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OBJECTIVE: The objective of this study was to investigate variations across hospitals in infection rates and associated costs, the latter reflected in 90-day Medicare payments. Despite high rates and expenditures of healthcare-associated infections associated with durable ventricular assist device implant, few studies have examined inter-hospital variation and associated costs. METHODS: Clinical data on 8688 patients who received primary durable ventricular assist devices from July 2008 to July 2017 from The Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) hospitals (n=120) were merged with post-implant 90-day Medicare claims. Terciles of hospital-specific, risk-adjusted infection rates per 100 patient-months were estimated using Intermacs and associated with Medicare payments (among 5440 Medicare beneficiaries). Primary outcomes included infections within 90 days of implant and Medicare payments. RESULTS: There were 3982 infections identified among 27.8% (2,417/8,688) of patients developing an infection. The median (25(th), 75(th) percentile) adjusted incidence of infections (per 100 patient-months) across hospitals was 14.3 (9.3, 19.5) and varied by hospital (range 0.0 – 35.6). Total Medicare payments from implant to 90-days were 9.0% (absolute difference: $13,652) greater in high versus low infection tercile hospitals, p

The protein histidine phosphatase PHPT1 is implicated in a variety of cellular signaling pathways. However, little is known about the precise biological roles of this enzyme and a dearth of chemical tools for studying histidine phosphorylation and dephosphorylation has hampered progress in the field. With the goal of identifying the first inhibitors of PHPT1 activity, we carried out an inhibitor screen using a facile fluorogenic assay for PHPT1 activity recently developed in our laboratory. From a panel of approximately 4000 compounds obtained from the Microsource Spectrum Collection and the NCI Diversity Set IV, we identified several potential hits with significant selectivity for inhibiting PHPT1 activity over other phosphatases. Of these, norstictic acid was the most potent inhibitor of PHPT1 activity with an IC

On a global scale, cerebro-and cardiovascular diseases have long been one of the leading causes of death and disability and their prevalence appears to be increasing in recent times. Understanding potential biomarkers and risk factors will help to identify individuals potentially at risk of suffering an ischemic stroke. However, the widely variable construction of the cerebral vasculature makes it difficult to provide a specific assessment without the knowledge of a patient’s physiology. In this paper we use the 3D blood flow simulator HemeLB to study flow within three common structural variations of the circle of Willis during and in the moments after a blockage of the basilar artery. This tool, based on the lattice Boltzmann method, allows the 3D flow entering the basilar artery to be finely controlled to replicate the cessation of blood feeding this particular vessel-we demonstrate this with several examples including a sudden halt to flow and a gradual loss of flow over three heartbeat cycles. In this work we start with an individualised 3D representation of a full circle of Willis and then construct two further domains by removing the left or right posterior communicating arteries from this geometry. Our results indicate how, and how quickly, the circle of Willis is able to redistribute flow following such a stroke. Due to the choice of infarct, the greatest reduction in flow was observed in the posterior cerebral arteries where flow was reduced by up to 70% in some cases. The high resolution domains used in this study permit the velocity magnitude and wall shear stress to be analysed at key points during and following the stroke. The model we present here indicates how personalised vessels are required to provide the best insight into stroke risk for a given individual.

BACKGROUND The United States National Organ Procurement Transplant Network (OPTN) implemented changes to the adult heart allocation system to reduce waitlist mortality by improving access for those at greater risk of pre-transplant death, including patients on short-term mechanical circulatory support (sMCS). While sMCS increased, it is unknown whether the increase occurred equitably across centers. METHODS The OPTN database was used to assess changes in use of sMCS at time of transplant in the 12 months before (pre-change) and after (post-change) implementation of the allocation system in October 2018 among 5,477 heart transplant recipients. An interrupted time series analysis comparing use of bridging therapies pre- and post-change was performed. Variability in the proportion of sMCS use at the center level pre- and post-change was determined. RESULTS In the month pre-change, 9.7% of patients were transplanted with sMCS. There was an immediate increase in sMCS transplant the following month to 32.4% - an absolute and relative increase of 22.7% and 312% (p < 0.001). While sMCS use was stable pre-change (monthly change 0.0%, 95% CI [-0.1%,0.1%]), there was a continuous 1.2%/month increase post-change ([0.6%,1.8%], p < 0.001). Center-level variation in sMCS use increased substantially after implementation, from a median (interquartile range) of 3.85% (10%) pre-change to 35.7% (30.6%) post-change (p < 0.001). CONCLUSIONS Use of sMCS at time of transplant increased immediately and continued to expand following heart allocation policy changes. Center-level variation in use of sMCS at the time of transplant increased compared to pre-change, which may have negatively impacted equitable access to heart transplantation.

