Timing of Complications in Open Airway Reconstruction.

OBJECTIVE: Tracheal resection (TR) and cricotracheal resection (CTR) are performed for patients with airway stenosis, tracheal tumor, and tracheoesophageal fistula. Post-operative complications include airway edema requiring reintubation, hematoma, anastomotic dehiscence, restenosis, and death. Although these complications and associated risk factors have been well described, the time where clinical suspicion should be highest post operatively has not been characterized. METHODS: Patients who underwent TR or CTR at a single center between 2015 and 2022 were reviewed. Variables including demographics and comorbidities were recorded. Rate, nature, and time in days of post-operative complications were evaluated. RESULTS: Sixty-nine cases were reviewed. Average patient age was 46.8 years old and 63.8% were male. The average follow-up period was 625 ± 724 days. 19 (27.5%) patients experienced one or more major complications including four (5.8%) who died. Eight (11.6%) patients required reintubation and 4 (5.8%) patients underwent revision tracheostomy. Most complications occurred within 8 days of surgery. Restenosis was noted an average of 42.6 days after surgery, with no new restenosis occurring after 3 months. CONCLUSIONS: In this single-center study, most post-operative complications after TR or CTR, including hematoma and anastomotic dehiscence, occurred within 8 days post-operatively. Restenosis was noted approximately 1-3 months after surgery. This may inform clinical decision-making regarding patient monitoring and surveillance after open airway surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

In Situ Photo-Crosslinkable Protein Bioadhesive for Bone Graft Fixation.

Bone grafting is a fundamental dental surgery procedure widely used for implant placement and periodontal disease management treatments. Despite its broad applications, vertical bone augmentation presents unique challenges, including the risk of graft displacement due to gravitational and masticatory forces. Traditional physical stabilization methods introduce additional complexities and risks, underscoring the need for innovative fixation technologies. This study aimed to develop an in situ photo-crosslinkable bioadhesive hydrogel (iPBAH) as a multifunctional bone graft binder to enhance the process of bone reconstruction. The bioadhesive is composed of mussel-derived adhesive protein (MAP) fused with the cell-adhesive peptide RGD. The numerous tyrosine residues in MAP facilitate rapid photo-crosslinking, enabling efficient hydrogel formation using visible blue light. Subsequently, iPBAH underwent comprehensive characterization to evaluate its suitability as a multifunctional bone graft binder. iPBAH efficiently underwent in situ crosslinking through harmless exposure to visible light within minutes and displayed several exceptional properties, including a microporous structure, underwater adhesion, extended durability, high compressive strength, and biocompatibility. In vivo assessments, using male Sprague-Dawley rats, demonstrated that iPBAH binder significantly enhanced bone regeneration in a rat calvarial bone defect model. The in situ crosslinking of the iPBAH binder during bone graft transplantation can effectively fill irregular and complex defect shapes while simultaneously preventing graft material leakage. The improved physical attributes of the bound graft material can enhance its resistance to external forces, thereby ensuring sustained retention over time. Moreover, the interaction between iPBAH and surrounding tissues promotes adhesion and integration of the graft material with host tissues in the defect area. In addition, the included RGD peptide in iPBAH can augment inherent cell recruitment, adhesion, and growth, consequently expediting osteogenesis.

Evaluation of Chelator-to-Antibody Ratio on Development of 89Zr-iPET Tracer for Imaging of PD-L1 Expression on Tumor.

