Rational Design of Lipid Nanoparticles for Enhanced mRNA Vaccine Delivery via Machine Learning.

Since the coronavirus pandemic, mRNA vaccines have revolutionized the field of vaccinology. Lipid nanoparticles (LNPs) are proposed to enhance mRNA delivery efficiency; however, their design is suboptimal. Here, a rational method for designing LNPs is explored, focusing on the ionizable lipid composition and structural optimization using machine learning (ML) techniques. A total of 213 LNPs are analyzed using random forest regression models trained with 314 features to predict the mRNA expression efficiency. The models, which predict mRNA expression levels post-administration of intradermal injection in mice, identify phenol as the dominant substructure affecting mRNA encapsulation and expression. The specific phospholipids used as components of the LNPs, as well as the N/P ratio and mass ratio, are found to affect the efficacy of mRNA delivery. Structural analysis highlights the impact of the carbon chain length on the encapsulation efficiency and LNP stability. This integrated approach offers a framework for designing advanced LNPs and has the potential to unlock the full potential of mRNA therapeutics.

Low-dose glucocorticoid increase the risk of fracture in postmenopausal women with low bone mass: a retrospective cohort study.

Long-term glucocorticoids (GCs) treatment is associated with osteoporosis and fractures. We investigated whether low-dose GC treatment also increased the risk of osteoporotic fractures, and the results showed that even low-dose GC treatment increased the risk of osteoporotic fractures, especially spine fractures. PURPOSE: The effect of low-dose glucocorticoid (GC) therapy on the fracture risk in postmenopausal women with low bone mass was investigated. METHODS: 119,790 66-year-old postmenopausal women with low bone mass based on bone mineral density (BMD) results were included. GC group consisted of patients who had been prescribed oral GCs within 6 months of BMD testing. In GC group, GCs dosage was calculated by a defined daily dose (DDD), and divided into five groups according to GC usage (Group 1[G1]; < 11.25 DDDs, G2; ≥ 11.25, < 22.5 DDDs, G3; ≥ 22.5, < 45 DDDs, G4; ≥ 45, < 90 DDDs, G5; ≥ 90 DDDs). The risk of major osteoporotic fractures (MOF) and non-MOF was analyzed and compared with that of the control group during the 1-year follow-up. RESULTS: The risk of total fracture was higher in G3-G5 than in the control group (G3, hazard ratio (HR) 1.25, 95% confidence interval [CI] 1.07-1.46; G4, 1.37 [1.13-1.66]; G5 1.45 [1.08-1.94]). The risk of MOF was higher in all groups except G2 than in the control group (G1, 1.23 [1.05-1.45]; G3, 1.37 [1.11-1.68]; G4, 1.41 [1.09-1.83]; G5, 1.66 [1.14-2.42]). The risk of spine fracture was significantly higher in all GC groups except G2 than in the control group. The risk of non-MOF was higher only in G4 than in the control group (G4, 1.48 [1.13-1.94]). CONCLUSION: Low-dose GC therapy can increase the risk of osteoporotic fractures, particularly spine fractures, in postmenopausal women with low bone mass.

SCREENING PRACTICES AND LATE DIAGNOSIS OF HYDROXYCHLOROQUINE RETINOPATHY IN ASIAN PATIENTS.

PURPOSE: To investigate the associations between screening practices and late diagnosis in Asian patients with hydroxychloroquine retinopathy. METHODS: In total, 92 Korean patients with hydroxychloroquine retinopathy were included and separated into late diagnosis and earlier diagnosis groups according to the retinopathy stage at the time of diagnosis. Details of screening practices regarding timing and modalities for baseline and annual monitoring examinations were compared between the two groups. Adherence to the current American Academy of Ophthalmology guidelines was compared between the two groups. RESULTS: Timing of baseline and initial monitoring examinations was appropriate as per the Academy of Ophthalmology guidelines in only 5.3% of patients with late diagnosis. There were significant differences in the proportions of patients receiving initial monitoring at 5 years of use and those receiving annual monitoring between the late and earlier diagnosis groups ( P = 0.003 and <0.001, respectively). The duration from the start date of hydroxychloroquine therapy to the first monitoring examination was significantly prolonged in the late diagnosis group ( P < 0.001). Multivariate logistic regression revealed significant association of the time duration with the first monitoring examination ( P = 0.042) and age ( P = 0.028) with late diagnosis. CONCLUSION: Results of this study suggest that poor adherence to the Academy of Ophthalmology guideline, particularly delayed initial monitoring, may be associated with late diagnosis of hydroxychloroquine retinopathy.

