A bacterial virulence protein promotes pathogenicity by inhibiting the bacterium's own F1Fo ATP synthase.

Several intracellular pathogens, including Salmonella enterica and Mycobacterium tuberculosis, require the virulence protein MgtC to survive within macrophages and to cause a lethal infection in mice. We now report that, unlike secreted virulence factors that target the host vacuolar ATPase to withstand phagosomal acidity, the MgtC protein acts on Salmonella's own F1Fo ATP synthase. This complex couples proton translocation to ATP synthesis/hydrolysis and is required for virulence. We establish that MgtC interacts with the a subunit of the F1Fo ATP synthase, hindering ATP-driven proton translocation and NADH-driven ATP synthesis in inverted vesicles. An mgtC null mutant displays heightened ATP levels and an acidic cytoplasm, whereas mgtC overexpression decreases ATP levels. A single amino acid substitution in MgtC that prevents binding to the F1Fo ATP synthase abolishes control of ATP levels and attenuates pathogenicity. MgtC provides a singular example of a virulence protein that promotes pathogenicity by interfering with another virulence protein.

Gcap14 is a microtubule plus-end-tracking protein coordinating microtubule-actin crosstalk during neurodevelopment.

Regulation of microtubule dynamics is required to properly control various steps of neurodevelopment. In this study, we identified granule cell antiserum-positive 14 (Gcap14) as a microtubule plus-end-tracking protein and as a regulator of microtubule dynamics during neurodevelopment. Gcap14 knockout mice exhibited impaired cortical lamination. Gcap14 deficiency resulted in defective neuronal migration. Moreover, nuclear distribution element nudE-like 1 (Ndel1), an interacting partner of Gcap14, effectively corrected the downregulation of microtubule dynamics and the defects in neuronal migration caused by Gcap14 deficiency. Finally, we found that the Gcap14-Ndel1 complex participates in the functional link between microtubule and actin filament, thereby regulating their crosstalks in the growth cones of cortical neurons. Taken together, we propose that the Gcap14-Ndel1 complex is fundamental for cytoskeletal remodeling during neurodevelopmental processes such as neuronal processes elongation and neuronal migration.

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell lines UMR-106 and MC3T3-E1. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. Furthermore, arginine vasopressin, which is often responsible for hyponatremia, did not affect FGF23 production. Next, we performed a comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low versus high [Na+], which revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9-mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.

A bacterial mRNA leader that employs different mechanisms to sense disparate intracellular signals.

Bacterial mRNAs often contain leader sequences that respond to specific metabolites or ions by altering expression of the associated downstream protein-coding sequences. Here we report that the leader RNA of the Mg(2+) transporter gene mgtA of Salmonella enterica, which was previously known to function as a Mg(2+)-sensing riboswitch, harbors an 18 codon proline-rich open reading frame-termed mgtL-that permits intracellular proline to regulate mgtA expression. Interfering with mgtL translation by genetic, pharmacological, or environmental means was observed to increase the mRNA levels from the mgtA coding region. Substitution of the mgtL proline codons by other codons abolished the response to proline and to hyperosmotic stress but not to Mg(2+). Our findings show that mRNA leader sequences can consist of complex regulatory elements that utilize different mechanisms to sense separate signals and mediate an appropriate cellular response.

Lactobacillus crispatus Limits Bladder Uropathogenic E. coli Infection by Triggering a Host Type I Interferon Response.

Many urinary tract infections (UTIs) are recurrent because uropathogens persist within the bladder epithelial cells (BECs) for extended periods between bouts of infection. Because persistent uropathogens are intracellular, they are often refractive to antibiotic treatment. The recent discovery of endogenous Lactobacillus spp. in the bladders of healthy humans raised the question of whether these endogenous bacteria directly or indirectly impact intracellular bacterial burden in the bladder. Here, we report that in contrast to healthy women, female patients experiencing recurrent UTIs have a bladder population of Lactobacilli that is markedly reduced. Exposing infected human BECs to L. crispatus in vitro markedly reduced the intracellular uropathogenic Escherichia coli (UPEC) load. The adherence of Lactobacilli to BECs was found to result in increased type I interferon (IFN) production, which in turn enhanced the expression of cathepsin D within lysosomes harboring UPECs. This lysosomal cathepsin D-mediated UPEC killing was diminished in germ-free mice and type I IFN receptor-deficient mice. Secreted metabolites of L. crispatus seemed to be responsible for the increased expression of type I IFN in human BECs. Intravesicular administration of Lactobacilli into UPEC-infected murine bladders markedly reduced their intracellular bacterial load suggesting that components of the endogenous microflora can have therapeutic effects against UTIs.

