RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease.

BACKGROUND: Despite consistent recommendations from clinical guidelines, data from randomized trials on a long-term antithrombotic treatment strategy for patients with atrial fibrillation and stable coronary artery disease are still lacking. METHODS: We conducted a multicenter, open-label, adjudicator-masked, randomized trial comparing edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with atrial fibrillation and stable coronary artery disease (defined as coronary artery disease previously treated with revascularization or managed medically). The risk of stroke was assessed on the basis of the CHA2DS2-VASc score (scores range from 0 to 9, with higher scores indicating a greater risk of stroke). The primary outcome was a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, and major bleeding or clinically relevant nonmajor bleeding at 12 months. Secondary outcomes included a composite of major ischemic events and the safety outcome of major bleeding or clinically relevant nonmajor bleeding. RESULTS: We assigned 524 patients to the edoxaban monotherapy group and 516 patients to the dual antithrombotic therapy group at 18 sites in South Korea. The mean age of the patients was 72.1 years, 22.9% were women, and the mean CHA2DS2-VASc score was 4.3. At 12 months, a primary-outcome event had occurred in 34 patients (Kaplan-Meier estimate, 6.8%) assigned to edoxaban monotherapy and in 79 patients (16.2%) assigned to dual antithrombotic therapy (hazard ratio, 0.44; 95% confidence interval [CI], 0.30 to 0.65; P<0.001). The cumulative incidence of major ischemic events at 12 months appeared to be similar in the trial groups. Major bleeding or clinically relevant nonmajor bleeding occurred in 23 patients (Kaplan-Meier estimate, 4.7%) in the edoxaban monotherapy group and in 70 patients (14.2%) in the dual antithrombotic therapy group (hazard ratio, 0.34; 95% CI, 0.22 to 0.53). CONCLUSIONS: In patients with atrial fibrillation and stable coronary artery disease, edoxaban monotherapy led to a lower risk of a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, or major bleeding or clinically relevant nonmajor bleeding at 12 months than dual antithrombotic therapy. (Funded by the CardioVascular Research Foundation and others; EPIC-CAD ClinicalTrials.gov number, NCT03718559.).

Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

PET imaging of TSPO expression in immune cells can assess organ-level pathophysiology in high-consequence viral infections.

Ebola virus (EBOV) disease is characterized by lymphopenia, breach in vascular integrity, cytokine storm, and multiorgan failure. The pathophysiology of organ involvement, however, is incompletely understood. Using [18F]-DPA-714 positron emission tomography (PET) imaging targeting the translocator protein (TSPO), an immune cell marker, we sought to characterize the progression of EBOV-associated organ-level pathophysiology in the EBOV Rhesus macaque model. Dynamic [18F]-DPA-714 PET/computed tomography imaging was performed longitudinally at baseline and at multiple time points after EBOV inoculation, and distribution volumes (Vt) were calculated as a measure of peripheral TSPO binding. Using a mixed-effect linear regression model, spleen and lung Vt decreased, while the bone marrow Vt increased over time after infection. No clear trend was found for liver Vt. Multiple plasma cytokines correlated negatively with lung/spleen Vt and positively with bone marrow Vt. Multiplex immunofluorescence staining in spleen and lung sections confirmed organ-level lymphoid and monocytic loss/apoptosis, thus validating the imaging results. Our findings are consistent with EBOV-induced progressive monocytic and lymphocytic depletion in the spleen, rather than immune activation, as well as depletion of alveolar macrophages in the lungs, with inefficient reactive neutrophilic activation. Increased bone marrow Vt, on the other hand, suggests hematopoietic activation in response to systemic immune cell depletion and leukocytosis and could have prognostic relevance. In vivo PET imaging provided better understanding of organ-level pathophysiology during EBOV infection. A similar approach can be used to delineate the pathophysiology of other systemic infections and to evaluate the effectiveness of newly developed treatment and vaccine strategies.

A point-of-care pilot randomized intervention to connect patients with cancer-induced financial toxicity to telehealth financial counseling.

