Development and Feasibility Evaluation of Smart Cancer Care 2.0 Based on Patient-Reported Outcomes for Post-Discharge Management of Patients with Cancer.

Purpose: A "Smart Cancer Care" platform that integrates patient-reported outcomes (PROs) with management has been established in Korea. This study focused on improving health behaviors and connecting patients to welfare services by introducing and assessing the feasibility of "Smart Cancer Care 2.0," an enhanced version designed for monitoring complications post-cancer treatment. Materials and Methods: Smart Cancer Care 2.0 was developed by conducting a literature review and consulting with expert panels to identify symptoms or variables requiring monitoring and management guidelines based on the treatment type. Qualitative and quantitative surveys were conducted to assess the feasibility of the app and web system based on the experiences of patients with cancer and healthcare workers. Results: A total of 81 symptoms or variables (chemotherapy-, surgery-, radiotherapy-, rehabilitation-, and health management-related) were selected for management in Smart Cancer Care 2.0. PROs for these symptoms were basically categorized into three severity grades: (1) preventive management, (2) self-treatment, and (3) consultation with a healthcare worker or visit to a healthcare institution. The overall mean scores in the feasibility evaluation by patients and healthcare workers were 3.83 and 3.90 points, respectively, indicating high usefulness. Conclusion: Smart Cancer Care 2.0 leverages the existing ICT-based platform, Smart Cancer Care, and further includes health behaviors and welfare services. Smart Cancer Care 2.0 may play a crucial role in establishing a comprehensive post-discharge management system for patients with cancer as it provides suitable interventions based on patients' responses and allows the regularly collected PROs to be easily viewed for streamlined care.

Exploring Molecular Genetic Alterations and RAF Fusions in Melanoma: A Belvarafenib Expanded Access Program in Patients with RAS/RAF-Mutant Melanoma.

BACKGROUND: Melanoma incidence is on the rise in East Asia, yet studies of the molecular landscape are lacking in this population. We examined patients with melanoma who underwent next-generation sequencing (NGS) at a single tertiary center in South Korea, focusing on patients harboring NRAS or RAF alterations who received belvarafenib, a pan-RAF dimer inhibitor, through the Expanded Access Program (EAP). PATIENTS AND METHODS: Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained and annotated. Patients in the EAP received 450 mg twice daily doses of belvarafenib. RESULTS: Alterations in the RAS/RTK pathway were the most prevalent, with BRAF and NRAS alteration rates of 22.4% and 17.7%, respectively. NGS enabled additional detection of fusion mutations, including 6 BRAF and 1 RAF1 fusion. Sixteen patients with NRAS or RAF alterations received belvarafenib through the EAP, and disease control was observed in 50%, with 2 patients demonstrating remarkable responses. CONCLUSIONS: Our study highlights the value of NGS in detecting BRAF, NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib.

Retrospective Analysis of Ultrasound-Guided Serial-Injection Triple Nerve Block Efficacy in Cementless Bipolar Hemiarthroplasty for Femoral Neck Fracture.

BACKGROUND: Femoral neck fractures are effectively treated with bipolar hemiarthroplasty (BHA) surgery, yet postoperative pain management remains a challenge. This study explores the efficacy of multimodal pain management in minimizing opioid use and enhancing recovery. METHODS: A retrospective analysis of 87 patients who underwent BHA between September 2016 and September 2020 was conducted. Patients were analyzed in two groups: Group I (n = 42), receiving serial-injection nerve blocks (SINBs) before and after surgery, and Group II (n = 41), with no SINB. Notably, all nerve blocks for Group I were performed after November 2017, following the implementation of this technique in our protocol. Pain and analgesic medication usage were assessed over 72 h post-surgery, along with hospitalization duration and perioperative complications. RESULTS: Group I patients exhibited significantly lower pain scores at 6, 12, 24, and 48 h post-surgery, alongside reduced incidences of postoperative nausea and vomiting (PONV) and delirium compared with Group II (p < 0.05). CONCLUSIONS: Utilizing sequential lower limb nerve blocks under ultrasound guidance in BHA surgeries effectively reduces early postoperative pain and associated adverse effects. This approach demonstrates potential benefits in pain management, leading to diminished narcotic usage and lower risks of PONV and delirium.