Swd2/Cps35 determines H3K4 tri-methylation via interactions with Set1 and Rad6.

BACKGROUND: Histone H3K4 tri-methylation (H3K4me3) catalyzed by Set1/COMPASS, is a prominent epigenetic mark found in promoter-proximal regions of actively transcribed genes. H3K4me3 relies on prior monoubiquitination at the histone H2B (H2Bub) by Rad6 and Bre1. Swd2/Cps35, a Set1/COMPASS component, has been proposed as a key player in facilitating H2Bub-dependent H3K4me3. However, a more comprehensive investigation regarding the relationship among Rad6, Swd2, and Set1 is required to further understand the mechanisms and functions of the H3K4 methylation. RESULTS: We investigated the genome-wide occupancy patterns of Rad6, Swd2, and Set1 under various genetic conditions, aiming to clarify the roles of Set1 and Rad6 for occupancy of Swd2. Swd2 peaks appear on both the 5' region and 3' region of genes, which are overlapped with its tightly bound two complexes, Set1 and cleavage and polyadenylation factor (CPF), respectively. In the absence of Rad6/H2Bub, Set1 predominantly localized to the 5' region of genes, while Swd2 lost all the chromatin binding. However, in the absence of Set1, Swd2 occupancy near the 5' region was impaired and rather increased in the 3' region. CONCLUSIONS: This study highlights that the catalytic activity of Rad6 is essential for all the ways of Swd2's binding to the transcribed genes and Set1 redistributes the Swd2 to the 5' region for accomplishments of H3K4me3 in the genome-wide level.

Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease.

OBJECTIVE: We explored clinical implications of the new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) by assessing its prevalence and associated cardiovascular disease (CVD) risk. DESIGN: From nationwide health screening data, we identified 9 775 066 adults aged 20-79 who underwent health examination in 2009. Participants were categorised into four mutually exclusive groups: (1) MASLD; (2) MASLD with increased alcohol intake (MetALD); (3) MASLD with other combined aetiology (the three collectively referred to as MASLD/related steatotic liver disease (SLD)); and (4) no MASLD/related SLD. SLD was determined by fatty liver index ≥30. The primary outcome was CVD event, defined as a composite of myocardial infarction, ischaemic stroke, heart failure or cardiovascular death. RESULTS: The prevalence of MASLD, MetALD and MASLD with other combined aetiology was 27.5%, 4.4% and 1.5%, respectively. A total of 8 808 494 participants without prior CVD were followed up for a median of 12.3 years, during which 272 863 CVD events occurred. The cumulative incidence and multivariable-adjusted risk of CVD were higher in participants with MASLD/related SLD than in those without (HR 1.38 (95% CI 1.37 to 1.39)). Multivariable-adjusted HR (95% CI) of CVD events was 1.39 (1.38 to 1.40) for MASLD, 1.28 (1.26 to 1.30) for MetALD and 1.30 (1.26 to 1.34) for MASLD with other combined aetiology compared to the absence of any of these conditions. CVD risk was also higher in participants with metabolic dysfunction-associated fatty liver disease or non-alcoholic fatty liver disease than in those without the respective condition. CONCLUSION: Over one-third of Korean adults have MASLD/related SLD and bear a high CVD risk.

Strategic combination of bacteriophages with highly susceptible cells for enhanced intestinal settlement and resistant cell killing.

