Metallo-ß-lactamase inhibitors: A continuing challenge for combating antibiotic resistance.

ß-lactam antibiotics are the most successful and commonly used antibacterial agents, but the emergence of resistance to these drugs has become a global health threat. The expression of ß-lactamase enzymes produced by pathogens, which hydrolyze the amide bond of the ß-lactam ring, is the major mechanism for bacterial resistance to ß-lactams. In particular, among class A, B, C and D ß-lactamases, metallo-ß-lactamases (MBLs, class B ß-lactamases) are considered crucial contributors to resistance in gram-negative bacteria. To combat ß-lactamase-mediated resistance, great efforts have been made to develop ß-lactamase inhibitors that restore the activity of ß-lactams. Some ß-lactamase inhibitors, such as diazabicyclooctanes (DBOs) and boronic acid derivatives, have also been approved by the FDA. Inhibitors used in the clinic can inactivate mostly serine-ß-lactamases (SBLs, class A, C, and D ß-lactamases) but have not been effective against MBLs until now. In order to develop new inhibitors particularly for MBLs, various attempts have been suggested. Based on structural and mechanical studies of MBL enzymes, several MBL inhibitor candidates, including taniborbactam in phase 3 and xeruborbactam in phase 1, have been introduced in recent years. However, designing potent inhibitors that are effective against all subclasses of MBLs is still extremely challenging. This review summarizes not only the types of ß-lactamase and mechanisms by which ß-lactam antibiotics are inactivated, but also the research finding on ß-lactamase inhibitors targeting these enzymes. These detailed information on ß-lactamases and their inhibitors could give valuable information for novel ß-lactamase inhibitors design.

Perilla-Leaf-Derived Extracellular Vesicles Selectively Inhibit Breast Cancer Cell Proliferation and Invasion.

Breast cancer is a common type of cancer characterized by high mortality rates. However, chemotherapy is not selective and often leads to side-effects. Therefore, there is a need for the development of highly efficient drugs. Recent studies have shown that some extracellular vesicles (EVs) derived from cell cultures possess anti-cancer activity and hold great potential as cancer therapeutics. However, the use of mammalian cell cultures for EV production results in low productivity and high costs. To address this issue, extracellular vesicles derived from perilla leaves (Perex) were isolated and investigated for their anti-cancer activity in various cancer cells. Initially, a high concentration of Perex with a low level of impurities was successfully purified through a combination of ultrafiltration and size-exclusion chromatography. Perex exhibited potent anti-cancer activities, inhibiting the proliferation, migration, and invasion of MDA-MB-231 cancer cells, which have high levels of caveolin-1 compared to other cancer and normal cells. This selective attack on cancer cells with high levels of caveolin-1 reduces unwanted side-effects on normal cells. Considering its high productivity, low production cost, selective anti-cancer activity, and minimal side-effects, Perex represents a promising candidate for the therapeutic treatment of breast cancer.

Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier.

Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier (BBB) permeability and lack of cancer-targeting ability. Herein, brain endothelial cell-derived extracellular vesicles (bEVs) were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB. To enhance PDT efficacy, the photosensitizer chlorin e6 (Ce6) was linked to mitochondria-targeting triphenylphosphonium (TPP) and entrapped into bEVs. TPP-conjugated Ce6 (TPP-Ce6) selectively accumulated in the mitochondria, which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation. Moreover, the encapsulation of TPP-Ce6 into bEVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6, leading to significantly enhanced PDT efficacy in U87MG GBM cells. An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that bEVs containing TPP-Ce6 [bEV(TPP-Ce6)] substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis. As such, bEV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity, suggesting that mitochondria are an effective target for photodynamic GBM therapy.

Risk factors for transmission in a COVID-19 cluster infection in a high school in the Republic of Korea.