Assessing bone mineral density in non-weight bearing regions of the body: a texture analysis approach using abdomen and pelvis computed tomography Hounsfield units-a cross-sectional study.

Background: Highlighting a gap in comprehending bone microarchitecture's intricacies using dual-energy X-ray absorptiometry (DXA), this study aims to bridge this chasm by analyzing texture in non-weight bearing regions on axial computed tomography (CT) scans. Our goal is to enrich osteoporosis patient management by enhancing bone quality and microarchitecture insights. Methods: Conducted at Busan Medical Center from March 1, 2013, to August 30, 2022, 1,320 cases (782 patients) were screened. After applying exclusion criteria, 458 samples (296 patients) underwent bone mineral density (BMD) assessment with both CT and DXA. Regions of interest (ROIs) included spine pedicle's maximum trabecular area, sacrum Zone 1, superior/inferior pubic ramus, and femur's greater/lesser trochanters. Texture features (n=45) were extracted from ROIs using gray-level co-occurrence matrices. A regression model predicted BMD, spotlighting the top five influential texture features. Results: Correlation coefficients ranged from 0.709 (lowest for total femur BMD) to 0.804 (highest for femur intertrochanter BMD). Mean squared error (MSE) values were also provided for lumbar and femur BMD/bone mineral content (BMC) metrics. The most influential texture features included contrast_32, correlation_32_v, and three other metrics. Conclusions: By melding traditional DXA and CT texture analysis, our approach presents a comprehensive bone health perspective, potentially revolutionizing osteoporosis diagnostics.

Effectiveness of ultrasound-guided dual nerve block in the below-knee amputation.

PURPOSE: Below knee amputation (BKA) is a common surgical procedure for diabetic foot ulcers and necrotizing lower limb fasciitis patients. However, it is a painful procedure and inadequate postoperative analgesia impedes rehabilitation and prolongs hospitalization. An ideal pain management regimen should provide superior analgesia while minimizing opioid consumption and improving rehabilitation. METHODS: We retrospectively reviewed medical charts of 218 patients who underwent BKA for diabetic foot ulcer or necrotizing lower limb fasciitis at a single center between January 2017 and September 2020. Two groups were analyzed: patients who received dual nerve block (DNB) before surgery (Group I; n = 104), and patients who did not (Group II; n = 93). By the exclusion criteria, 21 patients were excluded. The femoral and sciatic nerves were each blocked separately under ultrasound guidance. This procedure was performed immediately before the operation. RESULTS: Group I patients' subjective pain scores were significantly lower than that of Group II at 6, 12, and 24 h after BKA (P < 0.05). Group I's morphine milligram equivalent (MME) was significantly lower than those of Group II at 72 h after BKA (P < 0.05). Moreover, the rate of postoperative nausea and vomiting (PONV) and delirium was significantly lower in Group I patients than that in Group II patients. CONCLUSION: Ultrasound-guided lower extremity nerve block surgery is excellent for early postoperative pain control, could be used as an accurate and effective pain control method, and can reduce the side effects of opioid consumption after BKA.

Returning to golf after rotator cuff repair.

