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Abstract Caspase-2, one of the most evolutionarily conserved members of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that ferroptosis is suppressed by antioxidant defense pathways, such as that involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesized that caspase-2 may play a role in regulating ferroptosis. This study provides the first demonstration of an important and unprecedented function of caspase-2 in protecting cancer cells from undergoing ferroptotic cell death. Specifically, we show that depletion of caspase-2 leads to the downregulation of stress response genes including SESN2, HMOX1, SLC7A11, and sensitizes mutant-p53 cancer cells to cell death induced by various ferroptosis-inducing compounds. Importantly, the canonical catalytic activity of caspase-2 is not required for its role and suggests that caspase-2 regulates ferroptosis via non-proteolytic interaction with other proteins. Using an unbiased BioID proteomics screen, we identified novel caspase-2 interacting proteins (including heat shock proteins and co-chaperones) that regulate cellular responses to stress. Finally, we demonstrate that caspase-2 limits chaperone-mediated autophagic degradation of GPX4 to promote the survival of mutant-p53 cancer cells. In conclusion, we document a novel role for caspase-2 as a negative regulator of ferroptosis in cells with mutant p53. Our results provide evidence for a novel function of caspase-2 in cell death regulation and open potential new avenues to exploit ferroptosis in cancer therapy.

Abstract Autophagy, the process of elimination of cellular components by lysosomal degradation, is essential for animal development and homeostasis. Using the autophagy-dependent Drosophila larval midgut degradation model we identified an autophagy regulator, the RING domain ubiquitin ligase CG14435 (detour). Depletion of detour resulted in increased early-stage autophagic vesicles, premature tissue contraction, and overexpression of detour or mammalian homologues, ZNRF1 and ZNRF2, increased autophagic vesicle size. The ablation of ZNRF1 or ZNRF2 in mammalian cells increased basal autophagy. We identified detour interacting proteins including HOPS subunits, deep orange (dor/VPS18), Vacuolar protein sorting 16A (VPS16A), and light (lt/VPS41) and found that detour promotes their ubiquitination. The detour mutant accumulated autophagy-related proteins in young adults, displayed premature ageing, impaired motor function, and activation of innate immunity. Collectively, our findings suggest a role for detour in autophagy, likely through regulation of HOPS complex, with implications for healthy aging.

Although it is possible to generate neural stem cells (NSC) from somatic cells by reprogramming technologies with transcription factors, clinical utilization of patient-specific NSC for the treatment of human diseases remains elusive. The risk hurdles are associated with viral transduction vectors induced mutagenesis, tumor formation from undifferentiated stem cells, and transcription factors-induced genomic instability. Here we describe a viral vector-free and more efficient method to induce mouse fibroblasts into NSC using small molecules. The small molecule-induced neural stem (SMINS) cells closely resemble NSC in morphology, gene expression patterns, self-renewal, excitability, and multipotency. Furthermore, the SMINS cells are able to differentiate into astrocytes, functional neurons, and oligodendrocytes in vitro and in vivo. Thus, we have established a novel way to efficiently induce neural stem cells (iNSC) from fibroblasts using only small molecules without altering the genome. Such chemical induction removes the risks associated with current techniques such as the use of viral vectors or the induction of oncogenic factors. This technique may, therefore, enable NSC to be utilized in various applications within clinical medicine.

The processing of Amyloid precursor protein (APP) is multifaceted, comprising of protein transport, internalization and sequential proteolysis. However, the exact mechanism of APP intracellular trafficking and distribution remains unclear. To determine the interaction between sortilin and APP and the effect of sortilin on APP trafficking and processing, we studied the binding site and its function by mapping experiments, colocalization, coimmunoprecipitation and sucrose gradient fractionation. We identified for the first time that sortilin interacts with APP at both N- and C-terminal regions. The sortilin-FLVHRY (residues 787-792) and APP-NPTYKFFE (residues 759-766) motifs are crucial for the C-terminal interaction. We also found that lack of the FLVHRY motif reduces APP lysosomal targeting and increases APP distribution in lipid rafts in co-transfected HEK293 cells. These results are consistent with our in vivo data where sortilin knockout mice showed a decrease of APP lysosomal distribution and an increase of APP in lipid rafts. We further confirmed that overexpression of sortilin-FLVHRY mutants failed to rescue the lysosomal degradation of APP. Thus, our data suggests that sortilin is implicated in APP lysosomal and lipid raft targeting via its carboxyl-terminal F/YXXXXF/Y motif. Our study provides new molecular insights into APP trafficking and processing.

BackgroundNeurons extend their dendrites and axons to build functional neural circuits, which are regulated by both positive and negative signals during development. Brain-derived neurotrophic factor (BDNF) is a positive regulator for neurite outgrowth and neuronal survival but the functions of its precursor (proBDNF) are less characterized.Methodology/principal findingsHere we show that proBDNF collapses neurite outgrowth in murine dorsal root ganglion (DRG) neurons and cortical neurons by activating RhoA via the p75 neurotrophin receptor (p75NTR). We demonstrated that the receptor proteins for proBDNF, p75NTR and sortilin, were highly expressed in cultured DRG or cortical neurons. ProBDNF caused a dramatic neurite collapse in a dose-dependent manner and this effect was about 500 fold more potent than myelin-associated glycoprotein. Neutralization of endogenous proBDNF by using antibodies enhanced neurite outgrowth in vitro and in vivo, but this effect was lost in p75NTR(-/-) mice. The neurite outgrowth of cortical neurons from p75NTR deficient (p75NTR(-/-)) mice was insensitive to proBDNF. There was a time-dependent reduction of length and number of filopodia in response to proBDNF which was accompanied with a polarized RhoA activation in growth cones. Moreover, proBDNF treatment of cortical neurons resulted in a time-dependent activation of RhoA but not Cdc42 and the effect was absent in p75NTR(-/-) neurons. Rho kinase (ROCK) and the collapsin response mediator protein-2 (CRMP-2) were also involved in the proBDNF action.ConclusionsproBDNF has an opposing role in neurite outgrowth to that of mature BDNF. Our observations suggest that proBDNF collapses neurites outgrowth and filopodial growth cones by activating RhoA through the p75NTR signaling pathway.