Avian pathogenic Escherichia coli (APEC) causes enormous economic losses and is a primary contributor to the emergence of multidrug resistance (MDR)-related problems in the poultry industry. Bacteriophage (phage) therapy has been successful in controlling MDR, but phage-resistant variants have rapidly emerged through the horizontal transmission of diverse phage defense systems carried on mobile genetic elements. Consequently, while multiple phage cocktails are recommended for phage therapy, there is a growing need to explore simpler and more cost-effective phage treatment alternatives. In this study, we characterized two novel O78-specific APEC phages, φWAO78-1 and φHAO78-1, in terms of their morphology, genome, physicochemical stability and growth kinetics. Additionally, we assessed the susceptibility of thirty-two O78 APEC strains to these phages. We analyzed the roles of highly susceptible cells in intestinal settlement and fecal shedding (susceptible cell-assisted intestinal settlement and shedding, SAIS) of phages in chickens via coinoculation with phages. Furthermore, we evaluated a new strategy, susceptible cell-assisted resistant cell killing (SARK), by comparing phage susceptibility between resistant cells alone and a mixture of resistant and highly susceptible cells in vitro. As expected, high proportions of O78 APEC strains had already acquired multiple phage defense systems, exhibiting considerable resistance to φWAO78-1 and φHAO78-1. Coinoculation of highly susceptible cells with phages prolonged phage shedding in feces, and the coexistence of susceptible cells markedly increased the phage susceptibility of resistant cells. Therefore, the SAIS and SARK strategies were demonstrated to be promising both in vivo and in vitro.

Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Patients with Vision Loss.

Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response, plays a key role in endoplasmic reticulum function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones, clinically manifesting as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. Herein, this was investigated by analyzing bulk RNA-sequencing transcriptomes from retinal organoids generated from patients with ACHM, carrying homozygous loss-of-function ATF6 variants. Marked dysregulation in mitochondrial respiratory complex gene expression and disrupted mitochondrial morphology in ACHM retinal organoids were identified. This indicated that loss of ATF6 leads to previously unappreciated mitochondrial defects in the retina. Next, gene expression from control and ACHM retinal organoids were compared with transcriptome profiles of seven major retinal cell types generated from recent single-cell transcriptomic maps of nondiseased human retina. This indicated pronounced down-regulation of cone genes and up-regulation in Müller glia genes, with no significant effects on other retinal cells. Overall, the current analysis of ACHM patient retinal organoids identified new cellular and molecular phenotypes in addition to cone dysfunction: activation of Müller cells, increased endoplasmic reticulum stress, disrupted mitochondrial structure, and elevated respiratory chain activity gene expression.

Surgical Outcomes in Non-Small Cell Lung Cancer with Distant Metastasis: The Prognostic Significance of Delayed Metastasis Diagnosis.

BACKGROUND: The diagnosis of distant metastasis on preoperative examinations for non-small cell lung cancer (NSCLC) can be challenging, leading to surgery for some patients with uncertain metastasis. This study evaluated the prognostic impact of delayed diagnosis of metastasis on patients who underwent upfront surgery. METHODS: The study enrolled patients who underwent lobectomy or pneumonectomy for NSCLC between June 2010 and December 2017 and evaluated the presence of distant metastasis before surgery. Overall survival (OS) for patients with stage IV cancer was compared with that for patients without metastasis, and the prognostic factors were analyzed. RESULTS: Of 3046 patients (mean age, 63 years; 1770 men), 100 (3.3 %) had distant metastasis, diagnosed preoperatively in 1.4 % (42/3046) and postoperatively in 1.9 % (58/3046) of the patients. The two most common metastasis sites diagnosed after surgery were contralateral lung (22/58, 37.9 %) and ipsilateral pleura (16/58, 27.6 %). The OS (median, 42.7 months) for the patients with stage IV cancer diagnosed postoperatively was comparable with that for the patients with stage IIIB cancer (P = 0.865), whereas the OS (median OS, 91.7 months) for the patients with stage IV cancer diagnosed preoperatively was better than for the patients with stage IIIB cancer (P = 0.001). Among the patients with distant metastasis, squamous cell type (hazard ratio [HR], 3.15; P = 0.002) and systemic treatment for metastasis (HR, 2.42; P = 0.002) were independent predictors of worse OS. CONCLUSIONS: Among NSCLC patients undergoing upfront surgery, the OS for the patients with stage IV cancer diagnosed postoperatively was comparable with that for the patients with stage IIIB cancer. For patients with stage IV disease, squamous cell type and systemic treatment for metastasis were prognostic factors for poorer OS.

Prevalence and outcomes of chronic comorbid conditions in patients with sepsis in Korea: a nationwide cohort study from 2011 to 2016.

