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IntroductionGastrointestinal complications after total hip (THA) and knee arthroplasty (TKA) have been reported to be between 0.3 and 2.6% with bleeding and C. difficile infection in 0–1%, and 0.1–1.7%, respectively. The use of enhanced recovery or “fast-track” protocols have focused on optimizing all aspects of perioperative care resulting in reduced length of hospital stay (LOS) and potentially also gastrointestinal complications. This study is a detailed analysis on the occurrence of postoperative gastrointestinal complications resulting in increased hospital stay or readmissions in a large consecutive cohort of fast-track THA and TKA with complete 90 days follow-up.Materials and methodsThis is an observational study on a consecutive cohort of primary unilateral THAs and TKAs performed between January 2010 and August 2017 in nine Danish high-volume fast-track centers. Discharge summaries and relevant patient records were reviewed in patients with readmissions within 90 days or LOS > 4 days caused by gastrointestinal complications.ResultsThe cohort included 36,932 patients with 58.3% females and 54.1% THAs. Mean age and BMI were 68 years and 28. Median postoperative LOS was 2 days. Only n: 276 (0.75 %) had a LOS > 4 days or a readmission within 90 days due to a gastrointestinal complication (CI 0.67%–0.84%). Of these, only 34 (0.09%) were graded as severe ileus or gastrointestinal bleeding.ConclusionsThe risk of GI-complications within the first 90 postoperative days after fast-track THA and TKA was low (0.75%). IntroductionGastrointestinal complications after total hip (THA) and knee arthroplasty (TKA) have been reported to be between 0.3 and 2.6% with bleeding and C. difficile infection in 0–1%, and 0.1–1.7%, respectively. The use of enhanced recovery or “fast-track” protocols have focused on optimizing all aspects of perioperative care resulting in reduced length of hospital stay (LOS) and potentially also gastrointestinal complications. This study is a detailed analysis on the occurrence of postoperative gastrointestinal complications resulting in increased hospital stay or readmissions in a large consecutive cohort of fast-track THA and TKA with complete 90 days follow-up.Materials and methodsThis is an observational study on a consecutive cohort of primary unilateral THAs and TKAs performed between January 2010 and August 2017 in nine Danish high-volume fast-track centers. Discharge summaries and relevant patient records were reviewed in patients with readmissions within 90 days or LOS > 4 days caused by gastrointestinal complications.ResultsThe cohort included 36,932 patients with 58.3% females and 54.1% THAs. Mean age and BMI were 68 years and 28. Median postoperative LOS was 2 days. Only n: 276 (0.75 %) had a LOS > 4 days or a readmission within 90 days due to a gastrointestinal complication (CI 0.67%–0.84%). Of these, only 34 (0.09%) were graded as severe ileus or gastrointestinal bleeding.ConclusionsThe risk of GI-complications within the first 90 postoperative days after fast-track THA and TKA was low (0.75%).

Network statistics for network constructed from 89 genes with/near integration events.

The incidence of human papillomavirus (HPV)–related oropharynx cancer has steadily increased over the past two decades and now represents a majority of oropharyngeal cancer cases. Integration of the HPV genome into the host genome is a common event during carcinogenesis that has clinically relevant effects if the viral early genes are transcribed. Understanding the impact of HPV integration on clinical outcomes of head and neck squamous cell carcinoma (HNSCC) is critical for implementing deescalated treatment approaches for HPV+ HNSCC patients. RNA sequencing (RNA-seq) data from HNSCC tumors (n = 84) were used to identify and characterize expressed integration events, which were overrepresented near known head and neck, lung, and urogenital cancer genes. Five genes were recurrent, including CD274 (PD-L1). A significant number of genes detected to have integration events were found to interact with Tp63, ETS, and/or FOX1A. Patients with no detected integration had better survival than integration-positive and HPV− patients. Furthermore, integration-negative tumors were characterized by strongly heightened signatures for immune cells, including CD4+, CD3+, regulatory, CD8+ T cells, NK cells, and B cells, compared with integration-positive tumors. Finally, genes with elevated expression in integration-negative specimens were strongly enriched with immune-related gene ontology terms, while upregulated genes in integration-positive tumors were enriched for keratinization, RNA metabolism, and translation.Implications: These findings demonstrate the clinical relevancy of expressed HPV integration, which is characterized by a change in immune response and/or aberrant expression of the integration-harboring cancer-related genes, and suggest strong natural selection for tumor cells with expressed integration events in key carcinogenic genes. Mol Cancer Res; 16(1); 90–102. ©2017 AACR.

