A method to assess linear self-predictability of physiologic processes in the frequency domain: application to beat-to-beat variability of arterial compliance.

The concept of self-predictability plays a key role for the analysis of the self-driven dynamics of physiological processes displaying richness of oscillatory rhythms. While time domain measures of self-predictability, as well as time-varying and local extensions, have already been proposed and largely applied in different contexts, they still lack a clear spectral description, which would be significantly useful for the interpretation of the frequency-specific content of the investigated processes. Herein, we propose a novel approach to characterize the linear self-predictability (LSP) of Gaussian processes in the frequency domain. The LSP spectral functions are related to the peaks of the power spectral density (PSD) of the investigated process, which is represented as the sum of different oscillatory components with specific frequency through the method of spectral decomposition. Remarkably, each of the LSP profiles is linked to a specific oscillation of the process, and it returns frequency-specific measures when integrated along spectral bands of physiological interest, as well as a time domain self-predictability measure with a clear meaning in the field of information theory, corresponding to the well-known information storage, when integrated along the whole frequency axis. The proposed measure is first illustrated in a theoretical simulation, showing that it clearly reflects the degree and frequency-specific location of predictability patterns of the analyzed process in both time and frequency domains. Then, it is applied to beat-to-beat time series of arterial compliance obtained in young healthy subjects. The results evidence that the spectral decomposition strategy applied to both the PSD and the spectral LSP of compliance identifies physiological responses to postural stress of low and high frequency oscillations of the process which cannot be traced in the time domain only, highlighting the importance of computing frequency-specific measures of self-predictability in any oscillatory physiologic process.

Quality improvement project to reduce medicare 1-day write-offs due to inappropriate admission orders.

BACKGROUND: We identified that Stanford Health Care had a significant number of patients who after discharge are found by the utilization review committee not to meet Center for Mediare and Medicaid Services (CMS) 2-midnight benchmark for inpatient status. Some of the charges incurred during the care of these patients are written-off and known as Medicare 1-day write-offs. This study which aims to evaluate the use of a Best Practice Alert (BPA) feature on the electronic medical record, EPIC, to ensure appropriate designation of a patient's hospitalization status as either inpatient or outpatient in accordance with Center for Medicare and Medicaid services (CMS) 2 midnight length of stay benchmark thereby reducing the number of associated write-offs. METHOD: We incorporated a best practice alert (BPA) into the Epic Electronic Medical Record (EMR) that would prompt the discharging provider and the case manager to review the patients' inpatient designation prior to discharge and change the patient's designation to observation when deemed appropriate. Patients who met the inclusion criteria (Patients must have Medicare fee-for-service insurance, inpatient length of stay (LOS) less than 2 midnights, inpatient designation as hospitalization status at time of discharge, was hospitalized to an acute level of care and belonged to one of 37 listed hospital services at the time of signing of the discharge order) were randomized to have the BPA either silent or active over a three-month period from July 18, 2019, to October 18, 2019. RESULT: A total of 88 patients were included in this study: 40 in the control arm and 48 in the intervention arm. In the intervention arm, 8 (8/48, 16.7%) had an inpatient status designation despite potentially meeting Medicare guidelines for an observation stay, comparing to 23 patients (23/40, 57.5%) patients in the control group (p = 0.001). The estimated number of write-offs in the control arm was 17 (73.9%, out of 23 inpatient patients) while in the intervention arm was 1 (12.5%, out of 8 inpatient patient) after accounting for patients who may have met inpatient criteria for other reasons based on case manager note review. CONCLUSION: This is the first time to our knowledge that a BPA has been used in this manner to reduce the number of Medicare 1-day write-offs.

Inter-patient heterogeneity in the hepatic ischemia-reperfusion injury transcriptome: Implications for research and diagnostics.