Dielectric-Engineered High-Speed, Low-Power, Highly Reliable Charge Trap Flash-Based Synaptic Device for Neuromorphic Computing beyond Inference.

The coming of the big-data era brought a need for power-efficient computing that cannot be realized in the Von Neumann architecture. Neuromorphic computing which is motivated by the human brain can greatly reduce power consumption through matrix multiplication, and a device that mimics a human synapse plays an important role. However, many synaptic devices suffer from limited linearity and symmetry without using incremental step pulse programming (ISPP). In this work, we demonstrated a charge-trap flash (CTF)-based synaptic transistor using trap-level engineered Al2O3/Ta2O5/Al2O3 gate stack for successful neuromorphic computing. This novel gate stack provided precise control of the conductance with more than 6 bits. We chose the appropriate bias for highly linear and symmetric modulation of conductance and realized it with very short (25 ns) identical pulses at low voltage, resulting in low power consumption and high reliability. Finally, we achieved high learning accuracy in the training of 60000 MNIST images.

Cancer Prediction With Machine Learning of Thrombi From Thrombectomy in Stroke: Multicenter Development and Validation.

BACKGROUND: We aimed to develop and validate machine learning models to diagnose patients with ischemic stroke with cancer through the analysis of histopathologic images of thrombi obtained during endovascular thrombectomy. METHODS: This was a retrospective study using a prospective multicenter registry which enrolled consecutive patients with acute ischemic stroke from South Korea who underwent endovascular thrombectomy. This study included patients admitted between July 1, 2017 and December 31, 2021 from 6 academic university hospitals. Whole-slide scanning was performed for immunohistochemically stained thrombi. Machine learning models were developed using transfer learning with image slices as input to classify patients into 2 groups: cancer group or other determined cause group. The models were developed and internally validated using thrombi from patients of the primary center, and external validation was conducted in 5 centers. The model was also applied to patients with hidden cancer who were diagnosed with cancer within 1 month of their index stroke. RESULTS: The study included 70 561 images from 182 patients in both internal and external datasets (119 patients in internal and 63 in external). Machine learning models were developed for each immunohistochemical staining using antibodies against platelets, fibrin, and erythrocytes. The platelet model demonstrated consistently high accuracy in classifying patients with cancer, with area under the receiver operating characteristic curve of 0.986 (95% CI, 0.983-0.989) during training, 0.954 (95% CI, 0.937-0.972) during internal validation, and 0.949 (95% CI, 0.891-1.000) during external validation. When applied to patients with occult cancer, the model accurately predicted the presence of cancer with high probabilities ranging from 88.5% to 99.2%. CONCLUSIONS: Machine learning models may be used for prediction of cancer as the underlying cause or detection of occult cancer, using platelet-stained immunohistochemical slide images of thrombi obtained during endovascular thrombectomy.

Involvement of the kynurenine pathway in breast cancer: updates on clinical research and trials.

Breast cancer (BrCa) is the leading cause of cancer incidence and mortality in women worldwide. While BrCa treatment has been shown to be highly successful if detected at an early stage, there are few effective strategies to treat metastatic tumours. Hence, metastasis remains the main cause in most of BrCa deaths, highlighting the need for new approaches in this group of patients. Immunotherapy has been gaining attention as a new treatment for BrCa metastasis and the kynurenine pathway (KP) has been suggested as one of the potential targets. The KP is the major biochemical pathway in tryptophan (TRP) metabolism, catabolising TRP to nicotinamide adenine dinucleotide (NAD+). The KP has been reported to be elevated under inflammatory conditions such as cancers and that its activity suppresses immune surveillance. Dysregulation of the KP has previously been reported implicated in BrCa. This review aims to discuss and provide an update on the current mechanisms involved in KP-mediated immune suppression and cancer growth. Furthermore, we also provide a summary on 58 studies about the involvement of the KP and BrCa and five clinical trials targeting KP enzymes and their outcome.