Background: The prevalence of rotator cuff repair is increasing; however, no study has assessed patients who have returned to golf activity after arthroscopic rotator cuff repair. Methods: The subjects of the survey were 633 patients who were at least two years postoperative after rotator cuff repair from January 2005 to December 2017. From August 2019 to October 2019, survey responses were collected via an online questionnaire or phone calls and a total of 197 patients were reviewed retrospectively to study about returning to golf after rotator cuff repair. The detailed survey included 12 questions specific to the patient's golf career, performance, time of return to play, and symptoms related to golf activity. Depending on the size of the rotator cuff tear, each question was statistically analyzed to determine whether there were differences in the time of return to golf, uncomfortable symptoms when golfing, and distance of the driving. Results: Of the 197 patients who underwent arthroscopic rotator cuff repair, there were 145 patients (73.6%) returned to golf. In the analysis results of 145 patients, the longer the golf career, the greater the chance of returning to golf. Sixty (30.5%) people returned to golf at 1 year after surgery. Twenty-one patients (10.7%) improved and 46 patients (23.4%) maintained their driving distance, whereas 78 patients (39.6%) had a worse driving distance after surgery. Ten patients (5.1%) improved and 97 patients (49.2%) maintained their golf score, but 38 patients (19.3%) had worse golf scores after surgery. Symptoms when playing golf were reported in the order of no symptoms (62.1%), a limited range of motion (13.1%), muscle weakness (11.1%), and anxious about their operated shoulder (10.3 %). Men were 6.9 times more likely to return to golf than women (odds ratio, 6.9; 95% confidence interval, 3.2-14.8). The younger the age and the shorter the time since surgery, the higher the golfing return rate. The rate of returning to golf was high in the group of patients with good tissue quality during surgery (odds ratio, 3.9; 95% confidence interval, 0.01-2.6). Conclusion: The golfing return rate after arthroscopic rotator cuff repair was higher than expected (73.6%) and most players returned at 1 year after surgery. Especially, in the case of young males, their golf scores were maintained or improved and they were able to return to golf earlier after surgery. Better tissue quality in the intraoperative torn tendon was associated with a greater chance of returning to golf.

A nanoadjuvant that dynamically coordinates innate immune stimuli activation enhances cancer immunotherapy and reduces immune cell exhaustion.

Although conventional innate immune stimuli contribute to immune activation, they induce exhausted immune cells, resulting in suboptimal cancer immunotherapy. Here we suggest a kinetically activating nanoadjuvant (K-nanoadjuvant) that can dynamically integrate two waves of innate immune stimuli, resulting in effective antitumour immunity without immune cell exhaustion. The combinatorial code of K-nanoadjuvant is optimized in terms of the order, duration and time window between spatiotemporally activating Toll-like receptor 7/8 agonist and other Toll-like receptor agonists. K-nanoadjuvant induces effector/non-exhausted dendritic cells that programme the magnitude and persistence of interleukin-12 secretion, generate effector/non-exhausted CD8+ T cells, and activate natural killer cells. Treatment with K-nanoadjuvant as a monotherapy or in combination therapy with anti-PD-L1 or liposomes (doxorubicin) results in strong antitumour immunity in murine models, with minimal systemic toxicity, providing a strategy for synchronous and dynamic tailoring of innate immunity for enhanced cancer immunotherapy.

Human Pluripotent Stem Cell-Derived Alveolar Organoid with Macrophages.

Alveolar organoids (AOs), derived from human pluripotent stem cells (hPSCs) exhibit lung-specific functions. Therefore, the application of AOs in pulmonary disease modeling is a promising tool for understanding disease pathogenesis. However, the lack of immune cells in organoids limits the use of human AOs as models of inflammatory diseases. In this study, we generated AOs containing a functional macrophage derived from hPSCs based on human fetal lung development using biomimetic strategies. We optimized culture conditions to maintain the iMACs (induced hPSC-derived macrophages) AOs for up to 14 days. In lipopolysaccharide (LPS)-induced inflammatory conditions, IL-1ß, MCP-1 and TNF-α levels were significantly increased in iMAC-AOs, which were not detected in AOs. In addition, chemotactic factor IL-8, which is produced by mononuclear phagocytic cells, was induced by LPS treatment in iMACs-AOs. iMACs-AOs can be used to understand pulmonary infectious diseases and is a useful tool in identifying the mechanism of action of therapeutic drugs in humans. Our study highlights the importance of immune cell presentation in AOs for modeling inflammatory pulmonary diseases.

Adult re-expression of IRSp53 rescues NMDA receptor function and social behavior in IRSp53-mutant mice.

