An algorithm to identify patients aged 0-3 with rare genetic disorders.

BACKGROUND: With over 7000 Mendelian disorders, identifying children with a specific rare genetic disorder diagnosis through structured electronic medical record data is challenging given incompleteness of records, inaccurate medical diagnosis coding, as well as heterogeneity in clinical symptoms and procedures for specific disorders. We sought to develop a digital phenotyping algorithm (PheIndex) using electronic medical records to identify children aged 0-3 diagnosed with genetic disorders or who present with illness with an increased risk for genetic disorders. RESULTS: Through expert opinion, we established 13 criteria for the algorithm and derived a score and a classification. The performance of each criterion and the classification were validated by chart review. PheIndex identified 1,088 children out of 93,154 live births who may be at an increased risk for genetic disorders. Chart review demonstrated that the algorithm achieved 90% sensitivity, 97% specificity, and 94% accuracy. CONCLUSIONS: The PheIndex algorithm can help identify when a rare genetic disorder may be present, alerting providers to consider ordering a diagnostic genetic test and/or referring a patient to a medical geneticist.

IL-7-primed bystander CD8 tumor-infiltrating lymphocytes optimize the antitumor efficacy of T cell engager immunotherapy.

Bispecific T cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, enhancing the efficacy of TCE immunotherapy. rhIL-7-hyFc induces a dramatic increase in CD8 tumor-infiltrating lymphocytes (TILs) in various solid tumors, but the majority of these cells are PD-1-negative tumor non-responsive bystander T cells. However, they are non-exhausted and central memory-phenotype CD8 T cells with high T cell receptor (TCR)-recall capacity that can be triggered by tumor antigen-specific TCEs to acquire tumoricidal activity. Single-cell transcriptome analysis reveals that rhIL-7-hyFc-induced bystander CD8 TILs transform into cycling transitional T cells by TCE redirection with decreased memory markers and increased cytotoxic molecules. Notably, TCE treatment has no major effect on tumor-reactive CD8 TILs. Our results suggest that rhIL-7-hyFc treatment promotes the antitumor efficacy of TCE immunotherapy by increasing TCE-sensitive bystander CD8 TILs in solid tumors.

Early Rhythm Control and Incident Dementia in Patients With Atrial Fibrillation and Prior Stroke.

BACKGROUND: Although early rhythm control (ERC) in patients with atrial fibrillation (AF) reduces the risk of stroke, there is no evidence thus far on whether ERC reduces the risk of developing dementia in patients with AF and prior stroke. OBJECTIVES: This study sought to evaluate whether ERC reduces the risk of developing dementia in patients with new-onset AF and prior stroke. METHODS: Using the Korean nationwide claims database, we identified patients with new-onset AF and prior stroke between 2010 and 2016. Patients who received rhythm control therapy within 1 year after AF onset were defined as the ERC group, otherwise patients were categorized as the usual care group. A propensity score weighting method was used to balance the 2 groups. Incident dementia defined by relevant diagnostic codes was evaluated. RESULTS: A total of 41,370 patients were included (mean age 70 ± 11 years; mean CHA2DS2-VASc score 5.3±1.6): 10,213 in the ERC group and 31,157 in the usual care group. Compared with usual care, ERC was associated with lower risks of all dementia, Alzheimer's dementia, and vascular dementia (weighted HRs [95% CIs], 0.825 [0.776-0.876], 0.831 [0.774-0.893], and 0.800 [0.702-0.913], respectively, all P < 0.001). The benefit of ERC was slightly accentuated in the younger age group (<65 years). The beneficial effect of ERC in reducing the risk of dementia was consistent regardless of the characteristics of prior stroke. CONCLUSIONS: ERC might be beneficial in the prevention of dementia in patients with AF and prior stroke. To prevent the progression of cognitive dysfunction, ERC should be considered in this population.

Empowering powdered activated carbon (PAC) with 3D printing: Achieving highly efficient and reusable cationic dye removal.