Abstract Background Retrospective studies have demonstrated that the deep learning-based cardiac arrest risk management system (DeepCARS™) is superior to the conventional methods in predicting in-hospital cardiac arrest (IHCA). This prospective study aimed to investigate the predictive accuracy of the DeepCARS™ for IHCA or unplanned intensive care unit transfer (UIT) among general ward patients, compared with that of conventional methods in real-world practice. Methods This prospective, multicenter cohort study was conducted at four teaching hospitals in South Korea. All adult patients admitted to general wards during the 3-month study period were included. The primary outcome was predictive accuracy for the occurrence of IHCA or UIT within 24 h of the alarm being triggered. Area under the receiver operating characteristic curve (AUROC) values were used to compare the DeepCARS™ with the modified early warning score (MEWS), national early warning Score (NEWS), and single-parameter track-and-trigger systems. Results Among 55,083 patients, the incidence rates of IHCA and UIT were 0.90 and 6.44 per 1,000 admissions, respectively. In terms of the composite outcome, the AUROC for the DeepCARS™ was superior to those for the MEWS and NEWS (0.869 vs. 0.756/0.767). At the same sensitivity level of the cutoff values, the mean alarm counts per day per 1,000 beds were significantly reduced for the DeepCARS™, and the rate of appropriate alarms was higher when using the DeepCARS™ than when using conventional systems. Conclusion The DeepCARS™ predicts IHCA and UIT more accurately and efficiently than conventional methods. Thus, the DeepCARS™ may be an effective screening tool for detecting clinical deterioration in real-world clinical practice. Trial registration This study was registered at ClinicalTrials.gov ( NCT04951973 ) on June 30, 2021.

Abstract Rifampicin is an important agent for tuberculosis treatment; however, it is often discontinued because of adverse reactions. The treatment regimen then can be administered as that for rifampicin-resistant tuberculosis, which can be toxic. We retrospectively reviewed 114 patients with drug-susceptible pulmonary tuberculosis who discontinued rifampicin due to adverse reactions during an 18 year period at a tertiary referral center, of which 92 (80.7%) exhibited favorable response. Hepatotoxicity was the leading cause of intolerance. Patients with a favorable response were younger and less likely to have comorbidities. The majority of patients were administered four medications during the intensive phase and three to four during the consolidative phase. For those with a favorable response, the median duration of treatment was 10.2 months and the most common intensive regimen was a combination of isoniazid, ethambutol, pyrazinamide, and fluoroquinolone (25%). The most common consolidation regimen was a combination of isoniazid, ethambutol, and fluoroquinolone (22.8%). Among the patients with a favorable response, two (2.2%) experienced recurrence after a follow-up of 3.4 (interquartile range 1.8–6.8) years. For patients with drug-susceptible pulmonary tuberculosis who do not tolerate rifampicin owing to its toxicity, a shorter regimen may be a useful alternative.

Abstract Background Numerous epidemiological studies investigating gender-dependent clinical outcomes in sepsis have shown conflicting evidence. This study aimed to investigate the effect of gender on in-hospital mortality due to sepsis according to age group. Methods This study used data from the Korean Sepsis Alliance, an ongoing nationwide prospective multicenter cohort from 19 participating hospitals in South Korea. All adult patients diagnosed with sepsis in the emergency departments of the participating hospitals between September 2019 and December 2021 were included in the analysis. Clinical characteristics and outcomes were compared between male and female. Eligible patients were stratified by age into 19–50 years, 50–80 years, and ≥ 80 years old individuals. Results During the study period, 6442 patients were included in the analysis, and 3650 (56.7%) were male. The adjusted odds ratio (OR) [95% confidence interval (CI)] for in-hospital mortality for male compared with female was 1.15 (95% CI = 1.02–1.29). Interestingly, in the age 19–50 group, the risk of in-hospital mortality for males was significantly lower than that of females [0.57 (95% CI = 0.35–0.93)]. For female, the risk of death remained relatively stable until around age 80 (P for linearity = 0.77), while in males, there was a linear increase in the risk of in-hospital death until around age 80 (P for linearity

Abstract A uniform prognostic marker is needed for nontuberculous mycobacterial pulmonary disease (NTM-PD) due to the diverse clinical course. We aimed to seek the utility of the BACES score, originally derived to predict all-cause mortality, for various outcomes. To calculate the BACES score, one point was given for each of the following factors: body mass index

Background Coronavirus disease 2019 (COVID-19) is an ongoing global public health threat and different variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been identified. This study aimed to analyse the factors associated with negative conversion of polymerase chain reaction (PCR) and prognosis in critically ill patients according to the SARS-CoV-2 variant. Methods This study retrospectively analysed 259 critically ill patients with COVID-19 who were admitted to the intensive care unit of a tertiary medical center between January 2020 and May 2022. The Charlson comorbidity index (CCI) was used to evaluate comorbidity, and a negative PCR test result within 2 weeks was used to define negative PCR conversion. The cases were divided into the following three variant groups, according to the documented variant of SARS-CoV-2 at the time of diagnosis: non-Delta (January 20, 2020–July 6, 2021), Delta (July 7, 2021– January 1, 2022), and Omicron (January 30, 2022–April 24, 2022). Results The mean age of the 259 patients was 67.1 years and 93 (35.9%) patients were female. Fifty (19.3%) patients were smokers, and 50 (19.3%) patients were vaccinated. The CCI (hazard ratio [HR], 1.555; p

