study.

BACKGROUND AND AIMS: The safety and efficacy of solutions for submucosal injection are critical for endoscopic resection of gastric adenomas or early gastric cancers. Although several injectable solutions have been introduced for endoscopic resection, they have some limitations. We aimed to compare the efficacy of the new sodium alginate-based solution MC-003 with that of normal saline (NS; 0.9% sodium chloride). METHODS: In this randomized, triple-blind study, 70 patients were initially enrolled for EMR or endoscopic submucosal dissection (ESD). The main outcomes included the need for additional injections, completion of en bloc resection, and occurrence of adverse events. RESULTS: Each group ultimately included 34 patients. Complete en bloc resections were achieved in all patients (P = 1.000). The MC-003 group had more peri-neoplasm tissue fibrosis (P = .056) and needed fewer additional injections for lesions >15 mm (P = .037), located in the distal portion of the stomach (P = .007), and during ESD procedures (P = .001). The adverse event rate was comparable in both groups. CONCLUSIONS: MC-003 outperformed NS in reducing the need for additional injections during en bloc resection, particularly in larger lesions located in the distal portion of the stomach (where most lesions were found) during ESD procedures, without increasing the incidence of serious adverse events. MC-003 is a promising submucosal injectable solution in real-world clinical settings.

Validation of MELD 3.0 in patients with alcoholic liver cirrhosis using prospective KACLiF cohort.

BACKGROUND AND AIM: The Model for End-Stage Liver Disease (MELD) is a reliable prognostic tool for short-term outcome prediction in patients with end-stage liver disease. MELD 3.0 was introduced to enhance the predictive accuracy. This study assessed the performance of MELD 3.0, in comparison to MELD and MELD-Na, in patients with alcoholic liver cirrhosis. METHODS: This multicenter prospective cohort study comprised patients with alcoholic cirrhosis admitted for acute deterioration of liver function in the Republic of Korea between 2015 and 2019. This study compared the predictive abilities of MELD, MELD-Na, and MELD 3.0, for 30-day and 90-day outcomes, specifically death or liver transplantation, and explored the factors influencing these outcomes. RESULTS: A total of 1096 patients were included in the study, with a mean age of 53.3 ± 10.4 years, and 82.0% were male. The mean scores for MELD, MELD-Na, and MELD 3.0 at the time of admission were 18.7 ± 7.2, 20.6 ± 7.7, and 21.0 ± 7.8, respectively. At 30 and 90 days, 7.2% and 14.1% of patients experienced mortality or liver transplantation. The areas under the receiver operating characteristic curves for MELD, MELD-Na, and MELD 3.0 at 30 days were 0.823, 0.820, and 0.828; and at 90 days were 0.765, 0.772, and 0.776, respectively. Factors associated with the 90-day outcome included concomitant chronic viral hepatitis, prolonged prothrombin time, elevated levels of aspartate transaminase, bilirubin, and creatinine, and low albumin levels. CONCLUSION: MELD 3.0 demonstrated improved performance compared to previous models, although the differences were not statistically significant.

Predicting mild cognitive impairments from cognitively normal brains using a novel brain age estimation model based on structural magnetic resonance imaging.

Brain age prediction is a practical method used to quantify brain aging and detect neurodegenerative diseases such as Alzheimer's disease (AD). However, very few studies have considered brain age prediction as a biomarker for the conversion of cognitively normal (CN) to mild cognitive impairment (MCI). In this study, we developed a novel brain age prediction model using brain volume and cortical thickness features. We calculated an acceleration of brain age (ABA) derived from the suggested model to estimate different diagnostic groups (CN, MCI, and AD) and to classify CN to MCI and MCI to AD conversion groups. We observed a strong association between ABA and the 3 diagnostic groups. Additionally, the classification models for CN to MCI conversion and MCI to AD conversion exhibited acceptable and robust performances, with area under the curve values of 0.66 and 0.76, respectively. We believe that our proposed model provides a reliable estimate of brain age for elderly individuals and can identify those at risk of progressing from CN to MCI. This model has great potential to reveal a diagnosis associated with a change in cognitive decline.

Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians.

This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer's and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.

The Epidemiology of Hepatitis B Virus Infection in Korea: 15-Year Analysis.

