Expression of PD-L1, PD-L2, and inflammatory gene expression profile in locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The tumor immune microenvironment in cancer treatment response and resistance is of increasing interest. This retrospective study characterized and investigated programmed death-ligand 1 (PD-L1), PD-L2, and the immune gene expression signature and their association with clinical outcomes in locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC). PATIENTS AND METHODS: PD-L1 and PD-L2 expression on tumor and immune-infiltrating cells (positivity defined as combined positive score or immunohistochemistry proportion score >1) and T-cell-inflamed gene expression profile (TcellinfGEP) were evaluated in patients with LA HNSCC treated in South Korea from 2000 to 2015. Correlations among the three biomarkers and their associations with overall survival and recurrence-free survival were assessed. RESULTS: Among 366 patients, 38.8% had human papillomavirus-positive disease. PD-L1-positive, PD-L2-positive, and high TcellinfGEP (≤-0.162) status were observed in 83.6%, 85.4%, and 73.2% of patients, respectively; 4.1% were posttreatment samples. Correlation between PD-L1 and PD-L2 scores was moderate (rSpearman = 0.50), and each biomarker was slightly less correlated with TcellinfGEP (0.41-0.45). PD-L1 expression and high TcellinfGEP status were associated with human papillomavirus positivity. Higher levels of all biomarkers were observed in oral cavity and oropharyngeal cancers compared with other HNSCC sites. In a multivariable analysis that simultaneously adjusted for all three biomarkers, only high TcellinfGEP was significantly associated with longer overall survival (adjusted hazard ratio, 0.57; 95% confidence interval 0.33-0.98) and recurrence-free survival (adjusted hazard ratio, 0.41; 95% confidence interval 0.23-0.74). CONCLUSION: High TcellinfGEP status, but not PD-L1 or PD-L2 expression, was independently associated with longer survival in patients with LA HNSCC. Results may have implications for evaluating therapies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) in HNSCC.

Meta-analysis Driven Strain Design for Mitigating Oxidative Stresses Important in Biomanufacturing.

As the availability of data sets increases, meta-analysis leveraging aggregated and interoperable data types is proving valuable. This study leveraged a meta-analysis workflow to identify mutations that could improve robustness to reactive oxygen species (ROS) stresses using an industrially important melatonin production strain as an example. ROS stresses often occur during cultivation and negatively affect strain performance. Cellular response to ROS is also linked to the SOS response and resistance to pH fluctuations, which is important to strain robustness in large-scale biomanufacturing. This work integrated more than 7000 E. coli adaptive laboratory evolution (ALE) mutations across 59 experiments to statistically associate mutated genes to 2 ROS tolerance ALE conditions from 72 unique conditions. Mutant oxyR, fur, iscR, and ygfZ were significantly associated and hypothesized to contribute fitness in ROS stress. Across these genes, 259 total mutations were inspected in conjunction with transcriptomics from 46 iModulon experiments. Ten mutations were chosen for reintroduction based on mutation clustering and coinciding transcriptional changes as evidence of fitness impact. Strains with mutations reintroduced into oxyR, fur, iscR, and ygfZ exhibited increased tolerance to H2O2 and acid stress and reduced SOS response, all of which are related to ROS. Additionally, new evidence was generated toward understanding the function of ygfZ, an uncharacterized gene. This meta-analysis approach utilized aggregated and interoperable multiomics data sets to identify mutations conferring industrially relevant phenotypes with the least drawbacks, describing an approach for data-driven strain engineering to optimize microbial cell factories.

A meta-analysis of probiotic interventions to mitigate ruminal methane emissions in cattle: implications for sustainable livestock farming.