Mass spectrometry-based protein identification in proteomics-a review.

Statistically, accurate protein identification is a fundamental cornerstone of proteomics and underpins the understanding and application of this technology across all elements of medicine and biology. Proteomics, as a branch of biochemistry, has in recent years played a pivotal role in extending and developing the science of accurately identifying the biology and interactions of groups of proteins or proteomes. Proteomics has primarily used mass spectrometry (MS)-based techniques for identifying proteins, although other techniques including affinity-based identifications still play significant roles. Here, we outline the basics of MS to understand how data are generated and parameters used to inform computational tools used in protein identification. We then outline a comprehensive analysis of the bioinformatics and computational methodologies used in protein identification in proteomics including discussing the most current communally acceptable metrics to validate any identification.

Age- and dose-dependent effect of statin use on the risk of osteoporotic fracture in older adults.

Previous studies have revealed the protective effects of statins on bone but the association of statins use with osteoporosis-related measurement has shown controversial results. In this study, we found an age, dose andduration-dependent osteoprotective effect of statins in general older population. PURPOSE: Previous studies have revealed the protective effects of statins on bone but the association of statins use with osteoporotic fractures has shown controversial results. METHODS: In this study with Korean National Health Insurance Service-Senior cohort database, a total of 365,656 elderly without previous history of osteoporosis and who were started on statin since January 1 2004 were included and observed until December 31 2012. Hazard rations (HR) for major osteoporotic fractures were calculated using the weighted Cox proportional hazards model with inverse-probability of treatment weighting method. RESULTS: During 6.27 years of follow-up period, 54,959 osteoporotic fractures occurred and the majority of fractures (69.5%) were vertebral fractures. Compared with non-users, statin use was associated with a decreased risk of all outcomes with adjusted HR (95% CI) of 0.77 (0.72-0.83; P < 0.001) for major osteoporotic fractures, 0.49 (0.38-0.62; P < 0.001) for hip fractures, and 0.70 (0.64-0.77; P < 0.001) for vertebral fractures. When outcomes were examined separately by sex, the results were broadly comparable in terms of patterns of risk reduction by statin use. The patients with statin initiated at age ≥ 80 years had the highest risk reduction for most outcomes relative to non-users. Higher cumulative dose of statin was negatively associated with the osteoporotic fracture risk; 0.97 (0.91-1.02) for 30-364 cumulative daily defined dose (cDDD), 0.45 (0.40-0.51) for 365-1,094 cDDD, and 0.22 (0.15-0.33) for ≥ 1,095 cDDD. CONCLUSIONS: Our results showed that statin use was associated with significant reduction in the risk of osteoporotic fractures in general older population.

Intensive vs Conventional Blood Pressure Lowering After Endovascular Thrombectomy in Acute Ischemic Stroke: The OPTIMAL-BP Randomized Clinical Trial.

Importance: Optimal blood pressure (BP) control after successful reperfusion with endovascular thrombectomy (EVT) for patients with acute ischemic stroke is unclear. Objective: To determine whether intensive BP management during the first 24 hours after successful reperfusion leads to better clinical outcomes than conventional BP management in patients who underwent EVT. Design, Setting, and Participants: Multicenter, randomized, open-label trial with a blinded end-point evaluation, conducted across 19 stroke centers in South Korea from June 2020 to November 2022 (final follow-up, March 8, 2023). It included 306 patients with large vessel occlusion acute ischemic stroke treated with EVT and with a modified Thrombolysis in Cerebral Infarction score of 2b or greater (partial or complete reperfusion). Interventions: Participants were randomly assigned to receive intensive BP management (systolic BP target <140 mm Hg; n = 155) or conventional management (systolic BP target 140-180 mm Hg; n = 150) for 24 hours after enrollment. Main Outcomes and Measures: The primary outcome was functional independence at 3 months (modified Rankin Scale score of 0-2). The primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and death related to the index stroke within 3 months. Results: The trial was terminated early based on the recommendation of the data and safety monitoring board, which noted safety concerns. Among 306 randomized patients, 305 were confirmed eligible and 302 (99.0%) completed the trial (mean age, 73.0 years; 122 women [40.4%]). The intensive management group had a lower proportion achieving functional independence (39.4%) than the conventional management group (54.4%), with a significant risk difference (-15.1% [95% CI, -26.2% to -3.9%]) and adjusted odds ratio (0.56 [95% CI, 0.33-0.96]; P = .03). Rates of symptomatic intracerebral hemorrhage were 9.0% in the intensive group and 8.1% in the conventional group (risk difference, 1.0% [95% CI, -5.3% to 7.3%]; adjusted odds ratio, 1.10 [95% CI, 0.48-2.53]; P = .82). Death related to the index stroke within 3 months occurred in 7.7% of the intensive group and 5.4% of the conventional group (risk difference, 2.3% [95% CI, -3.3% to 7.9%]; adjusted odds ratio, 1.73 [95% CI, 0.61-4.92]; P = .31). Conclusions and Relevance: Among patients who achieved successful reperfusion with EVT for acute ischemic stroke with large vessel occlusion, intensive BP management for 24 hours led to a lower likelihood of functional independence at 3 months compared with conventional BP management. These results suggest that intensive BP management should be avoided after successful EVT in acute ischemic stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT04205305.