Abstract Higher blood monocyte counts are related to worse survival in idiopathic pulmonary fibrosis. However, studies evaluating the association between blood monocyte counts and clinical outcomes of idiopathic nonspecific interstitial pneumonia (iNSIP) are lacking. We evaluated the impact of monocyte counts on iNSIP prognosis. iNSIP patients (n = 126; median age, 60 years; female, n = 64 [50.8%]) diagnosed by surgical lung biopsy were enrolled and categorized into low (monocyte

Abstract The clinical implication of using serum tumor markers in patients with interstitial lung disease (ILD) is inconclusive. In this retrospective study, we analyzed the data of 1176 subjects (294 with ILDs and 882 healthy controls). Eligible patients were who had at least one or more available tumor marker results [carbohydrate antigen (CA) 19-9, CA 125, and carcinoembryonic antigen (CEA)] with no evidence of malignancies or other benign diseases that could be related to the increasing concentration of the values. The healthy controls selected from a health screening program were also screened for the presence of active cancer, and matched at a ratio of 1:3 with age and sex. The proportion of patients with abnormal values in the ILD group (121, idiopathic pulmonary fibrosis (IPF); 173, non-IPF-ILDs) was higher than in the matched control group (CEA, 21.5% vs. 5.5%; CA 19-9, 27.9% vs. 4.0%; CA 125, 36.4% vs. 2.0%). In the multivariable analysis, higher CEA levels were associated with shorter survival after adjusting for age, sex, lung function, and ILD subtypes (hazard ratio: 2.323, 95% confidence interval: 1.271–4.248, P = 0.006). In subgroup analysis, CEA remained a prognostic factor in patients with non-IPF-ILDs, but not in those with IPF.

Abstract There have been limited studies on the association between prognosis and body weight change in patients with idiopathic pulmonary fibrosis (IPF). This single-center retrospective observational study evaluated the impact of weight loss on outcomes in Korean patients with IPF receiving pirfenidone at a tertiary medical institution. We analyzed 215 IPF patients prescribed pirfenidone from January 1st, 2015 to December 31st, 2019. The patients were categorized into maintained weight (MW; weight gain or loss

Background Enteral nutrition (EN) supply within 48 hours after intensive care unit (ICU) admission improves clinical outcomes. The “new ICU evaluation & development of nutritional support protocol (NICE-NST)” was introduced in an ICU of tertiary academic hospital. This study showed that early EN through protocolized nutritional support would supply more nutrition to improve clinical outcomes. Methods This study screened 170 patients and 62 patients were finally enrolled; patients who were supplied nutrition without the protocol were classified as the control group (n=40), while those who were supplied according to the protocol were classified as the test group (n=22). Results In the test group, EN started significantly earlier (3.7±0.4 days vs. 2.4±0.5 days, P=0.010). EN calorie (4.0±1.0 kcal/kg vs. 6.7±0.9 kcal/kg, P=0.006) and protein (0.17±0.04 g/kg vs. 0.32±0.04 g/kg, P=0.002) supplied were significantly higher in the test group. Although EN was supplied through continuous feeding in the test group, there was no difference in complications such as feeding hold due to excessive gastric residual volume or vomit, and hyper- or hypo-glycemia between the two groups. Hospital mortality was significantly lower in the group that started EN within 1.5 days (42.9% vs. 11.8%, P=0.018). The proportion of patients who started EN within 1.5 days was higher in the test group (40.9% vs. 17.5%, P=0.044). Conclusions The NICE-NST may improve EN supply and mortality of critically ill patients without increasing complications.

Abstract Although previous studies have demonstrated increased depression related to COVID-19, the reasons for this are not well-understood. We investigated the association of compliance with COVID-19 public health measures with depression. Data from the 2020 Korea Community Health Survey were analyzed. The main independent variable was compliance with rules based on three performance variables (social distancing, wearing a mask in indoor facilities, and outdoors). Depression was assessed using Patient Health Questionnaire-9 scores. Of 195,243 participants, 5,101 participants had depression. Bad and moderate performance scores for compliance were associated with depression (Bad score, men: adjusted odds ratio [aOR] = 2.24, 95% confidence interval [CI] = 1.29–3.87; women: aOR = 2.42, 95% CI = 1.42–4.13; moderate score, men: aOR = 1.31, 95% CI = 1.02–1.68; women: aOR = 1.28, 95% CI = 1.07–1.53). In the subgroup analysis, among the quarantine rules, not wearing a mask indoors was the most prominently associated with depression. In participants with a high level of education, non-compliance with quarantine rules was significantly associated with depression. People who do not comply with public health measures are more likely to be depressed. The preparation and observance of scientific quarantine rules can help mental health in the ongoing COVID-19 pandemic and another infectious disease pandemic that may come.

Abstract Background Electromagnetic navigation bronchoscopy (ENB) is an emerging advanced imaging-guided bronchoscopy technique for diagnosing peripheral lung lesions. However, the selection strategy for the optimal biopsy device and whether adopting a multi-tool strategy increases the diagnostic yield remains undetermined. The CONFIDENT-ENB trial (NCT05110131) is a prospective randomized study on ENB, performed in a least-invasive setting. The primary aim is to evaluate whether a combination of needle aspiration and forceps biopsy improves the diagnostic performance, and assess the comparative diagnostic value and discordance of the two devices. Methods The trial will recruit 142 participants with lung lesions suspected of malignancy who are eligible for an elective ENB procedure under moderate sedation. Participants will undergo ENB-guided needle aspiration and forceps biopsy in a randomized order without the use of any complementary techniques. All participants will be followed up subsequently for up to 12 months to conclude the final diagnosis of the biopsied lesions. Primary outcomes include the diagnostic yield and sensitivity of each biopsy modality and the diagnostic yield of the combined modalities. Discussion The CONFIDENT-ENB trial will prospectively evaluate the synergistic effectiveness and comparative accuracy of ENB-guided needle aspiration and forceps biopsy in a least-invasive setting. The results are expected to improve our understanding of the optimal tool-selection strategy for ENB. Trial registration: ClinicalTrials.gov (NCT05110131). Prospectively registered on 5 November 2021.