BACKGROUND: This study aimed to examine the scale, characteristics, risk factors, and modes of transmission in a coronavirus disease 2019 (COVID-19) outbreak at a high school in Seoul, Republic of Korea. METHODS: An epidemiological survey was conducted of 1,118 confirmed cases and close contacts from a COVID-19 outbreak at an educational facility starting on May 31, 2021. In-depth interviews, online questionnaires, flow evaluations, and CCTV analyses were used to devise infection prevention measures. Behavioral and spatial risk factors were identified, and statistical significance was tested. RESULTS: Among 3rd-year students, there were 33 confirmed COVID-19 cases (9.6%). Students who used a study room in the annex building showed a statistically significant 4.3-fold elevation in their relative risk for infection compared to those who did not use the study room. Moreover, CCTV facial recognition analysis confirmed that 17.8% of 3rd-year students did not wear masks and had the lowest percentage of mask-wearers by grade. The air epidemiological survey conducted in the study room in the annex, which met the 3 criteria for a closed space, confirmed that there was only 10% natural ventilation due to the poor ventilation system. CONCLUSION: To prevent and manage the spread of COVID-19 in educational facilities, advance measures that consider the size, operation, and resources of each school are crucial. In addition, various survey methodologies should be used in future studies to quickly analyze a wider range of data that can inform an evidence-based quarantine response.

Bioreducible exosomes encapsulating glycolysis inhibitors potentiate mitochondria-targeted sonodynamic cancer therapy via cancer-targeted drug release and cellular energy depletion.

Nanocarrier-assisted sonodynamic therapy (SDT) has shown great potential for the effective and targeted treatment of deep-seated tumors by overcoming the critical limitations of sonosensitizers. However, in vivo SDT using nanocarriers is still constrained by their intrinsic toxicity and nonspecific cargo release. In this study, we developed bioreducible exosomes for the safe and tumor-specific delivery of mitochondria-targeting sonosensitizers [triphenylphosphonium-conjugated chlorin e6 (T-Ce6)] and glycolysis inhibitors (FX11). Redox-cleavable diselenide linker-bearing lipids were embedded into exosomes to trigger drug release in response to overexpressed glutathione in the tumor microenvironment. Bioreducible exosomes facilitate the cytoplasmic release of their payload in the reducing environment of tumor cells. They significantly enhance drug release and sonodynamic effects when irradiated with ultrasound (US). The mitochondria-targeted accumulation of T-Ce6 efficiently damaged the mitochondria of the cells under US irradiation, accelerating apoptotic cell death. FX11 substantially inhibited cellular energy metabolism, potentiating the antitumor efficacy of mitochondria-targeted SDT. Bioreducible exosomes effectively suppressed tumor growth in mice without significant systemic toxicity, via a combination of mitochondria-targeted SDT and energy metabolism-targeted therapy. This study offers new insights into the use of dual stimuli-responsive exosomes encapsulating sonosensitizers for safe and targeted sonodynamic cancer therapy.

Current status and needs in the primary healthcare system in Yangon, Myanmar: a mixed-method evaluation.

BACKGROUND: Many low- and middle-income countries and international organisations have invested resources to strengthen primary health care (PHC). This study aimed to identify the challenges and unmet needs in the current PHC by assessing the experiences and perceptions of healthcare workers in three townships (Htan Ta Pin, Hmawbi, and Taikkyi) in Yangon, Myanmar. METHODS: The study was conducted among healthcare professionals and community leaders in three townships. Adopting a mixed-method approach, a cross-sectional health needs assessment survey was conducted for quantitative data (n = 66), and focus group discussions (FGDs) were conducted online for qualitative data. FINDINGS: Enhancing the management and leadership capacity had the lowest average score on the current achievement (2.81 out of 5 ratings) while strengthening infectious disease control service and accessibility was perceived as the highest mean on the priority of intervention (4.28) and the impact of the intervention (4.7). The FGDs revealed that while specific infrastructures and equipment were reported insufficient and necessary, the need for financial support has been the recurrent theme throughout the discussions. INTERPRETATION: Utilising the World Health Organisation's six building block frameworks, our findings suggest that a long-term targeted financial investment in the PHC system is critical in Myanmar through increasing healthcare expenditure per capita.

