Electrical signature of heterogeneous human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) have gained traction in transplantation therapy due to their immunomodulatory, paracrine, immune-evasive, and multipotent differentiation potential. The inherent heterogeneity of hMSCs poses a challenge for therapeutic treatments and necessitates the identification of robust biomarkers to ensure reproducibility in both in vivo and in vitro experiments. In this study, we utilized dielectrophoresis (DEP), a label-free electrokinetic phenomenon, to investigate the heterogeneity of hMSCs derived from bone marrow (BM) and adipose tissue (AD). The electrical properties of BM-hMSCs were compared to homogeneous mouse fibroblasts (NIH-3T3), human fibroblasts (WS1), and human embryonic kidney cells (HEK-293). The DEP profile of BM-hMSCs differed most from HEK-293 cells. We compared the DEP profiles of BM-hMSCs and AD-hMSCs and found that they have similar membrane capacitances, differing cytoplasm conductivity, and transient slopes. Inducing both populations to differentiate into adipocyte and osteoblast cells revealed that they behave differently in response to differentiation-inducing cytokines. Histology and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses of the differentiation-related genes revealed differences in heterogeneity between BM-hMSCs and AD-hMSCs. The differentiation profiles correlate well with the DEP profiles developed and indicate differences in the heterogeneity of BM-hMSCs and AD-hMSCs. Our results demonstrate that using DEP, membrane capacitance, cytoplasm conductivity, and transient slope can uniquely characterize the inherent heterogeneity of hMSCs to guide robust and reproducible stem cell transplantation therapies.

Light-Induced Dielectrophoresis for Characterizing the Electrical Behavior of Human Mesenchymal Stem Cells.

Human mesenchymal stem cells (hMSCs) offer a patient-derived cell source for conducting mechanistic studies of diseases or for several therapeutic applications. Understanding hMSC properties, such as their electrical behavior at various maturation stages, has become more important in recent years. Dielectrophoresis (DEP) is a method that can manipulate cells in a nonuniform electric field, through which information can be obtained about the electrical properties of the cells, such as the cell membrane capacitance and permittivity. Traditional modes of DEP use metal electrodes, such as three-dimensional electrodes, to characterize the response of cells to DEP. In this paper, we present a microfluidic device built with a photoconductive layer capable of manipulating cells through light projections that act as in situ virtual electrodes with readily conformable geometries. A protocol is presented here that demonstrates this phenomenon, called light-induced DEP (LiDEP), for characterizing hMSCs. We show that LiDEP-induced cell responses, measured as cell velocities, can be optimized by varying parameters such as the input voltage, the wavelength ranges of the light projections, and the intensity of the light source. In the future, we envision that this platform could pave the way for technologies that are label-free and perform real-time characterization of heterogeneous populations of hMSCs or other stem cell lines.

Epidemiology of interstitial lung disease in patients with metastatic breast cancer at baseline and after treatment with HER2-directed therapy: a real-world data analysis.

PURPOSE: Using real-world data, interstitial lung disease (ILD) prevalence before and after HER2-directed therapy was estimated. Potential ILD risk factors in patients receiving HER2-directed therapy for metastatic breast cancer (mBC) were evaluated. METHODS: Adults with HER2-directed therapy for mBC initiated between September 25, 1998, and February 22, 2020 were, included. ILD was defined broadly as one or more of 64 lung conditions. Patients were followed until incident ILD, death, last contact, or study end. RESULTS: In total, 533 patients were identified with median age at mBC of 57, 51% had de novo mBC, 43% were ever smokers, 30% had lung metastases, 9% had thoracic radiation, 6% had chronic obstructive pulmonary disease, and 16% had prevalent ILD. ILD cumulative incidence at one year was 9% (95% CI 6%, 12%), with a median follow-up of 23 months. Smoking (HR 2.2, 95% CI 1.1, 4.8) and Black/African-American race (HR 3.4, 95% CI 1.6, 7.5) were significantly associated with ILD; HRs for preexisting lung conditions (HR 1.8, 95% CI 0.9, 3.8) and thoracic radiation (HR 2.3, 95% CI 0.8, 7.1) were not statistically significant. Prevalent ILD was associated with 13-fold greater occurrence of incident ILD. 85% of patients with prevalent or incident ILD were symptomatic. CONCLUSIONS: This real-world population of patients with mBC had a high prevalence of ILD prior to HER2-directed therapy, reflecting the multifactorial causation of interstitial lung changes. The cumulative incidence of ILD in patients receiving HER2-directed therapy for mBC augments prior reports. Symptomatic presentation suggests an opportunity for early intervention.