Cellular responses induced by surgical procedure or ischemia-reperfusion injury (IRI) may severely alter transcriptome profiles and complicate molecular diagnostics. To investigate this effect, we characterized such pre-analytical effects in 143 non-malignant liver samples obtained from 30 patients at different time points of ischemia during surgery from two individual cohorts treated either with the Pringle manoeuvre or total vascular exclusion. Transcriptomics profiles were analyzed by Affymetrix microarrays and expression of selected mRNAs was validated by RT-PCR. We found 179 mutually deregulated genes which point to elevated cytokine signaling with NFκB as a dominant pathway in ischemia responses. In contrast to ischemia, reperfusion induced pro-apoptotic and pro-inflammatory cascades involving TNF, NFκB and MAPK pathways. FOS and JUN were down-regulated in steatosis compared to their up-regulation in normal livers. Surprisingly, molecular signatures of underlying primary and secondary cancers were present in non-tumor tissue. The reported inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a set of 230 pre-analytically highly robust genes identified from histologically normal livers (<2% covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications.

Targeting repetitive laboratory testing with electronic health records-embedded predictive decision support: A pre-implementation study.

INTRODUCTION: Unnecessary laboratory testing contributes to patient morbidity and healthcare waste. Despite prior attempts at curbing such overutilization, there remains opportunity for improvement using novel data-driven approaches. This study presents the development and early evaluation of a clinical decision support tool that uses a predictive model to help providers reduce low-yield, repetitive laboratory testing in hospitalized patients. METHODS: We developed an EHR-embedded SMART on FHIR application that utilizes a laboratory test result prediction model based on historical laboratory data. A combination of semi-structured physician interviews, usability testing, and quantitative analysis on retrospective laboratory data were used to inform the tool's development and evaluate its acceptability and potential clinical impact. KEY RESULTS: Physicians identified culture and lack of awareness of repeat orders as key drivers for overuse of inpatient blood testing. Users expressed an openness to a lab prediction model and 13/15 physicians believed the tool would alter their ordering practices. The application received a median System Usability Scale score of 75, corresponding to the 75th percentile of software tools. On average, physicians desired a prediction certainty of 85% before discontinuing a routine recurring laboratory order and a higher certainty of 90% before being alerted. Simulation on historical lab data indicates that filtering based on accepted thresholds could have reduced âˆ¼22% of repeat chemistry panels. CONCLUSIONS: The use of a predictive algorithm as a means to calculate the utility of a diagnostic test is a promising paradigm for curbing laboratory test overutilization. An EHR-embedded clinical decision support tool employing such a model is a novel and acceptable intervention with the potential to reduce low-yield, repetitive laboratory testing.

Physicians Leading Physicians: A Physician Engagement Intervention Decreases Inappropriate Use of IICU Level of Care Accommodations.

Following the adoption of an acuity-adaptable unit model in an academic medical center, a $13M increase in cost of intermediate intensive care unit (IICU) accommodations was observed. The authors followed A3 methodology to determine the root cause of this increase and developed a 3-prong intervention centered on physician engagement, given that physicians have the ability to order a patient's level of care. This intervention consisted of: (1) identifying physician champions to promote appropriate IICU use, (2) visual changes to essential electronic medical record tools, and (3) data-driven feedback to physician champions. In the year following intervention deployment, average IICU length of stay decreased from 1.08 to 0.62 days and average IICU use decreased from 21.4% to 12.3%, corresponding to ~$5.7M cost savings with no significant change in balancing measures observed. Together, these results demonstrate that a multicomponent intervention aimed at engaging physicians reduced inappropriate IICU use with no increase in adverse events.

E-HeaRT BPA: electronic health record telemetry BPA.

INTRODUCTION: Continuous cardiac monitoring in non-critical care settings is expensive and overutilised. As such, it is an important target of hospital interventions to establish cost-effective, high-quality care. Since inappropriate telemetry use was persistently elevated at our institution, we devised an electronic best practice alert (BPA) and tested it in a randomised controlled fashion. METHODS: Between 4 March 2018 and 5 July 2018 at our 600-bed academic hospital, all non-critical care patients who had at least one telemetry order were randomised to the control or intervention group. The intervention group received daily BPAs if telemetry was active. RESULTS: 275 and 283 patients were randomised to the intervention and control groups, respectively. The intervention group triggered 1042 alerts and trended toward fewer telemetry days (3.8 vs 5.0, p=0.017). The intervention group stopped telemetry 31.7% of the alerted patient-days compared with 23.3% for the control group (OR 1.53, 95% CI 1.24 to 1.88, p<0.001). There were no significant differences in length of stay, rapid responses, code blues, or mortality between the two groups. CONCLUSIONS: Using a randomised controlled design, we show that BPAs significantly reduce telemetry without negatively affecting patient outcomes. They should have a role in promoting high-value telemetry use.