Domain swapping of the C-terminal helix promotes the dimerization of a novel ribonuclease protein from Mycobacterium tuberculosis.

Polyketide metabolism-associated proteins in Mycobacterium tuberculosis play an essential role in the survival of the bacterium, which makes them potential drug targets for the treatment of tuberculosis (TB). The novel ribonuclease protein Rv1546 is predicted to be a member of the steroidogenic acute regulatory protein-related lipid-transfer (START) domain superfamily, which comprises bacterial polyketide aromatase/cyclases (ARO/CYCs). Here, we determined the crystal structure of Rv1546 in a V-shaped dimer. The Rv1546 monomer consists of four α-helices and seven antiparallel ß-strands. Interestingly, in the dimeric state, Rv1546 forms a helix-grip fold, which is present in START domain proteins, via three-dimensional domain swapping. Structural analysis revealed that the conformational change of the C-terminal α-helix of Rv1546 might contribute to the unique dimer structure. Site-directed mutagenesis followed by in vitro ribonuclease activity assays was performed to identify catalytic sites of the protein. This experiment suggested that surface residues R63, K84, K88, and R113 are important in the ribonuclease function of Rv1546. In summary, this study presents the structural and functional characterization of Rv1546 and supplies new perspectives for exploiting Rv1546 as a novel drug target for TB treatment.

Required Elements for an Integrated Biosurveillance Platform: A Capacity and Needs Assessment of the Central Government in the Republic of Korea.

New and reemerging infectious disease outbreaks threaten human safety worldwide, increasing the urgency to implement biosurveillance systems that enhance government capacity in public health emergency preparedness and response. To do so, it is necessary to evaluate existing surveillance and response activities and identify potential barriers at the national level. This study aimed to assess the current status and readiness of government agencies in South Korea, particularly for information sharing and use, and to identify barriers and opportunities in developing an agency-integrated biosurveillance system. The target sample size was 66 government officials, working at 6 relevant government ministries. We invited a total of 100 officials to participate. A total of 34 government officials completed the survey (34.0% response rate), 18 (52.9%) of whom were affiliated with the Korea Disease Control and Prevention Agency or the Ministry of Health and Welfare. Findings revealed that information sharing between government agencies occurred frequently, but a discrepancy existed in terms of the type of information shared and stored. Although information sharing with other agencies and ministries occurred at all stages-prevention, preparation, response, and recovery-it mostly revolved around preventive activities, with no respondents reportedly sharing recovery-related information. An agency-integrated biosurveillance system is crucial in preparing for the next pandemic, as well as supporting information sharing, analysis, and interpretation across humans, animals, and the environment. It is key to national and global health security.

The Impact of Public Transfer Income on Catastrophic Health Expenditures for Households With Disabilities in Korea.

OBJECTIVES: Previous studies have reported that people with disabilities are more likely to be impoverished and affected by excessive medical costs than people without disabilities. Public transfer income (PTI) reduces financial strain in low-income households. This study examined the impact of PTI on catastrophic health expenditures (CHE), focusing on low-income households and households with Medical Aid beneficiaries that contained people with disabilities. METHODS: We constructed a panel dataset by extracting data on registered households with disabilities from the Korea Welfare Panel Study 2012-2019. We then used a generalized estimating equation model to estimate the impacts of PTI on CHE. A subgroup analysis was carried out to assess the moderating effects of family income levels and health insurance types. RESULTS: As PTI increased, the odds ratio (OR) of CHE in households that contained people with disabilities decreased significantly (OR, 0.92; 95% confidence interval [CI], 0.89 to 0.94; p<0.001). In particular, PTI effectively reduced the likelihood of CHE for low-income households (OR, 0.85; 95% CI, 0.81 to 0.89; p<0.001) and those who received medical benefits (OR, 0.78; 95% CI, 0.68 to 0.89; p<0.001). CONCLUSIONS: This study highlights the positive effect of PTI on decreasing CHE. Household income and the health insurance type were significant effect modifiers, but economic barriers seemed to persist among low-income households with non-Medical Aid beneficiaries. Federal policies or programs should consider increasing the total amount of PTI targeting low-income households with disabilities that are not covered by the Medical Aid program.