IRSp53 (or BAIAP2) is an abundant excitatory postsynaptic scaffolding/adaptor protein that is involved in actin regulation and has been implicated in autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. IRSp53 deletion in mice leads to enhanced NMDA receptor (NMDAR) function and social deficits that are responsive to NMDAR inhibition. However, it remains unclear whether IRSp53 re-expression in the adult IRSp53-mutant mouse brain after the completion of brain development could reverse these synaptic and behavioral dysfunctions. Here we employed a brain-blood barrier (BBB)-penetrant adeno-associated virus (AAV) known as PHP.eB to drive adult IRSp53 re-expression in IRSp53-mutant mice. The adult IRSp53 re-expression normalized social deficits without affecting hyperactivity or anxiety-like behavior. In addition, adult IRSp53 re-expression normalized NMDAR-mediated excitatory synaptic transmission in the medial prefrontal cortex. Our results suggest that adult IRSp53 re-expression can normalize synaptic and behavioral deficits in IRSp53-mutant mice and that BBB-penetrant adult gene re-expression has therapeutic potential.

IntraBrain Injector (IBI): A Stereotactic-Guided Device for Repeated Delivery of Therapeutic Agents Into the Brain Parenchyma.

BACKGROUND: To deliver therapeutics into the brain, it is imperative to overcome the issue of the blood-brain-barrier (BBB). One of the ways to circumvent the BBB is to administer therapeutics directly into the brain parenchyma. To enhance the treatment efficacy for chronic neurodegenerative disorders, repeated administration to the target location is required. However, this increases the number of operations that must be performed. In this study, we developed the IntraBrain Injector (IBI), a new implantable device to repeatedly deliver therapeutics into the brain parenchyma. METHODS: We designed and fabricated IBI with medical grade materials, and evaluated the efficacy and safety of IBI in 9 beagles. The trajectory of IBI to the hippocampus was simulated prior to surgery and the device was implanted using 3D-printed adaptor and surgical guides. Ferumoxytol-labeled mesenchymal stem cells (MSCs) were injected into the hippocampus via IBI, and magnetic resonance images were taken before and after the administration to analyze the accuracy of repeated injection. RESULTS: We compared the planned vs. insertion trajectory of IBI to the hippocampus. With a similarity of 0.990 ± 0.001 (mean ± standard deviation), precise targeting of IBI was confirmed by comparing planned vs. insertion trajectories of IBI. Multiple administrations of ferumoxytol-labeled MSCs into the hippocampus using IBI were both feasible and successful (success rate of 76.7%). Safety of initial IBI implantation, repeated administration of therapeutics, and long-term implantation have all been evaluated in this study. CONCLUSION: Precise and repeated delivery of therapeutics into the brain parenchyma can be done without performing additional surgeries via IBI implantation.

Magnetic resonance imaging analysis of screw in-type lateral anchor pull-out in large to massive rotator cuff repair in patients older than 60 years.

BACKGROUND: This study was performed to identify the incidence of screw in-type lateral anchor pull-out in patients older than 60 years who underwent rotator cuff repair for large to massive rotator cuff tear (RCT). METHODS: We reviewed 25 patients over 60 who were diagnosed with large to massive RCT and underwent arthroscopic rotator cuff repair in our hospital from March 2017 to February 2021. Preoperative tear size (anterior to posterior, medial to lateral) was measured via preoperative magnetic resonance imaging (MRI). All 25 patients underwent MRI scanning on postoperative day 1 and at 3 months after surgery. The change of anchor position was measured in axial views on MRI images postoperative day 1 and 3 months after surgery. And it was statistically compared according to bone mineral density (BMD), sex, and number of lateral anchors. RESULTS: Two MRIs (postoperative day 1 and 3 months) in 25 patients were compared. Anchor pull-out occurred in six patients during 3 months (6.7%), and the mean pull-out length difference was 1.56 mm (range, 0.16-2.58 mm). There was no significant difference in the number of pull-out anchors, degree of pull-out difference by comparing BMD (A, BMD≤-2.5; B, BMD>-2.5), sex, or number of anchors used in each surgery (C, two anchors; D, three anchors) (p>0.05). CONCLUSIONS: Pull-out of screw in-type anchors was rarely observed and the mean pull-out length difference was negligibly small in our study. The screw in-type lateral anchor seems to be a decent option without concern of anchor pull-out even in elderly patients.

