Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy.

BACKGROUND: Immune checkpoint therapy (ICT) provides durable responses in select cancer patients, yet resistance remains a significant challenge, prompting the exploration of underlying molecular mechanisms. Tyrosylprotein sulfotransferase-2 (TPST2), known for its role in protein tyrosine O-sulfation, has been suggested to modulate the extracellular protein-protein interactions, but its specific role in cancer immunity remains largely unexplored. METHODS: To explore tumor cell-intrinsic factors influencing anti-PD1 responsiveness, we conducted a pooled loss-of-function genetic screen in humanized mice engrafted with human immune cells. The responsiveness of cancer cells to interferon-γ (IFNγ) was estimated by evaluating IFNγ-mediated induction of target genes, STAT1 phosphorylation, HLA expression, and cell growth suppression. The sulfotyrosine-modified target gene of TPST2 was identified by co-immunoprecipitation and mass spectrometry. The in vivo effects of TPST2 inhibition were evaluated using mouse syngeneic tumor models and corroborated by bulk and single-cell RNA sequencing analyses. RESULTS: Through in vivo genome-wide CRISPR screening, TPST2 loss-of-function emerged as a potential enhancer of anti-PD1 treatment efficacy. TPST2 suppressed IFNγ signaling by sulfating IFNγ receptor 1 at Y397 residue, while its downregulation boosted IFNγ-mediated signaling and antigen presentation. Depletion of TPST2 in cancer cells augmented anti-PD1 antibody efficacy in syngeneic mouse tumor models by enhancing tumor-infiltrating lymphocytes. RNA sequencing data revealed TPST2's inverse correlation with antigen presentation, and increased TPST2 expression is associated with poor prognosis and altered cancer immunity across cancer types. CONCLUSIONS: We propose TPST2's novel role as a suppressor of cancer immunity and advocate for its consideration as a therapeutic target in ICT-based treatments.

Keratinocyte-derived circulating microRNAs in extracellular vesicles: a novel biomarker of psoriasis severity and potential therapeutic target.

BACKGROUND: Psoriasis is a chronic inflammatory disorder characterized by pathogenic hyperproliferation of keratinocytes and immune dysregulation. Currently, objective evaluation tools reflecting the severity of psoriasis are insufficient. MicroRNAs in extracellular vesicles (EV miRNAs) have been shown to be potential biomarkers for various inflammatory diseases. Our objective was to investigate the possibility of plasma-derived EV miRNAs as a marker for the psoriasis disease severity. METHODS: EVs were extracted from the plasma of 63 patients with psoriasis and 12 with Behçet's disease. We performed next-generation sequencing of the plasma-derived EV miRNAs from the psoriasis patients. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the level of EV miRNA expression. In situ hybridization was used to discern the anatomical location of miRNAs. qRT-PCR, western blotting, and cell counting kits (CCKs) were used to investigate IGF-1 signaling in cells transfected with miRNA mimics. RESULTS: We identified 19 differentially expressed EV miRNAs and validated the top three up-and down-regulated EV miRNAs. Among these, miR-625-3p was significantly increased in patients with severe psoriasis in both plasma and skin and most accurately distinguished moderate-to-severe psoriasis from mild-to-moderate psoriasis. It was produced and secreted by keratinocytes upon stimulation. We also observed a significant intensification of IGF-1 signalling and increased cell numbers in the miR-625-3p mimic transfected cells. CONCLUSIONS: We propose keratinocyte-derived EV miR-625-3p as a novel and reliable biomarker for estimating the severity of psoriasis. This biomarker could objectively evaluate the severity of psoriasis in the clinical setting and might serve as a potential therapeutic target. Trial registration None.

Integration of Tracking, Re-Identification, and Gesture Recognition for Facilitating Human-Robot Interaction.