Deciphering the Kidney Matrisome: Identification and Quantification of Renal Extracellular Matrix Proteins in Healthy Mice.

Precise characterization of a tissue's extracellular matrix (ECM) protein composition (matrisome) is essential for biomedicine. However, ECM protein extraction that requires organ-specific optimization is still a major limiting factor in matrisome studies. In particular, the matrisome of mouse kidneys is still understudied, despite mouse models being crucial for renal research. Here, we comprehensively characterized the matrisome of kidneys in healthy C57BL/6 mice using two ECM extraction methods in combination with liquid chromatography tandem mass spectrometry (LC-MS/MS), protein identification, and label-free quantification (LFQ) using MaxQuant. We identified 113 matrisome proteins, including 22 proteins that have not been previously listed in the Matrisome Database. Depending on the extraction approach, the core matrisome (structural proteins) comprised 45% or 73% of kidney ECM proteins, and was dominated by glycoproteins, followed by collagens and proteoglycans. Among matrisome-associated proteins, ECM regulators had the highest LFQ intensities, followed by ECM-affiliated proteins and secreted factors. The identified kidney ECM proteins were primarily involved in cellular, developmental and metabolic processes, as well as in molecular binding and regulation of catalytic and structural molecules' activity. We also performed in silico comparative analysis of the kidney matrisome composition in humans and mice based on publicly available data. These results contribute to the first reference database for the mouse renal matrisome.

Evaluation of the Antiviral Efficacy of Subcutaneous Nafamostat Formulated with Glycyrrhizic Acid against SARS-CoV-2 in a Murine Model.

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option.

Nelonemdaz for Patients With Acute Ischemic Stroke Undergoing Endovascular Reperfusion Therapy: A Randomized Phase II Trial.

BACKGROUND: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy. METHODS: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received-placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 12 weeks. RESULTS: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P=0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92-2.60) between the placebo and low-dose groups and 1.61 (0.94-2.76) between the placebo and high-dose groups. No serious adverse events were reported. CONCLUSIONS: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0-2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02831088.

Impact of Renal Function on Short-Term Outcome After Reperfusion Therapy in Patients With Ischemic Stroke.

BACKGROUND: A high and low estimated glomerular filtration rate (eGFR) could affect outcomes after reperfusion therapy for ischemic stroke. This study aimed to determine whether renal function based on eGFR affects mortality risk in patients with ischemic stroke within 6 months following reperfusion therapy. METHODS: This prospective registry-based cohort study included 2266 patients who received reperfusion therapy between January 2000 and September 2019 and were registered in the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) study or the Yonsei Stroke Cohort. A high and low eGFR were based on the Chronic Kidney Disease Epidemiology Collaboration equation and defined, respectively, as the 5th and 95th percentiles of age- and sex-specific eGFR. Occurrence of death within 6 months was compared among the groups according to their eGFR such as low, normal, or high eGFR. RESULTS: Of the 2266 patients, 2051 (90.5%) had a normal eGFR, 110 (4.9%) a low eGFR, and 105 (4.6%) a high eGFR. Patients with high eGFR were younger or less likely to have hypertension, diabetes, or atrial fibrillation than the other groups. Active cancer was more prevalent in the high-eGFR group. During the 6-month follow-up, there were 24 deaths (22.9%) in the high-eGFR group, 37 (33.6%) in the low-eGFR group, and 237 (11.6%) in the normal-eGFR group. After adjusting for variables with P<0.10 in the univariable analysis, 6-month mortality was independently associated with high eGFR (hazard ratio, 2.22 [95% CI, 1.36-3.62]; P=0.001) and low eGFR (HR, 2.29 [95% CI, 1.41-3.72]; P=0.001). These associations persisted regardless of treatment modality or various baseline characteristics. CONCLUSIONS: High eGFR as well as low eGFR were independently associated with 6-month mortality after reperfusion therapy. Kidney function could be considered a prognostic factor in patients with ischemic stroke after reperfusion therapy.