Does cerclage wiring interfere with fracture healing of osteosynthesis in comminuted midshaft clavicle fractures? A multicenter study.

INTRODUCTION: Historically, cerclage wires were not used in the treatment of clavicle fractures because of their invasiveness. The purpose of this study was to evaluate the radiologic results and the incidence of complications following cerclage wire application and plate fixation in the treatment of comminuted mid-shaft clavicle fractures. MATERIALS AND METHODS: A total of 116 patients with comminuted mid-shaft clavicle fractures who underwent open reduction and internal fixation were reviewed. We analyzed the postoperative length ratio and bone union period according to the fracture classification, patient age, the number of fragments and the number of applied wires. The thickness of the fracture site was compared with the normal contralateral clavicle shaft. RESULTS: Bone union was confirmed in all enrolled patients at an average of 14.9±4.67 weeks. There are no significant differences in the length ratio or bone union period among the subgroups (including the fracture types, age, number of fragments and applied wires). The diameter at the occupied area was not significantly from that on the normal side (p=.505). CONCLUSIONS: The application of a single cerclage or multiple cerclage wires around the fracture site did not hamper the clavicle shaft fracture healing. This result suggests that cerclage wires should not be avoided, but can be used as a viable treatment option for clavicle shaft fractures. LEVEL OF EVIDENCE: IV.

Lateral ulnar collateral ligament (LUCL) reconstruction for the treatment of recalcitrant lateral epicondylitis of the elbow: a comparison with open débridement of the extensor origin.

BACKGROUND: Based on the controversy over whether the extensor tendon is the only lesion of lateral epicondylitis of the elbow and numerous reports of concomitant lateral collateral ligament involvement, potential damage to the lateral collateral ligament complex should be considered for the treatment. METHODS: About 25 elbows in 23 patients (débridement group) and 22 elbows in 20 patients (reconstruction group) who were diagnosed with lateral epicondylitis and had an average of 22 months of symptoms revealing anatomical lesion on MRI were included. The capitellum-sublime tubercle-radial head (CSR) angle was measured on both sides preoperatively, and the visual analog scale (VAS) and Mayo elbow performance score (MEPS) were measured over 12 months, postoperatively. RESULTS: The initial preoperative mean VAS was statistically significant with 4.6 in the débridement group and 6.5 in the reconstruction group (P < .05). Postoperative VAS was continuously decreased in both groups with no significant difference at each assessment period (P < .05) but showed more rapid improvement in the reconstruction group compared with the débridement group. For MEPS, the reconstruction group showed significant improvement during the follow-up periods, and at the final follow-up MEPS, 3 cases in the débridement group and 0 cases in the reconstruction group showed a poor result, which was considered as surgery failure. The CSR angle of the affected side (7.2 ± 1.9) was significantly larger than that of the normal side (3.6 ± 1.5) (P < .05) in the reconstruction group. Increased CSR by more than 5 degrees was identified as a significant predictive indicator for potential concomitant ligament insufficiency (area under curve = 0.875, P < .001) showing 80.9% of the sensitivity, 82.1% of the specificity. CONCLUSIONS: In the surgical treatment of recalcitrant lateral epicondylitis, lateral ulnar collateral ligament reconstruction added to the débridement of extensor origin may provide better results for the patients with suspicious lateral ligament insufficiency or failed previous surgery.

A first-in-human study of KMRC011, a potential treatment for acute radiation syndrome, to explore tolerability, pharmacokinetics, and pharmacodynamics.

