Efficient enrichment of free target sequences in an integrated microfluidic device for point-of-care detection systems.

Nucleic acid biomarker detection has great importance in the diagnosis of disease, the monitoring of disease progression and the classification of patients according to treatment decision making. Nucleic acid biomarkers found in the blood of patients have generated a lot of interest due to the possibility of being detected non-invasively which makes them ideal for monitoring and screening tests and particularly amenable to point-of-care (POC) or self-testing. A major challenge to POC molecular diagnostics is the need to enrich the target to optimise detection. In this work, we describe a microfabricated device for the enrichment of short dsDNA target sequences, which is especially valuable for potential detection methods, as it improves the probability of effectively detecting the target in downstream analyses. The device integrated a heating element and a temperature sensor with a microfluidic chamber to carry out the denaturation of the dsDNA combined with blocking-probes to enrich the target. This procedure was validated by fluorescence resonance energy transfer (FRET) technique, labelling DNA with a fluorophore and a quencher. As proof of concept, a 23-mer long dsDNA sequence corresponding to the L858R mutation of the EGFR gene was used. The qualitative results obtained determined that the most optimal blocking rate was obtained with the incorporation of 11/12-mer blocking-probes at a total concentration of 6 µM. This device is a powerful DNA preparation tool, which is an indispensable initial step for subsequent detection of sequences via nucleic acid hybridisation methods.

Fusion of Raman and FTIR Spectroscopy Data Uncovers Physiological Changes Associated with Lung Cancer.

Due to the high mortality rate, more effective non-invasive diagnostic methods are still needed for lung cancer, the most common cause of cancer-related death worldwide. In this study, the integration of Raman and Fourier-transform infrared spectroscopy with advanced data-fusion techniques is investigated to improve the detection of lung cancer from human blood plasma samples. A high statistical significance was found for important protein-related oscillations, which are crucial for differentiating between lung cancer patients and healthy controls. The use of low-level data fusion and feature selection significantly improved model accuracy and emphasizes the importance of structural protein changes in cancer detection. Although other biomolecules such as carbohydrates and nucleic acids also contributed, proteins proved to be the decisive markers found using this technique. This research highlights the power of these combined spectroscopic methods to develop a non-invasive diagnostic tool for discriminating lung cancer from healthy state, with the potential to extend such studies to a variety of other diseases.

Identification of miRNAs and Their Target Genes Associated with Sunitinib Resistance in Clear Cell Renal Cell Carcinoma Patients.

Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (miR-223, miR-155, miR-200b, miR-130b) and target genes (FLT1, PRDM1 and SAV1) in 35 ccRCC patients. High levels of miR-223 and low levels of FLT1, SAV1 and PRDM1 were associated with worse overall survival (OS), and combined miR-223 + SAV1 levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (FLT1) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (PRDM1) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect miR-155 we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.

Chitranjan S. Ranawat Award: Tourniquet Use Does Not Impact Trajectory of Total Knee Arthroplasty Early Recovery: A Prospective, Randomized Controlled Trial.

BACKGROUND: The impact of tourniquet use on recovery after total knee arthroplasty (TKA) remains controversial. The purpose of this prospective, single blinded, randomized controlled trial was to investigate the effect of tourniquet use on early recovery after TKA using a smartphone app-based patient engagement platform (PEP) with a wrist-based activity monitor to obtain more robust data on early recovery. METHODS: There were 107 patients undergoing primary TKA for osteoarthritis who were enrolled (54 tourniquet [TQ+]; 53 no tourniquet [TQ-]). All patients utilized a PEP and wrist-based activity sensor for 2 weeks preoperatively and 90 days postoperatively to collect Visual Analog Scale (VAS) pain scores and opioid consumption, as well as weekly Oxford Knee Score (OKS) and monthly Forgotten Joint Score (FJS). There was no difference in demographics between groups. Formal physical therapy assessments were performed preoperatively and 3 months postoperatively. Independent sample t-tests were used for continuous data and Chi-square and Fisher's exact tests were used for discrete data. RESULTS: Tourniquet use did not have a statistically significant impact on daily VAS pain or opioid consumption during the first 30 days postoperatively (P > .05). Tourniquet use did not have a significant impact on OKS or FJS at 30 or 90 days postoperatively (P > .05), or on performance of formal physical therapy testing at 3 months postoperatively (P > .05). CONCLUSION: Using a digital technology to collect daily patient data, we found that tourniquet use has no clinically significant negative impact on pain and function in the first 90 days after primary TKA.