For successful human-robot collaboration, it is crucial to establish and sustain quality interaction between humans and robots, making it essential to facilitate human-robot interaction (HRI) effectively. The evolution of robot intelligence now enables robots to take a proactive role in initiating and sustaining HRI, thereby allowing humans to concentrate more on their primary tasks. In this paper, we introduce a system known as the Robot-Facilitated Interaction System (RFIS), where mobile robots are employed to perform identification, tracking, re-identification, and gesture recognition in an integrated framework to ensure anytime readiness for HRI. We implemented the RFIS on an autonomous mobile robot used for transporting a patient, to demonstrate proactive, real-time, and user-friendly interaction with a caretaker involved in monitoring and nursing the patient. In the implementation, we focused on the efficient and robust integration of various interaction facilitation modules within a real-time HRI system that operates in an edge computing environment. Experimental results show that the RFIS, as a comprehensive system integrating caretaker recognition, tracking, re-identification, and gesture recognition, can provide an overall high quality of interaction in HRI facilitation with average accuracies exceeding 90% during real-time operations at 5 FPS.

Apathy scores in Parkinson's disease relate to EEG components in an incentivized motor task.

Apathy is one of the most prevalent non-motor symptoms of Parkinson's disease and is characterized by decreased goal-directed behaviour due to a lack of motivation and/or impaired emotional reactivity. Despite its high prevalence, the neurophysiological mechanisms underlying apathy in Parkinson's disease, which may guide neuromodulation interventions, are poorly understood. Here, we investigated the neural oscillatory characteristics of apathy in Parkinson's disease using EEG data recorded during an incentivized motor task. Thirteen Parkinson's disease patients with apathy and 13 Parkinson's disease patients without apathy as well as 12 healthy controls were instructed to squeeze a hand grip device to earn a monetary reward proportional to the grip force they used. Event-related spectral perturbations during the presentation of a reward cue and squeezing were analysed using multiset canonical correlation analysis to detect different orthogonal components of temporally consistent event-related spectral perturbations across trials and participants. The first component, predominantly located over parietal regions, demonstrated suppression of low-beta (12-20 Hz) power (i.e. beta desynchronization) during reward cue presentation that was significantly smaller in Parkinson's disease patients with apathy compared with healthy controls. Unlike traditional event-related spectral perturbation analysis, the beta desynchronization in this component was significantly correlated with clinical apathy scores. Higher monetary rewards resulted in larger beta desynchronization in healthy controls but not Parkinson's disease patients. The second component contained gamma and theta frequencies and demonstrated exaggerated theta (4-8 Hz) power in Parkinson's disease patients with apathy during the reward cue and squeezing compared with healthy controls (HCs), and this was positively correlated with Montreal Cognitive Assessment scores. The third component, over central regions, demonstrated significantly different beta power across groups, with apathetic groups having the lowest beta power. Our results emphasize that altered low-beta and low-theta oscillations are critical for reward processing and motor planning in Parkinson's disease patients with apathy and these may provide a target for non-invasive neuromodulation.

NEGR1 Modulates Mouse Affective Discrimination by Regulating Adult Olfactory Neurogenesis.

Background: Affective recognition and sensory processing are impaired in people with autism. However, no mouse model of autism comanifesting these symptoms is available, thereby limiting the exploration of the relationship between affective recognition and sensory processing in autism and the molecular mechanisms involved. Methods: With Negr1 -/- mice, we conducted the affective state discrimination test and an odor habituation/dishabituation test. Data were analyzed using the k-means clustering method. We also employed a whole-cell patch clamp and bromodeoxyuridine incorporation assay to investigate underlying mechanisms. Results: When encountering mice exposed to restraint stress or chronic pain, wild-type mice discriminated between them by either approaching the stressed mouse or avoiding the painful mouse, whereas Negr1 -/- mice showed unbiased social interactions with them. Next, we demonstrated that both wild-type and Negr1 -/- mice used their olfaction for social interaction in the experimental context, but Negr1 -/- mice showed aberrant olfactory habituation and dishabituation against social odors. In electrophysiological studies, inhibitory inputs to the mitral cells in the olfactory bulb were increased in Negr1 -/- mice compared with wild-type mice, and subsequently their excitability was decreased. As a potential underlying mechanism, we found that adult neurogenesis in the subventricular zone was diminished in Negr1 -/- mice, which resulted in decreased integration of newly generated inhibitory neurons in the olfactory bulb. Conclusions: NEGR1 contributes to mouse affective recognition, possibly by regulating olfactory neurogenesis and subsequent olfactory sensory processing. We propose a novel neurobiological mechanism of autism-related behaviors based on disrupted adult olfactory neurogenesis.

