Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10 × 10-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61 × 10-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25 × 10-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in a TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

Enhancing rural B&B management through machine learning and evolutionary game: A case study of rural revitalization in Yunnan, China.

The rural B&B industry is a key component of rural tourism, local economic development, and the wider rural revitalization strategy. Despite the abundance of tourism resources in Yunnan, the B&B sector faces significant challenges. It is therefore imperative to accurately identify the most pressing issues within the current B&B industry and formulate appropriate solutions to advance Yunnan's rural revitalization efforts. This study uses recent reviews of rural B&Bs on Ctrip.com and employs machine learning techniques, including Bert, CNN, LSTM, and GRU, to identify the key management challenges currently facing Yunnan's rural B&B industry. An analysis is then conducted to identify the key stakeholders involved in the process of improving the management of Yunnan's B&Bs. To assess the willingness of each stakeholder to support the improvement of the rural B&B industry, this paper establishes a three-party evolutionary game model and examines the dynamic evolutionary process of management improvement within Yunnan's rural B&B industry. Two scenarios of evolutionarily stable strategies are analyzed, and parameters impacting stakeholders' strategy choices are simulated and evaluated. The results show that: i) Improving the "human factor" is the top priority for the current management improvement because tourists are most concerned about the emotional experience. Operators need to focus on improving service attitude and emotional experience; ii) The main stakeholders in the current management optimization process of Yunnan B&Bs are the local government, B&B operators, and tourists. Under appropriate conditions, the evolutionarily stable strategy of (1, 1, 1) is reachable. iii) variables such as additional costs, tourists' choice preferences, and government penalties significantly affect the strategy choices of stakeholders, especially B&B operators. This paper offers effective strategies for improving B&B management that can benefit the government, B&B operators, and tourists, and ultimately contribute to the promotion of quality rural revitalization. The paper not only identifies focal areas for improving B&B management in rural Yunnan, but also provides an in-depth understanding of stakeholder dynamics. As a result, it provides valuable insights to further the cause of quality rural revitalization.

A Model of Multi-Finger Coordination in Keystroke Movement.

In multi-finger coordinated keystroke actions by professional pianists, movements are precisely regulated by multiple motor neural centers, exhibiting a certain degree of coordination in finger motions. This coordination enhances the flexibility and efficiency of professional pianists' keystrokes. Research on the coordination of keystrokes in professional pianists is of great significance for guiding the movements of piano beginners and the motion planning of exoskeleton robots, among other fields. Currently, research on the coordination of multi-finger piano keystroke actions is still in its infancy. Scholars primarily focus on phenomenological analysis and theoretical description, which lack accurate and practical modeling methods. Considering that the tendon of the ring finger is closely connected to adjacent fingers, resulting in limited flexibility in its movement, this study concentrates on coordinated keystrokes involving the middle and ring fingers. A motion measurement platform is constructed, and Leap Motion is used to collect data from 12 professional pianists. A universal model applicable to multiple individuals for multi-finger coordination in keystroke actions based on the backpropagation (BP) neural network is proposed, which is optimized using a genetic algorithm (GA) and a sparrow search algorithm (SSA). The angular rotation of the ring finger's MCP joint is selected as the model output, while the individual difference information and the angular data of the middle finger's MCP joint serve as inputs. The individual difference information used in this study includes ring finger length, middle finger length, and years of piano training. The results indicate that the proposed SSA-BP neural network-based model demonstrates superior predictive accuracy, with a root mean square error of 4.8328°. Based on this model, the keystroke motion of the ring finger's MCP joint can be accurately predicted from the middle finger's keystroke motion information, offering an evaluative method and scientific guidance for the training of multi-finger coordinated keystrokes in piano learners.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Whole-genome sequencing provides insights into a novel species: Providencia hangzhouensis associated with urinary tract infections.

