Machine learning to detect the SINEs of cancer.

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature-the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.

Quantification and statistical modeling of droplet-based single-nucleus RNA-sequencing data.

In complex tissues containing cells that are difficult to dissociate, single-nucleus RNA-sequencing (snRNA-seq) has become the preferred experimental technology over single-cell RNA-sequencing (scRNA-seq) to measure gene expression. To accurately model these data in downstream analyses, previous work has shown that droplet-based scRNA-seq data are not zero-inflated, but whether droplet-based snRNA-seq data follow the same probability distributions has not been systematically evaluated. Using pseudonegative control data from nuclei in mouse cortex sequenced with the 10x Genomics Chromium system and mouse kidney sequenced with the DropSeq system, we found that droplet-based snRNA-seq data follow a negative binomial distribution, suggesting that parametric statistical models applied to scRNA-seq are transferable to snRNA-seq. Furthermore, we found that the quantification choices in adapting quantification mapping strategies from scRNA-seq to snRNA-seq can play a significant role in downstream analyses and biological interpretation. In particular, reference transcriptomes that do not include intronic regions result in significantly smaller library sizes and incongruous cell type classifications. We also confirmed the presence of a gene length bias in snRNA-seq data, which we show is present in both exonic and intronic reads, and investigate potential causes for the bias.

Evaluating the impact of multicancer early detection testing on health and economic outcomes: Toward a decision modeling strategy.

Emerging data provide initial support for the concept that a single, minimally invasive liquid biopsy test, performed in conjunction with confirmatory radiologic or other diagnostic testing, when indicated, could be deployed on a broad scale to screen individuals for multiple types of cancer. Ideally, such a test could do this in a way that yields a clinically important percentage of true-positive indications of cancer while minimizing false-positive signals. Modern decision modeling approaches can and should be deployed to investigate the health and economic consequences of such multicancer early detection (MCED) testing within defined at-risk populations. In this paper, through small-scale analyses involving 3 hypothetical MCED-detectible cancers, the authors illustrate the potential for MCED testing to be cost-effective, along with the pivotal role of test-induced stage shift on results. The time is ripe for additional, prospective investigations of the clinical value of MCED testing, the benefits versus the risks for screened populations, and the overall projected impact on health outcomes and costs over time.

Non-steroidal anti-inflammatory drugs, intravenous fluids, pancreatic stents, or their combinations for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a systematic review and network meta-analysis.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), intravenous fluid, pancreatic stents, or combinations of these have been evaluated in randomised controlled trials (RCTs) for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, but the comparative efficacy of these treatments remains unclear. Our aim was to do an exploratory network meta-analysis of previous RCTs to systematically compare the direct and indirect evidence and rank NSAIDs, intravenous fluids, pancreatic stents, or combinations of these to determine the most efficacious method of prophylaxis for post-ERCP pancreatitis. METHODS: We searched PubMed, Embase, and the Cochrane Central Register from inception to Nov 15, 2020, for full-text RCTs that evaluated the efficacy of NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for post-ERCP pancreatitis prevention in adult (aged ≥18 years) patients undergoing ERCP. Summary data from intention-to-treat analyses were extracted from published reports. We analysed incidence of post-ERCP pancreatitis across studies using network meta-analysis under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system for the confidence rating. This study is registered with PROSPERO, CRD42020172606. FINDINGS: We identified 1503 studies, of which 55 RCTs evaluating 20 interventions in 17 062 patients were included in the network meta-analysis. The mean incidence of post-ERCP pancreatitis in the placebo or active control group was 12·2% (95% CI 11·4-13·0). Normal saline plus rectal indometacin (OR 0·02, 95% CI 0·00-0·40), intramuscular diclofenac 75 mg (0·24, 0·09-0·69), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (0·30, 0·16-0·55), intravenous high-volume Ringer's lactate (0·31, 0·12-0·78), 5-7 Fr pancreatic stents (0·35, 0·26-0·48), rectal diclofenac 100 mg (0·36, 0·25-0·52), 3 Fr pancreatic stents (0·47, 0·26-0·87), and rectal indometacin 100 mg (0·60, 0·50-0·73) were all more efficacious than placebo for preventing post-ERCP pancreatitis in pairwise comparisons. 5-7 Fr pancreatic stents (0·59, 0·41-0·84), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (0·49, 0·26-0·94), intravenous standard-volume normal saline plus rectal indometacin 100 mg (0·04, 0·00-0·66), and rectal diclofenac 100 mg (0·59, 0·40-0·89) were more efficacious than rectal indometacin 100 mg. The GRADE confidence rating was low to moderate for 98·3% of the pairwise comparisons. INTERPRETATION: This systematic review and network meta-analysis summarises the available literature on NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for prophylaxis of post-ERCP pancreatitis. Rectal diclofenac 100 mg is the best performing rectal NSAID in this network meta-analysis. Combinations of prophylaxis might be more effective, but there is little evidence. These findings help to establish prophylaxis of post-ERCP pancreatitis for future research and practice, and could reduce costs and increase adoption of prophylaxis. FUNDING: None.