A deficit in affective discrimination is one of the major symptoms of autism spectrum disorder, the molecular/cellular mechanisms of which have yet to be explored. Here, we demonstrated that Negr1-deficient autism-relevant mice did not show preferential social interaction with affectively provoked mice (i.e., stress and pain) and showed its association with aberrant olfactory processing for other mice. As a potential underlying cellular mechanism, we found a decrease in adult-born neurons and excitatory/inhibitory imbalance in the olfactory bulb region. These results suggest that further investigation into the role of Negr1 and olfactory processing could provide valuable insights into molecular and cellular mechanisms of autism.

Differences of nutritional intake habits and Dietary Inflammatory Index score between occupational classifications in the Korean working population.

Background: Human nutrient intake is closely related to the conditions of their workplace. Methods: This study used data from the Korean National Health and Nutritional Examination Survey (KNHANES) conducted between 2016 and 2020. The study population comprised individuals aged 19 to 65 years who were engaged in paid work, excluding soldiers (total = 12,201, male = 5,872, female = 6,329). The primary outcome of interest was the Dietary Inflammatory Index (DII) score, which was calculated using dietary intake data. Generalized linear models were used for statistical analyses. Results: Pink-collar workers had higher DII scores, indicating a potentially higher inflammatory diet than white-collar workers (mean: 2.18 vs. 1.89, p < 0.001). Green and blue-collar workers displayed lower levels of dietary inflammation (green: 1.64 vs. 1.89, p = 0.019, blue: 1.79 vs. 1.89, p = 0.022). After adjusting for sex, age, income, education, and energy intake, the sole trend that persisted was the comparison between white-collar and pink-collar workers. Conclusions: DII scores and dietary patterns differed among occupational groups and genders.

The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease.

We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer's disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in cardiovascular deaths, schizophrenia, Alzheimer's and Parkinson's disease, and with the two antigens of the XG blood group located in the pseudoautosomal region of the sex chromosomes. We further reveal that the most deleterious modifiable risk factors for this vulnerable brain network are diabetes, nitrogen dioxide - a proxy for traffic-related air pollution - and alcohol intake frequency. The extent of these associations was uncovered by examining these modifiable risk factors in a single model to assess the unique contribution of each on the vulnerable brain network, above and beyond the dominating effects of age and sex. These results provide a comprehensive picture of the role played by genetic and modifiable risk factors on these fragile parts of the brain.

HDAC11 Regulates Palmitate-induced NLRP3 Inflammasome Activation by Inducing YAP Expression in THP-1 Cells and PBMCs.

Histone deacetylase 11 (HDAC11) has been implicated in the pathogenesis of metabolic diseases characterized by chronic low-grade inflammation, such as obesity. However, the influence of HDAC11 on inflammation and the specific effect of HDAC11 on the palmitic acid (PA)-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation are poorly understood. The effect of PA treatment on HDAC11 activity and the NLRP3 inflammasome was investigated in human peripheral blood mononuclear cells and THP-1 cells. The PA-induced responses of key markers of NLRP3 inflammasome activation, including NLRP3 gene expression, caspase-1 p10 activation, cleaved IL-1ß production, and extracellular IL-1ß release, were assessed as well. The role of HDAC11 was explored using a specific inhibitor of HDAC11 and by knockdown using small interfering (si)HDAC11 RNA. The relationship between HDAC11 and yes-associated protein (YAP) in the PA-induced NLRP3 inflammasome was investigated in THP-1 cells with HDAC11 or YAP knockdown. Following PA treatment, HDAC11 activity and protein levels increased significantly, concomitant with activation of the NLRP3 inflammasome. Notably, PA-induced the upregulation of NLRP3, caspase-1 p10 activation, the production of cleaved IL-1ß, and the release of IL-1ß into the extracellular space, all of which were attenuated by FT895 treatment and by HDAC11 knockdown. In THP-1 cells, PA induced the expression of YAP and its interaction with NLRP3, resulting in NLRP3 inflammasome activation, whereas both were inhibited by FT895 and siHDAC11 RNA. These findings demonstrate a pivotal role for HDAC11 in the PA-induced activation of the NLRP3 inflammasome. HDAC11 inhibition thus represents a promising therapeutic strategy for mitigating NLRP3 inflammasome-related inflammation in the context of obesity.