Providencia rettgeri is a clinically significant opportunistic pathogen that is involved in urinary tract infections. Due to the resolution limitations of identification, distinguishing P. rettgeri from closely related species is challenging by commercial biochemical test systems. Here, we first reported a novel species, Providencia hangzhouensis, which had been misidentified as P. rettgeri. Exhibiting ≤91.97% average nucleotide identity (ANI) and ≤46.10% in silico DNA-DNA hybridization values with all known Providencia species, P. hangzhouensis falls well beneath the established species-defining thresholds. We conducted a population genomics analysis of P. hangzhouensis isolates worldwide. Our study revealed that P. hangzhouensis has emerged in many countries and has formed several transmission clusters. We found that P. hangzhouensis shared the highest ANI values (91.54% and 91.97%) with P. rettgeri and P. huaxiensis, respectively. The pan-genome analysis revealed that these three species possessed a similar component of pan-genomes. Two genes associated with metabolism, folE2 and ccmM, were identified to be specific to P. hangzhouensis. Furthermore, we also observed that carbapenem-resistance genes frequently occur in P. hangzhouensis with the blaIMP-27 being the most prevalent (46.15%; 36/78). The emergence of P. hangzhouensis is often accompanied by extended-spectrum ß-lactamase and carbapenem-resistance genes, and calls for tailored surveillance of this species as a clinically relevant species in the future. IMPORTANCE Our study has identified and characterized a novel species, Providencia hangzhouensis, which is associated with urinary tract infections and was previously misidentified as Providencia rettgeri. Through this study, we have identified specific genes unique to P. hangzhouensis, which could serve as marker genes for rapid PCR identification. Additionally, our findings suggest that the emergence of P. hangzhouensis is often accompanied by extended-spectrum ß-lactamase and carbapenem-resistance genes, emphasizing the need for attention to clinical management and the importance of accurate species identification and proper drug use.

Genetically adjusted PSA levels for prostate cancer screening.

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGSPSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10-14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10-12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.

Transcriptome-Wide Association Analysis Identifies Novel Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility to screen for prostate cancer (PCa). We thus conducted a transcriptome-wide association study (TWAS) of PSA levels using genome-wide summary statistics from 95,768 PCa-free men, the MetaXcan framework, and gene prediction models trained in Genotype-Tissue Expression (GTEx) project data. Tissue-specific analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10e-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61e-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses that combined associations across 45 tissues identified 155 genes that were statistically significantly (p < 0.05/22,249 = 2.25e-6) associated with PSA levels. Based on conditional analyses that assessed whether TWAS associations were attributable to a lead GWAS variant, we found 20 novel genes (11 single-tissue, 9 cross-tissue) that were associated with PSA levels in the TWAS. Of these novel genes, five showed evidence of colocalization (colocalization probability > 0.5): EXOSC9, CCNA2, HIST1H2BN, RP11-182L21.6, and RP11-327J17.2. Six of the 20 novel genes are not known to impact PCa risk. These findings yield new hypotheses for genetic factors underlying PSA levels that should be further explored toward improving our understanding of PSA biology.

Germline genetic variants and pediatric rhabdomyosarcoma outcomes: a report from the Children's Oncology Group.

BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS. METHODS: The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal RMS) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group. RESULTS: We identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59 to 2.53, P = 5.39 × 10-9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48 to 2.27, P = 2.13 × 10-8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34 to 5.99, P = 3.54 × 10-8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12 to 4.86, P = 3.60 × 10-8) were associated with worse OS among individuals with alveolar RMS. CONCLUSIONS: We demonstrated that common germline variants are associated with EFS and OS among individuals with RMS. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.

Low expression of SEMA4D as a potential predictive molecular marker of poor survival in patients with melanoma combined with liver cancer.

This study explored the correlation between semaphorin 4D (SEMA4D) and the prognosis and survival time of patients with melanoma combined with liver cancer. A total of 272 patients were recruited, and clinical and follow-up data were recorded. The expression levels of SEMA4D and SEMA3B were determined. Pearson's χ2 test and Spearman's rank correlation coefficient were used to analyze the relationship between prognosis and the assessed parameters of melanoma patients. Univariate and multivariate Logistic regression and Cox proportional risk regression analyses were used for further analysis. Additionally, receiver operating characteristic curve and survival curves of subjects were plotted. The Pearson's χ2 test showed that the prognosis of melanoma patients was significantly correlated with age, tumor grade, and decreased SEMA4D expression. Additionally, Spearman's correlation coefficient analysis showed that age, tumor grade, and SEMA4D expression were significantly correlated with prognosis. Univariate logistic regression analysis showed that age and tumor grade, and SEMA4D expression, were significantly correlated with prognosis. Older patients, a higher tumor grade, and lower SEMA4D expression were associated with a poorer prognosis. Multivariate logistic regression analysis showed that older patients had a poorer prognosis, and patients with lower SEMA4D expression levels had a significantly worse prognosis than patients with higher SEMA4D expression levels. Kaplan-Meier analysis showed that the survival time of older patients was lower than that of the younger patients. The survival times of patients with lower SEMA4D expression levels were significantly lower than that of patients with higher SEMA4D expression levels. Multivariate Cox regression analysis showed that the survival time of older patients was lower than that of younger patients. The survival time of melanoma patients with low SEMA4D expression was significantly lower than that of patients with higher SEMA4D expression. SEMA4D was significantly associated with melanoma, and lower SEMA4D expression was associated with a poorer survival prognosis in melanoma patients.

