Genetic mapping across autoimmune diseases reveals shared associations and mechanisms.

Autoimmune and inflammatory diseases are polygenic disorders of the immune system. Many genomic loci harbor risk alleles for several diseases, but the limited resolution of genetic mapping prevents determining whether the same allele is responsible, indicating a shared underlying mechanism. Here, using a collection of 129,058 cases and controls across 6 diseases, we show that ~40% of overlapping associations are due to the same allele. We improve fine-mapping resolution for shared alleles twofold by combining cases and controls across diseases, allowing us to identify more expression quantitative trait loci driven by the shared alleles. The patterns indicate widespread sharing of pathogenic mechanisms but not a single global autoimmune mechanism. Our approach can be applied to any set of traits and is particularly valuable as sample collections become depleted.

Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

Erector spinae plane block level does not impact analgesic efficacy in enhanced recovery for lumbar spine surgery.

BACKGROUND CONTEXT: Postoperative pain control following spine surgery can be difficult. The Enhanced Recovery After Surgery (ERAS) programs use multimodal approaches to manage postoperative pain. While an erector spinae plane block (ESPB) is commonly utilized, the ideal distance for injection from the incision, referred to as the ES (ESPB to mid-surgical level) distance, remains undetermined. PURPOSE: We evaluated the impact of varying ES distances for ESPB on Numerical Rating Scale (NRS) measures of postoperative pain within the ERAS protocol. STUDY DESIGN/SETTING: Retrospective observational study. PATIENT SAMPLE: Adult patients who underwent elective lumbar spine fusion surgery. OUTCOME MEASURES: Primary outcome measures include the comparative postoperative NRS scores across groups at immediate (T1), 24 (T2), 48 (T3), and 72 (T4) hours postsurgery. For secondary outcomes, a propensity matching analysis compared these outcomes between the ERAS and non-ERAS groups, with opioid-related recovery metrics also assessed. METHODS: All included patients were assigned to one of three ERAS groups according to the ES distance: Group 1 (G1, ES > 3 segments), Group 2 (G2, ES = 2-3 segments), and Group 3 (G3, ES<2 segments). Each patient underwent a bilateral ultrasound-guided ESPB with 60 mL of diluted ropivacaine or bupivacaine. RESULTS: Patients within the ERAS cohort reported mild pain (NRS < 3), with no significant NRS variation across G1 to G3 at any time. Sixty-five patients were matched across ERAS and non-ERAS groups. The ERAS group exhibited significantly lower NRS scores from T1 to T3 than the non-ERAS group. Total morphine consumption during hospitalization was 26.7 mg for ERAS and 41.5 mg for non-ERAS patients. The ERAS group resumed water and food intake sooner and had less postoperative nausea and vomiting. CONCLUSIONS: ESPBs can be effectively administered at or near the mid-surgical level to the low thoracic region for lumbar spine surgeries. Given challenges with sonovisualization, a lumbar ESPB may be preferred to minimize the risk of inadvertent pleural injury.

Associations between Peritonsillar Abscess and Deep Neck Infection in Chronic Periodontitis Patients: Two Nested Case-Control Studies Using a National Health Screening Cohort.

Background/Introduction: Odontogenic infection is one of the main etiologies of deep neck infection (DNI). However, the relationship between chronic periodontitis (CP) and the incidence of DNI has not been examined. This study aimed to evaluate the incidence of DNI and peritonsillar abscess (PTA) after CP. Methods: The Korean National Health Insurance Service-National Sample Cohort 2002-2019 was used. In Study I, 4585 PTA patients were matched with 19,340 control I participants. A previous history of CP for 1 year was collected, and the odds ratios (ORs) of CP for PTA were analyzed using conditional logistic regression. In Study II, 46,293 DNI patients and 185,172 control II participants were matched. A previous history of CP for 1 year was collected, and conditional logistic regression was conducted for the ORs of CP for DNI. Secondary analyses were conducted in demographic, socioeconomic, and comorbidity subgroups. Results: In Study I, a history of CP was not related to the incidence of PTA (adjusted OR = 1.28, 95% confidence interval [CI] = 0.91-1.81). In Study II, the incidence of DNI was greater in participants with a history of CP (adjusted OR = 1.55, 95% CI = 1.41-1.71). The relationship between CP history and DNI was greater in groups with young, male, low-income, and rural residents. Conclusions: A prior history of CP was associated with a high incidence of DNI in the general population of Korea. Patients with CP need to be managed for the potential risk of DNI.