A locus coeruleus-dorsal CA1 dopaminergic circuit modulates memory linking.

Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we show that locus coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine. Additionally, we found that LC-to-dCA1-projecting neurons modulate the excitability of dCA1 neurons and the extent of overlap between dCA1 memory ensembles as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation reveals a fundamental separation between the brain mechanisms modulating these two distinct processes.

Mosquito cryptochromes expressed in Drosophila confer species-specific behavioral light responses.

Cryptochrome (CRY) is a short-wavelength light-sensitive photoreceptor expressed in a subset of circadian neurons and eyes in Drosophila that regulates light-evoked circadian clock resetting. Acutely, light evokes rapid electrical excitation of the ventral lateral subset of circadian neurons and confers circadian-modulated avoidance behavioral responses to short-wavelength light. Recent work shows dramatically different avoidance versus attraction behavioral responses to short-wavelength light in day-active versus night-active mosquitoes and that these behavioral responses are attenuated by CRY protein degradation by constant light exposure in mosquitoes. To determine whether CRY1s mediate species-specific coding for behavioral and electrophysiological light responses, we used an "empty neuron" approach and transgenically expressed diurnal Aedes aegypti (AeCRY1) versus nocturnal Anopheles gambiae (AgCRY1) in a cry-null Drosophila background. AeCRY1 is much less light sensitive than either AgCRY1 or DmCRY as shown by partial behavioral rhythmicity following constant light exposure. Remarkably, expression of nocturnal AgCRY1 confers low survival to constant white light as does expression of AeCRY1 to a lesser extent. AgCRY1 mediates significantly stronger electrophysiological cell-autonomous responses to 365 nm ultraviolet (UV) light relative to AeCRY1. AgCRY1 expression mediates electrophysiological sensitivity to 635 nm red light, whereas AeCRY1 does not, consistent with species-specific mosquito red light responses. AgCRY1 and DmCRY mediate intensity-dependent avoidance behavior to UV light at different light intensity thresholds, whereas AeCRY1 does not, thus mimicking mosquito and fly behaviors. These findings highlight CRY as a key non-image-forming visual photoreceptor that mediates physiological and behavioral light responses in a species-specific fashion.

Customizable Natural Language Processing Biomarker Extraction Tool.

PURPOSE: Natural language processing (NLP) in pathology reports to extract biomarker information is an ongoing area of research. MetaMap is a natural language processing tool developed and funded by the National Library of Medicine to map biomedical text to the Unified Medical Language System Metathesaurus by applying specific tags to clinically relevant terms. Although results are useful without additional postprocessing, these tags lack important contextual information. METHODS: Our novel method takes terminology-driven semantic tags and incorporates those into a semantic frame that is task-specific to add necessary context to MetaMap. We use important contextual information to capture biomarker results to support Community Health System's use of Precision Medicine treatments for patients with cancer. For each biomarker, the name, type, numeric quantifiers, non-numeric qualifiers, and the time frame are extracted. These fields then associate biomarkers with their context in the pathology report such as test type, probe intensity, copy-number changes, and even failed results. A selection of 6,713 relevant reports contained the following standard-of-care biomarkers for metastatic breast cancer: breast cancer gene 1 and 2, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and programmed death-ligand 1. RESULTS: The method was tested on pathology reports from the internal pathology laboratory at Henry Ford Health System. A certified tumor registrar reviewed 400 tests, which showed > 95% accuracy for all extracted biomarker types. CONCLUSION: Using this new method, it is possible to extract high-quality, contextual biomarker information, and this represents a significant advance in biomarker extraction.