Low Risk of Fracture Using a Cementless Triple-tapered Collared Femoral Stem with Automated Impaction in Direct Anterior Approach Total Hip Arthroplasty.

INTRODUCTION: Direct anterior approach (DAA) total hip arthroplasty (THA) has been associated with increased periprosthetic femoral fracture (PFF) risk. The aim of our study was to evaluate the fracture risk utilizing a triple tapered, collared stem with automated impaction through the anterior approach. METHODS: We retrospectively reviewed consecutive DAA THA procedures at a single institution performed by four experienced DAA THA surgeons between 2019 and 2021. We collected data on age, sex, body mass index, preoperative diagnosis, and intraoperative and early postoperative PFF within 6 weeks postoperatively. Preoperative radiographs were evaluated to determine femoral neck-shaft angle and Dorr classification. We used Wilcoxon Rank sum or Chi-square tests to assess differences between patients who did and did not have PFF. We also evaluated potential risk factors for PFF in unadjusted and adjusted regression analyses. In all, 24 PFFs (1.6%) occurred. There were eighteen fractures (1.2%) recognized and managed intraoperatively (15 calcar, 2 greater trochanter, 1 posterior cortical). There were six PFFs (0.4%) identified postoperatively (5 greater trochanter, 1 diaphyseal), of which 1 required a revision surgery. RESULTS: Identified risk factors for fracture in adjusted regression models included women (Odds Ratio (OR)=2.76, P=0.047), preoperative coxa valga (OR= 4.54, P=0.005), and coxa vara (OR=2.85, P=0.03). CONCLUSION: The incidence of periprosthetic femoral fractures is low using a triple tapered, collared cementless femoral stem with automated impaction through the DAA. Our findings agree with previous reports that have demonstrated women and preoperative valgus neck angle are risk factors for PFF.

Clear Cell Renal Cell Carcinomas with Aggressive Behavior Display Low Intratumor Heterogeneity at the Histological Level.

PURPOSE OF REVIEW: Intratumor heterogeneity (ITH) is an inherent characteristic of most tumors and its detection remains a key task for pathologists. However, the clinical significance of the degree of development of this feature is still poorly understood. RECENT FINDINGS: A series of 28 clear cell renal cell carcinomas (CCRCC) have been exhaustively analyzed with two different sampling protocols [multisite tumor sampling (MSTS) and total sampling] to evaluate to what point the level (low vs. high) of histological ITH detected in routine practice influences tumor behavior and patients' survival. All CCRCC (n = 14) pursuing an aggressive clinical course presented low levels of ITH. A significant worse survival was detected in CCRCC with low ITH (p < 0.001). The simple quantification of the level of ITH using extensive sampling protocol may be of help in predicting tumor evolution, since all CCRCC with aggressive behavior demonstrated low levels of histological ITH.

Circulating MicroRNAs as Cancer Biomarkers in Liquid Biopsies.

Biological fluids such as blood, saliva, and urine offer a rich source of biomarkers that have the potential to change the paradigm of cancer management. By allowing routine noninvasive sampling that can offer new insights into cancer progression and response to treatment so-called liquid biopsies can play an important role in personalized medicine. MicroRNAs (miRNAs) are a particularly attractive class of biomarkers as they are not only resistant to the high levels of RNases found in biological fluids, but also able to confer clinically useful information about the disease relating to diagnosis, prognosis, and the response to treatment. Circulating miRNAs are either associated with proteins or extracellular vesicles (EV) and although their origin and implied functions as intracellular messengers remain somewhat controversial, they are implicated in the progression and the establishment of metastatic niches. In this chapter, we review the rapidly emerging field of circulating miRNA cancer biomarkers, their origin and function, techniques to detect these molecules, and the use of bioinformatic tools to derive implied regulatory function, as well as the challenges that lie ahead for their clinical implementation.