Supplemental Methods, Tables S5-S14, and Figures S1-S3

Enriched GO terms for genes differentially expressed between HPV(+) and HPV(-) HNC tumors in the UM cohort.

Supplementary methods and figures. from Subtypes of HPV-Positive Head and Neck Cancers Are Associated with HPV Characteristics, Copy Number Alterations, PIK3CA Mutation, and Pathway Signatures

Purpose: There is substantial heterogeneity within human papillomavirus (HPV)-associated head and neck cancer (HNC) tumors that predispose them to different outcomes; however, the molecular heterogeneity in this subgroup is poorly characterized due to various historical reasons.Experimental Design: We performed unsupervised gene expression clustering on deeply annotated (transcriptome and genome) HPV+ HNC samples from two cohorts (84 total primary tumors), including 18 HPV− HNC samples, to discover subtypes and characterize the differences between subgroups in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number alterations, and mutation frequencies.Results: We identified two distinct HPV+ subtypes (namely HPV-KRT and HPV-IMU). HPV-KRT is characterized by elevated expression of genes in keratinocyte differentiation and oxidation–reduction process, whereas HPV-IMU has strong immune response and mesenchymal differentiation. The differences in expression are likely connected to the differences in HPV characteristics and genomic changes. HPV-KRT has more genic viral integration, lower E2/E4/E5 expression levels, and higher ratio of spliced to full-length HPV oncogene E6 than HPV-IMU; the subgroups also show differences in copy number alterations and mutations, in particular the loss of chr16q in HPV-IMU and gain of chr3q and PIK3CA mutation in HPV-KRT.Conclusions: Our characterization of two subtypes of HPV+ HNC tumors provides valuable molecular level information that point to two main carcinogenic paths. Together, these results shed light on stratifications of the HPV+ HNCs and will help to guide personalized care for HPV+ HNC patients. Clin Cancer Res; 22(18); 4735–45. ©2016 AACR.

BACKGROUND: Peripheral nerve blocks (PNB) have recently been recommended in total hip (THA) and knee (TKA) arthroplasty as they may reduce pain, morphine consumption, length of stay (LOS) and complications. However, whether PNBs are associated with early discharge within an enhanced recovery protocol including multimodal analgesia is uncertain.METHODS: An observational multicenter study from January to August 2017 in six Danish Arthroplasty Centers with established fast-track protocols. Prospective recording of preoperative characteristics and information on PNB, LOS and readmissions through the Danish National Patient Registry and medical records. Multiple logistic regression was used to investigate associations between PNB and a LOS >1 day, LOS >4 days, and 30-days readmissions. We also reported on mobilization, pain, opioid and fall-related complications leading to LOS >4 days or readmissions.RESULTS: A total of 2027 (58.6%) THA and 1432 (41.4%) TKAs with a median LOS of 1 day (IQR 1-2) and 5.3% (CI:4.6-6.1) 30-days readmission rate were identified. PNB was used in 40.7% (CI:38.2-43.3) of TKA and 2.7% (CI:2.0-3.5) of THA, but with considerable interdepartmental variation (0.0-89.0% for TKA). There was no association between PNB and LOS >1 day (OR:1.19 CI:0.82-1.72; p = .354), LOS >4 days (OR:1.4 CI:0.68-2.89; p = .359) or 30-days readmissions (OR:1.02 CI:0.63-1.65; p = .935) in TKA. Logistic regression in THA was not possible due to limited use of PNB. In TKA there were 12 (2.1% CI:1.2-3.6) with and 1 (0.1% CI:0.02-0.7) without a PNB, who had mobilization, pain or opioid-related complications, and 5 (0.9% CI:0.4-2.0) versus 4 (0.5% CI:0.2-1.2) who fell. Correspondingly, 2 (3.7% CI:1.0-12.6) and 11 (0.6% CI:0.3-1.0) of THA patients had these complications, while 0 (0.0% CI:0.0-6.6) and 17 (0.8% CI:0.5-1.3) fell.CONCLUSION: Routine use of peripheral nerve blocks was not associated with early discharge or 30-days readmissions in fast-track THA and TKA. Future studies should focus on benefits of PNB in high-risk patients.