Comparative analysis of del Nido cardioplegia versus blood cardioplegia in isolate coronary artery bypass grafting.

BACKGROUND: This study examined the efficacy of del Nido cardioplegia compared with traditional blood cardioplegia in adult cardiac surgery for isolated coronary artery bypass grafting by evaluating the early postoperative outcomes. METHODS: A total of 119 patients who underwent isolated conventional coronary artery bypass grafting were enrolled and divided into two groups (del Nido cardioplegia group [n = 36] and blood cardioplegia group [n = 50]) based on the type of cardioplegia used. This study compared the preoperative characteristics, intraoperative data, and early postoperative outcomes. Further subgroup analyses were conducted for high-risk patient groups. RESULTS: The 30-day mortality and morbidity rates were not significantly different between groups. The del Nido cardioplegia group exhibited advantageous myocardial protection outcomes, demonstrated by a significantly smaller rise in Troponin I levels post-surgery (2.8 [-0.4; 4.2] vs. 4.5 [2.9; 7.4] ng/mL, p = 0.004) and fewer defibrillation attempts during weaning off of cardiopulmonary bypass (0.0 ± 0.2 vs. 0.4 ± 1.1 times, p = 0.011) when compared to the blood cardioplegia group. Additionally, the del Nido group achieved a reduction in surgery duration, as evidenced by the reduced aortic cross-clamping time (64.0 [55.5; 75.5] vs. 77.5 [65.0; 91.0] min, p = 0.001) and total operative time (287.5 [270.0; 305.0] vs. 315.0 [285.0; 365.0] min, p = 0.008). Subgroup analyses consistently demonstrated that the del Nido cardioplegia group had a significantly smaller postoperative increase in Troponin I levels across all subgroups (p < 0.05). CONCLUSIONS: del Nido cardioplegia provided myocardial protection and favorable early postoperative outcomes compared to blood cardioplegia, making it a viable option for conventional coronary artery bypass grafting. Establishing a consensus on the protocol for Del Nido cardioplegia administration in adult surgeries is needed.

The impact of long working hours on daily sodium intake.

Background: Long working hours are associated with an increased risk of cardiovascular disease, yet the underlying mechanism(s) remain unclear. The study examines how occupational factors like working hours, shift work, and employment status correlate with dietary choices and sodium intake, impacting hypertension risk. Methods: This study used data from the Korea National Health and Nutrition Examination Survey conducted between 2013 and 2020. The dataset included 8,471 respondents, all of whom were wage workers aged 20 or older and reported working at least 36 hours per week. Individuals who have been previously diagnosed with or are currently diagnosed with hypertension, diabetes, or dyslipidemia were excluded. The average daily sodium intake was assessed via a 24-hour dietary recall method. Average weekly working hours were categorized into 3 groups: 36-40 hours, 41-52 hours, and over 52 hours. Multiple logistic regression models were used. Results: Study findings revealed that 83.7% of participants exceeded the recommended daily sodium intake of 2 g set by the World Health Organization. After adjusting for confounding factors, a positive correlation was observed between average working hours and daily sodium intake. Among males, statistical significance was found in the group with average weekly working hours of 41-52 hours (prevalence ratio [PR]: 1.17; 95% confidence interval [CI]: 1.05-1.30) and the group exceeding 52 hours (PR: 1.22; 95% CI: 1.09-1.38) when comparing the fourth quartile of daily sodium intake to the combined quartiles of Q1, Q2, and Q3. Among females, no significance was noted. Conclusions: Long working hours were associated with increased sodium intake, primarily among male workers. This connection is likely attributed to having less time for home-cooked meals, resulting in higher fast food consumption and dining out. A workplace intervention promoting healthy eating and reducing stress is essential to lower sodium consumption and mitigate hypertension risk.