Powdered activated carbon (PAC) has been extensively used as an effective adsorbent. Despite its excellent adsorption ability, PAC has drawbacks, including difficulty in filtration and reactivation after use, limitations of mass transfer in deeper areas because of its aggregated powder form, and limited applicability in high-flow systems. To overcome these limitations, we used a three-dimensional (3D) printing system to fabricate PAC into a 3D structure. Spectral and microscopic analyses indicated that PAC was embedded into 3D monolith and exhibited high porosity suitable for facile mass transfer. The designed 3D PAC filter effectively removed 200 ppm-methylene blue (MB) within 8 h and showed an adsorption efficiency of 93.4 ± 0.9%. The adsorption of MB onto the 3D PAC filter was described by the pseudo-first-order kinetic and Freundlich isotherm models. The negatively charged 3D PAC filter might attract the positively charged MB, thus favoring the physical adsorption of MB onto the 3D PAC filter. The adsorption performance of the 3D PAC filter was tested at various pH levels of 4-10 and against MB spiked in seawaters and freshwaters to evaluate its feasibility for use in real environments. Finally, the reproducibility and reusability of the 3D PAC filter were demonstrated through repeated adsorption and desorption processes against MB.

Clinical Impact of Early Rhythm Control and Healthy Lifestyles in Patients With Atrial Fibrillation.

BACKGROUND: There are limited data regarding the combined effect of early rhythm control (ERC) and healthy lifestyle (HLS) behaviors on the risk of ischemic stroke in patients with atrial fibrillation (AF). OBJECTIVES: This study sought to evaluate how the combination of ERC and HLS behaviors affects the risk of ischemic stroke in patients with AF. METHODS: Using the Korean National Health Insurance database, we included patients with new-onset AF between 2009 and 2016 (n = 208,662). Patients who received rhythm control therapy within 2 years after AF diagnosis were defined as the ERC group. Patients with ≥2 HLS behaviors were defined as the HLS group. Patients were categorized into 4 groups: group 1, without ERC and without HLS (n = 46,972); group 2, with HLS alone (n = 110,479); group 3, with ERC alone (n = 15,133); and group 4, with both ERC and HLS (n = 36,078). The primary outcome was ischemic stroke. RESULTS: Compared to group 1, group 2 and group 3 were associated with a lower risk of stroke (HR: 0.769 [95% CI: 0.728-0.881] and HR: 0.774 [95% CI: 0.703-0.852], respectively). Group 4 showed the lowest risk of stroke (HR: 0.575; 95% CI: 0.536-0.617). After propensity score weighting, the incorporation of additional ERC alongside HLS was associated with a relative risk reduction of 22% for stroke, and additional HLS alongside ERC were associated with a relative risk reduction of 27% for stroke. CONCLUSIONS: Each of ERC and HLS might reduce the risk of ischemic stroke in patients with new-onset AF. The presence of both ERC and HLS is associated with an enhanced benefit for stroke prevention in this population.

Surface potential-adjusted surface states in 3D topological photonic crystals.

Surface potential in a topological matter could unprecedentedly localize the waves. However, this surface potential is yet to be exploited in topological photonic systems. Here, we demonstrate that photonic surface states can be induced and controlled by the surface potential in a dielectric double gyroid (DG) photonic crystal. The basis translation in a unit cell enables tuning of the surface potential, which in turn regulates the degree of wave localization. The gradual modulation of DG photonic crystals enables the generation of a pseudomagnetic field. Overall, this study shows the interplay between surface potential and pseudomagnetic field regarding the surface states. The physical consequences outlined herein not only widen the scope of surface states in 3D photonic crystals but also highlight the importance of surface treatments in a photonic system.

Tissue-resident memory T cells in protective immunity to influenza virus.