Objective Infections are among the most common complications in recipients of durable left ventricular assist devices (LVAD). However, existing studies examining infections in LVAD recipients are limited is size and design. Comprehensive, systematic reviews of all types of infections occurring among recipients of contemporary LVADs have not been conducted. The goal of this scoping review was to synthesize all available evidence related to rates of infections (including location and types) in LVAD recipients. Methods In February 2019, 4,581 published studies were identified through searching five bibliographic databases: PubMed, Scopus, EMBASE, CINAHL and Web of Science Core Collection. Inclusion criteria required reporting of infectious complications among LVAD recipients receiving contemporary (HeartMate II, HeartMate 3 and HeartWare HVAD) LVADs. Study key characteristics were extracted by 2 independent reviewers and current literature described narratively. All analyses took place between Feb 2019 and Jan 2021. Results A total of 132 studies met inclusion criteria. Most studies were observational (n=118; 89.4%), single-center (n=93, 70.4%) and from the U.S. (n=88; 66.7%). Only 48 (36.3%) studies used the standardized International Society for Heart and Lung Transplantation (ISHLT) definition for reporting infections. Only 35 (26.5%) studies reported age, gender and racial distribution of their study population. Driveline infections were the most commonly reported infection type. Conclusions Most studies did not utilize standardized infection definitions or provide complete information on infection locations and types. In order to further advance the scientific rigor, published studies should (i) use standardized definitions for reporting infections and (ii) stratify rates by infection location and type.

Background: Older adults may experience a significant digital divide and need support with using technology to transition to telehealth. This study examines the role of social support for telehealt...

Vitamin D deficiency has long been associated with reduced immune function that can lead to viral infection. Several studies have shown that Vitamin D deficiency is associated with increases the risk of infection with COVID-19. However, it is unknown if treatment with Vitamin D can reduce the associated risk of COVID-19 infection, which is the focus of this study. In the population of US veterans, we show that Vitamin D2and D3fills were associated with reductions in COVID-19 infection of 28% and 20%, respectively [(D3Hazard Ratio (HR) = 0.80, [95% CI 0.77, 0.83]), D2HR = 0.72, [95% CI 0.65, 0.79]]. Mortality within 30-days of COVID-19 infection was similarly 33% lower with Vitamin D3and 25% lower with D2(D3HR = 0.67, [95% CI 0.59, 0.75]; D2HR = 0.75, [95% CI 0.55, 1.04]). We also find that after controlling for vitamin D blood levels, veterans receiving higher dosages of Vitamin D obtained greater benefits from supplementation than veterans receiving lower dosages. Veterans with Vitamin D blood levels between 0 and 19 ng/ml exhibited the largest decrease in COVID-19 infection following supplementation. Black veterans received greater associated COVID-19 risk reductions with supplementation than White veterans. As a safe, widely available, and affordable treatment, Vitamin D may help to reduce the severity of the COVID-19 pandemic.

Particle suspensions form a fundamental yet complex component of many scientific and engineering endeavours. This paper proposes a numerical coupling between the lattice Boltzmann and discrete element methods that resolves particle suspensions exposed to thermal influences due to temperature-dependent fluid viscosity and conjugate heat transfer between components. Validation of the model was performed via the study of the relative viscosity of suspensions. This numerically corroborated the proposed temperature-dependence of the relative viscosity of suspensions. The model was finally used to interrogate the macroscopic behaviour of sheared suspensions at a range of solid volume fractions. This demonstrated changes in suspension flow behaviour due to temperature related effects. Future work based on these results would examine how particle properties could be modified to exacerbate and control temperature-based phenomena potentially leading to improvements in domains such as industrial material processing and manufacture.

While left ventricular assist devices (LVADs) increase survival for patients with advanced heart failure (HF), racial and sex access and outcome inequities remain and are poorly understood.To assess risk-adjusted inequities in access and outcomes for both Black and female patients and to examine heterogeneity in treatment decisions among patients for whom clinician discretion has a more prominent role.This retrospective cohort study of 12 310 Medicare beneficiaries used 100% Medicare Fee-for-Service administrative claims. Included patients had been admitted for heart failure from 2008 to 2014. Data were collected from July 2007 to December 2015 and analyzed from August 23, 2020, to May 15, 2022.Beneficiary race and sex.The propensity for LVAD implantation was based on clinical risk factors from the 6 months preceding HF admission using XGBoost and the synthetic minority oversampling technique. Beneficiaries with a 5% or greater probability of receiving an LVAD were included. Logistic regression models were estimated to measure associations of race and sex with LVAD receipt adjusting for clinical characteristics and social determinants of health (eg, distance from LVAD center, Medicare low-income subsidy, neighborhood deprivation). Next, 1-year mortality after LVAD was examined.The analytic sample included 12 310 beneficiaries, of whom 22.9% (n = 2819) were Black and 23.7% (n = 2920) were women. In multivariable models, Black beneficiaries were 3.0% (0.2% to 5.8%) less likely to receive LVAD than White beneficiaries, and women were 7.9% (5.6% to 10.2%) less likely to receive LVAD than men. Individual poverty and worse neighborhood deprivation were associated with reduced use, 2.9% (0.4% to 5.3%) and 6.7% (2.9% to 10.5%), respectively, but these measures did little to explain observed disparities. The racial disparity was concentrated among patients with a low propensity score (propensity score0.52). One-year survival by race and sex were similar on average, but Black patients with a low propensity score experienced improved survival (7.2% [95% CI, 0.9% to 13.5%]).In this cohort study of Medicare beneficiaries hospitalized for HF, disparities in LVAD use by race and sex existed and were not explained by clinical characteristics or social determinants of health. The treatment and post-LVAD survival by race were equivalent among the most obvious LVAD candidates. However, there was differential use and outcomes among less clear-cut LVAD candidates, with lower use but improved survival among Black patients. Inequity in LVAD access may have resulted from differences in clinician decision-making because of systemic racism and discrimination, implicit bias, or patient preference.

