ObjectiveLaboratory tests are an important contributor to treatment decisions in the emergency department (ED). Rapid turnaround of laboratory tests can optimize ED throughout by reducing the length of stay (LOS) and improving patient outcomes. Despite evidence supporting the effect of shorter turnaround time (TAT) on LOS and outcomes, there is still a lack of large retrospective studies examining these associations. Here, we evaluated the effect of a reduction in laboratory TAT on ED LOS using retrospective analysis of Electronic Health Records (EHR).Materials and methodsRetrospective analysis of ED encounters from a large, US-based, de-identified EHR database and a separate analysis of ED encounters from the EHR of an ED at a top-tier tertiary care center were performed. Additionally, an efficiency model calculating the cumulative potential LOS time savings and resulting financial opportunity due to laboratory TAT reduction was created, assuming other factors affecting LOS are constant.ResultsMultivariate regression analysis of patients from the multisite study showed that a 1-minute decrease in laboratory TAT was associated with 0.50 minutes of decrease in LOS. The single-site analysis confirmed our findings from the multisite analysis that a positive correlation between laboratory TAT and ED LOS exists in the ED population as a whole, as well as across different patient acuity levels. In addition, based on the calculations from the efficiency model, for a 5-, 10- and 15-minute TAT reduction, the single-site ED can potentially admit a total of 127, 256 and 386 additional patients, respectively, annually.ConclusionA positive correlation between laboratory TAT and ED LOS was observed in a broad patient population and across distinct acuity levels.
Steric-blocking oligonucleotides (SBOs) are short, single-stranded nucleic acids designed to modulate gene expression by binding to RNA transcripts and blocking access from cellular machinery such as splicing factors. SBOs have the potential to bind to near-complementary sites in the transcriptome, causing off-target effects. In this study, we used RNA-seq to evaluate the off-target differential splicing events of 81 SBOs and differential expression events of 46 SBOs. Our results suggest that differential splicing events are predominantly hybridization driven, whereas differential expression events are more common and driven by other mechanisms (including spurious experimental variation). We further evaluated the performance of in silico screens for offtarget splicing events, and found an edit distance cutoff of three to result in a sensitivity of 14% and false discovery rate (FDR) of 99%. A machine learning model incorporating splicing predictions substantially improved the ability to prioritize low edit distance hits, increasing sensitivity from 4% to 26% at a fixed FDR of 90%. Despite these large improvements in performance, this approach does not detect the majority of events at an FDR <99%. Our results suggest that in silico methods are currently of limited use for predicting the off-target effects of SBOs, and experimental screening by RNA-seq should be the preferred approach.
Steric-blocking oligonucleotides (SBOs) are short, single-stranded nucleic acids designed to modulate gene expression by binding to mRNA and blocking access from cellular machinery such as splicing factors. SBOs have the potential to bind to near-complementary sites in the transcriptome, causing off-target effects. In this study, we used RNA-seq to evaluate the off-target differential splicing events of 81 SBOs and differential expression events of 46 SBOs. Our results suggest that differential splicing events are predominantly hybridization-driven, while differential expression events are more common and driven by other mechanisms. We further evaluated the performance of in silico screens for off-target events, and found an edit distance cutoff of three to result in a sensitivity of 14% and false discovery rate of 99%. A machine learning model incorporating splicing predictions substantially improved the ability to prioritize low edit distance hits, increasing sensitivity from 4% to 26% at a fixed FDR. Despite these large improvements in performance, the approach does not detect the majority of events at a false discovery rate below 99%. Our results suggest that in silico methods are currently of limited use for predicting the off-target effects of SBOs.