89Zr-iPET has been widely used for preclinical and clinical immunotherapy studies to predict patient stratification or evaluate therapeutic efficacy. In this study, we prepared and evaluated 89Zr-DFO-anti-PD-L1-mAb tracers with varying chelator-to-antibody ratios (CARs), including 89Zr-DFO-anti-PD-L1-mAb_3X (tracer_3X), 89Zr-DFO-anti-PD-L1-mAb_10X (tracer_10X), and 89Zr-DFO-anti-PD-L1-mAb_20X (tracer_20X). The DFO-anti-PD-L1-mAb conjugates with varying CARs were prepared using a random conjugation method and then subjected to quality control. The conjugates were radiolabeled with 89Zr and evaluated in a PD-L1-expressing CT26 tumor-bearing mouse model. Next, iPET imaging, biodistribution, pharmacokinetics, and ex vivo pathological and immunohistochemical examinations were conducted. LC-MS analysis revealed that DFO-anti-PD-L1-mAb conjugates were prepared with CARs ranging from 0.4 to 2.0. Radiochemical purity for all tracer groups was >99% after purification. The specific activity levels of tracer_3X, tracer_10X, and tracer_20X were 2.2 ± 0.6, 8.2 ± 0.6, and 10.5 ± 1.6 µCi/µg, respectively. 89Zr-iPET imaging showed evident tumor uptake in all tracer groups and reached the maximum uptake value at 24 h postinjection (p.i.). Biodistribution data at 168 h p.i. revealed that the tumor-to-liver, tumor-to-muscle, and tumor-to-blood uptake ratios for tracer_3X, tracer_10X, and tracer_20X were 0.46 ± 0.14, 0.58 ± 0.33, and 1.54 ± 0.51; 4.7 ± 1.3, 7.1 ± 3.9, and 14.7 ± 1.1; and 13.1 ± 5.8, 19.4 ± 13.8, and 41.3 ± 10.6, respectively. Significant differences were observed between tracer_3X and tracer_20X in the aforementioned uptake ratios at 168 h p.i. The mean residence time and elimination half-life for tracer_3X, tracer_10X, and tracer_20X were 25.4 ± 4.9, 24.2 ± 6.1, and 25.8 ± 3.3 h and 11.8 ± 0.5, 11.1 ± 0.7, and 11.7 ± 0.6 h, respectively. No statistical differences were found between-tracer in the aforementioned pharmacokinetic parameters. In conclusion, 89Zr-DFO-anti-PD-L1-mAb tracers with a CAR of 1.4-2.0 may be better at imaging PD-L1 expression in tumors than are traditional low-CAR 89Zr-iPET tracers.

Deep Learning of Time-Signal Intensity Curves from Dynamic Susceptibility Contrast Imaging Enables Tissue Labeling and Prediction of Survival in Glioblastoma.

BACKGROUND AND PURPOSE: An autoencoder can learn representative time-signal intensity patterns to provide tissue heterogeneity measures using dynamic susceptibility contrast MR imaging. The aim of this study was to investigate whether such an autoencoder-based pattern analysis could provide interpretable tissue labeling and prognostic value in isocitrate dehydrogenase (IDH) wild-type glioblastoma. MATERIALS AND METHODS: Preoperative dynamic susceptibility contrast MR images were obtained from 272 patients with IDH wild-type glioblastoma (training and validation, 183 and 89 patients, respectively). The autoencoder was applied to the dynamic susceptibility contrast MR imaging time-signal intensity curves of tumor and peritumoral areas. Representative perfusion patterns were defined by voxelwise K-means clustering using autoencoder latent features. Perfusion patterns were labeled by comparing parameters with anatomic reference tissues for baseline, signal drop, and percentage recovery. In the validation set (n = 89), a survival model was created from representative patterns and clinical predictors using Cox proportional hazard regression analysis, and its performance was calculated using the Harrell C-index. RESULTS: Eighty-nine patients were enrolled. Five representative perfusion patterns were used to characterize tissues as high angiogenic tumor, low angiogenic/cellular tumor, perinecrotic lesion, infiltrated edema, and vasogenic edema. Of these, the low angiogenic/cellular tumor (hazard ratio, 2.18; P = .047) and infiltrated edema patterns (hazard ratio, 1.88; P = .009) in peritumoral areas showed significant prognostic value. The combined perfusion patterns and clinical predictors (C-index, 0.72) improved prognostication when added to clinical predictors (C-index, 0.55). CONCLUSIONS: The autoencoder perfusion pattern analysis enabled tissue characterization of peritumoral areas, providing heterogeneity and dynamic information that may provide useful prognostic information in IDH wild-type glioblastoma.