Effectiveness of Liposomal Bupivacaine Compared With Standard-of-Care Measures in Pediatric Cardiothoracic Surgery: A Retrospective Cohort Study.

OBJECTIVE: Effective postsurgical pain management is important for pediatric patients to improve outcomes while reducing resource use and waste. The authors examined opioid consumption and economic outcomes associated with liposomal bupivacaine (LB) or non-LB analgesia use in pediatric patients undergoing cardiothoracic surgery. DESIGN: The authors retrospectively analyzed Premier Healthcare Database records. SETTING: The data extracted from the database included patient records from hospitals across the United States in both rural and urban locations. PARTICIPANTS: The records included data from patients aged 12-to-<18 years. INTERVENTIONS: The records belonged to patients undergoing video-assisted thoracoscopic procedures (VATS) who received LB or non-LB analgesia after surgery. MEASUREMENTS AND MAIN RESULTS: Outcomes included in-hospital postsurgical opioid consumption in morphine milligram equivalents (MMEs), hospital length of stay (LOS), and total hospital costs; the LB and non-LB cohorts were compared using a generalized linear model with inverse probability of treatment weighting to balance the cohorts. For VATS procedures, pediatric patients receiving LB had significant reductions in in-hospital opioid consumption (632 v 991 MMEs; p < 0.0001), shorter LOS (5.1 v 5.6 days; p = 0.0023), and lower total hospital costs ($18,084 v $21,962; p < 0.0001) compared with those receiving non-LB analgesia. CONCLUSIONS: These results support use of LB in multimodal analgesia regimens for managing pain in pediatric patients after cardiothoracic surgery.

Validation of a Mortality Composite Score in the Real-World Setting: Overcoming Source-Specific Disparities and Biases.

PURPOSE: This study tested whether a composite mortality score could overcome gaps and potential biases in individual real-world mortality data sources. Complete and accurate mortality data are necessary to calculate important outcomes in oncology, including overall survival. However, in the United States, there is not a single complete and broadly applicable mortality data source. It is further likely that available data sources are biased in their coverage of sex, race, age, and socioeconomic status (SES). METHODS: Six individual real-world data sources were combined to develop a high-quality composite mortality score. The composite score was benchmarked against the gold standard for mortality data, the National Death Index. Subgroup analyses were then conducted to evaluate the completeness and accuracy by sex, race, age, and SES. RESULTS: The composite mortality score achieved a sensitivity of 94.9% and specificity of 92.8% compared with the National Death Index, with concordance within 1 day of 98.6%. Although some individual data sources show significant coverage gaps related to sex, race, age, and SES, the composite score maintains high sensitivity (84.6%-96.1%) and specificity (77.9%-99.2%) across subgroups. CONCLUSION: A composite score leveraging multiple scalable sources for mortality in the real-world setting maintained strong sensitivity, specificity, and concordance, including across sex, race, age, and SES subgroups.

Integrative Review of Lower Extremity Nerve Injury During Vaginal Birth.

OBJECTIVE: To describe the incidence, health effects, risk factors, and practice implications of lower extremity nerve injury (LENI) related to vaginal births. DATA SOURCES: We searched MEDLINE, CINAHL, and PubMed from 2000 to 2020 for peer-reviewed published case reports and research studies of LENI related to vaginal births. STUDY SELECTION: We identified 188 potential records, and 20 met inclusion criteria (six research studies and 14 case studies). DATA EXTRACTION: Three independent reviewers extracted details of injuries and births into an Excel spreadsheet and analyzed data using SPSS. DATA SYNTHESIS: Using birth data from each case study and from four of the six research articles, we found the incidence of LENI in vaginal births was 0.3% to 1.8%. The description of health effects includes affected nerves and the location, description, and duration of symptoms. Analyses of risk factors were limited by missing birth data (length of second stage, birth weight, etc). Vaginal births with LENI were 76% spontaneous, 77% with neuraxial anesthesia, and 64% first vaginal birth. Practice implications focused on prevention through specific positioning strategies. Despite nurses being the primary caregivers during labor, LENI was reported most often in anesthesia journals with virtually no reports in nursing journals. CONCLUSION: LENI is a potential complication of vaginal birth, and little published research is available on prevention and prognosis. While obstetric and anesthesia factors can cause or contribute to nerve injury, LENI is usually caused by positioning and is considered preventable. Care recommendations include the following: avoid prolonged hyperflexion of women's thighs and knees; minimize time in lithotomy, squatting, or kneeling positions; prevent hand or other deep pressure on lateral knee and posterior thigh areas; avoid motor-blocking neuraxial (epidural) anesthesia; and implement frequent repositioning. The paucity of literature contributes to the lack of awareness of LENI among clinicians.