BACKGROUND: Chronic comorbid conditions are common in patients with sepsis and may affect the outcomes. This study aimed to evaluate the prevalence and outcomes of common comorbidities in patients with sepsis. METHODS: We conducted a nationwide retrospective cohort study. Using data from the National Health Insurance Service of Korea. Adult patients (age ≥ 18 years) who were hospitalized in tertiary or general hospitals with a diagnosis of sepsis between 2011 and 2016 were analyzed. After screening of all International Classification of Diseases 10th revision codes for comorbidities, we identified hypertension, diabetes mellitus (DM), liver cirrhosis (LC), chronic kidney disease (CKD), and malignancy as prevalent comorbidities. RESULTS: Overall, 373,539 patients diagnosed with sepsis were hospitalized in Korea between 2011 and 2016. Among them, 46.7% had hypertension, 23.6% had DM, 7.4% had LC, 13.7% had CKD, and 30.7% had malignancy. In-hospital mortality rates for patients with hypertension, DM, LC, CKD, and malignancy were 25.5%, 25.2%, 34.5%, 28.0%, and 33.3%, respectively, showing a decreasing trend over time (P < 0.001). After adjusting for baseline characteristics, male sex, older age, use of mechanical ventilation, and continuous renal replacement therapy, LC, CKD, and malignancy were significantly associated with in-hospital mortality. CONCLUSIONS: Hypertension is the most prevalent comorbidity in patients with sepsis, and it is associated with an increased survival rate. Additionally, liver cirrhosis, chronic kidney disease, and malignancy result in higher mortality rates than hypertension and DM, and are significant risk factors for in-hospital mortality in patients with sepsis.

Changes in the intrinsic severity of severe acute respiratory syndrome coronavirus 2 according to the emerging variant: a nationwide study from February 2020 to June 2022, including comparison with vaccinated populations.

BACKGROUND: As the population acquires immunity through vaccination and natural infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding the intrinsic severity of coronavirus disease (COVID-19) is becoming challenging. We aimed to evaluate the intrinsic severity regarding circulating variants of SARS-CoV-2 and to compare this between vaccinated and unvaccinated individuals. METHODS: With unvaccinated and initially infected confirmed cases of COVID-19, we estimated the case severity rate (CSR); case fatality rate (CFR); and mortality rate (MR), including severe/critical cases and deaths, stratified by age and compared by vaccination status according to the period regarding the variants of COVID-19 and vaccination. The overall rate was directly standardized with age. RESULTS: The age-standardized CSRs (aCSRs) of the unvaccinated group were 2.12%, 5.51%, and 0.94% in the pre-delta, delta, and omicron period, respectively, and the age-standardized CFRs (aCFRs) were 0.60%, 2.49%, and 0.63% in each period, respectively. The complete vaccination group had lower severity than the unvaccinated group over the entire period showing under 1% for the aCSR and 0.5% for the aCFR. The age-standardized MR of the unvaccinated group was 448 per million people per month people in the omicron period, which was 11 times higher than that of the vaccinated group. In terms of age groups, the CSR and CFR sharply increased with age from the 60 s and showed lower risk reduction in the 80 s when the period changed to the omicron period. CONCLUSIONS: The intrinsic severity of COVID-19 was the highest in the delta period, with over 5% for the aCSR, whereas the completely vaccinated group maintained below 1%. This implies that when the population is vaccinated, the impact of COVID-19 will be limited, even if a new mutation appears. Moreover, considering the decreasing intrinsic severity, the response to COVID-19 should prioritize older individuals at a higher risk of severe disease.

Long-term prognostic factors for cardiovascular events in patients with chest pain without diabetes mellitus nor significant coronary stenosis.