The Impact of Component Design and Fixation on Stress Shielding After Modern Total Knee Arthroplasty.

BACKGROUND: Total knee arthroplasty (TKA) tibial baseplate thickness, metallurgy, and implant fixation with cement may influence stress shielding. The purpose of the present study is to compare bone mineral density of 2 cemented and press-fit TKA designs with differing tibial baseplate thicknesses and metallurgy over a 2-year period to assess for changes in stress shielding. METHODS: One-hundred one TKAs were performed in this Institutional Review Board-approved, prospective study. There were 4 cohorts: DePuy Attune cemented and press-fit, and Stryker Triathlon cemented and press-fit. The Attune tibial baseplate was thicker; both cemented tibial and femoral components were cobalt-chromium. The DePuy Attune press-fit had a cobalt-chromium sintered bead porous coating while the Stryker Triathlon was 3-dimensional printed highly porous titanium alloy. All patients had quantitative dual-energy X-ray absorptiometry scans performed at baseline (4-6 weeks postoperatively) and at 1 and 2 years postoperatively. Stress shielding was evaluated by comparing percent change in bone mineral density in 11 radiographic zones over 2 years. RESULTS: Over a 2-year period, there were no differences in stress shielding on the tibial side in either cemented or press-fit between Stryker Triathlon and DePuy Attune; however, there were differences on the femoral side. The press-fit tibial components of the Stryker Triathlon and DePuy Attune had either similar or less stress shielding over a 2-year period compared to their cemented counterparts. CONCLUSION: This study comparing 2 TKA implants with differing tibial tray thickness did not find significant differences in tibial stress shielding between designs. There was a difference in stress shielding on the femoral side between designs, suggesting that longer term follow-up is warranted.

James A. Rand Young Investigator's Award: Questioning the "Nickel Free" Total Knee Arthroplasty.

BACKGROUND: A study was performed to measure metal ions present in the knee joint after performing a total knee arthroplasty (TKA) with standard cobalt chromium (CoCr) components as well as with "nickel-free" oxidized zirconium femoral and titanium tibial (OxZr/Ti) components. METHODS: Knee joint fluid was collected prior to arthrotomy, and on postoperative day one to determine the amount of metal debris generated when performing a TKA with standard instrumentation from consecutive cases with CoCr components (n = 24) and OxZr/Ti components (n = 16). RESULTS: CoCr implant patients had statistically higher levels of nickel (Ni) (29.7%, P = .033), cobalt (Co), (1,100.7%, P < .0001) and chromium (Cr) (118.9%, P < .0001) postoperatively. The cutting blocks and sawblades do not contain Co, which therefore must have come from the components. The metal ions generated from the sawblades and cutting blocks, therefore, could be discerned from the OxZr/Ti whose components don't contain Co, Cr, or Ni. The OxZr patients had significantly higher Cr (9.5×, P < .001) and Ni (5.1×, P < .001) post-TKA vs pre-TKA; Co levels were not significantly different as expected with the absence of Co in the components (P = .60). The Ni levels generated in performing an Oxinium TKA was 3.3 times higher than when performing a CoCr TKA (1.37 vs. 41 ppb, P < .001). CONCLUSIONS: The substantial degree of Ni generation resulting from performing a hypoallergenic "nickel-free" TKA calls into questions the rationale of utilizing more expensive lower Ni components on the basis of known or suspected Ni or Cr allergy.

High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML.

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.

Differential effects of HIF2α antagonist and HIF2α silencing in renal cancer and sensitivity to repurposed drugs.

BACKGROUND: In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. METHODS: We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385. RESULTS: PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. CONCLUSIONS: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

Is the Patient-Reported Outcome Measurement Information System Feasible in Bundled Payment for Care Improvement Total Knee Arthroplasty Patients?