Randomized clinical trial of a novel donor-derived cfDNA test to detect rejection in CPV-simulated renal transplant patients.

PURPOSE: Five-year kidney graft loss currently stands at about 30%. We evaluate the clinical utility of a blood test measuring donor-derived cell-free DNA that detects rejection earlier and, potentially, improves diagnostic and therapeutic accuracy. METHODS: In a randomized controlled experiment, we measured the clinical practice of 175 practicing nephrologists, both with and without the use of dd-cfDNA testing. Providers cared for six simulated post-renal transplant patient cases whose ages ranged from 30 to 75 years and were 3-24 months post-transplant with typical presentations. RESULTS: 154 nephrologists completed two rounds of simulated cases. At baseline, the study arms performed similarly, demonstrating no significant differences either in primary diagnosis (p = 0.853), decisions to biopsy or refer to transplant center (p = 1.000), or therapeutic management (p = 0.488). After introduction of the dd-cfDNA test, intervention nephrologists were more likely to arrive at the diagnosis of rejection (OR 4.00, 95% CI 1.93-8.30), make a correct decision on biopsy/transplant center referral (OR 11.07, 95% CI 4.87-25.16), and properly adjust therapeutic management (OR 2.37, 95% CI 1.07-5.24). CONCLUSION: A sample of nationally representative, practicing nephrologists given dd-cfDNA to evaluate post-transplant patients were more likely to correctly diagnose early and subclinical allograft rejection, to send for biopsy or refer to transplant center, and to appropriately change treatment than those nephrologists without dd-cfDNA access.

Variation in Diabetes Management: A National Assessment of Primary Care Providers.

BACKGROUND: Glucose control is monitored primarily through ordering HbA1c levels, which is problematic in patients with glycemic variability. Herein, we report on the management of these patients by board-certified primary care providers (PCPs) in the United States. METHODS: We measured provider practice in a representative sample of 156 PCPs. All providers cared for simulated patients with diabetes presenting with symptoms of glycemic variability. Provider responses were reviewed by trained clinicians against evidence-based care standards and accepted standard of care protocols. RESULTS: Care varied widely-overall quality of care averaged 51.3%±10.6%-with providers performing just over half the evidence-based practices necessary for their cases. More worryingly, provider identified the underlying etiology of the poor glycemic control only 36.3% of the time. HbA1c was routinely ordered in 91.3% of all cases but often (59.5%) inappropriately. Ordering other tests of glycemic control (done in 15% of cases) led to significant increases in identifying the etiology of the hyperglycemia. Correctly modifying their patient's treatment was more likely to occur if doctors first identified the underlying etiology (65.9% vs 49.0%, P<0.001). We conservatively estimated a US $65/patient/visit in unnecessary testing and US $389 annually in additional care costs when the etiology was missed, translating potentially into millions of dollars of wasteful spending. CONCLUSION: Despite established evidence that HbA1c misses short-term changes in diabetes, we found PCPs consistently ordered HbA1c, rarely using other available blood tests. However, if the factors leading to poor glycemic control were recognized, PCPs were more likely to correctly alter their patient's hypoglycemic therapy.

Clinical Utility of a Blood-based Protein Assay on Diagnostic Colonoscopy Referrals for Elevated-risk Colorectal Cancer Patients in Primary Care.