Chest pain is the most common symptom of coronary artery disease (CAD) and diabetes mellitus (DM) is a well-known single strongest risk factor for cardiovascular diseases. Thus, the impact of CAD nor DM on long-term clinical effects is reported widely, but the prognostic factors of non-DM patients presenting with chest pain without significant CAD are limited. A total of 1,046 patients with chest pain without DM and significant CAD who underwent coronary angiography (CAG) and acetylcholine (ACH) provocation tests were finally enrolled. Propensity score matching and multivariate Cox-proportional hazard ratio analysis were performed to adjust for baseline potential confounders. Major adverse cardiac and cerebrovascular events (MACCE) were defined as the composite of total death, myocardial infarction (MI), revascularization, stroke, and recurrent angina. This study aimed to evaluate the long-term prognostic factors for MACCE in patients with chest pain without DM and CAD up to 5 years. Coronary artery spasm (CAS) was the most common cause of chest pain. However, long-term MACCE of CAS was not worse than those of patients with chest pain without CAS when patients with CAS had subsequent optimal antianginal medication therapy. However, a recurrent chest pain remains a problem even with continuous antianginal medication therapy. Up to 5 years, the incidence of MACCE was in 7.3%, including recurrent angina 6.9%. Dyslipidemia (HR: 2.010, 95% CI 1.166-3.466, P = 0.012), mild-moderate (30-70%) coronary stenosis (HR: 2.369, 95% CI 1.118-5.018, P = 0.024), the use of aspirin (HR: 2.885, 95% CI 1.588-5.238, P < 0.001), and the use of nitrates (HR: 1.938, 95% CI 1.094-3.433, P = 0.023) were independent risk factors for MACCE. Among the patients with chest pain without DM and significant CAD, the incidence of MACE were rare, but recurrent angina was still a challenging problem who had treated with antianginal medications.

Long-Term Follow-Up of Interstitial Lung Abnormality: Implication in Follow-Up Strategy and Risk Thresholds.

Rationale: The optimal follow-up computed tomography (CT) interval for detecting the progression of interstitial lung abnormality (ILA) is unknown. Objectives: To identify optimal follow-up strategies and extent thresholds on CT relevant to outcomes. Methods: This retrospective study included self-referred screening participants aged 50 years or older, including nonsmokers, who had imaging findings relevant to ILA on chest CT scans. Consecutive CT scans were evaluated to determine the dates of the initial CT showing ILA and the CT showing progression. Deep learning-based ILA quantification was performed. Cox regression was used to identify risk factors for the time to ILA progression and progression to usual interstitial pneumonia (UIP). Measurements and Main Results: Of the 305 participants with a median follow-up duration of 11.3 years (interquartile range, 8.4-14.3 yr), 239 (78.4%) had ILA on at least one CT scan. In participants with serial follow-up CT studies, ILA progression was observed in 80.5% (161 of 200), and progression to UIP was observed in 17.3% (31 of 179), with median times to progression of 3.2 years (95% confidence interval [CI], 3.0-3.4 yr) and 11.8 years (95% CI, 10.8-13.0 yr), respectively. The extent of fibrosis on CT was an independent risk factor for ILA progression (hazard ratio, 1.12 [95% CI, 1.02-1.23]) and progression to UIP (hazard ratio, 1.39 [95% CI, 1.07-1.80]). Risk groups based on honeycombing and extent of fibrosis (1% in the whole lung or 5% per lung zone) showed significant differences in 10-year overall survival (P = 0.02). Conclusions: For individuals with initially detected ILA, follow-up CT at 3-year intervals may be appropriate to monitor radiologic progression; however, those at high risk of adverse outcomes on the basis of the quantified extent of fibrotic ILA and the presence of honeycombing may benefit from shortening the interval for follow-up scans.

Feasibility and usefulness of cognitive monitoring using a new home-based cognitive test in mild cognitive impairment: a prospective single arm study.

BACKGROUND: The risk of dementia is increased in subjects with mild cognitive impairment (MCI). Despite the plethora of in-person cognitive tests, those that can be administered over the phone are lacking. We hypothesized that a home-based cognitive test (HCT) using phone calls would be feasible and useful in non-demented elderly. We aimed to assess feasibility and validity of a new HCT as an optional cognitive monitoring tool without visiting hospitals. METHODS: Our study was conducted in a prospective design during 24 weeks. We developed a new HCT consisting of 20 questions (score range 0-30). Participants with MCI (n = 38) were consecutively enrolled and underwent regular HCTs during 24 weeks. Associations between HCT scores and in-person cognitive scores and Alzheimer's disease (AD) biomarkers were evaluated. In addition, HCT scores in MCI participants were cross-sectionally compared with age-matched cognitively normal (n = 30) and mild AD dementia (n = 17) participants for discriminative ability of the HCT. RESULTS: HCT had good intra-class reliability (test-retest Cronbach's alpha 0.839). HCT scores were correlated with the Mini-Mental State Examination (MMSE), verbal memory delayed recall, and Stroop test scores but not associated with AD biomarkers. HCT scores significantly differed among cognitively normal, MCI, and mild dementia participants, indicating its discriminative ability. Finally, 32 MCI participants completed follow-up evaluations, and 8 progressed to dementia. Baseline HCT scores in dementia progressors were lower than those in non-progressors (p = 0.001). CONCLUSION: The feasibility and usefulness of the HCT were demonstrated in elderly subjects with MCI. HCT could be an alternative option to monitor cognitive decline in early stages without dementia.