Influenza virus is an important human pathogen with significant pandemic potential. Tissue-resident memory T cells (Trm) in the lung provide critical protection against influenza, but unlike Trm at other mucosal sites, Trm in the respiratory tract (RT) are subject to rapid attrition in mice, mirroring the decline in protective immunity to influenza virus over time. Conversely, dysfunctional Trm can drive fibrosis in aged mice. The requirement for local antigen to induce and maintain RT Trm must be considered in vaccine strategies designed to induce this protective immune subset. Here, we discuss recent studies that inform our understanding of influenza-specific respiratory Trm, and the factors that influence their development and persistence. We also discuss how these biological insights are being used to develop vaccines that induce Trm in the RT, despite the limitations to monitoring Trm in humans.

Combination of early rhythm control and healthy lifestyle on the risk of stroke in elderly patients with new-onset atrial fibrillation: a nationwide population-based cohort study.

Background: The impact of early rhythm control (ERC) combined with healthy lifestyle (HLS) on the risk of ischemic stroke in elderly patients with atrial fibrillation (AF) remains unaddressed. Objective: To evaluate the impact of combined ERC and HLS on the risk of stroke in elderly patients with new-onset AF. Methods: Using the Korean National Health Insurance Service database, we included patients aged ≥75 years with new-onset AF from January 2009 to December 2016 (n = 41,315). Patients who received rhythm control therapy within 2 years of AF diagnosis were defined as the ERC group. Non-smoking, non-to-mild alcohol consumption (<105 g/week), and regular exercise were defined as HLS. Subjects were categorized into four groups: group 1 (without ERC and HLS, n = 25,093), 2 (HLS alone, n = 8,351), 3 (ERC alone, n = 5,565), and 4 (both ERC and HLS, n = 2,306). We assessed the incidence of ischemic stroke as the primary outcome, along with admissions for heart failure, all-cause death, and the composite of ischemic stroke, admission for heart failure, and all-cause death. Results: Median follow-up duration of the study cohort was 3.4 years. After adjusting for multiple variables, groups 2 and 3 were associated with a lower stroke risk (adjusted hazard ratio [aHR]: 95% confidence interval [CI]: 0.867, 0.794-0.948 and 0.713, 0.637-0.798, respectively) than that of group 1. Compared to Group 1, group 4 showed the lowest stroke risk (aHR: 0.694, 95% CI: 0.586-0.822) among all groups, followed by group 3 (0.713, 0.637-0.798) and group 2 (0.857, 0.794-0.948), respectively. Group 4 was associated with the lowest risk of all-cause death (aHR: 0.680, 95% CI: 0.613-0.754) and the composite outcome (aHR: 0.708, 95% CI: 0.649-0.772). Conclusion: ERC and HLS were associated with a lower risk of ischemic stroke in elderly patients with new-onset AF. Concurrently implementing ERC and maintaining HLS was associated with the lowest risk of death and the composite outcome, with a modest synergistic effect on stroke prevention.

Van der Waals Colloidal Crystals.

A general guiding principle for colloidal crystallization is to tame the attractive enthalpy such that it slightly overwhelms the repulsive interaction. As-synthesized colloids are generally designed to retain a strong repulsive potential for the high stability of suspensions, encoding appropriate attractive potentials into colloids has been key to their crystallization. Despite the myriad of interparticle attractions for colloidal crystallization, the van der Waals (vdW) force remains unexplored. Here, it is shown that the implementation of gold cores into silica colloids and the resulting vdW force can reconfigure the pair potential well depth to the optimal range between -1 and -4 kB T at tens of nanometer-scale colloidal distances. As such, colloidal crystals with a distinct liquid gap can be formed, which is evidenced by photonic bandgap-based diffractive colorization.

Harnessing the Power of IL-7 to Boost T Cell Immunity in Experimental and Clinical Immunotherapies.