Local Magnesium Sulfate Administration Ameliorates Nociception, Peripheral Inflammation, and Spinal Sensitization in a Rat Model of Incisional Pain.

OBJECTIVE: Postoperative pain remains one of the most common complaints after surgery, and appropriate treatments are limited. METHODS: We therefore investigated the effect of the anti-nociceptive properties of magnesium sulfate (MgSO4), an N-methyl-D-aspartate (NMDA) receptor antagonist, on incision-induced postoperative pain and peripheral and central nervous system inflammation. RESULTS: We found that local MgSO4 administration dose-dependently increases paw withdrawal latency, indicating reduced peripheral postoperative pain. Furthermore, MgSO4 inhibited the expression of interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS) and phosphorylation of the NMDA receptor NR1 subunit in injured paw tissue and significantly attenuated microglial and astrocytic activation in the ipsilateral lumbar spinal cord dorsal horn. CONCLUSION: Locally administered MgSO4 has potential for development as an adjunctive therapy for preventing central nociceptive sensitization.

Effect of NAMPT on the proliferation and apoptosis in odontoblast-like MDPC-23 cell.

This study aimed to evaluate the physiological role of NAMPT associated with MDPC-23 odontoblast cell proliferation. Cell viability was measured using the (DAPI) staining, caspase activation analysis and immunoblotting were performed. Visfatin promoted MDPC-23 odontoblast cell growth in a dose-dependent manner. Furthermore, the up-regulation of Visfatin promoted odontogenic differentiation and accelerated mineralization through an increase in representative odontoblastic biomarkers in MDPC-23 cells. However, FK-866 cell growth in a dose-dependent manner induced nuclear condensation and fragmentation. FK-866-treated cells showed H&E staining and increased apoptosis compared to control cells. The expression of anti-apoptotic factors components of the mitochondria-dependent intrinsic apoptotic pathway significantly decreased following FK-866 treatment. The expression of pro-apoptotic increased upon FK-866 treatment. In addition, FK-866 activated caspase-3 and PARP to induce cell death. In addition, after treating FK-866 for 72 h, the 3/7 activity of MDPC-23 cells increased in a concentration-dependent manner, and the IHC results also confirmed that Caspase-3 increased in a concentration-dependent. Therefore, the presence or absence of NAMPT expression in dentin cells was closely related to cell proliferation and formation of extracellular substrates.

Analgesia-nociception index accurately predicts inadequate pectoralis muscle fascia block (PECS) in patients undergoing breast surgery: A prospective observational study.

BACKGROUND: Postoperative opioid administration has been largely replaced by regional anesthesia techniques. We aimed to determine whether intraoperative Analgesia-Nociception Index (ANI) can aid in early evaluation of the effectiveness of regional blocks such as the pectoralis muscle fascia block (PECS, pectoserratus and interpectoral plane blocks) and predicting the need for analgesics postoperatively. METHODS: This prospective observational study enrolled 30 women (age: 20-80 years) undergoing unilateral, non-intubated, breast tumor excision alone or in conjunction with sentinel lymph node biopsy. PECS block was performed following sedation. ANI readings were obtained at 1-min intervals, and polar coordinates were assigned to the distance from the nipple (0.5-cm intervals) and o'clock position (15-min intervals) for each reading. Pain scores were assessed using a numeric rating scale from 0 to 10, and analgesics were administered depending on pain score post-operatively. RESULTS: 8 (27%), 19 (63%), and 3 (10%) patients received morphine, tramadol, and no analgesics, respectively. In total, 954 ANI measurements were obtained. At the proposed cut-off of 50, the sensitivity and specificity of the ANI nadir for need of post-operative opioids were 0.875 and 0.932, respectively. Block effectiveness was most satisfactory in the upper lateral quadrant of the breast with nipple-areolar complex (NAC) sparing effect. Most average ANI measurements for the NAC were <50. No patient experienced postoperative nausea/vomiting, although one reported dizziness. CONCLUSIONS: The intraoperative ANI nadir <50 was strongly correlated with need for postoperative opioids. The ANI may aid in objectively evaluating the effectiveness of pectoralis muscle fascial blocks and predicting postoperative need for analgesics.

A new model using deep learning to predict recurrence after surgical resection of lung adenocarcinoma.