In recent years, the significant impact of ruminants on methane emissions has garnered international attention. While dietary strategies have been implemented to solve this issue, probiotics gained the attention of researchers due to their sustainability. However, it is challenging to ascertain their effectiveness as an extensive range of strains and doses have been reported in the literature. Hence, the objective of this experiment was to perform a meta-analysis of probiotic interventions aiming to reduce ruminal methane emissions from cattle. From 362 articles retrieved from scientific databases, 85 articles were assessed independently by two reviewers, and 20 articles representing 49 comparisons were found eligible for meta-analysis. In each study, data such as mean, SD, and sample sizes of both the control and probiotic intervention groups were extracted. The outcomes of interest were methane emission, methane yield, and methane intensity. For the meta-analysis, effect sizes were pooled using a fixed effect or a random effect model depending on the heterogeneity. Afterward, sensitivity analyses were conducted to confirm the robustness of the findings. Overall pooled standardized mean differences (SMDs) with their confidence intervals (CIs) did not detect significant differences in methane emission (SMD = -0.04; 95% CI = -0.18-0.11; P = 0.632), methane yield (SMD = -0.08; 95% CI = -0.24-0.07; P = 0.291), and methane intensity (SMD = -0.22; 95% CI = -0.50-0.07; P = 0.129) between cattle supplemented with probiotics and the control group. However, subgroup analyses revealed that multiple-strain bacterial probiotics (SMD = -0.36; 95% CI = -0.62 to -0.11; P = 0.005), specifically the combination of bacteria involved in reductive acetogenesis and propionate production (SMD = -0.71; 95% CI = -1.04 to -0.36; P = 0.001), emerged as better interventions. Likewise, crossbreeds (SMD = -0.48; 95% CI = -0.78 to -0.18; P = 0.001) exhibited a more favorable response to the treatments. Furthermore, meta-regression demonstrated that longer periods of supplementation led to significant reductions in methane emissions (P = 0.001), yield (P = 0.032), and intensity (P = 0.012) effect sizes. Overall, the results of the current study suggest that cattle responses to probiotic interventions are highly dependent on the probiotic category. Therefore, extended trials performed with probiotics containing multiple bacterial strains are showing the most promising results. Ideally, further trials focusing on the use of probiotics to reduce ruminal methane in cattle should be conducted to complete the available literature.

Assisted reproductive techniques and subsequent risk of asthma and allergic rhinitis in offspring: a nationwide birth cohort study in South Korea.

OBJECTIVE: The relationship between assisted reproductive techniques (ART) and the risk of asthma and allergic rhinitis (AR) is controversial. Thus, we aimed to investigate the relationship between ART and the risk of asthma and AR in a nationwide, large-scale birth cohort. PATIENTS AND METHODS: This study utilized the National Health Insurance Service data in South Korea to conduct a nationwide, large-scale, population-based birth cohort. We included all infants born between 2017 and 2018. AR, asthma, food allergies, and atopic dermatitis were defined using the International Classification of Diseases tenth edition codes. Asthma was classified as allergic or non-allergic based on accompanying allergic diseases (AR, food allergy, or atopic dermatitis). Using 1:10 propensity score matching, we compared infants conceived through ART with those conceived naturally (non-ART). After matching, logistic regression was used to compare the hazard ratio for asthma and AR between the two groups. RESULTS: We included 543,178 infants [male infants, 280,194 (51.38%)]. After matching, 8,925 and 74,229 infants were selected for the ART and non-ART groups, respectively. The ART group showed a decreased risk of asthma in the offspring [adjusted hazard ratio (aHR), 0.45; 95% confidence interval (CI), 0.41-0.48]. Similarly, for AR, being conceived by ART was associated with a decreased risk of AR (aHR, 0.25; 95% CI, 0.12-0.37). ART offspring showed a decreased risk of asthma and AR in offspring compared to that observed in non-ART offspring. CONCLUSIONS: Our study offers important insights for clinicians, researchers, and parents regarding the health outcomes of ART-conceived infants and enhances our understanding of ART's impact on respiratory health.

Management of newborns and healthcare workers exposed to isoniazid-resistant congenital tuberculosis in the neonatal intensive care unit.