Time-resolved assessment of cortical venous drainage on multiphase CT angiography in patients with acute ischemic stroke.

PURPOSE: Cortical vein opacification is not routinely assessed in patients presenting with acute ischemic stroke (AIS), and the value of temporal assessment of venous outflow is not known. We evaluated the utility of assessing cortical venous drainage over time using multiphase CT angiography (mCTA). METHODS: Cortical venous drainage was assessed in patients from the Precise and Rapid Assessment of Collaterals Using Multi-Phase CTA in the Triage of Patients With Acute Ischemic Stroke for IA Therapy prospective multicenter cohort study of patients with symptoms of AIS with ICA and/or middle cerebral artery occlusion on baseline mCTA. Opacification of vein of Labbe, sphenoparietal sinus, superficial middle cerebral vein, and vein of Trolard of the affected hemisphere was graded as no (0), partial (1), or full (2) opacification in each mCTA phase. The venous opacification scores for each phase were added to generate a total venous score (TVS) (range 0-24). Primary outcome was 90-day modified Rankin score. Repeated measures analysis was used to assess the effect of phase timing on venous score on outcome. RESULTS: Of 432 patients, 284 (65.7%) had proximal arterial occlusions. Median venous opacification score per phase (range 0-8) was 3 (IQR 1-6) in the first phase and increased in the second and third phases [median (IQR): 6 (5-8) and 8 (6-8), respectively] of the mCTA. In a multivariable analysis adjusting for age, baseline National Institutes of Health Stroke Scale, and Alberta stroke program early CT score, a significant association between TVS and 90-day mRS was noted ([adjusted cOR for TVS 6-11: 0.16 (95% CI 0.05-0.51); TVS 12-17: 0.18 (95% CI 0.06-0.57); TVS 18-24: 0.20 (0.06-0.63)]. Repeated measures analysis of venous scores from all three phases showed a significant effect of time/phase on TVS (p < 0.001). CONCLUSION: This study concludes that venous opacification over time on multiphase CTA is associated with 90-day clinical outcome. There was however no added benefit of venous scoring vis-a-vis arterial collateral assessment in predicting outcome.

Relationships Between Pulmonary Function and Composite Indices of Femoral Neck Strength in Korean Men (KNHANES IV).

BACKGROUND: Despite the close relationship between osteoporosis and chronic pulmonary diseases, few studies have evaluated relationships between pulmonary functions and bone quality. We investigated associations between pulmonary function test results and femoral neck strength indices (SIs) in Korean men. METHODS: This population-based, cross-sectional study was conducted using data from the Korea National Health and Nutrition Examination Survey IV on 936 men aged ≥ 19 years. Pulmonary functions (forced vital capacity [FVC] and forced expiratory volume in one second [FEV1]) were measured using a dry rolling seal spirometer. Femoral neck SIs, relative to load, were calculated by hip dual-energy X-ray absorptiometry for compression strength index (CSI), bending strength index (BSI), and impact strength index (ISI). RESULTS: The 443 (47.3%) of the 936 men were current smokers. FVC, FVC percentage with respect to the expected normal value, FEV1, and FEV1 percentage with respect to the expected normal value (FEV1p) were positively associated with CSI and BSI after adjusting for confounders, including smoking history (ß = 0.003-0.223, P = 0.005-0.036). FEV1 and FEV1p were positively associated with ISI (ß = 0.000-0.014, P = 0.010-0.025). Of components of femoral neck SIs, bone mineral density was correlated with FEV1 and FEV1p (ß = 0.001-0.037, P = 0.017-0.019). After adjusting for all confounders, all femoral neck SIs increased with FVC quintiles (P for trends = 0.001-0.012), and CSI and BSI increased with FEV1 quintiles (P for trends = 0.034-0.043). CONCLUSION: Reduced pulmonary function was correlated with reduced femoral neck strength, even after adjusting for smoking history in Korean men. Femoral neck SIs might be useful tools for evaluating bone health in men with reduced pulmonary function.