BACKGROUND: The purpose of this study is to investigate the epidemiological changes in chronic hepatitis B (CHB) and assess the impact of coronavirus disease 2019 (COVID-19) over the past 15 years in a region endemic to hepatitis B virus (HBV). METHODS: National Health Insurance Service claims data of hepatitis B patients spanning from 2007 to 2021 was utilized. To compare the characteristics of the hepatitis B group, a control group adjusted for age and gender through propensity score matching analysis was established. RESULTS: The number of patients with CHB has consistently increased over the past 15 years. The average age of the CHB patient group has shown a yearly rise, while the prevalence of male dominance has gradually diminished. The proportions of hepatocellular carcinoma, liver cirrhosis, and decompensation have exhibited a declining pattern, whereas the proportion of liver transplants has continuously risen. Patients with CHB have demonstrated significantly higher medical and medication costs compared to the control group. Moreover, patients with CHB have shown a higher prevalence of comorbidities along with a significantly higher rate of concomitant medication usage. During the COVID period, the HBV group experienced a substantial decrease in the number of outpatient visits and overall medical costs compared to the control group. CONCLUSION: The epidemiology of CHB has undergone significant changes over the past 15 years, encompassing shifts in prevalence, severity, medical costs, and comorbidities. Furthermore, the impact of COVID-19 has been observed to decrease healthcare utilization among patients with CHB when compared to controls.

Chronic Gut Inflammation and Dysbiosis in IBS: Unraveling Their Contribution to Atopic Dermatitis Progression.

Emerging evidence suggests a link between atopic dermatitis (AD) and gastrointestinal disorders, particularly in relation to gut microbial dysbiosis. This study explored the potential exacerbation of AD by gut inflammation and microbial imbalances using an irritable bowel syndrome (IBS) mouse model. Chronic gut inflammation was induced in the model by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), followed by a 4-week development period. We noted significant upregulation of proinflammatory cytokines in the colon and evident gut microbial dysbiosis in the IBS mice. Additionally, these mice exhibited impaired gut barrier function, increased permeability, and elevated systemic inflammation markers such as IL-6 and LPS. A subsequent MC903 challenge on the right cheek lasting for 7 days revealed more severe AD symptoms in IBS mice compared to controls. Further, fecal microbial transplantation (FMT) from IBS mice resulted in aggravated AD symptoms, a result similarly observed with FMT from an IBS patient. Notably, an increased abundance of Alistipes in the feces of IBS mice correlated with heightened systemic and localized inflammation in both the gut and skin. These findings collectively indicate that chronic gut inflammation and microbial dysbiosis in IBS are critical factors exacerbating AD, highlighting the integral relationship between gut and skin health.

Contribution of monocyte and macrophage extracellular traps to neutrophilic airway inflammation in severe asthma.

BACKGROUND: Increased blood/sputum neutrophil counts are related to poor clinical outcomes of severe asthma (SA), where we hypothesized that classical monocytes (CMs)/CM-derived macrophages (Mφ) are involved. We aimed to elucidate the mechanisms of how CMs/Mφ induce the activation of neutrophils/innate lymphoid cells (ILCs) in SA. METHODS: Serum levels of monocyte chemoattractant protein-1 (MCP-1) and soluble suppression of tumorigenicity 2 (sST2) were measured from 39 patients with SA and 98 those with nonsevere asthma (NSA). CMs/Mφ were isolated from patients with SA (n = 19) and those with NSA (n = 18) and treated with LPS/interferon-gamma. Monocyte/M1Mφ extracellular traps (MoETs/M1ETs) were evaluated by western blotting, immunofluorescence, and PicoGreen assay. The effects of MoETs/M1ETs on neutrophils, airway epithelial cells (AECs), ILC1, and ILC3 were assessed in vitro and in vivo. RESULTS: The SA group had significantly higher CM counts with increased migration as well as higher levels of serum MCP-1/sST2 than the NSA group. Moreover, the SA group had significantly greater production of MoETs/M1ETs (from CMs/M1Mφ) than the NSA group. The levels of MoETs/M1ETs were positively correlated with blood neutrophils and serum levels of MCP-1/sST2, but negatively correlated with FEV1%. In vitro/in vivo studies demonstrated that MoETs/M1ETs could activate AECs, neutrophils, ILC1, and ILC3 by increased migration as well as proinflammatory cytokine production. CONCLUSIONS: CM/Mφ-derived MoETs/M1ETs could contribute to asthma severity by enhancing neutrophilic airway inflammation in SA, where modulating CMs/Mφ may be a potential therapeutic option.

Pulsed radiofrequency of lumbar dorsal root ganglion for lumbar radicular pain: A systematic review and meta-analysis.