Background: There is little information on the optimal storage conditions for recovery of nontuberculous Mycobacterium spp. (NTM) from refrigerated sputum. Objectives: We investigated the storage duration that could increase the culture-positive rate of NTM isolates. Design: In this prospective study, we collected NTM isolates and clinical data from patients with repeated culture-positive NTM pulmonary disease (NTM-PD). Methods: From June 2020 to July 2021, the participants were instructed to randomly collect six sputum samples and immediately store them in a refrigerator at 4°C until the date of their clinic visit. At the outpatient visits, expectorated spot sputum samples were collected. Results: A total of 226 sputum samples were collected from 35 patients. The median duration of refrigeration was 6 days (maximum duration: 36 days). The overall culture-positive rate was 81.6%. While there was a trend for a higher culture positivity rate when stored for ⩽3 weeks, this was not significant compared with those stored for >3 weeks ( p = 0.610). According to sputum microscopy, smear-positive sputum was 100% isolated, but smear-negative samples had a culture-positive rate of 77.5%. Similarly, there was no significant association between sputum storage duration and culture positivity ( p = 0.511). In addition, the recovery rate of the refrigerated sputum was comparable with the collected spot expectorated sputum (82.6% versus 80.6%, p = 0.795), which is suggestive of the long-term viability of NTM in refrigerated sputum. Conclusion: Our data demonstrated the long-term viability of refrigerated NTM, and the culture positivity rate of these samples was comparable with the spot expectorated sputum. These results suggest that implementing sputum refrigeration would enhance convenience in diagnosing and following patients with NTM-PD. Plain language summary Easy way to diagnose NTM lung diseases Under usual circumstances, most patients with suspected NTM submit spontaneously expectorated sputum rather than induced sputum for the purpose of testing the causative organism. By collecting and storing sputum specimens for a longer period than before, it is expected that more sufficient and adequate collection of sputum specimens will be possible.

This study investigated the influence of hypoxic culture conditions on human nasal inferior turbinate-derived stem cells (hNTSCs), a subtype of mesenchymal stem cells (MSCs). It aimed to discern how hypoxia affected hNTSC characteristics, proliferation, and differentiation potential compared to hNTSCs cultured under normal oxygen levels. After obtaining hNTSCs from five patients, the samples were divided into hypoxic and normoxic groups. The investigation utilized fluorescence-activated cell sorting (FACS) for surface marker analysis, cell counting kit-8 assays for proliferation assessment, and multiplex immunoassays for cytokine secretion study. Differentiation potential—osteogenic, chondrogenic, and adipogenic—was evaluated via histological examination and gene expression analysis. Results indicated that hNTSCs under hypoxic conditions preserved their characteristic MSC phenotype, as confirmed by FACS analysis demonstrating the absence of hematopoietic markers and presence of MSC markers. Proliferation of hNTSCs remained unaffected by hypoxia. Cytokine expression showed similarity between hypoxic and normoxic groups throughout cultivation. Nevertheless, hypoxic conditions reduced the osteogenic and promoted adipogenic differentiation potential, while chondrogenic differentiation was relatively unchanged. These insights contribute to understanding hNTSC behavior in hypoxic environments, advancing the development of protocols for stem cell therapies and tissue engineering.

Background A laparoscopic approach is widely used in abdominal surgery. Although several studies have compared surgical and oncological outcomes between laparoscopic surgery (LS) and open surgery (OS) in rectal cancer patients, there have been few studies on postoperative renal outcomes. Methods We conducted a retrospective cohort study involving 1,633 patients who underwent rectal cancer surgery between 2003 and 2017. Postoperative acute kidney injury (AKI) was diagnosed according to the serum creatinine criteria of the Kidney Disease: Improving Global Outcomes classification. Results Among the 1,633 patients, 1,072 (65.6%) underwent LS. After matching propensity scores, 395 patients were included in each group. The incidence of postoperative AKI in the LS group was significantly lower than in the OS group (9.9% vs. 15.9%; p = 0.01). Operation time, estimated blood loss, and incidence of transfusion in the LS group were significantly lower than those in the OS group. Cox proportional hazard models revealed that LS was associated with decreased risk of postoperative AKI (hazard ratio [HR], 0.599; 95% confidence interval [CI], 0.402–0.893; p = 0.01) and postoperative transfusion was associated with increased risk of AKI (HR, 2.495; 95% CI, 1.529–4.072; p < 0.001). In the subgroup analysis, the incidence of postoperative AKI in patients with middle or high rectal cancer who underwent LS was much lower than in those who underwent OS (HR, 0.373; 95% CI, 0.197–0.705; p = 0.002). Conclusion This study showed that LS may have a favorable effect on the development of postoperative AKI in patients with rectal cancer.