Aggressive Treatment Including Endonasal Surgical Sequestrectomy with Vascularized Nasoseptal Flap Can Improve Outcomes of Skull Base Osteoradionecrosis.

Objective Skull base osteoradionecrosis (SB-ORN) is a serious, potentially lethal complication of radiation therapy. We aimed to review the clinical characteristics and outcomes of SB-ORN according to the extent of treatment. Design Retrospective analysis design was used for this study. Setting The study was conducted in two tertiary care hospitals. Participants Patients included who had been clinically diagnosed with SB-ORN from January 2006 to 2017. Main Outcome Measures Clinical characteristics, including demographics, predisposing factors, presenting symptoms, radiological findings, treatment modalities, and treatment outcomes, were reviewed. Treatment was classified into conservative and aggressive types. Aggressive treatment included radical surgical removal of soft tissue and bony sequestrum with the placement of vascularized tissue. Treatment outcome was analyzed in terms of clinical control, survival, and carotid artery blow out. Results Fifteen patients (11 males and 4 females) were identified during the study period. Eight patients were managed conservatively, whereas seven patients were managed with aggressive treatment. The 2-year survival was 75% in the aggressive treatment group and 15% in the conservative group (log-rank, p = 0.049). The estimated 2-year blow out free rate was 46.7% for the conservative group and 100% for the aggressive group (log-rank, p = 0.100). Conclusion In patients with SB-ORN, aggressive management, including surgical removal of sequestrum and coverage with a pedicled flap, is associated with increased survival.

Gene-lifestyle interactions in the genomics of human complex traits.

The role and biological significance of gene-environment interactions in human traits and diseases remain poorly understood. To address these questions, the CHARGE Gene-Lifestyle Interactions Working Group conducted series of genome-wide interaction studies (GWIS) involving up to 610,475 individuals across four ancestries for three lipids and four blood pressure traits, while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and G×E interactions across phenotype-exposure-ancestry combinations, and to derive insights on the potential mechanistic underlying G×E through in-silico functional analyses. Our analyses show first that interaction effects likely contribute to the commonly reported ancestry-specific genetic effect in complex traits, and second, that some phenotype-exposures pairs are more likely to benefit from a greater detection power when accounting for interactions. It also highlighted modest correlation between marginal and interaction effects, providing material for future methodological development and biological discussions. We also estimated contributions to phenotypic variance, including in particular the genetic heritability conditional on the exposure, and heritability partitioned across a range of functional annotations and cell types. In these analyses, we found multiple instances of potential heterogeneity of functional partitions between exposed and unexposed individuals, providing new evidence for likely exposure-specific genetic pathways. Finally, along this work, we identified potential biases in methods used to jointly meta-analyze genetic and interaction effects. We performed simulations to characterize these limitations and to provide the community with guidelines for future G×E studies.

Accurate diagnosis of colorectal cancer based on histopathology images using artificial intelligence.

BACKGROUND: Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients' treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses. METHODS: Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany. RESULTS: Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. CONCLUSIONS: This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

All-cause mortality, cardiovascular mortality, and incidence of cardiovascular disease according to a screening program of cardiovascular risk in South Korea among young adults: a nationwide cohort study.