Predictive factors for size change of aorta in patients with acute blunt traumatic aortic injury.

OBJECTIVE: We aimed to investigate the changes in aorta size, the factors affecting size changes in patients with acute blunt traumatic aortic injury and to evaluate the adequacy of the current 120% thoracic endovascular aortic repair graft oversizing policy. DESIGN AND METHODS: This retrospective review study was conducted using the prospectively collected medical records of 45 patients (mean age: 53.5 years, male: 39 patients) with blunt traumatic aortic injury treated at a level 1 trauma center between 2012 and 2021. Aortic diameter was measured by computed tomography angiographic images at four different levels [ascending aorta (A), isthmus (B), descending thoracic aorta (C), and infrarenal aorta (D)] on arrival and follow-up (median time interval, 13 days). Associated factors including patient characteristics and hemodynamic parameters on arrival and follow-up were collected to determine their influence on changes in the aorta. RESULTS: The mean diameter of all four aortic levels increased on follow-up computed tomography compared to initial computed tomography (A: + 11.77%, B: + 10.19%, C: + 7.71%, D: + 12.04%). Patient age and injury severity score influenced changes in the diameter of the ascending aorta (P < 0.05). Patient age and blunt traumatic aortic injury grade were significantly associated with changes in the infrarenal aortic diameter (P < 0.05). Three cases of type 1 endoleak were observed at follow-up but all were spontaneously resolved without further intervention at next computed tomography follow-up. CONCLUSIONS: In patients with acute blunt traumatic aortic injury, aortic diameter is significantly smaller by about 10% under shock and is not considered a basis for oversizing the currently implemented 120% thoracic endovascular aortic repair graft sizing. However, in young patients under the age of 40, the change is significantly large and subsequent computed tomography follow-up is required.

The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD.

GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.

Impact of pericardial calcification on early postoperative outcomes after pericardiectomy: a retrospective observational study.

BACKGROUND: Owing to the lack of understanding of the clinical significance of pericardial calcification during pericardiectomy, whether pericardial calcification should be considered when determining the optimal timing for pericardiectomy is debatable. We aimed to investigate the effect of pericardial calcification on early postoperative outcomes in patients who underwent pericardiectomy for constrictive pericarditis. METHODS: Altogether, 44 patients who underwent pericardiectomy for constrictive pericarditis were enrolled. After excluding three patients who underwent concurrent surgeries, a total of 41 patients were categorized into two groups based on the presence of pericardial calcification as determined by preoperative computed tomography and pathological examination. Preoperative clinical and imaging characteristics, intraoperative data, and early postoperative outcomes were compared between the two groups. A multivariable analysis was performed to identify the factors associated with postoperative complications. RESULTS: The group with and without PC comprised 21 and 20 patients, respectively. No significant differences were observed in 30-day mortality (n = 1 [5%]) in the group with pericardial calcification and no mortality in the group without pericardial calcification (p > 0.999). Other early postoperative outcome variables did not demonstrate any significant differences between the two groups. However, the use of cardiopulmonary bypass was associated with postoperative complications (p < 0.009, odds ratio: 63.5, 95% confidence interval: 5.13-3400). CONCLUSIONS: Pericardial calcification did not significantly affect the postoperative outcomes after pericardiectomy. Further comprehensive studies, including those with larger sample sizes and longitudinal designs, are necessary to determine whether pericardial calcification can significantly influence the timing of surgical intervention.

Thrombocytopenia after Aortic Valve Replacement Using Sutureless Valves.