This study aimed to develop a deep learning (DL) model for predicting the recurrence risk of lung adenocarcinoma (LUAD) based on its histopathological features. Clinicopathological data and whole slide images from 164 LUAD cases were collected and used to train DL models with an ImageNet pre-trained efficientnet-b2 architecture, densenet201, and resnet152. The models were trained to classify each image patch into high-risk or low-risk groups, and the case-level result was determined by multiple instance learning with final FC layer's features from a model from all patches. Analysis of the clinicopathological and genetic characteristics of the model-based risk group was performed. For predicting recurrence, the model had an area under the curve score of 0.763 with 0.750, 0.633 and 0.680 of sensitivity, specificity, and accuracy in the test set, respectively. High-risk cases for recurrence predicted by the model (HR group) were significantly associated with shorter recurrence-free survival and a higher stage (both, p < 0.001). The HR group was associated with specific histopathological features such as poorly differentiated components, complex glandular pattern components, tumor spread through air spaces, and a higher grade. In the HR group, pleural invasion, necrosis, and lymphatic invasion were more frequent, and the size of the invasion was larger (all, p < 0.001). Several genetic mutations, including TP53 (p = 0.007) mutations, were more frequently found in the HR group. The results of stages I-II were similar to those of the general cohort. DL-based model can predict the recurrence risk of LUAD and identify the presence of the TP53 gene mutation by analyzing histopathologic features.

Impartial feature selection using multi-agent reinforcement learning for adverse glycemic event prediction.

We developed an attention model to predict future adverse glycemic events 30 min in advance based on the observation of past glycemic values over a 35 min period. The proposed model effectively encodes insulin administration and meal intake time using Time2Vec (T2V) for glucose prediction. The proposed impartial feature selection algorithm is designed to distribute rewards proportionally according to agent contributions. Agent contributions are calculated by a step-by-step negation of updated agents. Thus, the proposed feature selection algorithm optimizes features from electronic medical records to improve performance. For evaluation, we collected continuous glucose monitoring data from 102 patients with type 2 diabetes admitted to Cheonan Hospital, Soonchunhyang University. Using our proposed model, we achieved F1-scores of 89.0%, 60.6%, and 89.8% for normoglycemia, hypoglycemia, and hyperglycemia, respectively.

Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation.

RATIONALE: Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes (ISGs). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning ISG induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown. OBJECTIVES: To decipher the functions of gasdermin B (encoded by GSDMB) in respiratory virus-induced lung inflammation. METHODS: In two independent cohorts, we analysed expression correlation between GSDMB and ISG s. In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated GSDMB-overexpressing and GSDMB-deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISG induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of GSDMB in respiratory syncytial virus-induced lung inflammation in vivo. RESULTS: GSDMB is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB in mouse airway epithelium led to enhanced ISGs induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection. CONCLUSIONS: GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.

Comparisons in analgesic effects between ultrasound-guided erector spinae plane block and surgical intercostal nerve block after video-assisted thoracoscopic surgery: A randomized controlled trial.

STUDY OBJECTIVE: This study aimed to compare the analgesic effects of anesthesiologist-administrated erector spinae plane block (ESPB) and surgeon-administrated intercostal nerve block (ICNB) following video-assisted thoracoscopic surgery (VATS). DESIGN: Randomized, controlled, double-blinded study. SETTING: Operating room, postoperative recovery room and ward in two centers. PATIENTS: One hundred patients, ASA I-III and scheduled for elective VATS. INTERVENTIONS: The anesthesiologist-administrated ESPB under ultrasound guidance or surgeon-administrated ICNB under video-assisted thoracoscopy was randomly provided during VATS. Regular oral non-opioid analgesic combined with intravenous rescue morphine were prescribed for multimodal analgesia after surgery. MEASUREMENTS: The primary outcomes were the pain score and morphine consumption during 48 h after surgery. Postoperative pain intensity were assessed using the 10-cm visual analogue scale at 1 h, 24 h, and 48 h after surgery. Morphine consumption at these time points was compared between the two study groups. Furthermore, oral weak opioid rescue analgesic was also provided at 24 h after surgery. Postoperative quality of recovery at 24 h was also assessed using the QoR-15 questionnaire, along with duration of chest tube drainage and hospital stay were compared as secondary outcomes. MAIN RESULTS: Patients in the two study groups had comparable baseline characteristics, and surgical types were also similar. Postoperative VAS changes at 1 h, 24 h, and 48 h after surgery were also comparable between the two study groups. Both groups had low median scores (<4.0) at all time points (all p > 0.05). Patients in the ESPB group required statistically non-significant higher 48-h morphine consumption [3 (0-6) vs. 0 (0-6) mg in the ESPB group and ICNB group respectively; p = 0.135] and lower numbers of oral rescue analgesic (0.4 ± 1.2 vs. 1.0 ± 1.8 in the ESPB group and ICNB group respectively; p = 0.059). Additionally, patients in the two study groups had similar QoR15 scores and lengths of hospital stay. CONCLUSIONS: Both anesthesiologist-administered ultrasound-guided ESPB and surgeon-administered VATS ICNB were effective analgesic techniques for patients undergoing VATS for tumor resection.