BACKGROUND: Colonoscopies are effective in finding early stage colorectal cancer (CRC), which when found in a timely manner, dramatically improve survival rates. A significant number of at-risk patients are still not screened. We investigated the utility of a blood-based protein assay to assess for CRC in patients with elevated risk on the quality of preventive care delivered by board-certified primary care physicians (PCPs) in the United States. METHODS: We report on the results of a 3-part, longitudinal, randomized controlled trial. Part 1 assessed physicians' ability to identify simulated patients at risk for CRC and found PCPs missed colonoscopy referrals for high-risk patients ~40% of the time. Part 2 randomized PCPs into control and intervention arms and demonstrated that a novel blood-based protein assay increased referral rates for a diagnostic colonoscopy when caring for simulated patients. Part 3, reported herein, compares real-world colonoscopy rates of actual patients cared for by control versus intervention physicians. Part 3 was executed to confirm whether the use of the assay demonstrated the same utility in their real world, high-risk patients as found in part 2 using simulated patients. RESULTS: In the simulations, physicians with access to the assay were significantly more likely to order diagnostic colonoscopies. Similarly, in real-world practice, patients were also more likely to be referred for a diagnostic colonoscopy (odds ratio, 4.57; 95% confidence interval, 1.19-17.57). CONCLUSIONS: An increase in CRC risk, as indicated by the assay in simulated and real-life patients, was associated with a higher likelihood of appropriate patients being referred to diagnostic colonoscopy.

Establishing Clinical Utility for Diagnostic Tests Using a Randomized Controlled, Virtual Patient Trial Design.

Demonstrating clinical utility for diagnostic tests and securing coverage and reimbursement requires high quality and, ideally, randomized controlled trial (RCT) data. Traditional RCTs are often too costly, slow, and cumbersome for diagnostic firms. Alternative data options are needed. We evaluated four RCTs using virtual patients to demonstrate clinical utility. Each study used a similar pre-post intervention, two round design to facilitate comparison. Representative samples of physicians were recruited and randomized into control and intervention arms. All physicians were asked to care for their virtual patients during two assessment rounds, separated by a multi-week time interval. Between rounds, intervention physicians reviewed educational materials on the diagnostic test. All physician responses were scored against evidence-based care criteria. RCTs using virtual patients can demonstrate clinical utility for a variety of diagnostic test types, including: (1) an advanced multi-biomarker blood test, (2) a chromosomal microarray, (3) a proteomic assay analysis, and (4) a multiplex immunofluorescence imaging platform. In two studies, utility was demonstrated for all targeted patient populations, while in the other two studies, utility was only demonstrated for a select sub-segment of the intended patient population. Of these four tests, two received positive coverage decisions from Palmetto, one utilized the study results to support commercial payer adjudications, and the fourth company went out of business. RCTs using virtual patients are a cost-effective approach to demonstrate the presence or absence of clinical utility.

Variation in Assessing Renal Allograft Rejection: A National Assessment of Nephrology Practice.

BACKGROUND: The clinical utility of early detection and treatment of allograft rejection is well-established. Despite frequent testing called for by standard of care protocols, the five-year kidney allograft survival rate is estimated to be as low as 71%. Herein, we report on posttransplant care provided to kidney allograft recipients by board-certified nephrologists in the United States. METHODS: We measured clinical practice in a representative sample of 175 practicing nephrologists. All providers cared for simulated patients' status after renal transplant ranging from 30-75 years in age and 3-24 months after transplant. Our sample of nephrologists cared for a total of 525 allograft cases. Provider responses to the cases were reviewed by trained clinicians, and care was compared to evidence-based care standards and accepted standard of care protocols. RESULTS: Among nephrologists, practicing in settings ranging from transplant centers to community practice, we found that the clinical workup of kidney injury in posttransplant patients is highly variable and frequently deviates from evidence-based care. In cases with pathologic evidence of rejection, only 29.1% (102/350) received an appropriate, evidence-based biopsy, whereas, in cases with no pathological evidence of rejection, 41.3% (45/109) received low-value, unnecessary biopsies. CONCLUSION: Clinical care in the posttransplant setting is highly variable. Biopsies are often ordered in cases where their results do not alter treatment. Additionally, we found that misdiagnosis was common as were opportunities for earlier biopsy and detection of rejection. This evidence suggests that better diagnostic tools may be helpful to determine which transplant patients should be biopsied and which should not. This study suggests that nephrologists and transplant patients need better tests than creatinine and proteinuria and less invasive approaches than routine biopsies to determine when transplant patients should be investigated for rejection and additional treatment.