Malnutrition in critically ill patients is closely linked with clinical outcomes. During acute inflammatory states, nutrition cannot reverse the loss of body cell mass completely. Studies on nutritional screening and strategy considering metabolic changes have not yet been conducted. We aimed to identify nutrition strategies using the modified Nutrition Risk in the Critically ill (mNUTIRC) score. Nutrition support data, laboratory nutrition indicators, and prognosis indices were prospectively collected on the 2nd and 7th day after admission. It was to identify the effect of the changes on the metabolic status and critical target of nutrition intervention. To discriminate the high-risk group of malnutrition, receiver operating characteristic curves were plotted. Risk factors associated with 28 day-mortality were evaluated using multivariable Cox proportional hazards regression. A total of 490 and 266 patients were analyzed on the 2nd and 7th day, respectively. Only the mNUTRIC score showed significant differences in nutritional risk stratification. The use of vasopressors, hypoprotein supply (

Purpose: Due to the shortage of lung donors relative to the number of patients waiting for lung transplantation (LTx), more than one-third of patients on the waitlist have died without receiving LTx in Korea. Therefore, the importance of fair and effective allocation policies has been emphasized. This study investigated the characteristics of the current urgency-based allocation system in Korea by simulating the Eurotransplant lung allocation score (ET-LAS) using a nationwide multi-institutional registry for LTx in Korea. Materials and Methods: This study used data from the Korean Organ Transplantation Registry (KOTRY), along with additional retrospective data for ET-LAS calculation. A total of 194 patients were included in this study between January 2015 and December 2019. The Korean urgency definition classifies an LTx candidate as having statuses 0–3 according to urgency. The ET-LAS was analyzed according to the Korean urgency status. Results: In total, 92 patients received lung transplants at status 0, 85 at status 1, and 17 at status 2/3. The ET-LAS showed a bimodal distribution with distinct peaks corresponding to status 0 and non-status 0. There was no significant difference in the ET-LAS among non-status 0 patients. In logistic and decision tree analyses, oxygen supplementation methods, particularly oxygen masks and high-flow nasal cannulas, were significantly associated with a high ET-LAS (≥50) among non-status 0 patients. Conclusion: Simulation of the ET-LAS with KOTRY data showed that the Korean urgency definition may not allocate lungs by urgency, especially for patients in non-status 0; therefore, it needs to be revised. [ABSTRACT FROM AUTHOR]

Background/Aims Current evidence supports lung ultrasound as a point-of-care alternative diagnostic tool for various respiratory diseases. We sought to determine the utility of lung ultrasound for early detection of pneumonia and for assessment of respiratory failure among patients with coronavirus disease 2019 (COVID-19). Methods Six patients with confirmed COVID-19 by reverse transcription-polymerase chain reaction were enrolled. All had undergone chest X-ray and chest computed tomography (CT) on the day of admission and underwent multiple point-of-care lung ultrasound scans over the course of their hospitalization. Results Lung ultrasound detected early abnormal findings of representative B-lines in a patient with a normal chest X-ray, corresponding to ground-glass opacities on the chest CT scan. The ultrasound findings improved as her clinical condition improved and her viral load decreased. In another minimally symptomatic patient without significant chest X-ray findings, the ultrasound showed B-lines, an early sign of pneumonia before abnormalities were detected on the chest CT scan. In two critically ill patients, ultrasound was performed to assess for evaluation of disease severity. In both patients, the clinicians conducted emergency rapid sequence intubation based on the ultrasound findings without awaiting the laboratory results and radiological reports. In two children, ultrasound was used to assess the improvement in their pneumonia, thus avoiding further imaging tests such as chest CT. Conclusions Lung ultrasound is feasible and useful as a rapid, sensitive, and affordable point-of-care screening tool to detect pneumonia and assess the severity of respiratory failure in patients hospitalized with COVID-19.

Background/Aims Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been recently discovered and validated as sensitive biomarkers that can predict stage 2 or 3 acute kidney injury (AKI) development in high-risk patients. We aimed to assess whether these biomarkers could predict adverse outcomes and renal recovery in established AKI patients. Methods This was a single-center study prospectively enrolling 124 patients diagnosed with AKI. TIMP-2, IGFBP7, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (KIM-1) levels were measured at the time of diagnosis and the predictive performance of short-term outcomes and renal recovery was assessed. Results Patients were divided into 4 quartiles according to the initial urinary TIMP-2/IGFBP7 levels. Stage 3 AKI (odds ratio [OR], 17.86), classified by the Kidney Disease Improving Global Outcomes (KDIGO), as well as the third and fourth quartiles of TIMP-2/IGFBP7 (OR, 5.75 and 44.98, respectively), were found to be independent predictors of renal replacement therapy at the time of AKI diagnosis. In addition, KDIGO stage 3 AKI (OR, 2.468) or the third of fourth quartiles of urinary TIMP-2/IGFBP7 (OR, 1.896 and 3.622, respectively) were also found to be useful in predicting nonrecovery of renal function. In a separate analysis of patients with renal recovery at discharge, initial urinary TIMP-2/IGFBP7 or urinary IGFBP7 at discharge could also predict new-onset or progressive chronic kidney disease (CKD). Conclusions In AKI patients, urine TIMP-2/IGFBP7 could serve as a biomarker for predicting adverse outcomes, renal recovery, or the development and progression of CKD.

Background: Administration of pancreatic endoplasmic reticulum kinase inhibitor (PERKi) improved insulin secretion and hyperglycemia in obese diabetic mice. In this study, autophagic balance was studied whether to mediate it. Methods: Human islets were isolated from living patients without diabetes. PERKi GSK2606414 effects were evaluated in the islets under glucolipotoxicity by palmitate. Islet insulin contents and secretion were measured. Autophagic flux was assessed by microtubule associated protein 1 light chain 3 (LC3) conversion, a red fluorescent protein (RFP)-green fluorescent protein (GFP)- LC3 tandem assay, and P62 levels. For mechanical analyses, autophagy was suppressed using 3-methyladenine in mouse islets. Small interfering RNA for an autophagy-related gene autophagy related 7 (Atg7) was transfected to interfere autophagy. Results: PERKi administration to mice decreased diabetes-induced P62 levels in the islets. Glucolipotoxicity significantly increased PERK phosphorylation by 70% and decreased insulin contents by 50% in human islets, and addition of PERKi (40 to 80 nM) recovered both. PERKi also enhanced glucose-stimulated insulin secretion (6-fold). PERKi up-regulated LC3 conversion suppressed by glucolipotoxicity, and down-regulated P62 contents without changes in P62 transcription, indicating enhanced autophagic flux. Increased autophagosome-lysosome fusion by PERKi was visualized in mouse islets, where PERKi enhanced ATG7 bound to LC3. Suppression of Atg7 eliminated PERKi-induced insulin contents and secretion. Conclusion: This study provided functional changes of human islets with regard to autophagy under glucolipotoxicity, and suggested modulation of autophagy as an anti-diabetic mechanism of PERKi. [ABSTRACT FROM AUTHOR]