PURPOSE: Elevated costs of cancer treatment can result in economic and psychological "financial toxicity" distress. This pilot study assessed the feasibility of a point-of-care intervention to connect adult patients with cancer-induced financial toxicity to telehealth-delivered financial counseling. METHODS: We conducted a three-armed parallel randomized pilot study, allocating newly referred patients with cancer and financial toxicity to individual, group accredited telehealth financial counseling, or usual care with educational material (1:1:1). We assessed the feasibility of recruitment, randomization, retention, baseline and post-intervention COmprehensive Score for Financial Toxicity (COST), and Telehealth Usability Questionnaire (TUQ) scores. RESULTS: Of 382 patients screened, 121 were eligible and enrolled. 58 (48%) completed the intervention (9 individual, 9 group counseling, 40 educational booklet). 29 completed follow-up surveys: 45% female, 17% African American, 79% white, 7% Hispanic, 55% 45-64 years old, 31% over 64, 34% lived in rural areas, 24% had cancer stage I, 21% II, 7% III, 31% IV. Baseline characteristics were balanced across arms, retention status, surveys completion. Mean (SD) COST was 12.4 (6.1) at baseline and 16.0 (8.4) post-intervention. Mean (SD) COST score differences were 6.3 (11.6) after individual counseling, 5.8 (8.5) after group counseling, and 2.5 (6.4) after usual care. Mean TUQ score among nine counseling participants was 5.5 (0.9) over 7.0. Non-parametric comparisons were not statistically meaningful. CONCLUSION: Recruitment and randomization were feasible, while study retention presented challenges. Nine participants reported good usability and satisfaction with telehealth counseling. Larger-scale trials focused on improving participation, retention, and impact of financial counseling among patients with cancer are justified.

Empowering SARS-CoV-2 variant neutralization with a bifunctional antibody engineered with tandem heptad repeat 2 peptides.

With the global pandemic and the continuous mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the need for effective and broadly neutralizing treatments has become increasingly urgent. This study introduces a novel strategy that targets two aspects simultaneously, using bifunctional antibodies to inhibit both the attachment of SARS-CoV-2 to host cell membranes and viral fusion. We developed pioneering IgG4-(HR2)4 bifunctional antibodies by creating immunoglobulin G4-based and phage display-derived human monoclonal antibodies (mAbs) that specifically bind to the SARS-CoV-2 receptor-binding domain, engineered with four heptad repeat 2 (HR2) peptides. Our in vitro experiments demonstrate the superior neutralization efficacy of these engineered antibodies against various SARS-CoV-2 variants, ranging from original SARS-CoV-2 strain to the recently emerged Omicron variants, as well as SARS-CoV, outperforming the parental mAb. Notably, intravenous monotherapy with the bifunctional antibody neutralizes a SARS-CoV-2 variant in a murine model without causing significant toxicity. In summary, this study unveils the significant potential of HR2 peptide-driven bifunctional antibodies as a potent and versatile strategy for mitigating SARS-CoV-2 infections. This approach offers a promising avenue for rapid development and management in the face of the continuously evolving SARS-CoV-2 variants, holding substantial promise for pandemic control.

Intravital Imaging of the Human Cornea Reveals the Differential Effects of Season on Innate and Adaptive Immune Cell Morphodynamics.