Standardising practice in cardiology: reducing clinical variation and cost at Ochsner Health System.

Objective: Low quality and unwarranted clinical variation harm patients and increase unnecessary costs. Effective approaches to improve clinical and economic value have been difficult. The Ochsner Health System looked to improve clinical care quality and reduce unnecessary costs in cardiology using active measurement and customised feedback. Methods: We serially measured care decisions using online, simulated cases to capture clinical details of cardiology practice and provide individual feedback. Fifty cardiologists cared for two simulated patients in each of six assessment rounds occurring 4 months apart. Simulated patients presented with heart failure (HF), coronary artery disease (CAD), supraventricular tachyarrhythmia (SVT) or valvular heart disease. Using Ochsner's patient-level data, we performed real-world pre-post analyses of physician practice changes, patient outcomes and costs. Results: Between baseline and final rounds, overall simulated quality-of-care scores improved 14.1% (p<0.001). In the same period, we found cost-of-care variation decreased in patient-level data, with larger decreases for more severely ill patients. The total per-patient direct costs decreased $493 in SVT, $305 in HF and $55 in CAD (p<0.05 for SVT and HF). Readmission rates fell significantly for HF (from 20.0% to 11.9%) and SVT (from 14.5% to 7.8%) (both p<0.001) and non-significantly for CAD (from 13.7% to 11.3%, p=0.112). The cost avoidance/revenue generation opportunity from reduced readmissions and direct costs amounted to annual savings of $4.34 million, with no significant changes to in-hospital mortality rates (p>0.05). Conclusions: Using simulated patients to serially measure and provide individual feedback on clinical practice significantly raises quality and reduces practice variation and costs without negatively impacting outcomes.

Standardising hospitalist practice in sepsis and COPD care.

BACKGROUND: Hospitalist medicine was predicated on the belief that providers dedicated to inpatient care would deliver higher quality and more cost-effective care to acutely hospitalised patients. The literature shows mixed results and has identified care variation as a culprit for suboptimal quality and cost outcomes. Using a scientifically validated engagement and measurement approach such as Clinical Performance and Value (CPV), simulated patient vignettes may provide the impetus to change provider behaviour, improve system cohesion, and improve quality and cost efficiency for hospitalists. METHODS: We engaged 33 hospitalists from four disparate hospitalist groups practising at Penn Medicine Princeton Health. Over 16 months and four engagement rounds, participants cared for two patients per round (with a diagnosis of chronic obstructive pulmonary disease [COPD] and sepsis), then received feedback, followed by a group discussion. At project end, we evaluated both simulated and real-world data to measure changes in clinical practice and patient outcomes. RESULTS: Participants significantly improved their evidence-based practice (+13.7% points, p<0.001) while simultaneously reducing their variation (-1.4% points, p=0.018), as measured by the overall CPV score. Correct primary diagnosis increased significantly for both sepsis (+19.1% points, p=0.004) and COPD (+22.7% points, p=0.001), as did adherence to the sepsis 3-hour bundle (+33.7% points, p=0.010) and correct admission levels for COPD (+26.0% points, p=0.042). These CPV changes coincided with real-world improvements in length of stay and mortality, along with a calculated $5 million in system-wide savings for both disease conditions. CONCLUSION: This study shows that an engagement system-using simulated patients, benchmarking and feedback to drive provider behavioural change and group cohesion, using parallel tracking of hospital data-can lead to significant improvements in patient outcomes and health system savings for hospitalists.

A Quality Collaboration in Heart Failure and Pneumonia Inpatient Care at Novant Health: Standardizing Hospitalist Practices to Improve Patient Care and System Performance.