Background and purpose — Prediction of postoperative outcomes and length of hospital stay (LOS) of patients is vital for allocation of healthcare resources. We investigated the performance of prediction models based on machinelearning algorithms compared with a previous risk stratification model using traditional multiple logistic regression, for predicting the risk of a LOS of > 2 days after fast-track total hip and knee replacement. Patients and methods — 3 different machine learning classifiers were trained on data from the Lundbeck Centre for Fast-track Hip and Knee Replacement Database (LCDB) collected from 9,512 patients between 2016 and 2017. The chosen classifiers were a random forest classifier (RF), a support vector machine classifier with a polynomial kernel (SVM), and a multinomial Naïve-Bayes classifier (NB). Results — Comparing performance measures of the classifiers with the traditional model revealed that all the models had a similar performance in terms of F1 score, accuracy, sensitivity, specificity, area under the receiver operating curve (AUC), and area under the precision-recall curve (AUPRC). A feature importance analysis of the RF classifier found hospital, age, use of walking aid, living alone, and joint operated on to be the most relevant input features. None of the classifiers reached a clinically relevant performance with the input data from the LCDB. Interpretation — Despite the promising prospects of machine-learning practices for disease and risk prediction, none of the machine learning models tested outperformed the traditional multiple regression model in predicting which patients in this cohort had a LOS > 2 days.

The aim of this prospective multicentre study was to describe trends in length of stay and early complications and readmissions following unicompartmental knee arthroplasty (UKA) performed at eight different centres in Denmark using a fast-track protocol and to compare the length of stay between centres with high and low utilization of UKA.We included data from eight dedicated fast-track centres, all reporting UKAs to the same database, between 2010 and 2018. Complete (99%) data on length of stay, 90-day readmission, and mortality were obtained during the study period. Specific reasons for a length of stay oftwo days, length of stayfour days, and 30- and 90-day readmission were recorded. The use of UKA in the different centres was dichotomized into ≥ 20% versus20% of arthroplasties which were undertaken being UKAs, and ≥ 52 UKAs versus52 UKAs being undertaken annually.A total of 3,927 procedures were included. Length of stay (mean 1.1 days (SD 1.1), median 1 (IQR 0 to 1)) was unchanged during the study period. The proportion of procedures with a length of staytwo days was also largely unchanged during this time. The percentage of patients discharged on the day of surgery varied greatly between centres (0% to 50% (0 to 481)), with centres with high UKA utilization (both usage and volume) having a larger proportion of same-day discharges. The 30- and 90-day readmissions were 166 (4.2%) and 272 (6.9%), respectively; the 90-day mortality was 0.08% (n = 3).Our findings suggest general underutilization of the potential for quicker recovery following UKA in a fast-track setup. Cite this article

Identifying new gene functions and pathways underlying diseases and biological processes are major challenges in genomics research. Particularly, most methods for interpreting the pathways characteristic of an experimental gene list defined by genomic data are limited by their dependence on assessing the overlapping genes or their interactome topology, which cannot account for the variety of functional relations. This is particularly problematic for pathway discovery from single-cell genomics with low gene coverage or interpreting complex pathway changes such as during change of cell states. Here, we exploited the comprehensive sets of molecular concepts that combine ontologies, pathways, interactions and domains to help inform the functional relations. We first developed a universal concept signature (uniConSig) analysis for genome-wide quantification of new gene functions underlying biological or pathological processes based on the signature molecular concepts computed from known functional gene lists. We then further developed a novel concept signature enrichment analysis (CSEA) for deep functional assessment of the pathways enriched in an experimental gene list. This method is grounded on the framework of shared concept signatures between gene sets at multiple functional levels, thus overcoming the limitations of the current methods. Through meta-analysis of transcriptomic data sets of cancer cell line models and single hematopoietic stem cells, we demonstrate the broad applications of CSEA on pathway discovery from gene expression and single-cell transcriptomic data sets for genetic perturbations and change of cell states, which complements the current modalities. The R modules for uniConSig analysis and CSEA are available through https://github.com/wangxlab/uniConSig.