BACKGROUND: Pulsed radiofrequency (PRF) of the lumbar dorsal root ganglion (DRG) has been widely used as a method to relieve lumbar radicular pain (LRP). However, the value of PRF application in LRP patients remains uncertain. This systematic review aimed to compare the effects of PRF of lumbar DRG and LEI in patients with LRP. METHODS: A literature search was performed using well-known databases for articles published up to May 2023. We included randomized controlled trials (RCTs) that evaluated the effects of PRF compared to LEI with or without steroids. We screened articles, extracted data, and assessed risk of bias in duplicate. The pain scores and Oswestry Disability Index (ODI) scores at 1, 3, and 6 months after procedures were obtained. A random-effects meta-analysis model was applied for outcomes. We evaluated evidence certainty for each outcome using the GRADE scoring system. This review was registered in the PROSPERO (ID: CRD42021253628). RESULTS: A total of 10 RCTs were included and data of 613 patients were retrieved. We assessed the overall quality of the evidence as very low to moderate. PRF showed no difference in pain scores at 1 (mean difference [MD] -0.80, 95% confidence interval [CI] -1.59 to 0.00, low certainty) and 6 months (MD -2.37, 95% CI -4.79 to 0.05, very low certainty), and significantly improved pain scores at 3 months (MD -1.31, 95% CI -2.29 to -0.33, low certainty). There was no significant difference in ODI score at any interval (very low to low certainty). In the subgroup who underwent a diagnostic block, did not use steroids, and PRF duration greater than 360 s, PRF significantly reduced pain scores at 3 months after procedures. CONCLUSIONS: We found low quality of the evidence supporting adjuvant PRF to the lumbar DRG has a greater analgesic effect at 3 months after procedures in patients with LRP than LEI. We identified no convincing evidence to show that this treatment improves function. High-quality evidence is lacking, and data were largely derived from short-term effects. Given these limitations, high-quality trials with data on long-term effects are needed.

Long-Range Electrification of an Air/Electrolyte Interface and Probing Potential of Zero Charge by Conductive Amplitude-Modulated Atomic Force Microscopy.

The structure of an electrical double layer (EDL) at the interface of electrode/electrolyte or air/electrode/electrolyte is a fundamental aspect, however not fully understood. The potential of zero charge (PZC) is one of the clues to dictate the EDL, where the excess charge on the electrode surface is zero. Here, a nanoscale configuration of immersion method was proposed by integrating an electrochemical system into conductive atomic force spectroscopy under the amplitude modulation (AM) mode and agarose gel as the solid-liquid electrolyte. The PZC of boron-doped diamond was determined to be at 0.2 V (vs Ag/AgCl). By AM spectroscopy, the capacitive force shows remote electrification without direct electrode/electrolyte contact, which is dependent on the population of ions at the air/electrolyte interface. The surface potential by alignment of water is also evaluated. Prospectively, our study could benefit applications such as PZC measurement and non-electrode electrochemical processes at the air/electrolyte interface.

Hepatic steatosis and metabolic risk factors among patients with chronic hepatitis B: The multicentre, prospective CAP-Asia study.

We aimed to compare the severity of liver disease, metabolic profile and cardiovascular disease (CVD) risk of chronic hepatitis B (CHB) patients with and without hepatic steatosis and patients with non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD and CHB were prospectively enrolled from 10 Asian centres. Fibroscan was performed for all patients and hepatic steatosis was defined based on controlled attenuation parameter >248 dB/m. CVD risk was assessed using the Framingham risk score. The data for 1080 patients were analysed (67% NAFLD, 33% CHB). A high proportion (59%) of CHB patients had hepatic steatosis. There was a significant stepwise increase in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, controlled attenuation parameter and liver stiffness measurement, from CHB patients without hepatic steatosis to CHB patients with hepatic steatosis to NAFLD patients (p < 0.001 for all comparisons). There was a significant stepwise increase in the proportion of patients with metabolic syndrome and in CVD risk, with very high or extreme CVD risk seen in 20%, 48% and 61%, across the groups (p < 0.001 between CHB patients with and without hepatic steatosis and p < 0.05 between CHB patients with hepatic steatosis and NAFLD patients). In conclusion, there was a high proportion of CHB patients with hepatic steatosis, which should be diagnosed, as they may have more severe liver disease, so that this and their metabolic risk factors can be assessed and managed accordingly for a better long-term outcome.

Multidimensional Nomogram to Predict Postoperative Pancreatic Fistula after Minimally Invasive Pancreaticoduodenectomy.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) is an inherently severe risk of pancreatic resection. Previous research has proposed models that identify risk factors and predict CR-POPF, although these are rarely applicable to minimally invasive pancreaticoduodenectomy (MIPD). This study aimed to evaluate the individual risks of CR-POPF and to propose a nomogram for predicting POPF in MIPD. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 429 patients who underwent MIPD. In the multivariate analysis, the Akaike information criterion stepwise logistic regression method was used to select the final model to develop the nomogram. RESULTS: Of 429 patients, 53 (12.4%) experienced CR-POPF. On multivariate analysis, pancreatic texture (p = 0.001), open conversion (p = 0.008), intraoperative transfusion (p = 0.011), and pathology (p = 0.048) were identified as independent predictors of CR-POPF. The nomogram was developed based on patient, pancreatic, operative, and surgeon factors by using the following four additional clinical factors as variables: American Society of Anesthesiologists class ≥ III, size of pancreatic duct, type of surgical approach, and < 40 cases of MIPD experience. CONCLUSIONS: A multidimensional nomogram was developed to predict CR-POPF after MIPD. This nomogram and calculator can help surgeons anticipate, select, and manage critical complications.