Mitochondria-targeting sonosensitizer-loaded extracellular vesicles for chemo-sonodynamic therapy.

Sonodynamic therapy (SDT) has emerged as an effective therapeutic modality as it employs ultrasound (US) to eradicate deep-seated tumors noninvasively. However, the therapeutic efficacy of SDT in clinical settings remains limited owing to the low aqueous stability and poor pharmacokinetic properties of sonosensitizers. In this study, extracellular vesicles (EVs), which have low systemic toxicity, were used as clinically available nanocarriers to effectively transfer a sonosensitizer to cancer cells. Chlorin e6 (Ce6), a sonosensitizer, was conjugated to a mitochondria-targeting triphenylphosphonium (TPP) moiety and loaded into EVs to enhance the efficacy of SDT, because mitochondria are critical subcellular organelles that regulate cell survival and death. Additionally, piperlongumine (PL), a pro-oxidant and cancer-specific chemotherapeutic agent, was co-encapsulated into EVs to achieve efficient and selective anticancer activity. The EVs substantially amplified the cellular internalization of TPP-conjugated Ce6 (TPP-Ce6), resulting in the enhanced generation of intracellular reactive oxygen species (ROS) in MCF-7 human breast cancer cells upon US exposure. Importantly, EVs encapsulating TPP-Ce6 effectively destroyed the mitochondria under irradiation with US, leading to efficient anticancer activity. The co-encapsulation of pro-oxidant PL into EVs significantly enhanced the SDT efficacy in MCF-7 cells through the excessive generation of ROS. Moreover, the EV co-encapsulating TPP-Ce6 and PL [EV(TPP-Ce6/PL)] exhibited cancer-specific cell death owing to the cancer-selective apoptosis triggered by PL. In vivo study using MCF-7 tumor-xenograft mice revealed that EV(TPP-Ce6/PL) effectively accumulated in tumors after intravenous injection. Notably, treatment with EV(TPP-Ce6/PL) and US inhibited tumor growth significantly without causing systemic toxicity. This study demonstrated the feasibility of using EV(TPP-Ce6/PL) for biocompatible and cancer-specific chemo-SDT.

Engineering Approaches for the Development of Antimicrobial Peptide-Based Antibiotics.

Antimicrobial peptides (AMPs) have received increasing attention as potential alternatives for future antibiotics because of the rise of multidrug-resistant (MDR) bacteria. AMPs are small cationic peptides with broad-spectrum antibiotic activities and different action mechanisms to those of traditional antibiotics. Despite the desirable advantages of developing peptide-based antimicrobial agents, the clinical applications of AMPs are still limited because of their enzymatic degradation, toxicity, and selectivity. In this review, structural modifications, such as amino acid substitution, stapling, cyclization of peptides, and hybrid AMPs with conventional antibiotics or other peptides, will be presented. Additionally, nanodelivery systems using metals or lipids to deliver AMPs will be discussed based on the structural properties and action mechanisms of AMPs.

The Effect of Structural Gender Inequality Revealed in Small for Gestational Age.