Background: Sutureless valves are widely used in aortic valve replacement surgery, with Perceval valves and Intuity valves being particularly prominent. However, concerns have been raised about postoperative thrombocytopenia with Perceval valves (Corcym, UK). We conducted a comparative analysis with the Intuity valve (Edwards Lifesciences, USA), and assessed how thrombocytopenia affected patient and transfusion outcomes. Methods: Among 595 patients who underwent aortic valve replacement from June 2016 to March 2023, sutureless valves were used in 53 (Perceval: n=23; Intuity: n=30). Platelet counts were monitored during hospitalization and outpatient visits. Daily platelet count changes were compared between groups, and the results from patients who underwent procedures using Carpentier Edwards Perimount Magna valves were used as a reference group. Results: Compared to the Intuity group, the Perceval group showed a significantly higher amount of platelet transfusion (5.48±1.64 packs vs. 0.60±0.44 packs, p=0.008). During the postoperative period, severe thrombocytopenia (<50,000/µL) was significantly more prevalent in the Perceval group (56.5%, n=13) than in the Intuity group (6.7%, n=2). After initial postoperative depletion, daily platelet counts increased, with significant differences observed in the extent of improvement between the Perceval and Intuity groups (p<0.001). However, there was no significant difference in early mortality or the incidence of neurological complications between the 2 groups. Conclusion: The severity of postoperative thrombocytopenia differed significantly between the Perceval and Intuity valves. The Perceval group showed a significantly higher prevalence of severe thrombocytopenia and higher platelet transfusion volumes. However, thrombocytopenia gradually recovered during the postoperative period in both groups, and the early outcomes were similar in both groups.

Evaluation of risk stratification for acute kidney injury: a comparative analysis of EKFC, 2009 and 2021 CKD-EPI glomerular filtration estimating equations.

BACKGROUND: The adoption of the 2021 CKD-EPIcr equation for glomerular filtration rate (GFR) estimation provided a race-free eGFR calculation. However, the discriminative performance for AKI risk has been rarely validated. We aimed to evaluate the differences in acute kidney injury (AKI) prediction or reclassification power according to the three eGFR equations. METHODS: We performed a retrospective observational study within a tertiary hospital from 2011 to 2021. Acute kidney injury was defined according to KDIGO serum creatinine criteria. Glomerular filtration rate estimates were calculated by three GFR estimating equations: 2009 and 2021 CKD-EPIcr, and EKFC. In three equations, AKI prediction performance was evaluated with area under receiver operator curves (AUROC) and reclassification power was evaluated with net reclassification improvement analysis. RESULTS: A total of 187,139 individuals, including 27,447 (14.7%) AKI and 159,692 (85.3%) controls, were enrolled. In the multivariable regression prediction model, the 2009 CKD-EPIcr model (continuous eGFR model 2, 0.7583 [0.755-0.7617]) showed superior performance in AKI prediction to the 2021 CKD-EPIcr (0.7564 [0.7531-0.7597], < 0.001) or EKFC model in AUROC (0.7577 [0.7543-0.761], < 0.001). Moreover, in reclassification of AKI, the 2021 CKD-EPIcr and EKFC models showed a worse classification performance than the 2009 CKD-EPIcr model. (- 7.24 [- 8.21-- 6.21], - 2.38 [- 2.72-- 1.97]). CONCLUSION: Regarding AKI risk stratification, the 2009 CKD-EPIcr equation showed better discriminative performance compared to the 2021 CKD-EPIcr equation in the study population.

Risk of mortality and cause of death according to kidney function parameters: a nationwide observational study in Korea.