Efficacy and Safety of IDegAsp in a Real-World Korean Population with Type 2 Diabetes Mellitus.

Background: This study investigated the real-world efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in Korean adults with type 2 diabetes mellitus (T2DM), whose insulin treatment was switched to IDegAsp. Methods: This was a multicenter, retrospective, observational study comprising two 26-week treatment periods, before and after switching to IDegAsp, respectively. Korean adults with uncontrolled T2DM treated with basal or premix insulin (±oral antidiabetic drugs) were enrolled. The primary objective was to compare the degree of glycosylated hemoglobin (HbA1c) change in each 26-week observation period. The analyses included changes in HbA1c, fasting plasma glucose (FPG), body weight, proportion of participants achieving HbA1c <7.0%, hypoglycemic events, and total daily insulin dose (ClinicalTrials.gov, number NCT04656106). Results: In total, 196 adults (mean age, 65.95 years; mean T2DM duration, 18.99 years) were analyzed. The change in both HbA1c and FPG were significantly different between the pre-switching and the post-switching period (0.28% vs. -0.51%, P<0.001; 5.21 mg/dL vs. -23.10 mg/dL, P=0.005), respectively. After switching, the rate of achieving HbA1c <7.0% was significantly improved (5.10% at baseline vs. 11.22% with IDegAsp, P=0.012). No significant differences (before vs. after switching) were observed in body weight change, and total daily insulin dose. The rates of overall and severe hypoglycemia were similar in the two periods. Conclusion: In real-world clinical practice in Korea, the change of insulin regimen to IDegAsp was associated with an improvement in glycemic control without increase of hypoglycemia, supporting the use of IDegAsp for patients with T2DM uncontrolled with basal or premix insulin.

Effects of Social Defeat Stress on Microtubule Regulating Proteins and Tubulin Polymerization.

Objective: : Microtubule (MT) stability in neurons is vital for brain development; instability is associated with neuropsychiatric disorders. The present study examined the effects of social defeat stress (SDS) on MT-regulating proteins and tubulin polymerization. Methods: : After 10 days of SDS, defeated mice were separated into susceptible (Sus) and unsusceptible (Uns) groups based on their performance in a social avoidance test. Using extracted brain tissues, we measured the expression levels of α-tubulin, acetylated α-tubulin, tyrosinated α-tubulin, MT-associated protein-2 (MAP2), stathmin (STMN1), phospho stathmin serine 16 (p-STMN1 [Ser16]), phospho stathmin serine 25 (p-STMN1 [Ser25]), phospho stathmin serine 38 (p-STMN1 [Ser38]), stathmin2 (STMN2), phospho stathmin 2 serine 73 (p-STMN2 [Ser73]), 78-kDa glucose-regulated protein (GRP-78), and CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) using Western blot assay. The tubulin polymerization rate was also measured. Results: : We observed increased and decreased expression of acetylated and tyrosinated α-tubulin, respectively, decreased expression of p-STMN1 (Ser16) and increased expression of p-STMN1 (Ser25), p-STMN2 (Ser73) and GRP-78 and CHOP in the prefrontal cortex and/or hippocampus of defeated mice. A reduced tubulin polymerization rate was observed in the Sus group compared to the Uns and Con groups. Conclusion: : Our findings suggest that SDS has detrimental effects on MT stability, and a lower tubulin polymerization rate could be a molecular marker for susceptibility to SDS.

Comparative effectiveness of moderate-intensity statin with ezetimibe therapy versus high-intensity statin monotherapy in patients with acute coronary syndrome: a nationwide cohort study.