OBJECTIVES: We aimed to determine whether there are any differences in all-cause and cause-specific mortality with cardiovascular disease (CVD) risk between health screening attenders and non-attenders among young adults. STUDY DESIGN: We performed a retrospective cohort study using claim data from the Korean National Health Insurance Service database. METHODS: Individuals aged 20-39 years who had received health screening at least once between 2002 and 2005 were classified as attenders, and the others were classified as non-attenders. After propensity score matching according to attendance of health screening, 2,060,409 attenders and 2,060,409 non-attenders were included. We estimated adjusted hazard ratios (HRs) and 95% confidence interval (CI) for all-cause mortality, cause-specific mortality, and hospitalization of CVD from 2006 to 2015. RESULTS: Survival from all-cause mortality was greater among attenders than among non-attenders (log rank P < 0.001). Similarly, death from CVD (log rank P = 0.007) and CVD events (log rank P < 0.001) were less likely among attenders. The risk for all-cause mortality in attenders was significantly lower than that in non-attenders (HR = 0.83, 95% CI = 0.81 to 0.84). The risk for CVD mortality (HR = 0.80, 95% CI = 0.73 to 0.87) and hospitalization of CVD (HR = 0.92, 95% CI = 0.91 to 0.94) were lower in attenders. In stratified analyses, the risk for all-cause and cause-specific mortalities was lower among attenders regardless of insurance type. CONCLUSIONS: Among young adults, the risk for all-cause mortality, CVD mortality, and hospitalization of CVD were lower for those who underwent health screenings. Future studies that evaluate the cost-effectiveness of health screening with additional consideration of psychosocial aspects are needed.

Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow.

BACKGROUND: Besides long-term trans-differentiation into neural cells, benefits of stem cell therapy (SCT) in ischemic stroke may include secretion of protective factors, which partly reflects extracellular vesicle (EVs) released by stem cell. However, the mechanism(s) by which stem cells/EVs limit stroke injury have yet to be fully defined. METHODS: We evaluated the protection effect of human placenta mesenchymal stem cells (hPMSC) as a potential form of SCT in experimental ischemic stroke 'transient middle cerebral artery occusion (MCAO)/reperfusion' mice model. FINDINGS: We found for the first time that intraperitoneal administration of hPMSCs or intravenous hPMSC-derived EVs, given at the time of reperfusion, significantly protected the ipsilateral hemisphere from ischemic injury. This protection was associated with significant restoration of normal blood flow to the post-MCAO brain. More importantly, EVs derived from hPMSC promote paracrine-based protection of SCT in the MCAO model in a cholesterol/lipid-dependent manner. INTERPRETATION: Together, our results demonstrated beneficial effects of hPMSC/EVs in experimental stroke models which could permit the rapid "translation" of these cells into clinical trials in the near-term.

Preoperative evaluation of mammographic microcalcifications after neoadjuvant chemotherapy for breast cancer.

AIM: To assess the predictive value of preoperative residual mammographic microcalcifications for residual tumours after neoadjuvant chemotherapy (NAC) for breast cancer. MATERIALS AND METHODS: This single-centre retrospective study included breast cancer patients who underwent NAC and demonstrated suspicious microcalcifications within or near the tumour bed on mammography from June 2015 to August 2018. The residual microcalcifications and remnant lesion on magnetic resonance imaging (MRI) were correlated with histopathological findings of residual tumours and immunohistochemical markers. RESULTS: A total of 96 patients were included. Ten patients achieved pathological complete response (pCR) and previous suspicious microcalcifications were associated with benign pathology in 10.4% (10/96) of the patients. In the remaining 86 patients who did not achieve pCR, 61.5% (59/96) of the residual microcalcifications were associated with invasive or in situ carcinoma and 28.1% (27/96) with benign pathology. Hormone receptor-positive (HR+) patients had the highest proportion of residual malignant microcalcifications compared to HR- patients (48.9% versus 13.5%, respectively; p=0.019). MRI correlated better than residual microcalcifications on mammography in predicting residual tumour extent in all subtypes (ICC=0.709 versus 0.365). MRI also showed higher correlation with residual tumour size for the HR-/HER2+ and HR-/HER2- subtype (ICC=0.925 and 0.876, respectively). CONCLUSION: The extent of microcalcifications on mammography after NAC did not correlate with the extent of residual cancer in 38.5% of women. Regardless of the extent of microcalcifications, residual tumour extent on MRI after NAC and molecular subtype could be an accurate tool in evaluating residual cancer after NAC.

Comparative outcomes of robot-assisted minimally invasive versus open esophagectomy in patients with esophageal squamous cell carcinoma: a propensity score-weighted analysis.