PURPOSE: Defining how the in vivo immune status of peripheral tissues is shaped by the external environment has remained a technical challenge. We recently developed Functional in vivo confocal microscopy (Fun-IVCM) for dynamic, longitudinal imaging of corneal immune cells in living humans. This study investigated the effect of seasonal-driven environmental factors on the morphodynamic features of human corneal immune cell subsets. DESIGN: Longitudinal, observational clinical study. PARTICIPANTS: Sixteen healthy participants (aged 18-40 years) attended 2 visits in distinct seasons in Melbourne, Australia (Visit 1, November-December 2021 [spring-summer]; Visit 2, April-June 2022 [autumn-winter]). METHODS: Environmental data were collected over each period. Participants underwent ocular surface examinations and corneal Fun-IVCM (Heidelberg Engineering). Corneal scans were acquired at 5.5 ± 1.5-minute intervals for up to 5 time points. Time-lapse Fun-IVCM videos were created to analyze corneal immune cells, comprising epithelial T cells and dendritic cells (DCs), and stromal macrophages. Tear cytokines were analyzed using a multiplex bead-based immunoassay. MAIN OUTCOME MEASURES: Difference in the density, morphology, and dynamic parameters of corneal immune cell subsets over the study periods. RESULTS: Visit 1 was characterized by higher temperature, lower humidity, and higher air particulate and pollen levels compared with Visit 2. Clinical ocular surface parameters and the density of immune cell subsets were similar across visits. At Visit 1 , corneal epithelial DCs were larger, with a lower dendrite probing speed (0.38 ± 0.21 vs. 0.68 ± 0.33 µm/min; P < 0.001) relative to Visit 2; stromal macrophages were more circular and had less dynamic activity (Visit 1, 7.2 ± 1.9 vs. Visit 2, 10.3 ± 3.7 dancing index; P < 0.001). Corneal T cell morphodynamics were unchanged across periods. Basal tear levels of interleukin 2 and CXCL10 were relatively lower during spring-summer. CONCLUSIONS: This study identifies that the in vivo morphodynamics of innate corneal immune cells (DCs, macrophages) are modified by environmental factors, but such effects are not evident for adaptive immune cells (T cells). The cornea is a potential in vivo window to investigate season-dependent environmental influences on the human immune system. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Complement factor H-related protein 5 alleviates joint inflammation and osteoclast differentiation by disrupting RANK-JNK signaling in collagen antibody-induced arthritis mouse model.

BACKGROUND: Complement Factor H-Related protein 5 (CFHR5) belongs to the factor H/CFHR family and regulates the complement system by modulating factor H's inhibitory activity against C3b. Despite its known role, the impact of CFHR5 on autoimmune arthritis and its relationship to pathophysiological changes in arthritis and bone loss remain unclear. This study aimed to assess the effect of CFHR5 on aggressive osteoclast activity and arthritis using a murine model of collagen antibody-induced arthritis (CAIA). METHODS: The effect of recombinant CFHR5 protein (rCFHR5) on arthritis were evaluated in CAIA. The mice were divided into three group and intraperitoneally treated with rCFHR5, methotrexate (MTX) as positive control or PBS as negative control. In the CAIA mouse model, the rCFHR5-treated group significantly reduced the incidence and clinical arthritis equivalent to the MTX group. Clinical arthritis scores, incidence and body weight were measured, and histological analysis of ankle joints was performed by Hematoxylin and Eosin (H&E) and Safranin O - Fast green (SOFG), Tartrate-resistant acid phosphatase (TRAP) staining and Immunohistochemistry. Moreover, to investigate the rCFHR5 role, we isolated murine osteoclast precursor cells (OCPs) from each group, induced osteoclasts with M-CSF and RANKL, and performed TRAP and F-actin staining. To verify the mechanism, mRNA and protein analyses were performed in OCPs. RESULTS: Histological examination of ankle joints revealed substantial reductions in synovial hyperplasia, bone marrow inflammation, bone erosion, cartilage destruction and TRAP-positive cells in the rCFHR5 group compared to the vehicle group. The ankle joints of the rCFHR5 group showed markedly decreased expression of proinflammatory cytokines (TNF-α, IL-1ß and IL-6). Mechanically, treatment with rCFHR5 inhibited RANKL-mediated osteoclast differentiation from OCPs and disrupted the RANK-JNK signaling. These findings demonstrate that treatment with rCFHR5 attenuates joint inflammation and reduces osteoclast differentiation, indicating its potential anti-inflammatory effect in autoimmune arthritis models.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Single center experience with hourglass-like constriction neuropathy of suprascapular nerve.