BACKGROUND: Management of newborns and healthcare workers (HCWs) exposed to congenital tuberculosis (TB) in the neonatal intensive care unit (NICU) has been reported rarely. AIM: To outline a contact investigation process for individuals exposed to congenital TB in the NICU and investigate nosocomial transmission. Additionally, to assess the efficacy and safety of window prophylaxis in exposed newborns. METHODS: A baby, born at a gestational age of 28 + 1 weeks, was diagnosed with isoniazid-resistant congenital TB on the 39th day of admission to the level IV NICU. Newborns and HCWs exposed cumulatively for ≥8 h underwent contact investigation and follow-up for a year. FINDINGS: Eighty-two newborns underwent contact investigation. All newborns displayed normal chest X-rays, and 42 hospitalized newborns tested negative for acid-fast bacilli stain and Xpert® MTB/RIF assay in their endotracheal sputum or gastric juices. Eighty received window prophylaxis: six of 75 on rifampin experienced mild adverse events, and none of the five on levofloxacin. After 12 weeks, five (6.1%) had a positive tuberculin skin test, all of whom had already received the Bacillus Calmette-Guérin vaccine and tested negative on TB interferon-gamma releasing assay. Of 119 exposed HCWs, three (2.5%) were diagnosed with latent TB infection and completed a four-month rifampin therapy. There was no active TB disease among exposed newborns and HCWs during a one-year follow-up. CONCLUSION: Timely diagnosis of congenital TB is crucial for minimizing transmission among exposed neonates and HCWs in the NICU setting. In cases of isoniazid-resistant index patients, even premature newborns may consider the use of rifampin or levofloxacin for window prophylaxis.

The impact of discontinuing single-room isolation of patients with vancomycin-resistant enterococci: a quasi-experimental single-centre study in South Korea.

OBJECTIVES: There is limited data on the effects of discontinuing single-room isolation while maintaining contact precautions, such as the use of gowns and gloves. In April 2021, our hospital ceased single-room isolation for patients with vancomycin-resistant enterococci (VRE) because of single-room unavailability. This study assessed the impact of this policy by examining the incidence of hospital-acquired VRE bloodstream infections (HA-VRE BSI). METHODS: This retrospective quasi-experimental study was conducted at a tertiary-care hospital in Seoul, South Korea. Time-series analysis was used to evaluate HA-VRE BSI incidence at the hospital level and in the haematology unit before (phase 1) and after (phase 2) the policy change. RESULTS: At the hospital level, HA-VRE BSI incidence level (VRE BSI per 1000 patient-days per month) and trend did not change significantly between phase 1 and phase 2 (coefficient -0.015, 95% confidence interval (CI): -0.053 to 0.023, P=0.45 and 0.000, 95% CI: -0.002 to 0.002, P=0.84, respectively). Similarly, HA-VRE BSI incidence level and trend in the haematology unit (-0.285, 95% CI: -0.618 to 0.048, P=0.09 and -0.018, 95% CI: -0.036 to 0.000, P = 0.054, respectively) did not change significantly across the two phases. CONCLUSIONS: Discontinuing single-room isolation of VRE-colonized or infected patients was not associated with an increase in the incidence of VRE BSI at the hospital level or among high-risk patients in the haematology unit. Horizontal intervention for multi-drug-resistant organisms, including measures such as enhanced hand hygiene and environmental cleaning, may be more effective at preventing VRE transmission.

Ameliorating effect of 2'-fucosyllactose and 6'-sialyllactose on lipopolysaccharide-induced intestinal inflammation.