BackgroundPyrazinamide (PZA) is a common drug that causes serious adverse events (SAEs). The aim of this study was to determine the incidence of and risk factors for SAEs due to PZA during first-line anti-tuberculosis treatment.MethodsThe medical records of patients with tuberculosis (TB) treated with PZA-containing regimens including first-line drugs-ethambutol, rifampicin, and isoniazid-from January 2003 to June 2016 were reviewed. SAEs were defined as side effects that led to drug discontinuation. The causative drug was determined based on the disappearance of the SAEs upon drug withdrawal and/or the recurrence of the same SAEs with re-challenge.ResultsOf 2,478 patients with TB, 16.4% experienced SAEs. The incidence of SAEs increased significantly as age increased, except with rifampin. PZA accounted for most SAEs (55.8%). Hepatotoxicity was the most common SAE due to PZA (44.5%), followed by gastrointestinal (GI) intolerance (23.8%). The risk of SAEs due to PZA increased significantly as age increased, when sex and comorbidities were adjusted (odds ratio, 1.013; 95% confidence interval, 1.004-1.023; P = 0.007). In the subgroup analysis, older age was an independent risk factor for GI intolerance but not for hepatotoxicity.ConclusionPZA was the most common drug associated with SAEs among the first-line anti-TB drugs, and old age was an independent factor for SAE occurrence. This study suggests that the early recognition of whether the causative agent is PZA may improve effective treatment compliance, particularly in elderly patients.

Background: New variants of the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic continue to emerge. However, little is known about the effect of these variants on clinical outcomes. This study evaluated the risk factors for poor pulmonary lung function test (PFT). Methods: The study retrospectively analyzed 87 patients in a single hospital and followed up by performing PFTs at an outpatient clinic from January 2020 to December 2021. COVID-19 variants were categorized as either a non-delta variant (November 13, 2020-July 6, 2021) or the delta variant (July 7, 2021-January 29, 2022). Results: The median age of the patients was 62 years, and 56 patients (64.4%) were male. Mechanical ventilation (MV) was provided for 52 patients, and 36 (41.4%) had restrictive lung defects. Forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) were lower in patients on MV. Male sex (odds ratio [OR], 0.228) and MV (OR, 4.663) were significant factors for decreased DLCO. The duration of MV was associated with decreased FVC and DLCO. However, the type of variant did not affect the decrease in FVC (P=0.750) and DLCO (P=0.639). Conclusions: Among critically ill COVID-19 patients, 40% had restrictive patterns with decreased DLCO. The reduction of PFT was associated with MV, type of variants. [ABSTRACT FROM AUTHOR]

Research on vitamin D in patients with nontuberculous mycobacterial (NTM) pulmonary disease (PD) is limited. We aimed to compare the vitamin D parameters of patients with NTM-PD to those of a healthy control group, and to assess the possible predictive markers for a clinical response. We prospectively enrolled 53 patients with NTM-PD between January 2014 and December 2016. The clinical data and vitamin D indices, including total, free, bioavailable 25-(OH)D, and vitamin D binding protein (VDBP) genotyping, were measured at baseline and six months after enrollment. An external dataset of 226 healthy controls was compared with the NTM-PD group. The mean age of subjects was 53 years; 54.5% were male. The NTM-PD group was older, predominantly female, and had a lower body mass index (BMI) than the controls. The proportion of patients with vitamin D concentration p = 0.789). The bioavailable 25-(OH)D concentrations of the NTM-PD group and the controls were similar (6.9 nmol/L vs. 7.6 nmol/L, p = 0.280). In the multivariable analysis, bioavailable 25-(OH)D concentrations were associated with NTM-PD, adjusting for age, sex, BMI, and VDBP levels. Bioavailable 25-(OH)D concentrations were significantly associated with susceptibility to NTM-PD, but not with treatment outcomes. Lower bioavailable 25-(OH)D might be a risk factor for NTM-PD.

Low-tidal-volume ventilation decreases mortality in acute respiratory distress syndrome (ARDS) patients. This study investigated the effects of ultralow tidal ventilation under veno-venous extracorporeal membrane oxygenator (ECMO) support in pigs with ARDS. Eight pigs were intubated and inoculated with methicillin-resistant Staphylococcus aureus through bronchoscopy. Ultralow tidal ventilation (3 mL/kg) under extracorporeal membrane oxygenator (ECMO) support was applied to one group and high tidal ventilation (15 mL/kg) was applied to another group to maintain comparable oxygenation for 12 h without ECMO support. Each group had similar arterial blood gas values and hemodynamic variables at baseline and during the experiment. The high-tidal-volume ventilation group showed a gradual decline in arterial oxygen levels, and repeated ANOVA showed significant differences in oxygenation change over time in the ultralow tidal ventilation group. Inflammatory cytokine levels in the bronchoalveolar lavage fluid and lung ultrasound scores were similar between two groups. Histologic analysis showed that both groups developed pneumonia after 12 h; however, the ultralow tidal ventilation group had a lower lung injury score assessed by the pathologist. We developed the first ultralow-tidal-volume ventilation porcine model under veno-venous ECMO support. The ultralow-tidal-volume ventilation strategy can mitigate mechanical ventilator-associated lung injury.