Monocytes undergo multi-step differentiation in mice during oral infection by Toxoplasma gondii.

Monocytes play a major role in the defense against pathogens. They are rapidly mobilized to inflamed sites where they exert both proinflammatory and regulatory effector functions. It is still poorly understood how this dynamic and exceptionally plastic system is controlled at the molecular level. Herein, we evaluated the differentiation process that occurs in Ly6Chi monocytes during oral infection by Toxoplasma gondii. Flow cytometry and single-cell analysis revealed distinct activation status and gene expression profiles in the bone marrow, the spleen and the lamina propria of infected mice. We provide further evidence that acquisition of effector functions, such as the capacity to produce interleukin-27, is accompanied by distinct waves of epigenetic programming, highlighting a role for STAT1/IRF1 in the bone marrow and AP-1/NF-κB in the periphery. This work broadens our understanding of the molecular events that occur in vivo during monocyte differentiation in response to inflammatory cues.

Waiting it out: consultation delays prolong in-patient length of stay.

BACKGROUND: Decreasing delays for hospitalised patients results in improved hospital efficiency, increased quality of care and decreased healthcare expenditures. Delays in subspecialty consultations and procedures can cause increased length of stay due to reasons outside of necessary medical care. OBJECTIVE: To quantify, describe and record reasons for delays in consultations and procedures for patients on the general medicine wards. METHODOLOGY: We conducted weekly audits of all admitted patients on five Internal Medicine teams over 8 weeks. A survey was reviewed with attending physicians and residents on five internal medicine teams to identify patients with a delay due to consultation or procedure, quantify length of delay and record reason for delay. RESULTS: During the study period, 316 patients were reviewed and 48 were identified as experiencing a total of 53 delays due to consultations or procedures. The average delay was 1.8 days for a combined total of 83 days. Top reasons for delays included scheduling, late response to page and a busy service. The frequency in length of consult delays vary among different specialties. The highest frequency of delays was clustered in procedure-heavy specialties. CONCLUSION: This report highlights the importance of reviewing system barriers that lead to delayed service in hospitals. Addressing these delays could lead to reductions in length of stay for inpatients.

Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells.

Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents.

Reducing Telemetry Use Is Safe: A Retrospective Analysis of Rapid Response Team and Code Events After a Successful Intervention to Reduce Telemetry Use.

Interventions guiding appropriate telemetry utilization have successfully reduced use at many hospitals, but few studies have examined their possible adverse outcomes. The authors conducted a successful intervention to reduce telemetry use in 2013 on a hospitalist service using educational modules, routine review, and financial incentives. The association of reduced telemetry use with the incidence of rapid response team (RRT) and code activations was assessed in a retrospective cohort study of 210 patients who experienced a total of 233 RRT and code events on the inpatient internal medicine services from January 2012 through March 2015 at a tertiary care center. The incidence of adverse events for the hospitalist service was not significantly different during the intervention and postintervention period as compared to the preintervention period. Reducing inappropriate telemetry use was not associated with an increase in the incidence rates of RRT and code events.

A long wait: barriers to discharge for long length of stay patients.