Human milk oligosaccharides (HMO) affect gut microbiota during neonatal development, particularly with respect to the immune system. Bovine milk-based infant formulas have low oligosaccharide contents. Thus, efforts to fortify infant formulas with HMO are being undertaken. Two major HMO, 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL), exert anti-inflammatory effects; however, the associations between anti-inflammatory effects induced by 2'-FL and 6'-SL cotreatment and gut microbiota composition and metabolite modulation remain unclear. Therefore, in this study, we evaluated the effects of a mixture of these HMO. To determine the optimal HMO ratio for anti-inflammatory effects and elucidate its mode of action, LPS-induced inflammatory HT-29 epithelial cells and intestinal-inflamed suckling mice were treated with various mixtures of 2'-FL and 6'-SL. A 2'-FL:6'-SL ratio of 5:1 was identified as the most effective pretreatment HMO mixture in vitro; thus, this ratio was selected and used for low-, middle-, and high-dose treatments for subsequent in vivo studies. In vivo, high-dose HMO treatment restored LPS-induced inflammation symptoms, such as BW loss, colon length reduction, histological structural damage, and intestinal gene expression related to inflammatory responses. High-dose HMO was the only treatment that modulated the major phyla Bacteroidetes and Firmicutes and the genera Ihubacter, Mageeibacillus, and Saccharofermentans. These changes in microbial composition were correlated with intestinal inflammation-related gene expression and short-chain fatty acid production. To our knowledge, our study is the first to report the effects of Ihubacter, Mageeibacillus, and Saccharofermentans on short-chain fatty acid levels, which can subsequently affect inflammatory cytokine and tight junction protein levels. Conclusively, the HMO mixture exerted anti-inflammatory effects through changes in microbiota and metabolite production. These findings suggest that supplementation of infant formula with HMO may benefit formula-fed infants by forming unique microbiota contributing to neonatal development.

Saturation of Fishbone Instability by Self-Generated Zonal Flows in Tokamak Plasmas.

Gyrokinetic simulations of the fishbone instability in DIII-D tokamak plasmas find that self-generated zonal flows can dominate the nonlinear saturation by preventing coherent structures from persisting or drifting in the energetic particle phase space when the mode frequency down-chirps. Results from the simulation with zonal flows agree quantitatively, for the first time, with experimental measurements of the fishbone saturation amplitude and energetic particle transport. Moreover, the fishbone-induced zonal flows are likely responsible for the formation of an internal transport barrier that was observed after fishbone bursts in this DIII-D experiment. Finally, gyrokinetic simulations of a related ITER baseline scenario show that the fishbone induces insignificant energetic particle redistribution and may enable high performance scenarios in ITER burning plasma experiments.

Multi-peak Light-emitting Diode Curing Units and Polymerization of 3D-printed Crown and Bridge Resin.

PURPOSE: This study aimed to evaluate the substitutive and additive efficacy of multi-peak light-emitting diode (LED) curing units for post-curing of a three-dimensional- (3D-) printed crown and bridge resin. METHODS: A total of 792 disc- and 180 bar-shaped specimens were printed with a crown and bridge resin (NextDent C&B MFH) and post-cured using two LED curing units (VALO Cordless and Bluephase N G4) in fast and standard modes. Conventional post-curing (LC-3D Print Box, Group PC) was compared with LED-only curing (Groups V1, V2, B1, and B2) and LED-combined curing (Groups PV1, PV2, PB1, and PB2) in terms of microhardness, flexural strength, degree of conversion (DC), and CIE L*a*b* color and translucency parameters. Cytotoxicity of the resin eluates was evaluated using the WST-1 assay. Temperature increases on the resin surface were measured with infrared thermography. Data were statistically analyzed using ANOVA and Kruskal-Wallis tests (α=0.05). RESULTS: The microhardness and flexural strength in Groups V1, V2, B1, and DC in all LED-only groups were lower than in other groups (p<0.05). Larger color disparities existed between Group PC and all LED-only groups than between Group PC and the others (p<0.05). There was no significant difference in cytotoxicity among the groups. The temperature increase was lowest in Groups V1 and PV1 during light curing (p<0.05). CONCLUSIONS: Post-curing by multi-peak LED curing units was not as effective as the conventional post-curing device. Additional post-curing by LED curing units did not improve the material properties.

Search for Boosted Dark Matter in COSINE-100.