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7614.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of >30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. [ABSTRACT FROM AUTHOR]

Background/Aims: CD40 agonists are thought to generate antitumor effects on pancreatic cancer via macrophages and T cells. We aimed to investigate the role of CD40 agonists in the differentiation of macrophages and treatment of human pancreatic adenocarcinoma. Methods: Immunohistochemistry was performed on paraffin-embedded surgical blocks from patients with pancreatic cancers to evaluate macrophage phenotypes and their relationship with survival. The effects of CD40 agonists on macrophage phenotypes and human pancreatic cancer were evaluated utilizing cell cocultures and organotypic slice cultures. Results: CD163+ (predominant in M2 macrophages) and FOXP3+ (predominant in regulatory T cells) expression levels in the tumors were significantly lower in patients with stage IB pancreatic cancer than in those with stage II or III disease (p=0.002 and p=0.003, respectively). Patients with high CD163+ expression had shorter overall survival than those with low CD163+ expression (p=0.002). In vitro treatment of THP-1 macrophages with a CD40 agonist led to an increase in HLA-DR+ (predominant in M1 macrophages) and a decrease in CD163+ expression in THP-1 cells. Cell cocultures showed that CD40 agonists facilitate the suppression of PANC-1 human pancreatic cancer cells by THP-1 macrophages. Organotypic slice cultures showed that CD40 agonists alter the pancreatic cancer microenvironment by shifting the macrophage phenotype toward M1 (increase HLA-DR+ and decrease CD163+ expression), decreasing the abundance of regulatory T cells, and increasing tumor cell apoptosis. Conclusions: CD163 is related to advanced human pancreatic cancer stages and shorter overall survival. CD40 agonists alter macrophage phenotype polarization to favor the M1 phenotype and suppress human pancreatic cancer. [ABSTRACT FROM AUTHOR]

Caspases are a family of cysteine aspartyl proteases mostly involved in the execution of apoptotic cell death and in regulating inflammation. This article focuses primarily on the evolutionarily conserved function of caspases in apoptosis. We summarise which caspases are involved in apoptosis, how they are activated and regulated, and what substrates they target for cleavage to orchestrate programmed cell death by apoptosis. [ABSTRACT FROM AUTHOR]

Background: Limited data are available regarding the management of subsolid nodules detected on lung cancer screening with low-dose CT (LDCT). We aimed to determine the characteristics of screen-detected subsolid nodules, and to evaluate the probability of lung cancer and the clinical course of subsolid nodules detected at baseline and during follow-up screening.Methods: We evaluated 50 132 asymptomatic adults (22 631 never-smokers and 27 501 ever-smokers) who underwent LDCT screening for lung cancer between May 2003 and June 2019 at a tertiary centre in South Korea. The incidence, characteristics and clinical outcomes of the baseline and new screen-detected subsolid nodules were determined.Results: A total of 6725 subsolid nodules (5116 pure ground glass opacity nodules and 1609 part-solid nodules) were detected in 4545 participants (1484 new subsolid nodules detected in 937 (1.9%) participants; the overall incidence of subsolid nodules: 10.7% in never-smokers and 7.7% in ever-smokers, p<0.001). Among 4918 subsolid nodules that underwent follow-up with CT scans (the mean number of CT scans, including the baseline LDCT scan: 4.6), 2116 nodules (30.0% of baseline subsolid nodules and 78.9% of new subsolid nodules) resolved spontaneously. Among 293 biopsied subsolid nodules, 227 (77.5%) nodules were diagnosed as lung cancer, of which 226 (99.6%) were adenocarcinomas. No significant difference was observed in pathological invasiveness or the initial stage between the baseline and new cancerous subsolid nodules. Multivariable analyses revealed that new detection at follow-up screening was significantly associated with a lower probability of lung cancer (OR 0.26, 95% CI 0.14 to 0.49) and overall growth (OR 0.39, 95% CI 0.26 to 0.59), but with a higher probability of resolution (OR 6.30, 95% CI 5.09 to 7.81).Conclusions: LDCT screening led to a considerably high rate of subsolid nodule detection, particularly in never-smokers. Compared with the baseline subsolid nodules, the new subsolid nodules were associated with a lower probability of lung cancer and higher probability of spontaneous resolution, indicating their more inflammatory nature. Less aggressive follow-up may be allowed for new subsolid nodules, particularly in screening programmes for Asian populations. [ABSTRACT FROM AUTHOR]

Background: The present study was the first attempt to explore the characteristics of ginsenoside-Rg3 (Rg3) on release of catecholamines (CA) in the perfused rat adrenal medullae and also to verify the underlying action mechanism. Materials and Methods: The adrenal medulla was separated by some modification of the previous method and perfused with Krebs solution. CA was assayed directly by the fluorometry. Results: Rg3 reduced acetylcholine (ACh)-produced CA release in a dose- and time-dependent manner. Rg3 time-dependently depressed CA release produced by 3-(m-chloro-phenyl-carbamoyl-oxy)-2-butynyltrimethyl ammonium chloride (McN-A-343), 1,1-dimethyl-4-phenyl piperazinium iodide, and angiotensin II. In the presence of Rg3, the CA release produced by high K+, veratridine, cyclopiazonic acid, and methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl-phenyl)-pyridine-5-carboxylate (Bay-K-8644) was also markedly suppressed. However, during the simultaneous perfusion of Rg3 and N?-nitro-l-arginine methyl ester hydrochloride (l-NAME), the release of CA produced by ACh, angiotensin II, Bay-K-8644, and veratridine was restored closely to the level of each control, in contrast to that of Rg3-treatment alone. The nitric oxide (NO) release was significantly elevated by Rg3-treatment. Furthermore, in the coexistence of Rg3 and fimasartan, AChproduced CA release was more significantly reduced as compared to that of fimasartan-treatment alone. Conclusions: We present the first evidence that Rg3 markedly depresses the CA secretion produced by activation of neuronal cholinergic and angiotensinergic receptors. Rg3-produced inhibition appears to be evoked not only by blocking the inflow of Na+ and Ca2+ into adrenomedullary cells but also by preventing the Ca2+ release from intracellular storage, partly through enhancement of NO release by NO synthase activation. Coadministration of Rg3 and fimasartan may be clinically beneficial for the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Aβ) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aβ. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Aβ and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Aβ and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Aβ and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Maxillary sinus mucocele can occur due to many medical factors such as chronic infection, allergic sinonasal disease, trauma, and previous surgery. However, it occurs mainly after Caldwell-Luc operation, usually more than 10 years after surgery. There are a few cases of maxillary sinus mucocele with ocular symptoms. Also, a case causing ocular symptoms because of invasion to the orbital floor is rare. Therefore, we report a case of a 55-year-old male patient who underwent Caldwell-Luc operation about 30 years ago. Then, symptoms such as exophthalmos, diplopia, and visual disturbance developed suddenly 3 months prior to admission. Computed tomography showed a cyst invading the orbital floor which resulted in eyeball deviation. The orbital floor defect measured approximately 2.5x3.3 cm. Maxillary sinus mucocele was removed through an endoscopic approach. After this, we reconstructed the orbital floor through a subciliary incision. Observation was carried out after three years, and ocular symptoms such as diplopia and exophthalmos did not recur. [ABSTRACT FROM AUTHOR]