Phase Angle as a Reliable Biomarker of Frailty to Predict Postoperative Outcomes in Patients Undergoing Off-Pump Coronary Artery Grafting: A Prospective Observational Study.

OBJECTIVE: To elucidate the association between phase angle (PA) and a composite adverse outcome in patients requiring off-pump coronary artery bypass grafting (OPCAB). DESIGN: A prospective observational study. SETTING: High-volume single center. PARTICIPANTS: A total of 229 adult patients who underwent OPCAB from May 2019 to October 2020. INTERVENTIONS: Each patient underwent bioelectrical impedance analysis, including PA assessment before surgery (PApre), immediately postoperatively (PApost), and 1 day postoperatively (PAPOD1), using an Inbody S10. Frailty index and nutritional assessments also were obtained before surgery. MEASUREMENTS AND MAIN RESULTS: Patient outcomes were assessed using a composite adverse outcome comprising death, myocardial infarction, revascularization, new-onset atrial fibrillation, acute kidney injury, stroke, postoperative pulmonary complications, wound complications, sepsis, reoperation, and/or delirium occurring during hospitalization and over the following year. Patients for whom composite adverse outcomes were reported had lower PApre than those without complications (5.4 ± 0.9 v 6.0 ± 0.9, p < 0.001). The PA was significantly associated with in-hospital and 1-year composite postoperative outcomes. The odds ratios (OR, [95% confidence interval]) for PApre by time were in-hospital complications (0.435 [0.314, 0.604], p < 0.001; 1-year complications: 0.459 [0.330, 0.638], p < 0.001) and PAPOD1 (OR, in-hospital complications: 0.400 [0.277, 0.576], 1-year complications: 0.429 [0.298, 0.619], p < 0.001). The PApre was significantly associated with days alive and out of hospital until 1 year. The cut-off value of PApre for optimal prediction of in-hospital complications was 6.0 (area under the curve: 0.691 [0.623-0.758], p < 0.001). CONCLUSION: Low PA as an indicator of frailty is associated with adverse postoperative outcomes after OPCAB. Low PA may be employed as a noninvasive and practical tool for the prediction of prognosis in patients with coronary artery disease.

Neuroprotective effect of whey protein hydrolysate containing leucine-aspartate-isoleucine-glutamine-lysine on HT22 cells in hydrogen peroxide-induced oxidative stress.

This study aimed to investigate the neuroprotective effects of whey protein hydrolysate (WPH) containing the pentapeptide leucine-aspartate-isoleucine-glutamine-lysine (LDIQK). Whey protein hydrolysate (50, 100, and 200 µg/mL) demonstrated the ability to restore the viability of HT22 cells subjected to 300 µM hydrogen peroxide (H2O2)-induced oxidative stress. Furthermore, at a concentration of 200 µg/mL, it significantly reduced the increase in reactive oxygen species production and calcium ion (Ca2+) influx induced by H2O2 by 46.1% and 46.2%, respectively. Similarly, the hydrolysate significantly decreased the levels of p-tau, a hallmark of tauopathy, and BCL2 associated X (BAX), a proapoptosis factor, while increasing the protein levels of choline acetyltransferase (ChAT), an enzyme involved in acetylcholine synthesis, brain-derived neurotrophic factor (BDNF), a nerve growth factor, and B-cell lymphoma 2 (BCL2, an antiapoptotic factor. Furthermore, it increased nuclear factor erythroid 2-related factor 2 (Nrf2)-hemoxygenase-1(HO-1) signaling, which is associated with the antioxidant response, while reducing the activation of mitogen-activated protein kinase (MAPK) signaling pathway components, namely phosphor-extracellular signal-regulated kinases (p-ERK), phosphor-c-Jun N-terminal kinases (p-JNK), and p-p38. Column chromatography and tandem mass spectrometry analysis identified LDIQK as a compound with neuroprotective effects in WPH; it inhibited Ca2+ influx and regulated the BAX/BCL2 ratio. Collectively, WPH containing LDIQK demonstrated neuroprotective effects against H2O2-induced neuronal cell damage, suggesting that WPH or its active peptide, LDIQK, may serve as a potential edible agent for improving cognitive dysfunction.