Pyroptosis Provides New Strategies for the Treatment of Cancer.

Cancer is an important cause of death worldwide. The main types of cancer treatment are still surgery, chemotherapy and radiotherapy, and immunotherapy is becoming an important cancer treatment. Pyroptosis is a type of programmed cell death that accompanies an inflammatory response. This paper reviews the recent research progress in pyroptosis in tumors. Pyroptosis has been observed since 1986 and until recently has been recognized as programmed cell death mediated by GSDM family proteins. The molecular pathway of pyroptosis depends on the inflammasome-mediated caspase-1/GSDMD pathway, which is the canonical pathway, and the caspase-4/5/11/GSDMD pathway, which is the noncanonical pathway. Other pathways include caspase3/GSDME. Pyroptosis is a double-edged sword that is closely related to the tumor immune microenvironment. On the one hand, pyroptosis produces a chronic inflammatory environment, promotes the transition of normal cells to tumor cells, helps tumor cells achieve immune escape, and promotes tumor growth and metastasis. On the other hand, some tumor cell treatments can induce pyroptosis, which is a nonapoptotic form of cell death. Additionally, pyroptosis releases inflammatory molecules that promote lymphocyte recruitment and enhance the immune system's ability to kill tumor cells. With the advent of immunotherapy, pyroptosis has been shown to enhance the antitumor efficacy of immune checkpoint inhibitors. Some antineoplastic agents, such as chemotherapeutic agents, can also exert antineoplastic effects through the pyroptosis pathway. Pyroptosis, which is a programmed cell death mode, has been the focus of research in recent years, and the relationship between pyroptosis, tumors and tumor immunity has attracted attention, but there are still some questions to be answered regarding the specific mechanism. Further study of pyroptosis would aid in developing new antitumor therapies and has great clinical prospects.

Intraprocedural arrhythmia termination as an end point for hybrid ablation in patients with long-standing persistent atrial fibrillation: a 2-year follow-up study.

OBJECTIVES: Hybrid catheter and surgical ablation has emerged as an effective therapy for patients with persistent atrial fibrillation (AF). The aims of this study were to evaluate the relationship between intraprocedural arrhythmia termination and the long-term outcomes of hybrid ablation in patients with long-standing persistent AF. METHODS: From May 2015 through April 2019, 50 patients with persistent AF with a mean duration of 73.3 ± 62.1 (median 54) months underwent single-step hybrid ablation. Pulmonary vein isolation, left atrial posterior wall isolation and left atrial appendage excision or closure were performed through a left-sided thoracoscopic approach. Subsequently, all patients underwent high-density endocardial mapping and electrogram-based ablation with the end point of AF termination. RESULTS: We achieved intraprocedural AF termination in 84% (42/50) patients; this end point was reached in 16 patients during surgical ablation and in 26 patients during catheter ablation. Seven patients underwent repeat catheter ablation. After a mean follow-up period of 29 ± 13 months, the freedom from atrial tachyarrhythmia of a single procedure without the use of antiarrhythmic drugs was 70% (35/50). In the Cox regression model, intraprocedural termination of AF (hazard ratio 0.205, 95% confidence interval 0.058-0.730; P = 0.014) was the sole predictor of success. CONCLUSIONS: The 2-year outcomes of a one-stop hybrid ablation with an end point of AF termination are promising in patients with long-standing persistent AF.

New score for prediction of morbidity in patients undergoing open pancreaticoduodenectomy.

OBJECTIVE: The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) is commonly used to predict the risk of postoperative complications in general surgery. However, use of the POSSUM is not absolutely suitable for open pancreaticoduodenectomy (OPD), which has unique complications such as pancreatic fistula formation. This study was performed to establish a new risk score for assessing the incidence of postoperative complications of OPD. METHODS: This retrospective case-control study involved 159 patients who underwent standard OPD from 2 January 2017 to 1 February 2019. The risk factors for post-OPD complications were statistically investigated, and a risk score model was established by multivariate logistic regression. RESULTS: Among all 159 patients, 72 (42.28%) developed complications. A scoring system was developed based on the following five independent variables: sodium concentration of <141.20 mmol/L, white blood cell count of >6.35 × 109/L, pancreatic texture grade, body mass index of >25.06 kg/m2, and basic respiratory diseases. Our risk score model demonstrated better discriminating power, prediction power, and prediction probability than the POSSUM model in the receiver operating characteristic curve analysis. CONCLUSION: This novel risk score may help to predict postoperative complications after OPD with higher accuracy than the POSSUM system.