KMRC011 is a novel Toll-like receptor 5 agonist under development as a treatment for acute radiation syndrome (ARS). The aim of this first-in-human study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of a single intramuscular dose of KMRC011 in healthy subjects. A randomized, single-blind, placebo-controlled, single dose-escalation study was conducted with the starting dose of 5 µg. Eight (4 only for 5 µg cohort) subjects per cohort were randomly assigned to KMRC011 or placebo in a 3:1 ratio. Dose-limiting toxicity (DLT) was assessed throughout the study. Serum concentrations of KMRC011, granulocyte colony-stimulating factor (G-CSF), and interleukin-6 (IL-6) were measured up to 48 h postdose. Based on safety review, the dose of KMRC011 escalated up to 20 µg, and consequently, a total of 4 dose levels (5, 10, 15, and 20 µg) were explored. The most common adverse event was injection site reaction, showing no dose-related trend. Three DLTs (2 cases of hepatic enzyme increased and 1 of pyrexia) were observed; 1 in the 15 µg cohort and 2 in the 20 µg cohort. A developed method could not detect any KMRC011 in serum. KMRC011 15 µg and 20 µg showed significant increases of G-CSF, IL-6, and absolute neutrophil counts, compared with the placebo. A single intramuscular administration of KMRC011 ranging from 5 to 15 µg was tolerated in healthy subjects. Doses of KMRC011 equal to or greater than 15 µg exerted TLR5 agonist-like activities by increasing serum G-CSF and IL-6. It suggests that KMRC011 has the potential for a treatment for ARS.

ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

Olmutinib in T790M-positive non-small cell lung cancer after failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy: A global, phase 2 study.

BACKGROUND: In this open-label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy. METHODS: Patients aged ≥20 years received once-daily oral olmutinib 800 mg continuously in 21-day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression-free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Overall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03-21.68 months). Overall, 46.3% of patients (95% CI, 38.4%-54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%-59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%-91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3-15.4 months). Estimated median progression-free survival was 9.4 months (95% CI, 6.9-12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment-emergent adverse events, and 71.6% of patients had grade ≥3 treatment-emergent adverse events. CONCLUSIONS: Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M-positive non-small cell lung cancer who received previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

A Two Cascaded Network Integrating Regional-based YOLO and 3D-CNN for Cerebral Microbleeds Detection.

Cerebral Microbleeds (CMBs) are small chronic brain hemorrhages, which have been considered as diagnostic indicators for different cerebrovascular diseases including stroke, dysfunction, dementia, and cognitive impairment. In this paper, we propose a fully automated two-stage integrated deep learning approach for efficient CMBs detection, which combines a regional-based You Only Look Once (YOLO) stage for potential CMBs candidate detection and three-dimensional convolutional neural networks (3D-CNN) stage for false positives reduction. Both stages are conducted using the 3D contextual information of microbleeds from the MR susceptibility-weighted imaging (SWI) and phase images. However, we average the adjacent slices of SWI and complement the phase images independently and utilize them as a two- channel input for the regional-based YOLO method. The results in the first stage show that the proposed regional-based YOLO efficiently detected the CMBs with an overall sensitivity of 93.62% and an average number of false positives per subject (FPavg) of 52.18 throughout the five-folds cross-validation. The 3D-CNN based second stage further improved the detection performance by reducing the FPavg to 1.42. The outcomes of this work might provide useful guidelines towards applying deep learning algorithms for automatic CMBs detection.

Association between exposure to polycyclic aromatic hydrocarbons and brain cortical thinning: The Environmental Pollution-Induced Neurological EFfects (EPINEF) study.

BACKGROUND: Although some studies have suggested that exposure to polycyclic aromatic hydrocarbons (PAHs) induces neurodevelopmental disturbances in children and neurodegeneration in animals, the neurotoxic effect of PAH exposure is unclear in adults. The aim was to examine the associations of PAH exposure with brain structure and neuropsychological function in adults without known neurological diseases. METHODS: This study included 421 men and 528 women dwelling in four cities in the Republic of Korea. Urinary concentrations of four PAH metabolites (1-hydroxypyrene, 2-naphthol, 1-hydroxyphenanthrene, and 2-hydroxyfluorene) were obtained. Participants underwent brain 3 T magnetic resonance imaging and neuropsychological tests. Cortical thickness and volume were estimated using the region-of-interest method. Separate generalized linear models were constructed for each sex, adjusting for age, years of education, cohabitation status, income, tobacco use, alcohol consumption, and vascular risk factors. RESULTS: The mean (standard deviation) age was 68.3 (6.6) years in men and 66.4 (6.1) years in women. In men, those in quartile 4 (versus quartile 1, the lowest) of urinary 2-naphthol concentration had cortical thinning in the global (ß = -0.03, P = .02), parietal (ß = -0.04, P = .01), temporal (ß = -0.06, P < .001), and insular lobes (ß = -0.05, P = .02). Higher quartiles of urinary 2-naphthol concentration were associated with cortical thinning in the global (P = .01), parietal (P = .004), temporal (P < .001), and insular lobes (P = .01). In women, those in quartile 4 (versus quartile 1) of urinary 1-hydroxypyrene concentration had cortical thinning in the frontal (ß = -0.03, P = .006) and parietal lobes (ß = -0.03, P = .003). Higher quartiles of urinary 1-hydroxypyrene concentration were associated with cortical thinning in the frontal (P = .006) and parietal lobes (P = .001). In both sexes, verbal learning and memory scores significantly declined with an increase in quartile of urinary 1-hydroxypyrene concentration. CONCLUSIONS: PAH exposure was associated with cortical thinning and decline in verbal learning and memory function in cognitively healthy adults. This suggests PAHs as an environmental risk factor for neurodegeneration.