INTRODUCTION/AIMS: Hourglass-like constriction (HGC) may occur in several peripheral nerves. However, data on the prognosis of motor weakness in patients with HGC of the suprascapular nerve (SSN) are limited compared with other nerves. Here, we aimed to describe the clinical and imaging features of HGC of the SSN. METHODS: We retrospectively reviewed patients diagnosed with suprascapular neuropathy using magnetic resonance imaging (MRI) or electrodiagnostic studies over 16 years. After excluding extrinsic causes, patients with HGC of the SSN detected using MRI were included. RESULTS: Fourteen patients with HGC of the SSN were identified. MRI revealed that all HGCs were located between the origin of the SSN from the upper trunk of the brachial plexus and the suprascapular notch. Seven patients exhibited HGC precisely at the origin of the SSN from the brachial plexus. Four patients showed T2 hyperintensity of the SSN extending to the upper trunk of the brachial plexus or the extraforaminal cervical root. The initial treatments included observation (n = 1), steroid therapy (n = 12), suprascapular notch release (n = 1). Of the 12 patients with a sufficient follow-up period, nine fully recovered from motor weakness of the SSN with non-operative treatments. Six of the nine patients who recovered fully experienced their first clinical improvement more than 6 months after onset. DISCUSSION: Treatment strategies for HGC differ depending on the affected nerve. For HGC of the SSN, due to the high spontaneous recovery rate observed in our study, conservative management for at least 6 months should be initially considered.

Developing a deep learning model for sleep stage prediction in obstructive sleep apnea cohort using 60 GHz frequency-modulated continuous-wave radar.

Given the significant impact of sleep on overall health, radar technology offers a promising, non-invasive, and cost-effective avenue for the early detection of sleep disorders, even prior to relying on polysomnography (PSG)-based classification. In this study, we employed an attention-based bidirectional long short-term memory (Attention Bi-LSTM) model to accurately predict sleep stages using 60 GHz frequency-modulated continuous-wave (FMCW) radar. Our dataset comprised 78 participants from an ongoing obstructive sleep apnea (OSA) cohort, recruited between July 2021 and November 2022, who underwent overnight polysomnography alongside radar sensor monitoring. The dataset encompasses comprehensive polysomnography recordings, spanning both sleep and wakefulness states. The predictions achieved a Cohen's kappa coefficient of 0.746 and an overall accuracy of 85.2% in classifying wakefulness, rapid-eye-movement (REM) sleep, and non-REM (NREM) sleep (N1 + N2 + N3). The results demonstrated that the models incorporating both Radar 1 and Radar 2 data consistently outperformed those using only Radar 1 data, indicating the potential benefits of utilising multiple radars for sleep stage classification. Although the performance of the models tended to decline with increasing OSA severity, the addition of Radar 2 data notably improved the classification accuracy. These findings demonstrate the potential of radar technology as a valuable screening tool for sleep stage classification.

Accurate and fast small p-value estimation for permutation tests in high-throughput genomic data analysis with the cross-entropy method.

Permutation tests are widely used for statistical hypothesis testing when the sampling distribution of the test statistic under the null hypothesis is analytically intractable or unreliable due to finite sample sizes. One critical challenge in the application of permutation tests in genomic studies is that an enormous number of permutations are often needed to obtain reliable estimates of very small p-values, leading to intensive computational effort. To address this issue, we develop algorithms for the accurate and efficient estimation of small p-values in permutation tests for paired and independent two-group genomic data, and our approaches leverage a novel framework for parameterizing the permutation sample spaces of those two types of data respectively using the Bernoulli and conditional Bernoulli distributions, combined with the cross-entropy method. The performance of our proposed algorithms is demonstrated through the application to two simulated datasets and two real-world gene expression datasets generated by microarray and RNA-Seq technologies and comparisons to existing methods such as crude permutations and SAMC, and the results show that our approaches can achieve orders of magnitude of computational efficiency gains in estimating small p-values. Our approaches offer promising solutions for the improvement of computational efficiencies of existing permutation test procedures and the development of new testing methods using permutations in genomic data analysis.

Establishment of high-performance liquid chromatography-photodiode array method for 43 weight loss agents and effect of basic environment on bisacodyl degradation.