Clinical Outcome of Patients with Poor-Grade Aneurysmal Subarachnoid Hemorrhage with Bundled Treatments: A Propensity Score-Matched Analysis.

BACKGROUND: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH), defined as Hunt and Hess (HH) grades IV and V, is a challenging disease because of its high mortality and poor functional outcomes. The effectiveness of bundled treatments has been demonstrated in critical diseases. Therefore, poor-grade aSAH bundled treatments have been established. This study aims to evaluate whether bundled treatments can improve long-term outcomes and mortality in patients with poor-grade aSAH. METHODS: This is a comparative study using historical control from 2008 to 2022. Bundled treatments were introduced in 2017. We compared the rate of favorable outcomes (modified Rankin Scale score 0-2) at 6 months and mortality before and after the introduction of the bundled treatments. To eliminate confounding bias, the propensity score matching method was used. RESULTS: A total of 90 consecutive patients were evaluated. Forty-three patients received bundled treatments, and 47 patients received conventional care. The proportion of patients with HH grade V was higher in the bundle treatment group (41.9% vs. 27.7%). Conversely, the proportion of patients with fixed pupils on the initial examination was higher in the conventional group (30.2% vs. 38.3%). After 1:1 propensity score matching, 31 pairs were allocated to each group. The proportion of patients with 6-month favorable functional outcomes was significantly higher in the bundled treatments group (46.4% vs. 20.7%, p = 0.04). The 6-month mortality rate was 14.3% in the bundled treatments group and 27.3% in the conventional group (p = 0.01). Bundled treatments (odd ratio 14.6 [95% confidence interval 2.1-100.0], p < 0.01) and the presence of an initial pupil reflex (odd ratio 12.0 [95% confidence interval 1.4-104.6], p = 0.02) were significantly associated with a 6-month favorable functional outcome. CONCLUSIONS: The bundled treatments improve 6-month functional outcome and mortality in patients with poor-grade aSAH.

Epidemiology of Respiratory Viruses in Korean Children Before and After the COVID-19 Pandemic: A Prospective Study From National Surveillance System.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic led to a decrease in the seasonal incidence of many respiratory viruses worldwide due to the impact of nonpharmaceutical interventions (NPIs). However, as NPI measures were relaxed, respiratory viral infections re-emerged. We aimed to characterize the epidemiology of respiratory viruses in Korean children during post-COVID-19 pandemic years compared to that before the pandemic. METHODS: A nationwide prospective ongoing surveillance study has been conducted for detection of respiratory viruses between January 2017 and June 2023. We included data on adenovirus (AdV), human bocavirus (HBoV), human coronavirus (HCoV), human metapneumovirus (HMPV), human rhinovirus (HRV), influenza virus (IFV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV), which were detected in children and adolescents younger than 20 years. We analyzed the weekly detection frequency of individual viruses and the age distribution of the affected children. The study period was divided into prepandemic (2017-2019) and postpandemic (2021-2023) periods. RESULTS: A total of 19,589 and 14,068 samples were collected in the pre- and postpandemic periods, respectively. The overall detection rate of any virus throughout the study period was 63.1%, with the lowest occurring in the 2nd half of 2020 (50.6%) and the highest occurring in the 2nd half of 2021 (72.3%). Enveloped viruses (HCoV, HMPV, IFV, PIV, and RSV) almost disappeared, but nonenveloped viruses (AdV, HBoV, and HRV) were detected even during the peak of the COVID-19 pandemic. The codetection rate increased from 15.0% prepandemic to 19.1% postpandemic (P < 0.001). During the postpandemic period, a large out-of-season PIV and HMPV epidemic occurred, but the usual seasonality began to be restored in 2023. The mean age of children with each virus detected in 2023 was significantly greater than that in prepandemic years (P = 0.003 and 0.007 for AdV and HCoV, respectively; P < 0.001 for others). The mean age of children with IFV increased in 2022 (11.1 ± 5.2 years) from prepandemic years (7.9 ± 4.6 years) but decreased to 8.7 ± 4.1 years in 2023. CONCLUSION: With the relaxation of NPI measures, several seasonal respiratory viruses cocirculated with unusual seasonal epidemic patterns and were associated with increasing age of infected children.