BACKGROUND: Heart failure and pneumonia are among the most measured and expensive conditions to treat in the United States across all payer types and are top of mind for value-driven hospital organizations and payers seeking to not only improve the quality of care for patients but also reduce unnecessary spending. Care standardization potentially leads to better patient outcomes and reduced excess costs but is a difficult objective to achieve. METHODS: A pre-post analysis of clinical practice, patient outcomes, and cost was designed to determine if serial measurement and feedback using simulated patients improves patient care quality and reduces costs for two common conditions cared for by hospitalists: pneumonia and heart failure. Care decisions measured using the simulations were compared to patient-level data collected by the system. RESULTS: Intrafacility care variation seen among Novant Health's 11 facilities employing hospitalists decreased from 14.9% to 8.5%, and overall quality-of-care scores by individual providers improved by 14.6 percentage points from study start to end. Overall, care changes (for example, troponin usage, palliative care consults, beta blocker orders) documented in the simulated patients matched the available patient-level data. Care standardization around evidence-based practices, as measured by the simulations, was associated with appreciable decreases in patient length of stay and readmissions, amounting to nearly $1.1 million in savings for Novant Health. CONCLUSION: An approach using simulated patients that includes serial measurement and feedback may help significantly reduce practice variation between different facilities in a health system and reduce costs substantially without negatively affecting outcomes.

Drug-Drug Interaction Assessment and Identification in the Primary Care Setting.

BACKGROUND: Drug-drug interactions (DDIs) are ubiquitous, harmful and a leading cause of morbidity and mortality. With an aging population, growth in polypharmacy, widespread use of supplements, and the rising opioid abuse epidemic, primary care physicians (PCPs) are increasingly challenged with identifying and preventing DDIs. We set out to evaluate current clinical practices related to identifying and treating DDIs and to determine if opportunities to increase prevention of DDIs and their adverse events could be identified. METHODS: In a nationally representative sample of 330 board-certified family and internal medicine practitioners, we evaluated whether PCPs assessed DDIs in the care they provided for three simulated patients. The patients were taking common prescription medications (e.g. opioids and psychiatric medications) along with other common ingestants (e.g. supplements and food) and presented with symptoms of DDIs. Physicians were scored on their ability to inquire about the patient's medications, investigate possible DDIs, evaluate the patient, and provide treatment recommendations. We scored the physicians' care recommendations against evidence-based criteria, including overall care quality and treatment for DDIs. RESULTS: Average overall quality of care score was 50.5% ± 12.0%. Despite >99% self-reported use of medication reconciliation practices and tools, physicians identified DDIs in only 15.3% of patients, with 15.5% ± 20.3% of DDI-specific treatment by the physicians. CONCLUSIONS: PCPs in this study did not recognize or adequately treat DDIs. Better methods are needed to screen for DDIs in the primary care setting.

Clinical Utility of Definitive Drug⁻Drug Interaction Testing in Primary Care.

Drug⁻drug interactions (DDIs) are a leading cause of morbidity and mortality. New tools are needed to improve identification and treatment of DDIs. We conducted a randomized controlled trial to assess the clinical utility of a new test to identify DDIs and improve their management. Primary care physicians (PCPs) cared for simulated patients presenting with DDI symptoms from commonly prescribed medications and other ingestants. All physicians, in either control or one of two intervention groups, cared for six patients over two rounds of assessment. Intervention physicians were educated on the DDI test and given access to these test reports when caring for their patients in the second round. At baseline, we saw no significant differences in making the DDI diagnosis (p = 0.071) or DDI-related treatment (p = 0.640) between control and intervention arms. By round two, providers who accessed the DDI test performed significantly better in making the DDI diagnosis (+41.6%) and performing DDI-specific treatment (+12.2%) than in the previous round, and were 9.8 and 20.4 times more likely to diagnose and identify the DDI (p < 0.001 for all). The introduction of a definitive DDI test significantly increased identification, appropriate management, and counseling of DDIs among PCPs, which has the potential to improve clinical care.