The superior gluteal artery perforator flap technique has increasingly been used for soft tissue defects in the sacral area following its introduction nearly 25 years ago. Advantages in covering sacral defects include muscle sparing, versatility in design, and low donor side morbidity. The bilateral superior gluteal artery perforator flap procedure is planned in cases of large sacral defects that cannot be covered with the unilateral superior gluteal artery perforator flap. Here, we report two cases of large sacral defects in which patient factors of poor general health, such as old age, pneumonia, and previous operation scar, led to use of a large unilateral superior gluteal artery perforator super-flap with parasacral perforator. The approach was utilized to reduce the operation time and prevent unpredictable flap failure due to the large flap size. Even though the parasacral perforator was included, the versatility of the large superior gluteal artery perforator flap was preserved because sufficient perforator length was acquired after adequate dissection. [ABSTRACT FROM AUTHOR]

Due to the fact that it reliably results in positive outcomes, lymph node flap transfer is becoming an increasingly popular surgical procedure for the prevention and treatment of lymphedema. This technique has been shown to stimulate lymphoangiogenesis and restore lymphatic function, as well as decreasing infection rates, minimizing pain, and preventing the recurrence of lymphedema. In this article, we investigate possible additional benefits of lymph node flap transfer, primarily the possibility that sentinel lymph nodes may be used to detect micrometastasis or in-transit metastasis and may function as an additional lymphatic station after the excision of advanced skin cancer. [ABSTRACT FROM AUTHOR]

There are two forms of brain-derived neurotrophic factor (BDNF), precursor of BDNF (proBDNF) and mature BDNF, which each exert opposing effects through two different transmembrane receptor signaling systems, consisting of p75 neurotrophin receptor (p75NTR) and tyrosine receptor kinase B (TrkB). Previous studies have demonstrated that proBDNF promotes cell death and inhibits the growth and migration of C6 glioma cells through p75NTR in vitro, while mature BDNF has opposite effects on C6 glioma cells. It is hypothesized that mature BDNF is essential in the development of malignancy in gliomas. However, histological data obtained in previous studies were unable distinguish mature BDNF from proBDNF due to the lack of specific antibodies. The present study investigated the expression of mature BDNF using a specific sheep monoclonal anti-mature BDNF antibody in 42 human glioma tissues of different grades and 10 control tissues. The correlation between mature BDNF and TrkB was analyzed. Mature BDNF expression was significantly increased in high-grade gliomas, and was positively correlated with the malignancy of the tumor and TrkB receptor expression. The present data have demonstrated that increased levels of mature BDNF contribute markedly to the development of malignancy of human gliomas through the primary BDNF receptor TrkB. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate whether ginsenoside-Rb2 (Rb2) can affect the secretion of catecholamines (CA) in the perfused model of the rat adrenal medulla. Rb2 (3∼ 30 μM), perfused into an adrenal vein for 90 min, inhibited ACh (5.32 mM)-evoked CA secretory response in a dose- and time-dependent fashion. Rb2 (10 μM) also time-dependently inhibited the CA secretion evoked by DMPP (100 μM, a selective neuronal nicotinic receptor agonist) and high K+ (56 mM, a direct membrane depolarizer). Rb2 itself did not affect basal CA secretion (data not shown). Also, in the presence of Rb2 (50 μg/mL), the secretory responses of CA evoked by veratridine (a selective Na+ channel activator (50 μM), Bay-K-8644 (an L-type dihydropyridine Ca2+ channel activator, 10 μM), and cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor, 10 μM) were significantly reduced, respectively. Interestingly, in the simultaneous presence of Rb2 (10 μM) and L-NAME (an inhibitor of NO synthase, 30 μM), the inhibitory responses of Rb2 on ACh-evoked CA secretory response was considerably recovered to the extent of the corresponding control secretion compared with the inhibitory effect of Rb2-treatment alone. Practically, the level of NO released from adrenal medulla after the treatment of Rb2 (10 μM) was greatly elevated compared to the corresponding basal released level. Collectively, these results demonstrate that Rb2 inhibits the CA secretory responses evoked by nicotinic stimulation as well as by direct membrane-depolarization from the isolated perfused rat adrenal medulla. It seems that this inhibitory effect of Rb2 is mediated by inhibiting both the influx of Ca2+ and Na+ into the adrenomedullary chromaffin cells and also by suppressing the release of Ca2+ from the cytoplasmic calcium store, at least partly through the increased NO production due to the activation of nitric oxide synthase, which is relevant to neuronal nicotinic receptor blockade. [ABSTRACT FROM AUTHOR]