First report of Puccinia xanthii causing rust disease on Xanthium orientale in Korea.

Puccinia xanthii Schw. is a microcyclic rust fungus, first found on Xanthium strumarium Lour in North Carolina, the United States. This rust fungus is native to the continental United States, Hawaii, Mexico, and the West Indies (Arthur 1934). It has become notoriously invasive and is now distributed in the Europe (Bulgaria, France, Hungary, Italy, Romania, Spain, and the former Yugoslavia), India, Indonesia, Australia, and South Africa (Parmelee 1969; Alcorn 1976; Wahyuno 2012). In East Asia, the fungus has been reported in Japan (Hiratsuka et al. 1992) and China (Zhao et al. 2014) but not in Korea. It has been reported mainly on the invasive weeds Xanthium and Ambrosia species. In addition, it rarely occurs on sunflowers (Helianthus spp.) in Australia (Alcorn 1976), South Africa (Pretorius et al. 2000), and North America (Gulya and Charlet 2002). In Korea, rust disease symptoms caused by a Puccinia fungus were first found on X. orientale L. at the roadside of Okcheon-gun, Chungcheongbuk-do (36 27'95.428"N 127 66'26.378"E) in October 2021 and were repeatedly observed in the same site in 2022. The similar symptom was additionally found on X. orientale in Yesan-gun, Oct. 2022. The symptoms were brown spots on round chlorotic haloes on the adaxial leaf surface and dark brown pustules on the abaxial leaf surface. Telia were brown to dark brown, round, mostly grouped, 0.28-0.61 mm in diameter, and mainly formed on the abaxial leaf surface but sometimes on the adaxial leaf surface. Teliospores were two-celled, pedicellate, and measured 37.6-110 × 12.4-21.5 µm in size; the wall was yellowish or almost colorless, smooth, 1.2-2.6 µm thick at the sides, and up to 7.4 µm thick at the apex. The morphological characteristics of the teliospores were identical to those of P. xanthii described by Arthur (1934) and Parmelee (1969). Based on phylogenetic analyses (e-Xtra 2) of the internal transcribed spacer (ITS) and partial large subunit (LSU) rDNA extracted from the teliospores, they were identified as P. xanthii. BLAST analysis showed that the sequences had high homologies (over 99.82%) with the reference strains of P. xanthii (EF635903 and KX999896). The representative specimens were preserved at the Animal and Plant Quarantine Agency Herbarium (PQK211005 for Okcheon-gun isolate and PQK220913 for Yesan-gun) and the sequences were deposited in GenBank (OR958716 and OR958692). A pathogenicity test was performed by dropping a suspension of germinating teliospores and basidiospores onto the adaxial leaf surfaces of apparently healthy X. orientale plants in Oct. 2022, using the isolate PQK220913 (OR958692). The three inoculated plants were placed together with three controls treated with only distilled water, in the dark at saturated humidity for 24 hours in an isolated greenhouse. After two weeks, typical rust symptoms were observed in the three infected plants, whereas no symptoms appeared in the control plants (e-Xtra 1). The causal fungus was identified as P. xanthii based on host relationships, successful experimental inoculation, morphological characteristics, and sequence similarity of partial DNA fragments. To our knowledge, this is the first report of P. xanthii on X. orientale in Korea. P. xanthii was additionally confirmed on X. orientale in Gumi-si, Boeun-gun, Seongju-gun, Naju-si, and Gunsan-si in 2023, indicating its wide distribution in Korea. It is expected that P. xanthii could be a candidate as a biological agent for controlling the invasive weed, X. orientale.