The cytokine IL-7 plays critical and nonredundant roles in T cell immunity so that the abundance and availability of IL-7 act as key regulatory mechanisms in T cell immunity. Importantly, IL-7 is not produced by T cells themselves but primarily by non-lymphoid lineage stromal cells and epithelial cells that are limited in their numbers. Thus, T cells depend on cell extrinsic IL-7, and the amount of in vivo IL-7 is considered a major factor in maximizing and maintaining the number of T cells in peripheral tissues. Moreover, IL-7 provides metabolic cues and promotes the survival of both naïve and memory T cells. Thus, IL-7 is also essential for the functional fitness of T cells. In this regard, there has been an extensive effort trying to increase the protein abundance of IL-7 in vivo, with the aim to augment T cell immunity and harness T cell functions in anti-tumor responses. Such approaches started under experimental animal models, but they recently culminated into clinical studies, with striking effects in re-establishing T cell immunity in immunocompromised patients, as well as boosting anti-tumor effects. Depending on the design, glycosylation, and the structure of recombinantly engineered IL-7 proteins and their mimetics, recombinant IL-7 molecules have shown dramatic differences in their stability, efficacy, cellular effects, and overall immune functions. The current review is aimed to summarize the past and present efforts in the field that led to clinical trials, and to highlight the therapeutical significance of IL-7 biology as a master regulator of T cell immunity.

Correlation between early postnatal body weight changes and lung ultrasound scores as predictors of bronchopulmonary dysplasia in preterm infants: A secondary analysis of a prospective study.

Recent research links early weight changes (EWC) with bronchopulmonary dysplasia (BPD) in preterm neonates, while lung ultrasound score (LUS) has shown promise in predicting BPD. We aimed to explore the correlation between LUS and EWC as markers of extravascular lung edema and to investigate the correlation between LUS and EWC in preterm infants with respiratory distress syndrome regarding future BPD development. This secondary analysis of a prospective study involved infants ≤ 28 weeks gestation. Enrolled infants underwent lung ultrasound assessment on postnatal days 3, 7 and 14, measuring LUS. EWC was computed on the same time points. Infants were classified as either having BPD or not. Descriptive statistics, correlation coefficient, and area under the receiver operating characteristic (AUROC) curve analysis were utilized. Of 132 infants, 70 (53%) had BPD. Univariate analysis revealed statistically significant differences in LUS and EWC at days 3, 7, and 14 between BPD and no-BPD groups (p < 0.001). A statistically significant but weak positive correlation existed between LUS and EWC (r0.37, r0.29, r0.24, and p < 0.01) at postnatal days 3, 7, and 14, respectively. AUROC analysis indicated LUS having superior predictive capacity for the need for invasive mechanical ventilation at day 14 as well as the later BPD development compared to EWC (p < 0.0001). CONCLUSION: In a cohort of extreme preterm infants, our study revealed a positive yet weak correlation between LUS and EWC, suggesting that EWC was not the major contributing to the evolving chronic lung disease. WHAT IS KNOWN: • Recent evidence links Early Weight-Changes with bronchopulmonary dysplasia in preterm neonates. • Lung ultrasound score has shown promise in early prediction of the subsequent development of bronchopulmonary dysplasia in preterm infants. No studies have examined the correlation between Early Weight-Changes and Lung ultrasound score in preterm infants during first 2 weeks after birth. WHAT IS NEW: • Our study demonstrated a positive and statistically significant correlation between early LUS and EWC, indicating their potential role as early predictors for the subsequent development of BPD in extreme preterm infants. • The weak correlation between the two parameters may stem from the possible restricted influence of EWC, given that it may not be the primary factor contributing to the evolving chronic lung disease.

Fc-fused IL-7 provides broad antiviral effects against respiratory virus infections through IL-17A-producing pulmonary innate-like T cells.