The long-term outcome of first-line moderate-intensity statin with ezetimibe combination therapy for secondary prevention after percutaneous coronary intervention in patients with acute coronary syndrome (ACS) compared to high-intensity statin monotherapy remains elusive. The objective of this study was to compare the effectiveness of moderate-intensity statin and ezetimibe combination therapy with high-intensity statin monotherapy. We conducted a nationwide, population-based, retrospective, cohort study of patients with ACS from 2013 to 2019. The patients using combination therapy were matched (1:1) to those using monotherapy. The primary outcome was a composite of myocardial infarction, stroke and all-cause mortality. We estimated the hazard ratios (HR) and 95% confidence intervals (CIs) using the Cox proportional hazards regression. After propensity score matching, 10,723 pairs were selected. Men accounted for 70% of the patients and 37% aged > 70 years. The primary endpoint occurred in 1297 patients (12.1%) in the combination group and in 1426 patients (13.3%) in the monotherapy group, and decreased risk (HR 0.85, 95% CI 0.78-0.92, P < 0.001) in the combination group. Among the patients with ACS, moderate-intensity statin with ezetimibe combination therapy was associated with decreased risk of adverse cardiovascular outcomes compared with high-intensity statin monotherapy in a nationwide population-based study representing routine clinical practice.

Revolutionizing Non-Small Cell Lung Cancer Diagnosis: Ultra-High-Sensitive ctDNA Analysis for Detecting Hotspot Mutations with Long-term Stored Plasma.

PURPOSE: Circulating cell-free DNA (cfDNA) has great potential in clinical oncology. The prognostic and predictive values of cfDNA in non-small cell lung cancer (NSCLC) have been reported, with epidermal growth factor receptor (EGFR), KRAS, and BRAF mutations in tumor-derived cfDNAs acting as biomarkers during the early stages of tumor progression and recurrence. However, extremely low tumor-derived DNA rates hinder cfDNA application. We developed an ultra-high-sensitivity lung version 1 (ULV1) panel targeting BRAF, KRAS, and EGFR hotspot mutations using small amounts of cfDNA, allowing for semi-quantitative analysis with excellent limit-of-detection (0.05%). MATERIALS AND METHODS: Mutation analysis was performed on cfDNAs extracted from the plasma of 104 patients with NSCLC by using the ULV1 panel and targeted next-generation sequencing (CT-ULTRA), followed by comparison analysis of mutation patterns previously screened using matched tumor tissue DNA. RESULTS: The ULV1 panel demonstrated robust selective amplification of mutant alleles, enabling the detection of mutations with a high degree of analytical sensitivity (limit-of-detection, 0.025%-0.1%) and specificity (87.9%-100%). Applying ULV1 to NSCLC cfDNA revealed 51.1% (23/45) samples with EGFR mutations, increasing with tumor stage: 8.33% (stage I) to 78.26% (stage IV). Semi-quantitative analysis proved effective for low-mutation-fraction clinical samples. Comparative analysis with PANAMutyper EGFR exhibited substantial concordance (κ=0.84). CONCLUSION: Good detection sensitivity (~80%) was observed despite the limited volume (1 mL) and long-term storage (12-50 months) of plasma used and is expected to increase with high cfDNA inputs. Thus, the ULV1 panel is a fast and cost-effective method for early diagnosis, treatment selection, and clinical follow-up of patients with NSCLC.

Effectiveness of low-intensity atorvastatin 5 mg and ezetimibe 10 mg combination therapy compared with moderate-intensity atorvastatin 10 mg monotherapy: A randomized, double-blinded, multi-center, phase III study.

BACKGROUND: We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy. METHODS: At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters. RESULTS: Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline. CONCLUSIONS: The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks.

BRCA-mutated gastric adenocarcinomas are associated with chromosomal instability and responsiveness to platinum-based chemotherapy.