BACKGROUND: Further study is warranted to determine the association between estimated glomerular filtration rate (eGFR) or albuminuria and the risk of death from diverse causes. METHODS: We screened >10 million general health screening examinees who received health examinations conducted in 2009 using the claims database of Korea. After the exclusion of those previously diagnosed with renal failure and those with missing data, 9,917,838 individuals with available baseline kidney function measurements were included. The primary outcome was mortality and cause-specific death between 2009 and 2019 identified through death certificates based on the diagnostic codes of International Classification of Diseases, 10th revision. Multivariable Cox regression analysis adjusted for various clinicodemographic and social characteristics was used to assess mortality risk. RESULTS: The hazard ratio of death was significantly high in both the eGFR <60 mL/min/1.73 m2 and in the eGFR ≥120 mL/ min/1.73 m2 groups in univariable and multivariable regression analyses when compared to those within the reference range (eGFR of 90-120 mL/min/1.73 m2). The results were similar for death by cardiovascular, cancer, infection, endocrine, respiratory, and digestive causes. We also found that albuminuria was associated with higher risk of death regardless of eGFR range, and those in the higher categories of dipstick albuminuria showed higher risk. CONCLUSION: We reconfirmed the significant association between eGFR, albuminuria, and mortality. Healthcare providers should keep in mind that albuminuria and decreased eGFR as well as kidney hyperfiltration are independent predictors of mortality.

Associations of metabolic variabilities and cardiovascular outcomes according to estimated glomerular filtration rate in chronic kidney disease: a nationwide observational cohort study.

Background: The impact of baseline estimated glomerular filtration rate (eGFR) on the risk of adverse outcomes according to metabolic parameter variabilities in chronic kidney disease has rarely been investigated. Methods: We conducted a retrospective nationwide cohort study using the National Health Insurance System data in Korea from 2007 to 2013 to identify individuals with three or more health screenings. The metabolic components variability was defined as intraindividual variability between measurements using the variability independent of the mean. The metabolic variability score was defined as the total number of high-variability metabolic components. Multivariable-adjusted Cox regression analysis was conducted to evaluate the risks of all-cause mortality, myocardial infarction, and ischemic stroke. Results: During a mean follow-up of 6.0 ± 0.7 years, 223,531 deaths, 107,140 myocardial infarctions, and 116,182 ischemic strokes were identified in 9,971,562 patients. Low eGFR categories and higher metabolic variability scores were associated with a higher risk of adverse outcomes. The degree of association between metabolic variability and adverse outcomes was significantly larger in those with low eGFR categories than in those with preserved eGFR (p for interaction < 0.001). Representatively, those with high metabolic variability in the eGFR of <15 mL/min/1.73 m2 group showed a prominently higher risk for all-cause mortality (adjusted hazard ratio [aHR], 5.28; 95% confidence interval [CI], 4.02-6.94) when the degree was compared to the findings in those with preserved (eGFR of ≥60 mL/min/1.73 m2) kidney function (aHR, 2.55; 95% CI, 2.41-2.69). Conclusion: The degree of adverse association between metabolic variability and poor prognosis is accentuated in patients with impaired kidney function.

Non-indicated initiation of proton pump inhibitor and risk of adverse outcomes in patients with underlying chronic kidney disease: a nationwide, retrospective, cohort study.

OBJECTIVE: Evidence related to the risk of kidney damage by proton pump inhibitor (PPI) initiation in patients with 'underlying' chronic kidney disease (CKD) remains scarce, although PPI use is generally associated with acute interstitial nephritis or incident CKD. We aimed to investigate the association between PPI initiation and the risk of adverse outcomes in patients with CKD in the absence of any deterministic indications for PPI usage. DESIGN: Retrospective observational study. SETTING: Korea National Health Insurance Service database from 2009 to 2017. PARTICIPANTS: A retrospective cohort of new PPI and histamine H2-receptor antagonists (H2RA) users among people with CKD. Patients with a history of gastrointestinal bleeding or those who had an endoscopic or image-based upper gastrointestinal tract evaluation were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: The study subjects were followed to ascertain clinical outcomes including mortality, end-stage kidney disease (ESKD), myocardial infarction and stroke. The HRs of outcomes were measured using a Cox regression model after adjusting for multiple variables. We applied an inverse probability of treatment weighting (IPTW) model to control for residual confounders. RESULTS: We included a total of 1038 PPI and 3090 H2RA users without deterministic indications for treatment. IPTW-weighted Cox regression analysis showed that PPI initiation was more significantly associated with a higher ESKD risk compared with that of H2RA initiation (adjusted HR 1.72 (95% CI 1.19 to 2.48)), whereas the risks of mortality or cardiovascular outcomes were similar between the two groups. In the subgroup analysis, multivariable Cox regression analysis showed that the association between PPI use and the progression to ESKD remained significant in non-diabetic and low estimated glomerular filtration rate (<60 mL/min/1.73 m2) groups (adjusted HR 1.72 (95% CI 1.19 to 2.48) and 1.63 (95% CI 1.09 to 2.43), respectively). CONCLUSIONS: Initiation of PPI administration may not be recommended in patients with CKD without deterministic indication, as their usage was associated with a higher risk of ESKD.