SARS-CoV-2 Delta Variant Breakthrough Infection and Onward Secondary Transmission in Household.

BACKGROUND: Despite the extraordinary speed of mass vaccination efforts, an outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant in a vaccinee with coronavirus disease 2019 (COVID-19) mRNA vaccine was identified in an adult day service center (ADSC) of Jeju, South Korea. The primary objective of this study was to investigate the epidemiologic features in infection-vulnerable facilities with a high vaccination rate of BNT162b2 mRNA COVID-19 vaccine. The second was to estimate the secondary transmission prevention effect of the vaccine in the household members by vaccination status. METHODS: We included all ADSC participants, staff and their household members. All COVID-19 infected cases were confirmed by reverse transcriptase polymerase chain reaction. We calculated attack rate in ADSC and the secondary attack rate (SAR) in household members by vaccination status. RESULTS: Among a total of 42 participants and 16 staff, of which 96.6% were fully vaccinated with BNT162b2 mRNA COVID-19 vaccine, 12 symptomatic cases and 13 asymptomatic confirmed cases of COVID-19 were found. The attack rate was 43.1%, with 13 isolates identified as SARS-CoV-2 virus, delta variant. The SAR in unvaccinated and partially vaccinated household members were 27.8% (5/18) and 25.0% (5/20), respectively, while the SAR in fully vaccinated household members was 12.5% (1/8). CONCLUSION: We describe a SARS-CoV-2 delta variant outbreak in ADSC with high vaccine coverage rate, characterized by high infection rate, high transmissibility, and low clinical severity. The outbreak proceeded to unvaccinated or partially vaccinated household members, emphasizing the need for immunizing close contacts of high-risk groups.

Nuclear mRNA Export and Aging.

The relationship between transcription and aging is one that has been studied intensively and experimentally with diverse attempts. However, the impact of the nuclear mRNA export on the aging process following its transcription is still poorly understood, although the nuclear events after transcription are coupled closely with the transcription pathway because the essential factors required for mRNA transport, namely TREX, TREX-2, and nuclear pore complex (NPC), physically and functionally interact with various transcription factors, including the activator/repressor and pre-mRNA processing factors. Dysregulation of the mediating factors for mRNA export from the nucleus generally leads to the aberrant accumulation of nuclear mRNA and further impairment in the vegetative growth and normal lifespan and the pathogenesis of neurodegenerative diseases. The optimal stoichiometry and density of NPC are destroyed during the process of cellular aging, and their damage triggers a defect of function in the nuclear permeability barrier. This review describes recent findings regarding the role of the nuclear mRNA export in cellular aging and age-related neurodegenerative disorders.

An Evaluation of a New Quantitative Point-of Care Diagnostic to Measure Glucose-6-phosphate Dehydrogenase Activity.

Malaria continues to be one of the most crucial infectious burdens in endemic areas worldwide, as well as for travelers visiting malaria transmission regions. It has been reported that 8-aminoquinolines are effective against the Plasmodium species, particularly primaquine, for anti-hypnozoite therapy in P. vivax malaria. However, primaquine causes acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Therefore, G6PD deficiency testing should precede hypnozoite elimination with 8-aminoquinoline. Several point-of-care devices have been developed to detect G6PD deficiency. The aim of the present study was to evaluate the performance of a novel, quantitative G6PD diagnostics based on a metagenomic blue fluorescent protein (mBFP). We comparatively evaluated the sensitivity and specificity of the G6PD diagnostic modality with standard methods using 120 human whole blood samples. The G6PD deficiency was spectrophotometrically confirmed. The performance of the G6PD quantitative test kit was compared with that of a licensed control medical device, the G6PD strip. The G6PD quantitative test kit had a sensitivity of 95% (95% confidence interval (CI): 89.3-100%) and a specificity of 100% (95% CI: 94.3-100%). This study shows that the novel diagnostic G6PD quantitative test kit could be a cost-effective and time-efficient, and universally mandated screening tool for G6PD deficiency.