BACKGROUND: Several bundled payment plans, like the Bundled Payment for Care Improvement (BPCI) initiative for total joint arthroplasty, have been introduced to decrease costs and improve clinical care. Measuring clinical outcomes with efficient, standardized methodologies is essential to determine the relative value of total joint arthroplasty care. We investigated feasibility and responsiveness of the recently developed Patient-Reported Outcomes Measurement Information System (PROMIS) in total knee arthroplasty (TKA) patients. METHODS: We included patients with preoperative and 1-year PROMIS Physical Function (PF), Pain Interference (PI), and Depression (DEP) scores who received unilateral primary TKA. Burden was assessed using the number of questions and time required for PROMIS completion. The minimum clinically important difference was defined as 5. Floor/ceiling effects were noted if more than 15% of patients responded with the lowest/highest possible score, respectively. Wilcoxon rank-sum test was used to compare categorical data. Analysis of variance was used for PROMIS comparisons. RESULTS: In total, 172 knees (54 BPCI) were included. Floor effects were identified for DEP at baseline (non-BPCI) and follow-up (both groups), and for PI at follow-up only (BPCI). Patients required 140 seconds and 16 questions to answer all 3 PROMIS domains. Sixty-seven percent, 60%, and 44% of knees achieved minimum clinically important difference in PI, PF, and DEP scores respectively, with no significant difference between groups. The BPCI cohort was older (P < .001) with a higher American Society of Anesthesiologists score (P = .028). There were no significant differences in scores between BPCI and non-BPCI patients. CONCLUSION: PROMIS is feasible and time-efficient in BPCI patients undergoing primary TKA. There were no significant differences in outcomes between BPCI and non-BPCI knees. LEVEL OF EVIDENCE: Level III.

Is Apixaban Safe and Effective for Venous Thromboembolism Prophylaxis After Primary Total Hip and Total Knee Arthroplasties?

BACKGROUND: Venous thromboembolism (VTE) is a serious complication of total hip arthroplasty (THA) and total knee arthroplasty (TKA). Apixaban is approved for VTE prophylaxis. This study seeks to ascertain the risk of VTE and bleeding complications in patients undergoing primary THA and TKA receiving apixaban for postoperative VTE prophylaxis for one of the following indications: high risk for VTE, previously on apixaban, and contraindication to the use of aspirin. METHODS: This is a retrospective cohort study of patients who underwent primary THA or TKA over a 17-month period and were prescribed apixaban for thromboprophylaxis postoperatively. RESULTS: 230 patients were included in the study, 110 TKA and 120 THA. The primary reasons for high-risk VTE status included personal and family history of VTE, and 13% were taking apixaban preoperatively for atrial fibrillation. 1 patient (0.43%) who underwent TKA had a DVT with PE. 2.6% of patients had wound complications requiring operative treatment, and 0.87% of THA patients underwent revision arthroplasty. CONCLUSION: The use of apixaban for VTE prophylaxis after primary THA and TKA in patients at high risk for VTE, in patients previously on apixaban, and in patients with a contraindication to the use of aspirin is associated with a low risk of VTE and bleeding complications.

Does the Patient-Reported Outcomes Measurement Information System Correlate to Legacy Scores in Measuring Physical Health in Young Total Hip Arthroplasty Patients?

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) was developed by the National Institutes of Health to collect outcome data in rapid dynamic fashion on electronic platforms. The potential role of PROMIS in monitoring pain and function in young total hip arthroplasty (THA) patients has been under-investigated. The purpose of this study is to investigate correlation between PROMIS Physical Function (PF) and PROMIS Pain Interference (PI) and legacy scores with similar considerations. METHODS: We identified 298 hips who underwent primary THA over 40 months. Patients without preoperative PROMIS or legacy scores, or >50 years were excluded. Demographic data included age, gender, and body mass index. Outcome data included PF, PI, modified Harris Hip Score (mHHS), Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) domains, and Short Form 12 components. Floor/ceiling effects were considered to be significant if ≥15% of patients responded with the lowest or highest possible score. Spearman correlation (R) was performed to investigate correlation between legacy scores and PROMIS domains. RESULTS: Mean age was 40 years, mean body mass index was 30.1 kg/m2, and 55% were female. None of the patient-reported outcome measures showed any floor/ceiling effects. PI showed moderate correlation to mHHS (R = -0.60), WOMAC Pain (R = -0.62), and WOMAC PF (R = -0.60). PF showed moderate correlation to mHHS (R = 0.66) and WOMAC PF (R = 0.55). Mean PF and PI scores differed significantly from the general population mean of 50 (36.7, 65.4, respectively; both P < .001). CONCLUSION: PROMIS is an attractive alternative to legacy scoring measures, showing moderate correlations between PROMIS physical domains and legacy PROMs of WOMAC and mHHS in young patients undergoing THA.