RATIONALE: The demand for weight loss products is increasing as slimness emerges as the new aesthetic standard and people's desire to achieve it increases. In addition, the distribution and sale of products containing illegal ingredients, pharmaceuticals, and chemicals for which safety is not guaranteed and that cannot be used as foods or dietary supplements are increasing. Thus, the development of an analytical method that could monitor these illegal products is required. METHODS: A high-performance liquid chromatography-photodiode array method capable of rapid and reliable qualitative and quantitative analyses of 43 weight loss agents was established and validated. RESULTS: The process involved dividing analytes into three groups for rapid analysis; when bisacodyl was mixed with chlorocyclopentylsibutramine, it decomposed into its metabolites: monoacetyl bisacodyl and bis-(p-hydroxypheny)-pyridyl-2-methane. This decomposition was due to NaOH that was used to prepare the chlorocyclopentylsibutramine standard solution. Bisacodyl did not degrade when mixed with neutralized chlorocyclopentylsibutramine, whereas when NaOH was added, it rapidly degraded. We identified the bisacodyl degradation products using liquid chromatography-quadrupole-Orbitrap/mass spectrometry. MS2 spectra with proposed structures of fragment peaks were also obtained. CONCLUSIONS: The developed method could be used to regulate slimming products that threaten public health, and knowledge of bisacodyl degradation will be used as the basis for developing an analytic method.

Comparison between catheter ablation versus permanent pacemaker implantation as an initial treatment for tachycardia-bradycardia syndrome patients: a prospective, randomized trial.

BACKGROUND: Clinical outcomes after catheter ablation (CA) or pacemaker (PM) implantation for the tachycardia-bradycardia syndrome (TBS) has not been evaluated adequately. We tried to compare the efficacy and safety outcomes of CA and PM implantation as an initial treatment option for TBS in paroxysmal atrial fibrillation (AF) patients. METHODS: Sixty-eight patients with paroxysmal AF and TBS (mean 63.7 years, 63.2% male) were randomized, and received CA (n = 35) or PM (n = 33) as initial treatments. The primary outcomes were unexpected emergency room visits or hospitalizations attributed to cardiovascular causes. RESULTS: In the intention-to-treatment analysis, the rates of primary outcomes were not significantly different between the two groups at the 2-year follow-up (19.8% vs. 25.9%; hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.25-2.20, P = 0.584), irrespective of whether the results were adjusted for age (HR 1.12, 95% CI 0.34-3.64, P = 0.852). The 2-year rate of recurrent AF was significantly lower in the CA group compared to the PM group (33.9% vs. 56.8%, P = 0.038). Four patients (11.4%) in the CA group finally received PMs after CA owing to recurrent syncope episodes. The rate of major or minor procedure related complications was not significantly different between the two groups. CONCLUSION: CA had a similar efficacy and safety profile with that of PM and a higher sinus rhythm maintenance rate. CA could be considered as a preferable initial treatment option over PM implantation in patients with paroxysmal AF and TBS. TRIAL REGISTRATION: KCT0000155.

Human glioblastoma arises from subventricular zone cells with low-level driver mutations.

Glioblastoma (GBM) is a devastating and incurable brain tumour, with a median overall survival of fifteen months1,2. Identifying the cell of origin that harbours mutations that drive GBM could provide a fundamental basis for understanding disease progression and developing new treatments. Given that the accumulation of somatic mutations has been implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates3-5. However, there is a lack of direct genetic evidence from human patients with GBM4,6-10. Here we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that contains the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of (i) normal SVZ tissue away from the tumour mass, (ii) tumour tissue, and (iii) normal cortical tissue (or blood), from 28 patients with isocitrate dehydrogenase (IDH) wild-type GBM or other types of brain tumour. We found that normal SVZ tissue away from the tumour in 56.3% of patients with wild-type IDH GBM contained low-level GBM driver mutations (down to approximately 1% of the mutational burden) that were observed at high levels in their matching tumours. Moreover, by single-cell sequencing and laser microdissection analysis of patient brain tissue and genome editing of a mouse model, we found that astrocyte-like NSCs that carry driver mutations migrate from the SVZ and lead to the development of high-grade malignant gliomas in distant brain regions. Together, our results show that NSCs in human SVZ tissue are the cells of origin that contain the driver mutations of GBM.