INTRODUCTION: Limited information is available on the views of children taking medicines and participating in clinical trials. These views may contribute to a better understanding of what can be improved on in the development of medicines from their perspective. OBJECTIVE: To collect children's views on taking medicines and participating in clinical trials. MATERIALS AND METHODS: A question-based survey was conducted among children living in European Union countries between January and August 2015. RESULTS: Almost 900 children aged 10-17 years from Finland, Germany, Sweden, Spain and Hungary responded. Almost 40% had a chronic health condition. The most commonly used pharmaceutical forms were solid or liquid medicines for oral use and injectable medicines. Bad taste and pain during administration were reported as common problems. Of 785 respondents, 17% had been taking part in a clinical trial. Most respondents would potentially agree to take part in a clinical trial because the investigational medicine might improve their own health or that of other children. Concern that the investigational medicine might be harmful was the main reason to refuse participation, if asked to. Over half of the respondents were willing to learn more about clinical trials, preferably online. CONCLUSIONS: It is necessary to involve children in the development of age-appropriate pharmaceutical forms and in the design of clinical trials. Children and their carers should be provided with age-appropriate medical information in the most suitable channels. We have identified some common problems that children experience when taking medicines, and we conclude that children are interested in learning more and giving their opinions on clinical trials.

Purpose: There is substantial heterogeneity within human papillomavirus (HPV)-associated head and neck cancer (HNC) tumors that predispose them to different outcomes; however, the molecular heterogeneity in this subgroup is poorly characterized due to various historical reasons. Experimental Design: We performed unsupervised gene expression clustering on deeply annotated (transcriptome and genome) HPV+ HNC samples from two cohorts (84 total primary tumors), including 18 HPV− HNC samples, to discover subtypes and characterize the differences between subgroups in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number alterations, and mutation frequencies. Results: We identified two distinct HPV+ subtypes (namely HPV-KRT and HPV-IMU). HPV-KRT is characterized by elevated expression of genes in keratinocyte differentiation and oxidation–reduction process, whereas HPV-IMU has strong immune response and mesenchymal differentiation. The differences in expression are likely connected to the differences in HPV characteristics and genomic changes. HPV-KRT has more genic viral integration, lower E2/E4/E5 expression levels, and higher ratio of spliced to full-length HPV oncogene E6 than HPV-IMU; the subgroups also show differences in copy number alterations and mutations, in particular the loss of chr16q in HPV-IMU and gain of chr3q and PIK3CA mutation in HPV-KRT. Conclusions: Our characterization of two subtypes of HPV+ HNC tumors provides valuable molecular level information that point to two main carcinogenic paths. Together, these results shed light on stratifications of the HPV+ HNCs and will help to guide personalized care for HPV+ HNC patients. Clin Cancer Res; 22(18); 4735–45. ©2016 AACR.

The incidence of human papillomavirus (HPV)–related oropharynx cancer has steadily increased over the past two decades and now represents a majority of oropharyngeal cancer cases. Integration of the HPV genome into the host genome is a common event during carcinogenesis that has clinically relevant effects if the viral early genes are transcribed. Understanding the impact of HPV integration on clinical outcomes of head and neck squamous cell carcinoma (HNSCC) is critical for implementing deescalated treatment approaches for HPV+ HNSCC patients. RNA sequencing (RNA-seq) data from HNSCC tumors (n = 84) were used to identify and characterize expressed integration events, which were overrepresented near known head and neck, lung, and urogenital cancer genes. Five genes were recurrent, including CD274 (PD-L1). A significant number of genes detected to have integration events were found to interact with Tp63, ETS, and/or FOX1A. Patients with no detected integration had better survival than integration-positive and HPV− patients. Furthermore, integration-negative tumors were characterized by strongly heightened signatures for immune cells, including CD4+, CD3+, regulatory, CD8+ T cells, NK cells, and B cells, compared with integration-positive tumors. Finally, genes with elevated expression in integration-negative specimens were strongly enriched with immune-related gene ontology terms, while upregulated genes in integration-positive tumors were enriched for keratinization, RNA metabolism, and translation. Implications: These findings demonstrate the clinical relevancy of expressed HPV integration, which is characterized by a change in immune response and/or aberrant expression of the integration-harboring cancer-related genes, and suggest strong natural selection for tumor cells with expressed integration events in key carcinogenic genes. Mol Cancer Res; 16(1); 90–102. ©2017 AACR.