BACKGROUND: Homologous recombination defect is an important biomarker of chemotherapy in certain tumor types, and the presence of pathogenic or likely pathogenic mutations involving BRCA1 or BRCA2 (p-BRCA) mutations is the most well-established marker for the homologous recombination defect. Gastric cancer, one of the most prevalent tumor types in Asia, also harbors p-BRCA mutations. METHODS: To investigate the clinical significance of p-BRCA mutations, we analyzed 366 gastric cancer cases through next-generation sequencing. We determined the zygosity of p-BRCA mutations based on the calculated tumor purity through variant allelic fraction patterns and investigated whether the presence of p-BRCA mutations is associated with platinum-based chemotherapy and a certain molecular subtype. RESULTS: Biallelic p-BRCA mutation was associated with better response to platinum-based chemotherapy than heterozygous p-BRCA mutation or wild type BRCA genes. The biallelic p-BRCA mutations was observed only in the chromosomal instability subtype, while all p-BRCA mutations were heterozygous in microsatellite instability subtype. CONCLUSIONS: In conclusion, patients with gastric cancer harboring biallelic p-BRCA mutations were associated with a good initial response to platinum-based chemotherapy and those tumors were exclusively chromosomal instability subtype. Further investigation for potential association with homologous recombination defect is warranted.

Neuroprotective Effects of Water Extract from Brown Algae Petalonia binghamiae in an Experimental Model of Focal Cerebral Ischemia In Vitro and In Vivo.

Focal cerebral ischemia (fCI) can result in brain injury and sensorimotor deficits. Brown algae are currently garnering scientific attention as potential therapeutic candidates for fCI. This study investigated the therapeutic effects of the hot water extract of Petalonia binghamiae (wPB), a brown alga, in in vitro and in vivo models of fCI. The neuroprotective efficacy of wPB was evaluated in an in vitro excitotoxicity model established using HT-22 cells challenged with glutamate. Afterward, C57/BL6 mice were administered wPB for 7 days (10 or 100 mg/kg, intragastric) and subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) operation, which was used as an in vivo fCI model. wPB co-incubation significantly inhibited cell death, oxidative stress, and apoptosis, as well as stimulated the expression of heme oxygenase-1 (HO-1), an antioxidant enzyme, and the nuclear translocation of its upstream regulator, nuclear factor erythroid 2-related factor 2 (Nrf2) in HT-22 cells challenged with glutamate-induced excitotoxicity. Pretreatment with either dose of wPB significantly attenuated infarction volume, neuronal death, and sensorimotor deficits in an in vivo fCI model. Furthermore, the attenuation of oxidative stress and apoptosis in the ischemic lesion accompanied the wPB-associated protection. This study suggests that wPB can counteract fCI via an antioxidative effect, upregulating the Nrf2/HO-1 pathway.

Occult pneumothorax in patients with blunt chest trauma: key findings on supine chest radiography.

Background: In patients with multiple trauma, a supine chest radiography [chest X-ray (CXR)] is preferred over a erect CXR. However, this method has limitations in detecting post-traumatic pneumothorax. The use of chest computed tomography (CT) to detect traumatic pneumothorax is well known. However, pneumothorax that is not detected before a chest CT scan is known as an occult pneumothorax (OP), and it can cause serious complications in the patient. This study sought to evaluate the frequency and risk factors for OP in trauma patients. Methods: Patients who suffered thoracic trauma at the Level 1 Regional Trauma Center of Wonju Severance Christian Hospital between 2015 and 2022 were included in this study. All patients were at least 18 years old. The study reviewed all patients' supine CXR and chest CT images and classified them into five radiographic diagnoses: pneumothorax, rib fracture, subcutaneous emphysema, lung contusion, and pneumomediastinum. Results: The study included 1,284 patients, all with diagnoses of pneumothorax, rib fracture, subcutaneous emphysema, lung contusion, and pneumomediastinum following supine CXR and chest CT. The patient's average age was 58.3±15.2 years. Pneumothorax diagnosis on supine CXR had the lowest accuracy, at 46.7%, and the lowest sensitivity, at 12.7%. In univariate analysis, rib fracture, lung contusion, and subcutaneous emphysema on supine CXR were all found to be statistically significant regarding traumatic OP. In multivariate analysis, the risk factors for OP were lung contusion [odds ratio (OR), 1.440; 95% confidence interval (CI): 1.115-1.860; P=0.005] and subcutaneous emphysema (OR, 25.883; 95% CI: 13.155-50.928; P<0.001) on supine CXR. Conclusions: The lung contusion and subcutaneous emphysema in supine CXR of trauma patients indicate the presence of OP. Therefore, if chest CT cannot be performed immediately due to unstable vital signs or other circumstances, recognizing the above radiological findings of traumatic pneumothorax may be necessary.

A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities.

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.