Use of a Recombinant Biomarker Protein DDA Library Increases DIA Coverage of Low Abundance Plasma Proteins.

Credible detection and quantification of low abundance proteins from human blood plasma is a major challenge in precision medicine biomarker discovery when using mass spectrometry (MS). In this proof-of-concept study, we employed a mixture of selected recombinant proteins in DDA libraries to subsequently identify (not quantify) cancer-associated low abundance plasma proteins using SWATH/DIA. The exemplar DDA recombinant protein spectral library (rPSL) was derived from tryptic digestion of 36 recombinant human proteins that had been previously implicated as possible cancer biomarkers from both our own and other studies. The rPSL was then used to identify proteins from nondepleted colorectal cancer (CRC) EDTA plasmas by SWATH-MS. Most (32/36) of the proteins used in the rPSL were reliably identified from CRC plasma samples, including 8 proteins (i.e., BTC, CXCL10, IL1B, IL6, ITGB6, TGFα, TNF, TP53) not previously detected using high-stringency protein inference MS according to PeptideAtlas. The rPSL SWATH-MS protocol was compared to DDA-MS using MARS-depleted and postdigestion peptide fractionated plasmas (here referred to as a human plasma DDA library). Of the 32 proteins identified using rPSL SWATH, only 12 could be identified using DDA-MS. The 20 additional proteins exclusively identified using the rPSL SWATH approach were almost exclusively lower abundance (i.e., <10 ng/mL) proteins. To mitigate justified FDR concerns, and to replicate a more typical library creation approach, the DDA rPSL library was merged with a human plasma DDA library and SWATH identification repeated using such a merged library. The majority (33/36) of the low abundance plasma proteins added from the rPSL were still able to be identified using such a merged library when high-stringency HPP Guidelines v3.0 protein inference criteria were applied to our data set. The MS data set has been deposited to ProteomeXchange Consortium via the PRIDE partner repository (PXD022361).

Thrombus Migration and Fragmentation After Intravenous Alteplase Treatment: The INTERRSeCT Study.

BACKGROUND AND PURPOSE: There is interest in what happens over time to the thrombus after intravenous alteplase. We study the effect of alteplase on thrombus structure and its impact on clinical outcome in patients with acute stroke. METHODS: Intravenous alteplase treated stroke patients with intracranial internal carotid artery or middle cerebral artery occlusion identified on baseline computed tomography angiography and with follow-up vascular imaging (computed tomography angiography or first run of angiography before endovascular therapy) were enrolled from INTERRSeCT study (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography). Thrombus movement after intravenous alteplase was classified into complete recanalization, thrombus migration, thrombus fragmentation, and no change. Thrombus migration was diagnosed when occlusion site moved distally and graded according to degrees of thrombus movement (grade 0-3). Thrombus fragmentation was diagnosed when a new distal occlusion in addition to the primary occlusion was identified on follow-up imaging. The association between thrombus movement and clinical outcome was also evaluated. RESULTS: Among 427 patients in this study, thrombus movement was seen in 54% with a median time of 123 minutes from alteplase administration to follow-up imaging, and sub-classified as marked (thrombus migration grade 2-3 + complete recanalization; 27%) and mild to moderate thrombus movement (thrombus fragmentation + thrombus migration grade 0-1; 27%). In patients with proximal M1/internal carotid artery occlusion, marked thrombus movement was associated with a higher rate of good outcome (90-day modified Rankin Scale, 0-2) compared with mild to moderate movement (52% versus 27%; adjusted odds ratio, 5.64 [95% CI, 1.72-20.10]). No difference was seen in outcomes between mild to moderate thrombus movement and no change. In M1 distal/M2 occlusion, marked thrombus movement was associated with improved 90-day good outcome compared with no change (70% versus 56%; adjusted odds ratio, 2.54 [95% CI, 1.21-5.51]). CONCLUSIONS: Early thrombus movement is common after intravenous alteplase. Marked thrombus migration leads to good clinical outcomes. Thrombus dynamics over time should be further evaluated in clinical trials of acute reperfusion therapy.