INTRODUCTION: Reducing long length of stay (LLOS, or inpatient stays lasting over 30 days) is an important way for hospitals to improve cost efficiency, bed availability and health outcomes. Discharge delays can cost hundreds to thousands of dollars per patient, and LLOS represents a burden on bed availability for other potential patients. However, most research studies investigating discharge barriers are not LLOS-specific. Of those that do, nearly all are limited by further patient subpopulation focus or small sample size. To our knowledge, our study is the first to describe LLOS discharge barriers in an entire Department of Medicine. METHODS: We conducted a chart review of 172 LLOS patients in the Department of Medicine at an academic tertiary care hospital and quantified the most frequent causes of delay as well as factors causing the greatest amount of delay time. We also interviewed healthcare staff for their perceptions on barriers to discharge. RESULTS: Discharge site coordination was the most frequent cause of delay, affecting 56% of patients and accounting for 80% of total non-medical postponement days. Goals of care issues and establishment of follow-up care were the next most frequent contributors to delay. CONCLUSION: Together with perspectives from interviewed staff, these results highlight multiple different areas of opportunity for reducing LLOS and maximising the care capacity of inpatient hospitals.

Preamplification with dUTP and Cod UNG Enables Elimination of Contaminating Amplicons.

Analyzing rare DNA and RNA molecules in limited sample sizes, such as liquid biopsies and single cells, often requires preamplification, which makes downstream analyses particularly sensitive to polymerase chain reaction (PCR) generated contamination. Herein, we assessed the feasibility of performing Cod uracil-DNA N-glycosylase (Cod UNG) treatment in combination with targeted preamplification, using deoxyuridine triphosphate (dUTP) to eliminate carry-over DNA. Cod UNG can be completely and irreversibly heat inactivated, a prerequisite in preamplification methods, where any loss of amplicons is detrimental to subsequent quantification. Using 96 target assays and quantitative real-time PCR, we show that replacement of deoxythymidine triphosphate (dTTP) with dUTP in the preamplification reaction mix results in comparable dynamic range, reproducibility, and sensitivity. Moreover, Cod UNG essentially removes all uracil-containing template of most assays, regardless of initial concentration, without affecting downstream analyses. Finally, we demonstrate that the use of Cod UNG and dUTP in targeted preamplification can easily be included in the workflow for single-cell gene expression profiling. In summary, Cod UNG treatment in combination with targeted preamplification using dUTP provides a simple and efficient solution to eliminate carry-over contamination and the generation of false positives and inaccurate quantification.

Gene Expression Analysis of Immunomagnetically Enriched Circulating Tumor Cell Fraction in Castration-Resistant Prostate Cancer.

BACKGROUND: Molecular characterization of tumors could be a key to therapeutic decision-making with regards to targeted therapies in castration-resistant prostate cancer (CRPC). A convenient solution may be non-invasive liquid biopsy testing of circulating tumor cells (CTCs). For this reason, CTC-enriched samples obtained by immunomagnetic separation (AdnaTest®) were studied as a source material for high-throughput gene expression analysis using BioMark™. PATIENTS AND METHODS: CTC-enriched samples from 41 CRPC patients previously determined to be CTC positive using the AdnaTest® were retrospectively re-analysed for androgen receptor (AR) messenger RNA (mRNA), using the updated AdnaTest®. Blood samples were drawn two times from each patient: at the time of CRPC diagnosis and after the third docetaxel cycle. A gene expression panel of 27 genes related to CRPC therapeutic decision-making, including AR full length (ARFL) and splice variant 7 (ARV7), was retrospectively analyzed on a BioMark™ platform in 29 of 41 patients. RESULTS: The AdnaTest® detected AR mRNA in three-quarters of CTC-positive samples taken at the time of CRPC diagnosis and after the third docetaxel cycle. AR detection was associated with a shorter disease-specific survival (45.0 vs. 20.4 months) at the time of CRPC diagnosis. ARFL expression at the time of CRPC diagnosis, measured on the BioMark™ platform, was associated with a lower decrease of serum level of prostate-specific antigen (sPSA) (p = 0.029), i.e., worse therapy response. ARV7 was found in 38% of the ARFL--positive samples at both analyzed timepoints. CONCLUSION: Detection of AR expression by AdnaTest® in CTC-enriched samples may help predict patients' survival. These AdnaTest® CTC-enriched samples can be used in a high-throughput quantitative polymerase chain reaction (qPCR) analysis of gene expression, provided that the specificity of the assay for each individual gene is properly validated. The BioMark™ platform can be used for the simultaneous detection of ARFL and ARV7 and other genes in CTC-enriched samples from CRPC patients.