Background: This study proposes that being small for gestational age (SGA) is not only an important indicator for neonatal health but also could be a consequence of gender inequality. Low birth weight (LBW) has been widely used as a measurement for adverse birth outcomes, whereas much less attention has been given to the use of small for gestational age (SGA). Despite the importance and worldwide acknowledgement of promoting gender equality and women's empowerment to improve maternal and infant health, previous studies on SGA have focused on nutritional status, social and medical infrastructures, and socioeconomic status. The impact of structural violence against women on SGA has not been explored sufficiently. Therefore, the aim of this study was to examine the effect of gender inequality on SGA, using the Gender Inequality Index (GII). Methods: A total of 106 low- and middle-income countries (LMICs) from the most recent three global datasets-Institute of Health Metrics and Evaluation (IHME), the UN Development Programme (UNDP), and World Bank-were assessed. Results: Findings from generalized linear model analysis suggest that significant links exist between years of potential life lost (YLL) from SGA and gender inequality, maternal health status, and country level of income. Conclusions: Our findings advance the understanding of the role of gender inequality on SGA and reiterate the importance of considering structural violence in maternal and infant health research. These associations can support the message of designing public health and socioeconomic development as well as creating campaigns to promote gender equality in efforts to advance maternal and infant health and to prevent adverse birth outcomes across the globe. Supplementary Information: The online version contains supplementary material available at 10.1007/s40609-022-00245-8.

Size-selective filtration of extracellular vesicles with a movable-layer device.

This paper presents a microfluidic device that can isolate extracellular vesicles (EVs) with multiple size intervals in a simple, effective, and automated manner. We accomplish this size-selective separation using a vertically movable plunger and a rotationally movable chip. The chip has open chambers with nanoporous filters that are sequentially connected by check valves. The plunger speed is adjusted to reduce chamber pressurization in order to prevent EV deformation, thereby achieving a high separation resolution. Herein, high-purity EVs with a purity ten times higher than that of ultracentrifugation were obtained by washing three times with a high EV recovery rate of 89%. For the analysis of device performance, we used polymer nanobeads, preformed liposomes, and canine blood plasma. To demonstrate the utility of the device, we applied size-selective isolation to EVs that were secreted by endothelial cells under shear flow. The results revealed that the cells secreted more EVs of larger size, the expression of CD63 protein was higher for EVs with a larger size, and a high amount of TSG101 protein was expressed under the condition of no shear flow. This device is envisioned to facilitate molecular analysis and EV-based biomarker discovery that use various biofluids, including blood plasma, urine, and cell culture supernatants. Our device automates size-selective EV filtration that requires laborious multiple washing and separation steps.

Chemical Conformation of the Essential Glutamate Site of the c-Ring within Thermophilic Bacillus FoF1-ATP Synthase Determined by Solid-State NMR Based on its Isolated c-Ring Structure.

Proton translocation through the membrane-embedded Fo component of F-type ATP synthase (FoF1) is facilitated by the rotation of the Fo c-subunit ring (c-ring), carrying protons at essential acidic amino acid residues. Cryo-electron microscopy (Cryo-EM) structures of FoF1 suggest a unique proton translocation mechanism. To elucidate it based on the chemical conformation of the essential acidic residues of the c-ring in FoF1, we determined the structure of the isolated thermophilic Bacillus Fo (tFo) c-ring, consisting of 10 subunits, in membranes by solid-state NMR. This structure contains a distinct proton-locking conformation, wherein Asn23 (cN23) CγO and Glu56 (cE56) CδOH form a hydrogen bond in a closed form. We introduced stereo-array-isotope-labeled (SAIL) Glu and Asn into the tFoc-ring to clarify the chemical conformation of these residues in tFoF1-ATP synthase (tFoF1). Two well-separated 13C signals could be detected for cN23 and cE56 in a 505 kDa membrane protein complex, respectively, thereby suggesting the presence of two distinct chemical conformations. Based on the signal intensity and structure of the tFoc-ring and tFoF1, six pairs of cN23 and cE56 surrounded by membrane lipids take the closed form, whereas the other four in the a-c interface employ the deprotonated open form at a proportion of 87%. This indicates that the a-c interface is highly hydrophilic. The pKa values of the four cE56 residues in the a-c interface were estimated from the cN23 signal intensity in the open and closed forms and distribution of polar residues around each cE56. The results favor a rotation of the c-ring for ATP synthesis.