Allergies, Preoperative Narcotic Use, and Increased Age Predict Failed Same-Day Discharge After Joint Replacement.

BACKGROUND: Identifying predictors of failed same-day discharge (SDD) is critical for patient selection. We evaluated patient factors associated with failure of SDD in patients undergoing elective total joint arthroplasty (TJA) in a hospital setting. METHODS: We retrospectively reviewed consecutive patients who underwent primary total knee arthroplasty (TKA) and total hip arthroplasty (THA) between January 31, 2018 and February 1, 2020 by one of the 3 fellowship-trained arthroplasty surgeons. Patient demographics, comorbidities, and clinical data were collected. Analysis was performed to assess risk factors for failed SDD. RESULTS: In total, 2615 TJAs (1425 TKAs, 1190 THAs) were performed over the study period. Two hundred seventy-one (10.4%) were SDDs (80 TKAs, 191 THAs). There were fewer TKAs than THAs (5.6% vs 16.1%, P < .001). Forty-five patients failed SDD (16.6%). Failure rates were similar in TKA and THA (18.8%, 15.7%, P = .54). The most common reasons for failure of SDD were hypotension (11, 24.4%), delayed resolution of spinal anesthesia (11, 24.4%), and nausea (5, 11.1%). Age over 70 years (P = .007), greater than 2 self-reported allergies (P < .001), and preoperative narcotic use (P = .01) were associated with failure of SDD. Gender, body mass index, American Society of Anesthesiologists class, and prior TJA were not significantly associated (P > .05). CONCLUSION: Success of SDD was greater than 80%. Hypotension, delayed resolution of spinal anesthesia, and nausea accounted for 60% of failures of SDD. Patients >70 years, those with >2 self-reported drug allergies, or patients who used preoperative narcotics were at high risk for failure of SDD after THA or TKA.

MicroRNAs in Metastasis and the Tumour Microenvironment.

Metastasis is the process whereby cancer cells migrate from the primary tumour site to colonise the surrounding or distant tissue or organ. Metastasis is the primary cause of cancer-related mortality and approximately half of all cancer patients present at diagnosis with some form of metastasis. Consequently, there is a clear need to better understand metastasis in order to develop new tools to combat this process. MicroRNAs (miRNAs) regulate gene expression and play an important role in cancer development and progression including in the metastatic process. Particularly important are the roles that miRNAs play in the interaction between tumour cells and non-tumoral cells of the tumour microenvironment (TME), a process mediated largely by circulating miRNAs contained primarily in extracellular vesicles (EVs). In this review, we outline the accumulating evidence for the importance of miRNAs in the communication between tumour cells and the cells of the TME in the context of the pre-metastatic and metastatic niche.

The circulating transcriptome as a source of cancer liquid biopsy biomarkers.

Non-invasive biomarkers or liquid biopsies have the potential to revolutionise cancer patient management as repeated sampling allows real-time monitoring of disease progression and response to treatment. This allows for earlier intervention and dynamic treatment management; both cornerstones of personalised medicine. The circulating transcriptome represents a rich source of potential cancer biomarkers that includes many classes of RNA, both coding and non-coding, that are only now beginning to be explored. In particular the increasing power and availability of RNAseq techniques have pushed studies beyond circulating miRNAs, to other classes of RNA including mRNA, snRNA, snoRNA, piRNA, YRNA, lncRNA and circRNA. In this review we focus on the emerging potential for these different classes of RNA as cancer biomarkers, and in particular the barriers and limitations that remain to be overcome if these molecules are to become part of routine clinical practice.

CircRNAs and cancer: Biomarkers and master regulators.