Atopic Dermatitis Severity and Risk for Psoriasis: A Nationwide Population-Based Study.

INTRODUCTION: As research on the role of the Th17/IL-23 pathway gains importance, the relationship between atopic dermatitis (AD) and psoriasis is becoming elucidated. OBJECTIVE: The objective of this study wasto evaluate whether AD and its severity affect the risk for psoriasis. METHODS: This retrospective population-based study used the database from the 2009 National Health Insurance Services-Health Screening Cohort in Korea. A total of 3,957,922 adult subjects were included and observed until 2018. The primary outcome was newly diagnosed psoriasis. RESULTS: After adjusting for possible confounding factors, the moderate-to-severe AD group had the highest hazard ratio (HR) for psoriasis (HR = 2.50; 95% confidence interval (CI), 2.40-2.61), followed by the mild AD group (HR = 2.31; 95% CI: 2.19-2.44) compared with the non-AD group during a median 8.11 ± 1.19 years of follow-up. LIMITATIONS: It is difficult to define AD, which is not standardized, using a claims database and exclude patients who were misdiagnosed with AD. CONCLUSION: Patients with severe AD showed an increased risk for psoriasis compared to controls, and the risk for psoriasis was increased according to AD severity. This suggests that psoriasis and AD could share inflammatory, immune, and genetic features.

Fluid Resolution Without Shortening Injection Interval During Subretinal Fluid-tolerating Treatment in Neovascular Age-related Macular Degeneration.

PURPOSE: To investigate the incidence and factors associated with subretinal fluid(SRF) resolution during SRF-tolerating treatment in patients with neovascular age-related macular degeneration(AMD). METHODS: This retrospective study included patients diagnosed with neovascular AMD who exhibited fovea-involving residual SRF persisting for at least 6 months during aflibercept treatment. Patients who showed SRF resolution despite maintaining the injection intervals were included in the resolution group, while those who exhibited persisting SRF throughout the study period were included in the non-resolution group. The incidence and associated factors of SRF resolution without reducing the injection interval were evaluated. Furthermore, the frequency of successfully extending the injection intervals while maintaining SRF resolution was identified. RESULTS: In total, 65 patients with neovascular AMD were included(32 and 33 in the resolution and non-resolution groups, respectively). When compared to the non-resolution group, the resolution group showed a lower mean height of SRF(67.7±33.4 vs 109.9±44.9 µm, P<0.001) and a lower maximum height of SRF(138.3±88.6 vs 176.2±76.9 µm, P=0.034). In multivariate analysis, the mean SRF height(P=0.001), maximum SRF height(P=0.006), and interval of anti-vascular endothelial growth factor injections(P=0.023) were significantly associated with the resolution of SRF. In the resolution group, 14 patients(43.8%) successfully expanded the injection interval. CONCLUSIONS: During SRF-tolerating treatment for neovascular AMD, a substantial proportion of patients exhibited resolution of fluid without shortening the injection interval. Patients with lesser residual SRF during treatment were more likely to achieve fluid resolution. Following SRF resolution, injection intervals can be extended in more than 40% of patients.

Onepot-Seq: capturing single-cell transcriptomes simultaneously in a continuous medium via transient localization of mRNA.

The development of single-cell RNA-seq has broadened the spectrum for biological research by providing a high-resolution analysis of cellular heterogeneity. However, the requirement for sophisticated devices for the compartmentalization of cells has limited its widespread applicability. Here, we develop Onepot-Seq, a device-free method, that harnesses the transient localization of mRNA after lysis to capture single-cell transcriptomes simultaneously in a continuous fluid medium. In mixed-species experiments, we obtained high-quality single-cell profiles. Further, cell type-specific poly(A)-conjugated antibodies allow Onepot-Seq to effectively capture target cells in complex populations. Chemical perturbations to cells can be profiled by Onepot-Seq at single-cell resolution. Onepot-Seq should allow routine transcriptional profiling at single-cell resolution, accelerating clinical and scientific discoveries in many fields of science.