Immediate electrophysiological characteristics following modified thoracoscopic ablation via unilateral approach for non-valvular atrial fibrillation.

BACKGROUND: Thoracoscopic ablation has emerged as an effective therapy for patients with long-standing persistent Atrial fibrillation (LsPAF). We aimed to investigate the immediate electrophysiological characteristics following modified ablation with 3 circular and 3 linear lesions in the thoracoscopic procedure via a unilateral approach. METHODS: Between May 2015 and October 2018, 40 patients underwent the one-stage hybrid procedure for LsPAF. Isolation of the pulmonary veins (PV) and left atrium posterior wall (LAPW), excision of the left atrial appendage (LAA), and high-density endocardial mapping and individualized percutaneous catheter ablation for AF termination were performed. RESULTS: The modified thoracoscopic procedure may enable successful PV and LAPW isolation and LAA removal. Endocardial electrophysiological examination showed 6 out of 40 (15%) patients with a right PV gap, 3 (7.5%) patients with incomplete roof lesions, and 8 (20%) patients with incomplete Dallas lesions. A total of 44 driving areas were mapped and ablated. Thirty-five patients achieved procedural AF termination. After a mean follow-up period of 26 months, the success rate of a single procedure was 85%. Cox regression analysis demonstrated that the failure of procedural AF termination may be a risk factor in atrial tachyarrhythmia recurrence. DISCUSSION: Endocardial electrophysiological examination is a necessary partner to thoracoscopic ablation. Our modified thoracoscopic ablation and driving areas-based ablation contribute to high rates of procedural AF termination, which may lead to reduced recurrence rate. The hybrid procedure may be an effective strategy for the management of LsPAF.

Circ_LDLR Knockdown Suppresses Progression of Hepatocellular Carcinoma via Modulating miR-7/RNF38 Axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a horrible malignancy derived from liver. Circular RNAs (circRNAs) act important roles in the pathogenesis and progression of human diseases, including HCC. The current assay intended to investigate the function of circRNA low-density lipoprotein receptor (circ_LDLR) in HCC and clarify the underlying mechanism. MATERIALS AND METHODS: Expression of circ_LDLR, microRNA (miR)-7 and ring finger protein 38 (RNF38) was determined by quantitative real-time PCR (qRT-PCR) or Western blot analysis. Flow cytometry was used to detect cell cycle distribution and apoptosis. Cell colony formation ability and viability were examined by colony formation and methyl thiazolyl tetrazolium (MTT) assays, respectively. Levels of cell proliferation and epithelia-mesenchymal transition (EMT) biomarker proteins were analyzed via Western blot assay. Cell migration and invasion were monitored by Transwell assay, and target relationship between miR-7 and circ_LDLR or RNF38 was validated by dual-luciferase reporter assay. Xenograft model was established to explore the role of circ_LDLR in vivo. RESULTS: Expression of circ_LDLR and RNF38 was upregulated, but miR-7 expression was downregulated in HCC tissues and cells. Circ_LDLR knockdown significantly inhibited cell proliferation, migration, invasion and EMT in HCC cells. Circ_LDLR acted as a sponge of miR-7, and interference of miR-7 could attenuate circ_LDLR knockdown-induced inhibitory effects on malignant behaviors of HCC cells. Besides, miR-7 also repressed cell proliferation and metastasis of HCC cells, by targeting RNF38. Depletion of circ_LDLR could suppress tumor growth in vivo. CONCLUSION: Depletion of circ_LDLR restrained HCC cell proliferation, metastasis and tumorigenesis through the regulation on miR-7/RNF38 axis, affording a promising therapeutic target for HCC.

Higher neutrophil-lymphocyte ratio is associated with better prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide; its morbidity and mortality have both recently increased. Lately, the role played by the neutrophil-lymphocyte ratio (NLR) in the development of HCC has attracted attention. However, the exact relationship is not fully understood.A total of 538 participants diagnosed with HCC were recruited between 2010 and 2018. Their relevant routine blood parameters were measured, including NLR. Pearson Chi-Squared test, Spearman Rho test, and logistic regression analysis were performed to explore any correlations between NLR and HCC. A receiver operating characteristic (ROC) curve analysis was performed to determine the usefulness of NLR for predicting HCC. Univariate and multivariate Cox regression analysis for relevant routine blood parameters and any relationships with overall survival (OS) were performed. The Kaplan-Meier method was used to explore any further relationships with OS.NLR was significantly correlated with HCC tumor size by Pearson Chi-Squared test (P = .008). Furthermore, Spearman correlation coefficient showed that HCC tumor size was significantly correlated with NLR (P = .115, P = .008). NLR could sensitively and specifically predict HCC tumor size (area under the curve [AUC], 0.605; 95% confidence interval [CI], 0.429-0.743; P = .000). Higher NLR in patients with HCC was correlated with better OS (hazard ratio [HR] = 0.584; P = .000).A close correlation existed between increased NLR and HCC; NLR could sensitively and specifically predict HCC. High NLR might be an independent protective factor in the prognosis of patients with HCC.