Hypoxia Pretreatment Promotes Chondrocyte Differentiation of Human Adipose-Derived Stem Cells via Vascular Endothelial Growth Factor.

BACKGROUND: Human adipose tissue-derived stem cells (ADSCs) are attractive multipotent stem cell sources with therapeutic potential in various fields requiring repair and regeneration, such as acute and chronically damaged tissues. ADSC is suitable for cell-based therapy, but its use has been hampered due to poor survival after administration. Potential therapeutic use of ADSC requires mass production of cells through in vitro expansion. Many studies have consistently observed the tendency of senescence by mesenchymal stem cell (MSC) proliferation upon expansion. Hypoxia has been reported to improve stem cell proliferation and survival. METHODS: We investigated the effects of hypoxia pretreatment on ADCS proliferation, migration capacity, differentiation potential and cytokine production. We also analyzed the effects of vascular endothelial growth factor (VEGF) on osteogenic and chondrogenic differentiation of ADSCs by hypoxia pretreatment. RESULTS: Hypoxia pretreatment increased the proliferation of ADSCs by increasing VEGF levels. Interestingly, hypoxia pretreatment significantly increased chondrogenic differentiation but decreased osteogenic differentiation compared to normoxia. The osteogenic differentiation of ADSC was decreased by the addition of VEGF but increased by the depletion of VEGF. We have shown that hypoxia pretreatment increases the chondrogenic differentiation of ADSCs while reducing osteogenic differentiation in a VEGF-dependent manner. CONCLUSION: These results show that hypoxia pretreatment can provide useful information for studies that require selective inhibition of osteogenic differentiation, such as cartilage regeneration.

Gene expression network analysis of lymph node involvement in colon cancer identifies AHSA2, CDK10, and CWC22 as possible prognostic markers.

Colon cancer has been well studied using a variety of molecular techniques, including whole genome sequencing. However, genetic markers that could be used to predict lymph node (LN) involvement, which is the most important prognostic factor for colon cancer, have not been identified. In the present study, we compared LN(+) and LN(-) colon cancer patients using differential gene expression and network analysis. Colon cancer gene expression data were obtained from the Cancer Genome Atlas and divided into two groups, LN(+) and LN(-). Gene expression networks were constructed using LASSO (Least Absolute Shrinkage and Selection Operator) regression. We identified hub genes, such as APBB1, AHSA2, ZNF767, and JAK2, that were highly differentially expressed. Survival analysis using selected hub genes, such as AHSA2, CDK10, and CWC22, showed that their expression levels were significantly associated with the survival rate of colon cancer patients, which indicates their possible use as prognostic markers. In addition, protein-protein interaction network, GO enrichment, and KEGG pathway analysis were performed with selected hub genes from each group to investigate the regulatory relationships between hub genes and LN involvement in colon cancer; these analyses revealed differences between the LN(-) and LN(+) groups. Our network analysis may help narrow down the search for novel candidate genes for the treatment of colon cancer, in addition to improving our understanding of the biological processes underlying LN involvement. All R implementation codes are available at journal website as Supplementary Materials.