Isolation and Characterization of Urinary Extracellular Vesicles from Healthy Donors and Patients with Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) is the most commonly diagnosed malignancy among men in developed countries. The five-year survival rate for men diagnosed with early-stage PCa is approximately 100%, while it is less than 30% for castration-resistant PCa (CRPC). Currently, the detection of prostate-specific antigens as biomarkers for the prognosis of CRPC is criticized because of its low accuracy, high invasiveness, and high false-positive rate. Therefore, it is important to identify new biomarkers for prediction of CRPC progression. Extracellular vesicles (EVs) derived from tumors have been highlighted as potential markers for cancer diagnosis and prognosis. Specifically, urinary EVs directly reflect changes in the pathophysiological conditions of the urogenital system because it is exposed to prostatic secretions. Thus, detecting biomarkers in urinary EVs provides a promising approach for performing an accurate and non-invasive liquid biopsy for CPRC. In this study, we effectively isolated urinary EVs with low protein impurities using size-exclusion chromatography combined with ultrafiltration. After EV isolation and characterization, we evaluated the miRNAs in urinary EVs from healthy donors and patients with CRPC. The results indicated that miRNAs (miR-21-5p, miR-574-3p, and miR-6880-5p) could be used as potential biomarkers for the prognosis of CRPC. This analysis of urinary EVs contributes to the fast and convenient prognosis of diseases, including CRPC, in the clinical setting.

The structural and functional investigation of the VapBC43 complex from Mycobacterium tuberculosis.

Toxin - Antitoxin systems are crucial for bacterial survival against harsh circumstances such as antibiotic treatment. The VapBC systems are the most abundant Toxin-Antitoxin systems among the Toxin - Antitoxin systems in the Mycobacterium tuberculosis. The VapBC43 system is one of them, which is related to the response to the vancomycin treatment. However, the structure of the VapBC43 complex remained unknown. Here, we present the crystal structure of the VapBC43 complex in which a single VapB43 molecule binds to the VapC43 dimer. The electrophoretic mobility shift assay shows that the VapB43 can bind to its promoter DNA. In addition, this structure reveals that the VapC43 contains a PIN (PilT N-terminus) domain motif which is essential for ribonuclease activity but has less conserved acidic residues than other homologs. The results of ribonuclease assays show that the VapC43 exhibits ribonuclease activity despite the lack of acidic residues which are well conserved in a PIN domain superfamily. Based on the previous finding that the VapBC43 contributes to the survival of Mycobacterium tuberculosis under vancomycin treatment, the structural information of the VapBC43 complex may enable the development of the inhibitor of VapC43 that can be used as an adjuvant for vancomycin therapy against M. tuberculosis.

Extracellular vesicles with high dual drug loading for safe and efficient combination chemo-phototherapy.

Extracellular vesicles (EVs) have emerged as biocompatible nanocarriers for efficient delivery of various therapeutic agents, with intrinsic long-term blood circulatory capability and low immunogenicity. Here, indocyanine green (ICG)- and paclitaxel (PTX)-loaded EVs [EV(ICG/PTX)] were developed as a biocompatible nanoplatform for safe and efficient cancer treatment through near-infrared (NIR) light-triggered combination chemo/photothermal/photodynamic therapy. High dual drug encapsulation in EVs was achieved for both the hydrophilic ICG and hydrophobic PTX by simple incubation. The EVs substantially improved the photostability and cellular internalization of ICG, thereby augmenting the photothermal effects and reactive oxygen species production in breast cancer cells upon NIR light irradiation. Hence, ICG-loaded EVs activated by NIR light irradiation showed greater cytotoxic effects than free ICG. EV(ICG/PTX) showed the highest anticancer activity owing to the simultaneous chemo/photothermal/photodynamic therapy when compared with EV(ICG) and free ICG. In vivo study revealed that EV(ICG/PTX) had higher accumulation in tumors and improved pharmacokinetics compared to free ICG and PTX. In addition, a single intravenous administration of EV(ICG/PTX) exhibited a considerable inhibition of tumor proliferation with negligible systemic toxicity. Thus, this study demonstrates the potential of EV(ICG/PTX) for clinical translation of combination chemo-phototherapy.