Identification of inhibitors regulating cell proliferation and FUS-DDIT3 expression in myxoid liposarcoma using combined DNA, mRNA, and protein analyses.

FUS-DDIT3 belongs to the FET (FUS, EWSR1, and TAF15) family of fusion oncogenes, which collectively are considered to be key players in tumor development. Even though over 90% of all myxoid liposarcomas (MLS) have a FUS-DDIT3 gene fusion, there is limited understanding of the signaling pathways that regulate its expression. In order to study cell proliferation and FUS-DDIT3 regulation at mRNA and protein levels, we first developed a direct cell lysis approach that allows DNA, mRNA, and protein to be analyzed in the same sample using quantitative PCR, reverse transcription quantitative qPCR and proximity ligation assay, respectively. We screened 70 well-characterized kinase inhibitors and determined their effects on cell proliferation and expression of FUS-DDIT3 and FUS at both mRNA and protein levels in the MLS 402-91 cell line, where twelve selected inhibitors were evaluated further in two additional MLS cell lines. Both FUS-DDIT3 and FUS mRNA expression correlated with cell proliferation and both transcripts were co-regulated in most conditions, indicating that the common 5' FUS promotor is important in transcriptional regulation. In contrast, FUS-DDIT3 and FUS protein levels displayed more cell line dependent expression. Furthermore, most JAK inhibitors caused FUS-DDIT3 downregulation at both mRNA and protein levels. In conclusion, defining factors that regulate FUS-DDIT3 expression opens new means to understand MLS development at the molecular level.

Interprofessional Collaboration: A Qualitative Study of Non-Physician Perspectives on Resident Competency.

BACKGROUND: The Association of American Medical Colleges (AAMC) includes the ability to collaborate in an interprofessional team as a core professional activity that trainees should be able to complete on day 1 of residency (Med Sci Educ. 26:797-800, 2016). The training that medical students require in order to achieve this competency, however, is not well established (Med Sci Educ. 26:457-61, 2016), and few studies have examined non-physician healthcare professionals' perspectives regarding resident physicians' interprofessional skills. OBJECTIVE: This study aims to describe non-physicians' views on barriers to collaboration with physicians, as well as factors that contribute to good collaborative relationships. PARTICIPANTS: Nurses, social workers, case managers, dietitians, rehabilitation therapists, and pharmacists at one academic medical center, largely working in the inpatient setting. APPROACH: A qualitative study design was employed. Data were collected from individual interviews and focus groups comprising non-physician healthcare professionals. KEY RESULTS: Knowledge gaps identified as impeding interprofessional collaboration included inadequate understanding of current roles, potential roles, and processes for non-physician healthcare professionals. Specific physician behaviors that were identified as contributing to good collaborative relationships included mutual support such as backing up other team members and prioritizing multidisciplinary rounds, and communication including keeping team members informed, asking for their input, physicians explaining their rationale, and practicing joint problem-solving with non-physicians. CONCLUSIONS: Discussion of how physician trainees can best learn to collaborate as members of an interprofessional team must include non-physician perspectives. Training designed to provide medical students and residents with a better understanding of non-physician roles and to enhance mutual support and communication skills may be critical in achieving the AAMC's goals of making physicians effective members of interprofessional teams, and thus improving patient-centered care. We hope that medical educators will include these areas identified as important by non-physicians in targeted team training for their learners.

Cyclophosphamide treatment regulates the balance of functional/exhausted tumor-specific CD8+ T cells.

An important question is how chemotherapy may (re-)activate tumor-specific immunity. In this study, we provide a phenotypic, functional and genomic analysis of tumor-specific CD8+ T cells in tumor (P815)-bearing mice, treated or not with cyclophosphamide. Our data show that chemotherapy favors the development of effector-type lymphocytes in tumor bed, characterized by higher KLRG-1 expression, lower PD-1 expression and increased cytotoxicity. This suggests re-engagement of T lymphocytes into the effector program. IFN-I appears involved in this remodeling. Our findings provide some insight into how cyclophosphamide regulates the amplitude and quality of tumor-specific immune responses.