Introduction: Characterize the burden of illness in pediatric patients with congen ital athymia who were receiving supportive care. Methods: This cross-sectional study of adult caregivers of patients with congenital athymia used both a quantitative survey and qualitative
Background: Point of Care (POC) diagnostics are an essential component of modern medicine and are employed in a variety of clinical disciplines to improve patient outcomes and provider efficiency. Despite these benefits, there are aspects of POC testing which may still hold room for improvement. In the present study, a group of healthcare professionals familiar with different facets of blood-based POC testing provided their perspectives on the benefits and challenges of POC testing within their respective fields. Materials and methods: The study was conducted from April to June 2019, in Colorado, United States of America. Five healthcare professionals, each working in a distinct field (anesthesiology, nursing, emergency medicine, trauma surgery, and POC management) were interviewed. Results from each of the interviews were transcribed as qualitative perspectives on POC diagnostics. Discussion: The general consensus among participants in this study is that POC testing is tremendously beneficial, providing rapid test results, increased access to diagnostics, and improvements in hospital efficiency. However, significant challenges remain in blood-based POC diagnostics, particularly in maintaining sample quality, due to the fact that devices used for sample acquisition and handling are not designed for POC. This raises the possibility for interferents like hemolysis to occur, which may alter diagnostic results. Errors in POC diagnostics, whether due to sample, operator, or instrument error, may cause providers to lose confidence in the test. This lack of confidence can lead to duplicate testing and delayed patient diagnoses. Conclusion: The perspectives presented in this study suggest there is a significant need for improvement in the pre-analytical phase of POC testing, and that current practice employs specimen collection technology not designed for POC. Therefore, one hypothesis is that the introduction of a collection device designed specifically for POC could reduce pre-analytical errors, standardize sample quality, improve efficiency, and further benefit patient care.
To assess the correspondence between ideal and actual monitoring for disease-modifying anti-rheumatic drugs and the reasons for protocol failure, and the sharing of this task between primary and secondary care, we studied 249 patients with rheumatoid arthritis in a single district general hospital. Ideal monitoring protocols were derived from data sheets and from the rheumatological literature. Overall the ideal protocol was followed in 65% of cases: this ranged from 93% for methotrexate to 26% for sodium aurothiromalate. Most of the monitoring was done in general practice (e.g. 67% of all blood tests) and, with some exceptions, general practitioners (GPs) were willing to perform this task. However, many GPs reported logistic differences with specimen transfer and expressed the need for more information and support. Poor communication between hospital, patient and GP was also found to be a cause of protocol failure.
Wilson disease is a recessive genetic disorder caused by pathogenic loss-of-function variants in the ATP7B gene. It is characterized by disrupted copper homeostasis resulting in liver disease and/or neurological abnormalities. The variant NM_000053.3:c.1934T > G (Met645Arg) has been reported as compound heterozygous, and is highly prevalent among Wilson disease patients of Spanish descent. Accordingly, it is classified as pathogenic by leading molecular diagnostic centers. However, functional studies suggest that the amino acid change does not alter protein function, leading one ClinVar submitter to question its pathogenicity. Here, we used a minigene system and gene-edited HepG2 cells to demonstrate that c.1934T > G causes~70% skipping of exon 6. Exon 6 skipping results in frameshift and stop-gain, leading to loss of ATP7B function. The elucidation of the mechanistic effect for this variant resolves any doubt about its pathogenicity and enables the development of genetic medicines for restoring correct splicing.
Aims: Congenital athymia is an ultra-rare pediatric condition characterized by the lack of thymus in utero and the naïve T cells critical for infection defense and immune regulation. Patients with congenital athymia receive supportive care to minimize and treat infections, autoimmune phenomena, and autologous graft-versus-host disease (aGVHD) manifestations, but historically, die within the first 3 years of life with supportive care only. We estimated the healthcare resource utilization and economic burden of supportive care over patients' first 3 years of life in the United States. Methods: A medical chart audit by the treating physician was used to collect patient data from birth to age 3 on clinical manifestations associated with congenital athymia (clinical manifestations due to underlying syndromic conditions excluded). Using costs and charges from publicly available sources, the total economic burden of direct medical costs and charges for the first 3 years of life (considered "lifetime" for patients receiving supportive care) and differences in economic burden between patients with higher and lower inpatient hospitalization durations were estimated. Results: All patients (n ¼ 10) experienced frequent infections and aGVHD manifestations; 40% experienced !1 episode of sepsis, and 20% had recurrent sepsis episodes annually. The estimated mean 3year economic burden per patient was US$5,534,121 (2020 US dollars). The annual mean inpatient hospitalization duration was 150.6 days. Inpatient room charges accounted for 79% of the economic burden, reflecting the high costs of specialized care settings required to prevent infection, including isolation. Patients with high inpatient utilization (n ¼ 5; annual mean inpatient hospitalization duration, 289.6 days) had an estimated 3-year economic burden of US$9,926,229. Limitations: The total economic burden may not be adequately represented due to underestimation of some direct costs or overestimation of others. Conclusions: Current treatment of patients with congenital athymia (supportive care) presents a high economic burden to the healthcare system.
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