Engineered extracellular vesicle-based sonotheranostics for dual stimuli-sensitive drug release and photoacoustic imaging-guided chemo-sonodynamic cancer therapy.

Sonodynamic therapy has shown promise as an effective alternative to conventional photodynamic therapy owing to its ability to treat deep-seated tumors. However, the development of stimuli-responsive sonosensitizers with high biocompatibility faces a significant challenge. Methods: In this study, we developed dual stimuli-responsive sonosensitizers with desirable biosafety using extracellular vesicles (EVs), a class of naturally occurring nanoparticles. Indocyanine green (ICG), which functions as both a sonosensitizer and photoacoustic (PA) imaging agent, was loaded into EVs, together with paclitaxel (PTX) and sodium bicarbonate (SBC), to achieve pH-responsive PA imaging-guided chemo-sonodynamic combination therapy. Results: The EVs significantly improved the cellular uptake of ICG, thus triggering enhanced sonodynamic effects in breast cancer cells. SBC-, ICG-, and PTX-loaded EV [SBC-EV(ICG/PTX)] efficiently released the PTX in response to acidic pH in the endo/lysosomes because CO2 bubbles generated from the SBC caused the EV membranes to burst. The drug release was further facilitated by ultrasound (US) treatment, demonstrating dual pH/US-responsive drug release. The ICG- and PTX-loaded EVs exhibited efficient anticancer activity against breast tumor cells owing to the combination of chemo-sonodynamic therapy. High-resolution PA imaging visualized the preferential tumor accumulation of SBC-EV(ICG/PTX) in tumor-bearing mice. Notably, a single intravenous injection of SBC-EV(ICG/PTX) with US irradiation significantly suppressed tumor growth in mice without systemic toxicity. Conclusions: Our findings demonstrate that dual stimuli-responsive SBC-EV(ICG/PTX) are promising sonotheranostic nanoplatforms for safe and efficient chemo-sonodynamic combination cancer therapy and photoacoustic imaging.

Reconstructing a COVID-19 outbreak within a religious group using social network analysis simulation in Korea.

OBJECTIVES: We reconstructed a coronavirus disease 2019 (COVID-19) outbreak to examine how a large cluster at a church setting spread before being detected and estimate the potential effectiveness of complying with mask-wearing guidelines recommended by the government. METHODS: A mathematical model with a social network analysis (SNA) approach was used to simulate a COVID-19 outbreak. A discrete-time stochastic simulation model was used to simulate the spread of COVID-19 within the Sarang Jeil church. A counterfactual experiment using a calibrated baseline model was conducted to examine the potential benefits of complying with a mask-wearing policy. RESULTS: Simulations estimated a mask-wearing ratio of 67% at the time of the outbreak, which yielded 953.8 (95% confidence interval [CI], 937.3 to 970.4) cases and was most consistent with the confirmed data. The counterfactual experiment with 95% mask-wearing estimated an average of 45.6 (95% CI, 43.4 to 47.9) cases with a standard deviation of 20.1. The result indicated that if the church followed government mask-wearing guidelines properly, the outbreak might have been one-twentieth the size. CONCLUSIONS: SNA is an effective tool for monitoring and controlling outbreaks of COVID-19 and other infectious diseases. Although our results are based on simulations and are thus limited, the precautionary implications of social distancing and mask-wearing are still relevant. Since person-to-person contacts and interactions are unavoidable in social and economic life, it may be beneficial to develop precise measures and guidelines for particular organizations or places that are susceptible to cluster outbreaks.