Repeated pandemics caused by the influenza virus and severe acute respiratory syndrome coronavirus (SARS-CoV) have resulted in serious problems in global public health, emphasizing the need for broad-spectrum antiviral therapeutics against respiratory virus infections. Here, we show the protective effects of long-acting recombinant human interleukin-7 fused with hybrid Fc (rhIL-7-hyFc) against major respiratory viruses, including influenza virus, SARS-CoV-2, and respiratory syncytial virus. Administration of rhIL-7-hyFc in a therapeutic or prophylactic regimen induces substantial antiviral effects. During an influenza A virus (IAV) infection, rhIL-7-hyFc treatment increases pulmonary T cells composed of blood-derived interferon γ (IFNγ)+ conventional T cells and locally expanded IL-17A+ innate-like T cells. Single-cell RNA transcriptomics reveals that rhIL-7-hyFc upregulates antiviral genes in pulmonary T cells and induces clonal expansion of type 17 innate-like T cells. rhIL-7-hyFc-mediated disease prevention is dependent on IL-17A in both IAV- and SARS-CoV-2-infected mice. Collectively, we suggest that rhIL-7-hyFc can be used as a broadly active therapeutic for future respiratory virus pandemic.

Distributed quantum sensing of multiple phases with fewer photons.

Distributed quantum metrology has drawn intense interest as it outperforms the optimal classical counterparts in estimating multiple distributed parameters. However, most schemes so far have required entangled resources consisting of photon numbers equal to or more than the parameter numbers, which is a fairly demanding requirement as the number of nodes increases. Here, we present a distributed quantum sensing scenario in which quantum-enhanced sensitivity can be achieved with fewer photons than the number of parameters. As an experimental demonstration, using a two-photon entangled state, we estimate four phases distributed 3 km away from the central node, resulting in a 2.2 dB sensitivity enhancement from the standard quantum limit. Our results show that the Heisenberg scaling can be achieved even when using fewer photons than the number of parameters. We believe our scheme will open a pathway to perform large-scale distributed quantum sensing with currently available entangled sources.

Intracellular delivery of nuclear localization sequence peptide mitigates COVID-19 by inhibiting nuclear transport of inflammation-associated transcription factors.

The novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), can trigger dysregulated immune responses known as the cytokine release syndrome (CRS), leading to severe organ dysfunction and respiratory distress. Our study focuses on developing an improved cell-permeable nuclear import inhibitor (iCP-NI), capable of blocking the nuclear transport of inflammation-associated transcription factors, specifically nuclear factor kappa B (NF-κB). By fusing advanced macromolecule transduction domains and nuclear localization sequences from human NF-κB, iCP-NI selectively interacts with importin α5, effectively reducing the expression of proinflammatory cytokines. In mouse models mimic SARS-CoV-2-induced pneumonitis, iCP-NI treatment demonstrated a significant decrease in mortality rates by suppressing proinflammatory cytokine production and immune cell infiltration in the lungs. Similarly, in hamsters infected with SARS-CoV-2, iCP-NI effectively protected the lung from inflammatory damage by reducing tumor necrosis factor-α, interleukin-6 (IL-6), and IL-17 levels. These promising results highlight the potential of iCP-NI as a therapeutic approach for COVID-19-related lung complications and other inflammatory lung diseases.

Impact of Unhealthy Lifestyles on Patients with Atrial Fibrillation at Low Risk of Stroke: A Nationwide Cohort Study.