Supervised mutational signatures for obesity and other tissue-specific etiological factors in cancer.

Determining the etiologic basis of the mutations that are responsible for cancer is one of the fundamental challenges in modern cancer research. Different mutational processes induce different types of DNA mutations, providing 'mutational signatures' that have led to key insights into cancer etiology. The most widely used signatures for assessing genomic data are based on unsupervised patterns that are then retrospectively correlated with certain features of cancer. We show here that supervised machine-learning techniques can identify signatures, called SuperSigs, that are more predictive than those currently available. Surprisingly, we found that aging yields different SuperSigs in different tissues, and the same is true for environmental exposures. We were able to discover SuperSigs associated with obesity, the most important lifestyle factor contributing to cancer in Western populations.

Intracranial hemorrhage after prehospital administration of intramuscular epinephrine.

BACKGROUND: The administration of epinephrine by the intramuscular route can be life-saving in cases of anaphylaxis or severe allergic reactions. However, the use of this drug can lead to a rapid rise in blood pressure, which theoretically could lead to deleterious effects in patients of any age, with elderly patients at greatest risk. OBJECTIVES: To present a rare case of intracranial hemorrhage potentially resulting from the administration of intramuscular epinephrine in an elderly patient with an allergic reaction. CASE REPORT: We present a case report of a 65-year-old woman who developed an intracranial hemorrhage after a single, therapeutic, intramuscular dose of epinephrine for a wasp sting to the tongue. The patient underwent successful craniotomy with evacuation of the intracranial hematoma. CONCLUSIONS: In circumstances where the severity of the allergic reaction remains unclear (lack of airway compromise, cardiovascular collapse, or true anaphylaxis), careful consideration of the potential risks of intramuscular epinephrine, such as a rapid rise in blood pressure leading to intracranial hemorrhage, should be undertaken when using this medication in elderly patients.

Simulation of water quality and plankton dynamics in the Danshuei River estuary, Taiwan.

An ecosystem model was developed to simulate the water quality and plankton dynamics in the Danshuei River estuary, Taiwan. The model simulates the hydrodynamics with a laterally integrated 2-dimensional intratidal numerical model, which supplies the physical transport processes for simulation of water quality and plankton state variables. The application of the model to the Danshuei River estuary indicates that the point source loadings are mainly responsible for the degraded water quality and very high nutrient concentrations in the estuary. The impacts of wastewater discharges are tightly controlled by the transport processes. Frequent occurrence of high river flow and flood events rapidly cleanses the estuary by flushing out both pollutants and plankton populations. The plankton is allowed to grow to significant populations if low river flow lasts for a period much longer than the biological time scale.

Water quality modeling to determine minimum instream flow for fish survival in tidal rivers.