A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback.

PURPOSE: Most residency programmes do not have a formal high value care curriculum. Our goal was to design and implement a multidisciplinary high value care curriculum specifically targeted at interns. DESIGN: Our curriculum was designed with multidisciplinary input from attendings, fellows and residents at Stanford. Curricular topics were inspired by the American Board of Internal Medicine's Choosing Wisely campaign, Alliance for Academic Internal Medicine, American College of Physicians and Society of Hospital Medicine. Our topics were as follows: introduction to value-based care; telemetry utilisation; lab ordering; optimal approach to thrombophilia work-ups and fresh frozen plasma use; optimal approach to palliative care referrals; antibiotic stewardship; and optimal approach to imaging for low back pain. Our curriculum was implemented at the Stanford Internal Medicine residency programme over the course of two academic years (2014 and 2015), during which 100 interns participated in our high value care curriculum. After each high value care session, interns were offered the opportunity to complete surveys regarding feedback on the curriculum, self-reported improvements in knowledge, skills and attitudinal module objectives, and quiz-based knowledge assessments. RESULTS: The overall survey response rate was 67.1%. Overall, the material was rated as highly useful on a 5-point Likert scale (mean 4.4, SD 0.6). On average, interns reported a significant improvement in their self-rated knowledge, skills and attitudes after the six seminars (mean improvement 1.6 points, SD 0.4 (95% CI 1.5 to 1.7), p<0.001). CONCLUSIONS: We successfully implemented a novel high value care curriculum that specifically targets intern physicians.

Barriers to timely discharge from the general medicine service at an academic teaching hospital.

BACKGROUND: Reducing delays for patients who are safe to be discharged is important for minimising complications, managing costs and improving quality. Barriers to discharge include placement, multispecialty coordination of care and ineffective communication. There are a few recent studies that describe barriers from the perspective of all members of the multidisciplinary team. STUDY OBJECTIVE: To identify the barriers to discharge for patients from our medicine service who had a discharge delay of over 24 hours. METHODOLOGY: We developed and implemented a biweekly survey that was reviewed with attending physicians on each of the five medicine services to identify patients with an unnecessary delay. Separately, we conducted interviews with staff members involved in the discharge process to identify common barriers they observed on the wards. RESULTS: Over the study period from 28 October to 22 November 2013, out of 259 total discharges, 87 patients had a delay of over 24 hours (33.6%) and experienced a total of 181 barriers. The top barriers from the survey included patient readiness, prolonged wait times for procedures or results, consult recommendations and facility placement. A total of 20 interviews were conducted, from which the top barriers included communication both between staff members and with the patient, timely notification of discharge and lack of discharge standardisation. CONCLUSIONS: There are a number of frequent barriers to discharge encountered in our hospital that may be avoidable with planning, effective communication methods, more timely preparation and tools to standardise the discharge process.

Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells.

Recently, we showed that generation of tumours in syngeneic mice by cells devoid of mitochondrial (mt) DNA (ρ0 cells) is linked to the acquisition of the host mtDNA. However, the mechanism of mtDNA movement between cells remains unresolved. To determine whether the transfer of mtDNA involves whole mitochondria, we injected B16ρ0 mouse melanoma cells into syngeneic C57BL/6Nsu9-DsRed2 mice that express red fluorescent protein in their mitochondria. We document that mtDNA is acquired by transfer of whole mitochondria from the host animal, leading to normalisation of mitochondrial respiration. Additionally, knockdown of key mitochondrial complex I (NDUFV1) and complex II (SDHC) subunits by shRNA in B16ρ0 cells abolished or significantly retarded their ability to form tumours. Collectively, these results show that intact mitochondria with their mtDNA payload are transferred in the developing tumour, and provide functional evidence for an essential role of oxidative phosphorylation in cancer.