Robots are increasingly used in minimally invasive surgery. We evaluated the clinical benefits of robot-assisted minimally invasive esophagectomy (RAMIE) in comparison with the conventional open esophageal surgery. From 2012 to 2016, 371 patients with esophageal squamous cell carcinoma underwent an Ivor Lewis or McKeown procedure at our institution. Of these, 130 patients underwent laparoscopic gastric conduit formation followed by RAMIE, whereas 241 patients underwent conventional esophageal surgery, including laparotomy and open esophagectomy (OE). We compared the short- and long-term clinical outcomes of these patients using the propensity score-based inverse probability of treatment weighting technique (IPTW). Among the early outcomes, the OE group showed a higher incidence of pneumonia (P = 0.035) and a higher requirement for vasopressors (P = 0.001). Regarding the long-term outcomes, all-cause mortality was significantly higher (P = 0.001) and disease-free survival was lower (P = 0.006) in the OE group. Wound-related problems also occurred more frequently in the OE group (P = 0.020) during the long-term follow-up. There was no statistical intergroup difference in the recurrence rates (P = 0.191). The Cox proportional-hazard analysis demonstrated that wound problems (HR 0.16, 95% CI 0.02-0.57; P = 0.017), pneumonia (HR 0.23, 95% CI 0.06-0.68; P = 0.019), and use of vasopressors (HR 0.14, 95% CI 0.08-0.25; P = 0.001) were independent predictors of mortality. RAMIE could be a better surgical option for selected patients with esophageal squamous cell carcinoma.

Brain Endothelial Cells Release Apical and Basolateral Microparticles in Response to Inflammatory Cytokine Stimulation: Relevance to Neuroinflammatory Stress?

Microparticles (MP) are regarded both as biomarkers and mediators of many forms of pathology, including neurovascular inflammation. Here, we characterized vectorial release of apical and basolateral MPs (AMPs and BMPs) from control and TNF-α/IFN-γ treated human brain endothelial monolayers, studied molecular composition of AMPs and BMPs and characterized molecular pathways regulating AMP and BMP release. The effects of AMPs and BMPs on blood-brain barrier properties and human brain microvascular smooth muscle tonic contractility in vitro were also evaluated. We report that human brain microvascular endothelial cells release MPs both apically and basolaterally with both AMP and BMP release significantly increased following inflammatory cytokine challenge (3.5-fold and 3.9-fold vs. control, respectively). AMPs and BMPs both carry proteins derived from parent cells including those in BBB junctions (Claudin-1, -3, -5, occludin, VE-cadherin). AMPs and BMPs represent distinct populations whose release appears to be regulated by distinctly separate molecular pathways, which depend on signaling from Rho-associated, coiled-coil containing protein kinase (ROCK), calpain as well as cholesterol depletion. AMPs and BMPs modulate functions of neighboring cells including BBB endothelial solute permeability and brain vascular smooth muscle contractility. While control AMPs enhanced brain endothelial barrier, cytokine-induced AMPs impaired BBB. Cytokine-induced but not control BMPs significantly impaired human brain smooth muscle contractility as early as day 1. Taken together these results indicate that AMPs and BMPs may contribute to neurovascular inflammatory disease progression both within the circulation (AMP) and in the brain parenchyma (BMP).

[Determination of Sevoflurane, Isoflurane and Enflurane in the air of workplace by gas chromatography].