We search for energetic electron recoil signals induced by boosted dark matter (BDM) from the galactic center using the COSINE-100 array of NaI(Tl) crystal detectors at the Yangyang Underground Laboratory. The signal would be an excess of events with energies above 4 MeV over the well-understood background. Because no excess of events are observed in a 97.7 kg·yr exposure, we set limits on BDM interactions under a variety of hypotheses. Notably, we explored the dark photon parameter space, leading to competitive limits compared to direct dark photon search experiments, particularly for dark photon masses below 4 MeV and considering the invisible decay mode. Furthermore, by comparing our results with a previous BDM search conducted by the Super-Kamionkande experiment, we found that the COSINE-100 detector has advantages in searching for low-mass dark matter. This analysis demonstrates the potential of the COSINE-100 detector to search for MeV electron recoil signals produced by the dark sector particle interactions.

A RARE CASE OF GRAVES' THYROTOXICOSIS WITH CONCOMITANT PULMONARY ALVEOLAR PROTEINOSIS.

Background: Graves' disease results in various clinical cardio-pulmonary manifestations such as tachycardia, atrial fibrillation, and pulmonary edema. Clinical Case: A 62-year-old woman presented with palpitations and dyspnea. Laboratory and radiologic examination revealed markedly elevated free T4 (4.79 ng/dL), T3 (4.42 ng/mL), lowered TSH (0.01 uIU/mL), atrial fibrillation and multifocal lung haziness. She was initially diagnosed with atrial fibrillation with pulmonary edema, which subsequently changed to pulmonary alveolar proteinosis by further evaluations such as computed tomography and bronchoscopic biopsy. Conclusion: Pulmonary alveolar proteinosis is a rare lung disease. Clinicians should carefully assess lung lesions in thyrotoxicosis patients as they can be easily mistaken for pulmonary edema in clinical practice.

Synaptic Activity Causes Minute-scale Changes in BAF Complex Composition and Function.

Genes encoding subunits of the SWI/SNF or BAF ATP-dependent chromatin remodeling complex are among the most enriched for deleterious de novo mutations in intellectual disabilities and autism spectrum disorder, but the causative molecular pathways are not fully known 1,2 . Synaptic activity in neurons is critical for learning and memory and proper neural development 3 . Neural activity prompts calcium influx and transcription within minutes, facilitated in the nucleus by various transcription factors (TFs) and chromatin modifiers 4 . While BAF is required for activity-dependent developmental processes such as dendritic outgrowth 5-7 , the immediate molecular consequences of neural activity on BAF complexes and their functions are unknown. Here we mapped minute-scale biochemical consequences of neural activity, modeled by membrane depolarization of embryonic mouse primary cortical neurons, on BAF complexes. We used acute chemical perturbations of BAF ATPase activity and kinase signaling to define the activity-dependent effects on BAF complexes and activity-dependent BAF functions. Our studies found that BAF complexes change in subunit composition and are selectively phosphorylated within 10 minutes of depolarization. Increased levels of the core PBAF subunit Baf200/ Arid2 , uniquely containing an RFX-like DNA-binding domain, are concurrent with ATPase-dependent opening of chromatin at RFX/X-box motifs. Changes in BAF composition and phosphorylation lead to the regulation of chromatin accessibility for critical neurogenesis TFs. These biochemical effects are a convergent phenomenon downstream of multiple growth factor signaling pathways in mouse neurons and fibroblasts suggesting that BAF integrates signaling information from the membrane. In support of such a membrane-to-nucleus signaling cascade, we also identified a BAF-interacting kinase, Dclk2, whose inhibition attenuates BAF phosphorylation selectively. Our findings support a direct role of BAF complexes in responding to synaptic activity to regulate TF binding and transcription.

Impact of carbapenem-targeted antimicrobial stewardship interventions: an interrupted time-series analysis.