Prediction of the number of asthma patients using environmental factors based on deep learning algorithms.

BACKGROUND: Air pollution, weather, pollen, and influenza are typical aggravating factors for asthma. Previous studies have identified risk factors using regression-based and ensemble models. However, studies that consider complex relationships and interactions among these factors have yet to be conducted. Although deep learning algorithms can address this problem, further research on modeling and interpreting the results is warranted. METHODS: In this study, from 2015 to 2019, information about air pollutants, weather conditions, pollen, and influenza were utilized to predict the number of emergency room patients and outpatients with asthma using recurrent neural network, long short-term memory (LSTM), and gated recurrent unit models. The relative importance of the environmental factors in asthma exacerbation was quantified through a feature importance analysis. RESULTS: We found that LSTM was the best algorithm for modeling patients with asthma. Our results demonstrated that influenza, temperature, PM10, NO2, CO, and pollen had a significant impact on asthma exacerbation. In addition, the week of the year and the number of holidays per week were an important factor to model the seasonality of the number of asthma patients and the effect of holiday clinic closures, respectively. CONCLUSION: LSTM is an excellent algorithm for modeling complex epidemiological relationships, encompassing nonlinearity, lagged responses, and interactions. Our study findings can guide policymakers in their efforts to understand the environmental factors of asthma exacerbation.

Distinguishing between DNA-Loaded Full and Empty Capsids of Adeno-Associated Virus with Atomic Force Microscopy Imaging.

Recently, miraculous therapy approaches involving adeno-associated virus (AAV) for incurable diseases such as spinal muscular atrophy and inherited retinal dysfunction have been introduced. Nonreplicative, nonpathogenic, low rates of chromosome insertional properties and the existence of neutralizing antibodies are main safety reasons why the FDA approved its use in gene delivery. To date, AAV production always results in a mixture of nontherapeutic (empty) and therapeutic (DNA-loaded) full capsids (10-98%). Such existence of empty viral particles inevitably increases viral doses to human. Thus, the rapid monitoring of empty capsids and reducing the empty-to-full ratio are critical in AAV science. However, transmission electron microscopy (TEM) is the primary tool for distinguishing between empty and full capsids, which creates a research bottleneck because of instrument accessibility and technical difficulty. Herein, we demonstrate that atomic force microscopy (AFM) can be an alternative tool to TEM. The simple, noncontact-mode imaging of AAV particles allows the distinct height difference between full capsids (∼22 nm) and empty capsids (∼16 nm). The sphere-to-ellipsoidal morphological distortion observed for empty AAV particles clearly distinguishes them from full AAV particles. Our study indicates that AFM imaging can be an extremely useful, quality-control tool in AAV particle monitoring, which is beneficial for the future development of AAV-based gene therapy.

Prevalence and trends of multiple antimicrobial resistance of Helicobacter pylori in one tertiary hospital for 20 years in Korea.

BACKGROUND: Failure of Helicobacter pylori (H. pylori) eradication is principally caused by antimicrobial resistance. Nowadays, multidrug resistance could be a major determinant of eradication failure. To assess minimal inhibitory concentration (MIC), antimicrobial resistance rates and trends in H. pylori isolated from patients with upper gastrointestinal disease with long-term period. MATERIALS AND METHODS: Patients who had H. pylori colonies isolated from culture were consecutively enrolled during the period of 2003-2022. From each patient, one to ten isolates were collected from culture of mucosal biopsy. MIC test was performed for amoxicillin, clarithromycin, metronidazole, tetracycline, levofloxacin, and moxifloxacin using agar dilution method. Trends in MIC distribution, prevalence of resistances with single and multiple were investigated which were suspected to be related to the failure of empirical H. pylori eradication treatment. RESULTS: From 2003 to 2022, a total of 873 patients were enrolled and 2735 H. pylori isolates were successfully collected. Increase in the primary resistance rate was found in clarithromycin (16.1%-31.0%, p = .022), metronidazole (30.6%-38.1%, p < 0.001), and both of levofloxacin and moxifloxacin (7.3%-35.7%, p < 0.001). The prevalence of multidrug resistance to both clarithromycin and metronidazole (9.2%-37.9%, p < 0.001), clarithromycin and fluoroquinolone (2.8%-41.7%, p < 0.001), and clarithromycin, metronidazole, and fluoroquinolone (1.4%-28.2%, p < 0.001) was found to significantly increase. CONCLUSIONS: The prevalence of multiple resistance against H. pylori in Korea is ongoing. Its trend should be considered when establishing an empirical treatment strategy (ClinicalTrials. gov: NCT05247112).