The Hsintien Stream is one of the major branches of the Danshuei River system, which runs through the metropolitan capital city of Taipei, Taiwan and receives a large amount of wastewater. The dissolved oxygen concentration is generally low in the tidal portion of the Hsintien Stream. Hypoxia/anoxia occurs often, particularly during the low-flow period when the Feitsui Reservoir, Chingtan Dam and Chihtan Dam impound the freshwater for municipal water supply. Fish kills happen from time to time. This paper describes the application of a numerical hydrodynamic and water quality model to the Danshuei River system, with special attention to the tidal portion of the Hsintien Stream. The model is recalibrated with the prototype conditions of the year 2000. The hydrodynamic portion of the model is recalibrated with measured surface elevation and velocity at various stations in the river system. The water quality portion of the model is recalibrated with respect to the field data provided by Taiwan EPA. The input data of point and nonpoint sources are also estimated. The model simulates the concentrations of various forms of nutrients, CBOD and dissolved oxygen. A series of sensitivity runs was conducted to investigate the effects of point source loadings and river flow on the DO level in the river. It is demonstrated that the augmentation of river flow has as much effect on raising DO level as the reduction of point source loadings. The completion of the Taipei sewer project is expected to reduce the point source loadings by at least 75%. Under these reduced loadings, if the daily instream flow is maintained above the monthly Q75 flow throughout the year, the minimum DO concentration in the river would not fall below 1mg/L, which is the suffocation level for most fish species in the Hsintien Stream. (Q75 is the flow which is equaled or exceeded 75% of the days in the month.) The Feitsui Reservoir, Chingtan Dam and Chihtan Dam may impound water during the high flow periods and release freshwater to maintain the flow at the Q75 value in the Hsintien Stream during the drought periods.

Recognition of undiagnosed HIV infection: an evaluation of missed opportunities in a predominantly urban minority population.

The goals of this study were to quantify delays in diagnosing HIV infection in patients presenting for medical care prior to the identification of their HIV infection, and to determine characteristics of visits preceding the identification of HIV infection. This was a retrospective cohort study of consecutive newly diagnosed HIV infected patients in a large urban setting. Patients were predominantly minorities and identified from all inpatient and outpatient HIV tests performed between December 29, 1998 and December 27, 1999. Data were collected from all emergency department and clinic visits for each patient included in this study for a 3-year period preceding the first diagnosis of HIV infection. Two hundred seventy-eight patients tested positive for HIV during the study period. Of these, 76 (27%) met inclusion criteria. Twenty-three patients made a total of 53 health care visits preceding the diagnosis of their HIV infection. The median delay in diagnosis of HIV infection was 2 days (interquartile range [IQR], 1-22 days; range, 0-1093 days) for all subjects, although 19 (25%; 95% confidence interval [CI]: 16%-36%) patients had a delay in diagnosis of 30 days or more. Among those patients who had made prior health care visits, the median delay in diagnosis was 112 days (IQR, 33-690 days; range, 2-1093 days). No specific risk factor, historical clue, physical examination finding, or laboratory finding reliably identified patients with HIV infection. Documentation in the medical record of specific risk factors and clinical characteristics suggestive of HIV infection was poor. This study documented missed opportunities and delays in diagnosis of patients with unrecognized HIV infection. Clinicians must maintain a high index of suspicion for HIV infection in all patients.

Modelling of hydrodynamics and cohesive sediment transport in Tanshui River estuarine system, Taiwan.

A laterally averaged two-dimensional numerical model is used to simulate hydrodynamics and cohesive sediment transport in the Tanshui River estuarine system. The model handles tributaries as well as the main stem of the estuarine system. Observed time series of salinity data and tidally averaged salinity distributions have been compared with model results to calibrate the turbulent diffusion coefficients. The overall model verification is achieved with comparisons of residual currents and salinity distribution. The model reproduces the prototype water surface elevation, currents and salinity distributions. Comparisons of the suspended cohesive sediment concentrations calculated by the numerical model and the field data at various stations show good agreement. The validated model is applied to investigate the tidally averaged salinity distributions, residual circulation and suspended sediment concentration under low flow conditions in the Tanshui River estuarine system. The model results show that the limit of salt intrusion in the mainstem estuary is located at Hsin-Hai bridge in Tahan Stream, 26 km from the River mouth under Q75 flow. The null point is located at the head of salt intrusion, using 1 ppt isohaline as an indicator. The tidally averaged sediment concentration distribution exhibits a local maximum around the null point.