Investigation of Atyp.C using UF-5000 flow cytometer in patients with a suspected diagnosis of urothelial carcinoma: a single-center study.

BACKGROUND: This study evaluated the predictive power of Atyp.C (a parameter of UF-5000 flow cytometer) for patients with a suspected diagnosis of urothelial carcinoma. METHODS: We analyzed 163 urine specimens from 128 patients with suspected urothelial carcinoma using a fully automated fluorescence flow cytometry analyzer (UF-5000) and evaluated its performance on identifying atypical/malignant urothelial cells. From January 1, 2019 to April 4, 2019, all consecutive specimens for urinary cytopathology were enrolled. RESULTS: Of the specimens with urinary cytopathology, 67 specimens (41.1%) revealed abnormal findings in cytology analysis. Among them, 20 specimens (12.3%) were diagnosed as atypical urothelial cells, 26 specimens (16.0%) as suspicious for malignancy (S-malignancy), and 21 specimens (12.9%) as confirmed malignancy. The UF-5000 findings were positive in 59 specimens (36.2%); therefore, the agreement with cytopathology was 73.0%. Using follow-up histologic diagnosis of urothelial carcinoma with or without urinary tract cytology (UTCy) as a reference standard (suspicious and confirmed malignancy were the positive criteria for UTCy), the sensitivity was 59.0%, specificity was 82.1%, positive predictive value was 75.0%, negative predictive value was 68.8%, and the agreement was 71.1%. CONCLUSIONS: It is worth knowing and reporting that the Atyp.C assay may be used as an accessory test for patients with suspected urothelial carcinoma, based on its ability to identify high-risk patients who might need closer follow-up or additional medical treatment.

Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.

Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 × 10-13) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10-6). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1∗03:01, (OR 1.66, p = 1.52 × 10-7), DPB1∗10:01 (OR 2.12, p = 0.0003), and DPB1∗01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 × 10-9) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.

A newly improved POSSUM scoring system for prediction of morbidity in patients with pancreaticoduodenectomy.

BACKGROUND: Postoperative morbidity of pancreaticoduodenectomy (PD) is still prevalent in hospitals around the world all over the world. Chirurgia B and Chen Yingtai et al. compared the existing POSSUM and p-POSSUM scoring system in pancreatoduodenectomy. However, in this retrospective cohort study our aim was to investigate the risk factors associated with post-PD complications, and develop a POSSUM scoring system more specific to PD, which we define as PD-POSSUM. METHODS: Data was gathered from 201 patients who underwent PD procedure at No.4 Hospital of Hebei Medical University between January 2016 and December 2018. All 201 patients were included in the modeling group. The morbidity and associated risk factors were collected and analyzed. The risk factors of complication were investigated by the Pearson χ2 test, Spearman rho test, multivariable linear regression, univariate/multivariate logistic regression. In addition, the discriminating ability of the PD-POSSUM system to predict morbidity is estimated by the area under the receiver operating characteristic curve (ROC-AUC). RESULTS: Morbidity was 45.5% for the 201 patients. Multivariate logistic regression analysis demonstrated a significant connection between postoperative complications and body mass index (BMI) [odd ratio (OR): 3.700; 95% confidence interval (95% CI): 1.594-4.572], pre-existing respiratory diseases (OR: 3.000; 95% CI: 1.542-5.837), international normalized ratio of prothrombin time (OR: 0.321; 95% CI: 0.099-1.038), alanine aminotransferase (OR: 0.573; 95% CI: 0.375-0.874); total bilirubin level (OR: 1.477; 95% CI: 1.068-2.043); diameter of pancreatic duct (OR: 1.837; 95% CI: 1.221-2.763) and diameter of tumor diameter (OR: 1.837; 95% CI: 1.221-2.763). CONCLUSIONS: Ln R/(1 - R) = Score PD - POSSUM  = 0 .140*Score PS - 0 .053*Score OS - 5 .850 . This risk assessment formula can help estimate and predict postoperative morbidity rate after PD.

Associations of autozygosity with a broad range of human phenotypes.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.