Botanical formulation HX110B ameliorates PPE-induced emphysema in mice via regulation of PPAR/RXR signaling pathway.

Chronic obstructive pulmonary disease (COPD), an inflammatory lung disease, causes approximately 3 million deaths each year; however, its pathological mechanisms are not fully understood. In this study, we examined whether HX110B, a mixture of Taraxacum officinale, Dioscorea batatas, and Schizonepeta tenuifolia extracts, could suppress porcine pancreatic elastase (PPE)-induced emphysema in mice and its mechanism of action. The therapeutic efficacy of HX110B was tested using a PPE-induced emphysema mouse model and human bronchial epithelial cell line BEAS-2B. In vivo data showed that the alveolar wall and air space expansion damaged by PPE were improved by HX110B administration. HX110B also effectively suppresses the expression levels of pro-inflammatory mediators including IL-6, IL-1ß, MIP-2, and iNOS, while stimulating the expression of lung protective factors such as IL-10, CC16, SP-D, and sRAGE. Moreover, HX110B improved the impaired OXPHOS subunit gene expression. In vitro analysis revealed that HX110B exerted its effects by activating the PPAR-RXR signaling pathways. Overall, our data demonstrated that HX110B could be a promising therapeutic option for COPD treatment.

Associations of MRI-derived kidney volume, kidney function, body composition and physical performance in ≈38 000 UK Biobank participants: a population-based observational study.

Background: Kidney volume is used as a predictive and therapeutic marker for several clinical conditions. However, there is a lack of large-scale studies examining the relationship between kidney volume and various clinicodemographic factors, including kidney function, body composition and physical performance. Methods: In this observational study, MRI-derived kidney volume measurements from 38 526 UK Biobank participants were analysed. Major kidney volume-related measures included body surface area (BSA)-adjusted total kidney volume (TKV) and the difference in bilateral kidneys. Multivariable-adjusted linear regression and cubic spline analyses were used to explore the association between kidney volume-related measures and clinicodemographic factors. Cox or logistic regression was used to identify the risks of death, non-kidney cancer, myocardial infarction, ischaemic stroke and chronic kidney disease (CKD). Results: The median of BSA-adjusted TKV and the difference in kidney volume were 141.9 ml/m2 [interquartile range (IQR) 128.1-156.9] and 1.08-fold (IQR 1.04-1.15), respectively. Higher BSA-adjusted TKV was significantly associated with higher estimated glomerular filtration rate {eGFR; ß = 0.43 [95% confidence interval (CI) 0.42-0.44]; P < .001}, greater muscle volume [ß = 0.50 (95% CI 0.48-0.51); P < .001] and greater mean handgrip strength [ß = 0.15 (95% CI 0.13-0.16); P < .001] but lower visceral adipose tissue volume [VAT; ß = -0.09 (95% CI -0.11 to -0.07); P < .001] in adjusted models. A greater difference in bilateral kidney volumes was associated with lower eGFR, muscle volume and physical performance but with higher proteinuria and VAT. Higher BSA-adjusted TKV was significantly associated with a reduced risk of CKD [odds ratio (OR) 0.7 (95% CI 0.63-0.77); P < .001], while a greater difference in kidney volume was significantly associated with an increased risk of CKD [OR 1.13 (95% CI 1.07-1.20); P < .001]. Conclusion: Higher BSA-adjusted TKV and lower differences in bilateral kidney volumes are associated with higher kidney function, muscle volume and physical performance and a reduced risk of CKD.