Circular RNAs (circRNAs) are a novel class of regulatory RNAs that despite being relatively abundant have only recently begun to be explored. There are many thousands of genes that appear capable of producing circRNAs, however the function of all but a handful remain to be determined. What is emerging about these highly conserved molecules is that they play important roles in biology and cancer biology in particular. The most explored function of circRNAs is as master regulators of gene expression that act to sequester or ´sponge´ other gene expression regulators, in particular miRNAs. They have also been demonstrated to function via direct modulation of transcription, and by interfering with splicing mechanisms. Although generally expressed in low abundance when compared to their linear counterparts, they are often expressed in a tissue- and developmental stage- specific manner. Coupled with their remarkable resistance to RNAse activity due to a covalent closed cyclic structure, circRNAs show great promise as novel biomarkers of cancer and other diseases. In this review we consider the current state of knowledge regarding these molecules, their synthesis, function, and association with cancer. We will also review some of the challenges that remain to be resolved if this emerging class of RNAs are really to become useful in the clinic.

Serum levels of hsa-miR-16-5p, hsa-miR-29a-3p, hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-223-3p and subsequent risk of chronic lymphocytic leukemia in the EPIC study.

Chronic lymphocytic leukemia (CLL) is an incurable disease accounting for almost one-third of leukemias in the Western world. Aberrant expression of microRNAs (miRNAs) is a well-established characteristic of CLL, and the robust nature of miRNAs makes them eminently suitable liquid biopsy biomarkers. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), the predictive values of five promising human miRNAs (hsa-miR-16-5p, hsa-miR-29a-3p, hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-223-3p), identified in a pilot study, were examined in serum of 224 CLL cases (diagnosed 3 months to 18 years after enrollment) and 224 matched controls using Taqman based assays. Conditional logistic regressions were applied to adjust for potential confounders. The median time from blood collection to CLL diagnosis was 10 years (p25-p75: 7-13 years). Overall, the upregulation of hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-29a-3p was associated with subsequent risk of CLL [OR1∆Ct-unit increase (95%CI) = 1.42 (1.18-1.72), 1.64 (1.31-2.04) and 1.75 (1.31-2.34) for hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-29a-3p, respectively] and the strongest associations were observed within 10 years of diagnosis. However, the predictive performance of these miRNAs was modest (area under the curve <0.62). hsa-miR-16-5p and hsa-miR-223-3p levels were unrelated to CLL risk. The findings of this first prospective study suggest that hsa-miR-29a, hsa-miR-150-5p and hsa-miR-155-5p were upregulated in early stages of CLL but were modest predictive biomarkers of CLL risk.

Development of a Visual Analytics Tool for Polytrauma Patients: Proof of Concept for a New Assessment Tool Using a Multiple Layer Sankey Diagram in a Single-Center Database.

INTRODUCTION: Early physiological assessment of multiple injured patients is crucial for decision making and has relied on personal experience of trauma experts. We have developed a new visual analytics tool (Sankey diagram, Watson Trauma Health care tool) that includes known prognostic parameters for polytrauma patients to help guide assessment and treatment decisions for physicians involved in trauma care. METHODS: A prospectively collected trauma database of a single level I trauma center (3655 patients) was used. INCLUSION CRITERIA: age >16 years, an injury severity score (ISS) >16 and presence of a complete data set in the database. Data collected included admission values of patient age, injury scoring, shock classification, temperature, acid-base and hemostasis parameters. All of these parameters were collected daily as longitudinal parameters. Endpoints of the clinical course we considered were sepsis, SIRS and early in hospital mortality (<72 h). A proof of concept of the visualization was developed over a 2-year period in a cooperation between physicians and engineers. Statistically, the most predictive parameters were selected by binary logistic regression and ROC analysis. RESULTS: A dynamic interactive multilayer Sankey diagram, based on cohort similarities, was developed in a collaboration between the University Hospital of Zurich, Department of Trauma and IBM, from August 2017 until January 2018. It is a modular tool and allows any user to add a new patient, or work with an existing case. The visualization used the data-driven documents (D3) interactive visualization library to create a responsive graphic. CONCLUSIONS: This application summarizes the experience of 3655 polytrauma patients and might serve as a guide for clinical decisions and educative purposes, as well as new scientific questions for the polytrauma patient. LEVEL OF EVIDENCE: IV.