BACKGROUND: The impact of unhealthy lifestyles on clinical outcomes among patients with atrial fibrillation (AF) who are at low risk of stroke remains uncertain. The study objective was to evaluate the association between unhealthy lifestyles and clinical outcomes among low-risk AF patients with 0-1 non-sex risk factor of the CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke or transient ischemic attack [TIA], Vascular disease, Age 65-74 years, female Sex;) score. METHODS: A total of 52,451 low-risk AF patients (mean age 51.6 ± 10.4 years) were evaluated with the National Health Insurance Service of the Republic of Korea database between 2009 and 2016. Using the survey on health habits, an unhealthy lifestyle score (ULS) was calculated by adding one point each if a respondent had a sedentary lifestyle, drinking, or smoking. The primary outcome was the composite of myocardial infarction, ischemic stroke, heart failure, and all-cause death. Multivariable Cox regression analysis was used to estimate the risk of the study outcome according to the ULS. RESULTS: There was a total of 12,792 (24.4%), 24,785 (47.3%), 11,602 (22.1%), and 3272 (6.2%) low-risk AF patients with 0 to 3 points of the ULS, respectively. The median follow-up period was 4.1 (2.1-6.1) years. Compared with the healthiest-lifestyle group (ULS 0), the other groups were associated with significantly higher risks of the primary outcome, with a gradually increasing trend according to the ULS (adjusted hazard ratio [95% confidence interval] =1.17 [1.05-1.31], 1.37 [1.21-1.56], 1.82 [1.53-2.17], for the groups with ULS 1, 2, and 3, respectively). CONCLUSION: Unhealthy lifestyles, including a sedentary lifestyle, drinking, and smoking, may synergistically impact poor clinical outcomes in AF patients who are deemed to be at low risk of stroke.

Angle-resolving spectral ellipsometry using structured light for direct measurement of ellipsometric parameters.

We propose a compact angle-resolving spectral ellipsometry. Using the structured light generated from a digital micro-mirror device (DMD), what we believe to be a novel pattern is illuminated to the back focal plane of the high numerical aperture (NA) objective lens. As a result, ellipsometric parameters with fine resolution of both the wavelength and incidence angle domain can be directly measured. The incidence angle can be resolved by resolution under 1° ranging from 35° to 59° by the radius of the projected images. A spectrometer as a detector enables acquisition by the resolution of 0.7 nm from 410 to 700 nm, and the fiber reduces measurement spot size to a single micrometer. Additionally, the measurement process does not require any rotating optical components or moving parts, needing only digital modification of the projected image. This simplifies the sequences and reduces the measurement time. The 2D (angle of incidence and spectral domain) ellipsometric parameter plane measured by the proposed method was used to measure the thickness of various samples. The measurement result was verified in comparison with a commercial ellipsometer. The accuracy and precision of the result show that the proposed method is capable of precise measurement of thin films.

Impact of components of metabolic syndrome on the risk of adverse renal outcomes in patients with atrial fibrillation: a nationwide cohort study.

Background: The renal effect of metabolic syndrome components is unclear in patients with atrial fibrillation. This study aimed to investigate the association between metabolic syndrome components and incident end-stage renal disease among patients with atrial fibrillation. Methods: A total of 202,434 atrial fibrillation patients without prevalent end-stage renal disease were identified from the National Health Insurance Service database between 2009 and 2016. We defined the metabolic score range from 0 to 5 points such that a patient received every 1 point if the patient met each component listed in the diagnostic criteria of metabolic syndrome. The population was divided into 6 groups: MS0-MS5 for a metabolic score of 0-5, respectively. Multivariate Cox regression analysis was used to estimate the risks of end-stage renal disease. Results: There were 12,747, 31,059, 40,361, 48,068, 46,630, and 23,569 patients for MS0-MS5, respectively. Compared with MS0, MS5 had a higher CHA2DS2-VASc score (3.8 vs. 1.0) (P < .001). During a median follow-up of 3.5 years, compared with MS0, MS1-MS5 were associated with a gradually increasing incidence of end-stage renal disease, in relation to an increase in the metabolic score, (log-rank P < .001). After multivariate adjustment, a higher metabolic score was associated with a greater risk of incident end-stage renal disease: adjusted hazard ratio [95% confidence interval] = 1.60 [0.78-3.48], 2.08 [1.01-4.31], 2.94 [1.43-6.06], 3.71 [1.80-7.66], and 4.82 [2.29-10.15], for MS1-MS5, respectively. Conclusions: Metabolic syndrome components additively impacts the risk of incident end-stage renal disease among patients with atrial fibrillation.