BACKGROUND: The development of carbapenem-resistant Gram-negative bacilli (CR-GNB) is largely favoured by indiscriminate and prolonged carbapenem use, which is a significant contributing factor. AIM: To evaluate the impact of two carbapenem antibiotic stewardship programme interventions on both carbapenem prescriptions and the clinical isolation rates of CR-GNBs, using interrupted time-series analysis. METHODS: A time-series analysis was performed using data for carbapenem usage from a tertiary hospital in South Korea from January 2017 to July 2022. Two carbapenem antibiotic stewardship programme interventions were implemented sequentially: (i) a prospective audit and feedback (PAF) from November 2018 to April 2020 (intervention 1), and (ii) preauthorization from May 2020 to August 2020 (intervention 2). Monthly carbapenem usage and incidence of CR-GNB before and after each intervention were compared using an autoregressive integrated moving average model. FINDINGS: Implementation of PAF resulted in a significant reduction in carbapenem consumption, followed by an additional decrease after the preauthorization was implemented. The incidence of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae increased after intervention 1, but there was a significant change from an increasing trend to a stationary trend after intervention 2. The incidence of carbapenem-resistant Pseudomonas aeruginosa, which had increased during the baseline period, became stationary after intervention 1. A significant decrease was observed in the incidence of carbapenem-resistant Acinetobacter baumannii during the implementation of intervention 1 and 2. CONCLUSION: This study emphasizes the importance of adopting comprehensive antibiotic management and rigorous infection control to prevent infections caused by antibiotic-resistant bacteria.

Appropriateness of antibiotic use for patients with asymptomatic bacteriuria or urinary tract infection with positive urine culture: a retrospective observational multi-centre study in Korea.

BACKGROUND: Antibiotic resistance threatens public health worldwide, and inappropriate use of antibiotics is one of the main causes. AIM: To evaluate qualitative use of antibiotics in asymptomatic bacteriuria (ABU) and urinary tract infection (UTI). METHODS: Cases of positive urine culture (≥105 colony-forning units/mL) performed in inpatient, outpatient and emergency departments in April 2021 were screened in 26 hospitals in the Republic of Korea. The cases were classified as ABU, lower UTI and upper UTI. The appropriateness of antibiotic use was evaluated retrospectively by infectious disease specialists using quality indicators based on clinical guidelines for ABU and UTI. RESULTS: This study included a total of 2697 patients with ABU or UTI. The appropriateness of antibiotic use was assessed in 1157 patients with ABU, and in 677 and 863 patients with lower and upper UTI, respectively. Among the 1157 patients with ABU, 251 (22%) were prescribed antibiotics without appropriate indications. In 66 patients with ABU in which antibiotics were prescribed with appropriate indications, the duration was adequate in only 23 (34.8%) patients. The appropriateness of empirical and definite antibiotics was noted in 527 (77.8%) and 353 (68.0%) patients with lower UTI, and 745 (86.3%) and 583 (78.2%) patients with upper UTI, respectively. The duration of antibiotics was adequate in 321 (61.8%) patients with lower UTI and 576 (78.7%) patients with upper UTI. CONCLUSIONS: This nationwide qualitative assessment of antibiotic use in ABU and UTI revealed that antibiotics were often prescribed inappropriately, and the duration of antibiotics was unnecessarily prolonged.

First Observation of the ß3αp Decay of

The ß-delayed proton decay of ^{13}O has previously been studied, but the direct observation of ß-delayed 3αp decay has not been reported. Rare 3αp events from the decay of excited states in ^{13}N^{⋆} provide a sensitive probe of cluster configurations in ^{13}N. To measure the low-energy products following ß-delayed 3αp decay, the Texas Active Target (TexAT) time projection chamber was employed using the one-at-a-time ß-delayed charged-particle spectroscopy technique at the Cyclotron Institute, Texas A&M University. A total of 1.9×10^{5} ^{13}O implantations were made inside the TexAT time projection chamber. A total of 149 3αp events were observed, yielding a ß-delayed 3αp branching ratio of 0.078(6)%. Four previously unknown α-decaying excited states were observed in ^{13}N at 11.3, 12.4, 13.1, and 13.7 MeV decaying via the 3α+p channel.