Objective: To establish a solvent desorption gas chromatographic method for determination of Sevoflurane, Isoflurane and Enflurane in the air of the Workplace. Methods: Sevoflurane, Isoflurane and Enflurane were collected with activated carbon tube and desorbed with dichloromethane, separated with DB-1 capillary columns, and then detected with flame ionization detector. Results: The linearity ranges were 1.9-304.8 µg/ml for Sevoflurane, 2.1-300.4 µg/ml for Isoflurane and 1.7-305.2 µg/ml for Enflurane, The correlation coefficient was both >0.999. Their limits of detection were 0.6 µg/ml, 0.6 µg/ml and 0.5 µg/ml, and Their limits of quatification were 1.9 µg/ml, 2.1 µg/ml and 1.7 µg/ml, and their minimum detectable concentrations were 0.1、0.2 and 0.1 mg/m(3) per 4.5 L of air. Their relative standard deviations (RSD) were 2.5%-3.0%, 2.3%-3.1% and 2.2%-3.0%. The average desorption efficiencies were 101.1%-103.3%, 100.7%-102.7% and 101.0%-102.9%. The sampling efficiency was both 100%. The breakthrough volume of 100 mg actived carbon was 3.7 mg, 3.4 mg and 3.4 mg. Sevoflurane, Isoflurane and Enflurane in activated carbon tube could be kept at least 10 days at room temperature without significant losses. Conclusion: The method shows lower detection limit, high accuracy and precision. It is feasible for determination of Sevoflurane, Isoflurane and Enflurane in the air of workplace.

Neurolymphatic biomarkers of brain endothelial inflammatory activation: Implications for multiple sclerosis diagnosis.

AIMS: Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults, and its diagnosis is often delayed due to the lack of diagnostic markers. Initiation of disease -modifying therapy in the early stages of MS is especially critical because currently available therapy mostly target relapsing-remitting MS, and is less effective as disease progresses into the more chronic form of secondary-progressive MS. Therefore, exploring specific and sensitive biomarkers will facilitate an expedited and more accurate diagnosis to allow currently available therapies to be more effective. MAIN METHODS: Western blotting was conducted to detect the expression of neurolymphatic proteins in human brain endothelial cells in culture. Additionally, using a cohort of 150 patients with relapsing remitting MS, 26 with secondary progressive MS, and 60 healthy control samples, neurolymphatic protein expression was detected in serum samples using dot blot analysis. KEY FINDINGS: Human brain microvascular endothelial cells express neurolymphatic markers. Neurolymphatic protein abundance increases with tumor necrosis factor (TNF)-α stimulation but decreases with interferon (IFN)- γ or combined (TNF + IFN) treatment. Circulating neurolymphatic protein levels is significantly lower in MS patients. Further, one of the markers, FOXC2, is associated with the clinical stages of MS, with significantly lower expression in secondary progressive MS compared to relapsing remitting MS. SIGNIFICANCE: Our findings describe brain endothelial expression of neurolymphatic proteins, which is altered under inflammatory stress, and provide a possibility of using a collective pool of circulating neurolymphatic proteins as a diagnostic and prognostic biomarker of MS.

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

Radiation Dose Due to Naturally Occurring Radionuclides in Soils from Varying Geological Environments.

Field radiation monitoring and radionuclide analysis of soils were performed at various geological areas in Taiwan. The field-observed dose rate was 0.031-0.107 µGy h. The dose rate ascribed to naturally occurring radionuclides in soils that were geologically characterized varied from 0.002 to 0.079 µGy h. A linear correlation was observed between the activity-derived and field-observed dose, which indicated that the absorbed dose rate from the cosmic rays is almost constant (0.030 µGy h) throughout the flat area on the island.

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

[Interpretation of the fourth edition of WHO pathological classification of the thyroid tumors in 2017].

In recent years, the incidence of thyroid carcinoma gradually increased in China. The pathology diagnosis and classification was based on WHO classification of Tumors of Endocrine Organs, the third edition which published in 2004. The fourth edition, WHO classification of Tumors of Endocrine Organs was published in July 2017. Compared with the third, some important aspects (or points) were revised: the ICD-O code of hyalinizing trabecular tumor was changed from 0 to 1; three other encapsulated follicular-patterned thyroid tumors were added; the variants of well differentiation thyroid carcinoma (including papillary carcinoma and follicular carcinoma ) which was originated from thyroid epithelial cells were updated; oncocytic cell tumors were separated from follicular tumors; the ICD-O code of ectopic thymoma was changed from 1 to 3. Refinement and standardization part of the concepts and diagnostic criterias were done which can solve practical problems in pathology diagnosis.