This article describes a strategy for single-cell RNA sequencing that avoids the usual imitation required by first physically compartmentalizing single cells. Based on the slow rate of mRNA diffusion relative to mRNA capture on beads, the authors devised a method that profiles single-cell mRNA among a multiple cell population, within one reaction mixture, termed 'Onepot-Seq'. This approach uses a time-constrained, transient reaction chamber that forms around each cell, with only slow diffusion of the cell contents after gentle lysis. The sparse distribution of cells and beads allows the beads to capture the profile of a single cell with minimal intercellular mRNA contamination.

Effect of positive end expiratory pressure on non-hypoxic apnea time and atelectasis during induction of anesthesia in infant: A randomized controlled trial.

INTRODUCTION: This study aimed to assess the impact of positive-end-expiratory pressure (PEEP) on the non-hypoxic apnea time in infants during anesthesia induction with an inspired oxygen fraction of 0.8. METHODS: This age stratified randomized controlled trial included patients under 1 year of age. Preoxygenation was performed using an inspired oxygen fraction of 0.8 for 2 min. Inspired oxygen fraction of 0.8 was administered via a face mask with volume-controlled ventilation at a tidal volume of 6 mL.kg-1, with or without 7 cmH2O of PEEP. Tracheal intubation was performed after 3 min of ventilation; however, it was disconnected from the breathing circuit. Ventilation was resumed once the pulse oximetry readings reached 95%. The primary outcome was the non-hypoxic apnea time, defined as the time from the cessation of ventilation to achieving a pulse oximeter reading of 95%. The secondary outcome measures included the degree of atelectasis assessed by ultrasonography and the presence of gastric air insufflation. RESULTS: Eighty-four patients were included in the final analysis. In the positive end-expiratory pressure group, the atelectasis score decreased (17.0 vs. 31.5, p < .001; mean difference and 95% CI of 11.6, 7.5-15.6), while the non-hypoxic apnea time increased (80.1 s vs. 70.6 s, p = .005; mean difference and 95% CI of -9.4, -16.0 to -2.9), compared to the zero end-expiratory pressure group, among infants who are 6 months old or younger, not in those aged older than 6 months. DISCUSSION: The application of positive end-expiratory pressure reduced the incidence of atelectasis and extended the non-hypoxic apnea time in infants who are 6 months old or younger. However, it did not affect the incidence of atelectasis nor the non-hypoxic apnea time in patients aged older than 6 months.

Effect of high-flow nasal and buccal oxygenation on safe apnea time in children with open mouth: A randomized controlled trial.

BACKGROUND: High-flow nasal oxygenation is reported to prolong duration of apnea while maintaining adequate oxygen saturation with the mouth closed. Also, buccal oxygenation is known to have similar effects in obese adults. We compared the effect of these two methods on prolongation of acceptable apnea time in pediatric patients with their mouth open. METHODS: Thirty-eight patients, aged 0-10 years were randomly allocated to either the high-flow nasal oxygenation group (n = 17) or the buccal oxygenation group (n = 21). After induction of anesthesia including neuromuscular blockade, manual ventilation was initiated until the expiratory oxygen concentration reached 90%. Subsequently, ventilation was paused, and the patient's head was extended, and mouth was opened. The HFNO group received 2 L·min-1·kg-1 of oxygen, and the BO group received 0.5 L·min-1·kg-1 of oxygen. We set a target apnea time according to previous literature. When the apnea time reached the target, we defined the case as "success" in prolongation of safe apnea time and resumed ventilation. When the pulse oximetry decreased to 92% before the target apnea time, it was recorded as "failure" and rescue ventilation was given. RESULTS: The success rate of safe apnea prolongation was 100% in the high-flow nasal oxygenation group compared to 76% in the buccal oxygenation group (p = .04). Oxygen reserve index, end-tidal or transcutaneous carbon dioxide partial pressure, and pulse oximetry did not differ between groups. CONCLUSION: High-flow nasal oxygenation is effective in maintaining appropriate arterial oxygen saturation during apnea even in children with their mouth open and is superior to buccal oxygenation. Buccal oxygenation may be a good alternative when high-flow nasal oxygenation is not available.