Failure to rescue (FTR), defined as death after a complication, is recognized as a principal driver of variation in mortality among hospitals. We evaluated FTR as a quality metric in patients who received durable left ventricular assist devices (LVADs) using the Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support.Data on 13,617 patients who received primary durable LVADs from April 2012 to October 2017 at 131 hospitals that performed at least 20 implants were analyzed from the Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support. Rates of major complications and FTR were compared across risk-adjusted in-hospital mortality terciles (low, medium, high) and hospital volume. Logistic regression was used to estimate expected FTR rates on the basis of patient factors for each major complication.The overall unadjusted in-hospital mortality rate was 6.96%. Risk-adjusted in-hospital mortality rates varied 3.1-fold across terciles (low, 3.3%; high, 10.3%; P trend.001). Rates of major complications varied 1.1-fold (low, 34.0%; high, 38.8%; P .0001). Among patients with a major complication, 854 died in-hospital for an FTR rate of 17.7%, with 2.8-fold variation across mortality terciles (low, 8.5%; high, 23.9%; P .0001). FTR rates were highest for renal dysfunction requiring dialysis (45.3%) and stroke (36.5%). Higher average annual LVAD volume was associated with higher rates of major complications (10 per year, 26.7%; 10-20 per year, 34.0%; 20-30 per year, 34.0%;30 per year, 40.1%; P trend.0001) whereas hospitals implanting10 per year had the highest FTR rate (10 per year, 23.5%; 10-20 per year, 16.5%; 20-30 per year, 17.0%;30 per year, 17.9%; P = .03).FTR might serve as an important quality metric for durable LVAD implant procedures, and identifying strategies for successful rescue after complications might reduce hospital variations in mortality.

Substantial effort is being invested in the creation of a virtual human — a model which will improve our understanding of human physiology and diseases and assist clinicians in the design of personalised medical treatments. A central challenge of achieving blood flow simulations at full-human scale is the development of an efficient and accurate approach to imposing boundary conditions on many outlets. A previous study proposed an efficient method for implementing the two-element Windkessel model to control the flow rate ratios at outlets. However, no study to date has examined the conditions for this approach to hold in complex geometries. Here we clarify the general role of the resistance and capacitance in this approach. We show that the error of the flow rate ratios decreases exponentially as the resistance increases. The errors fall below 4% in a simple five-outlets model and 7% in a human artery model comprising 10 outlets. Moreover, the flow rate ratios converge faster and suffer from weaker fluctuations as the capacitance decreases. Our findings also establish constraints on the parameters controlling the numerical stability of the simulations. The findings from this work are directly applicable to larger and more complex vascular domains encountered at full-human scale.

OBJECTIVE: The 23-valent pneumococcal polysaccharide vaccine is routinely recommended for adults with diabetes, but little is known about adherence to this recommendation and how vaccination of these adults affects costs related to pneumococcal disease. RESEARCH DESIGN AND METHODS: We used data from a commercial insurance claims dataset to examine a cohort of non-elderly adults with a new diagnosis of diabetes and adults with no diagnosis of diabetes from 2005–2014. We examined rates of pneumococcal polysaccharide vaccination and the relationship between vaccination and pneumococcal disease costs, comparing results for persons with a diagnosis of diabetes and those with no diagnosis of diabetes. RESULTS: Overall rates of pneumococcal polysaccharide vaccination among adults 30–60 years old were

During the COVID-19 pandemic, many primary care practices adopted telehealth in place of in-person care to preserve access to care for patients with acute and chronic conditions. The extent to which this change was associated with their rates of acute care visits (ie, emergency department visits and hospitalizations) for these conditions is unknown.To examine whether a primary care practice's level of telehealth use is associated with a change in their rate of acute care visits for ambulatory care-sensitive conditions (ACSC visits).This retrospective cohort analysis used a difference-in-differences study design to analyze insurance claims data from 4038 Michigan primary care practices from January 1, 2019, to September 30, 2020.Low, medium, or high tertile of practice-level telehealth use based on the rate of telehealth visits from March 1 to August 31, 2020, compared with prepandemic visit volumes.Risk-adjusted ACSC visit rates before (June to September 2019) and after (June to September 2020) the start of the COVID-19 pandemic, reported as an annualized average marginal effect. The study examined overall, acute, and chronic ACSC visits separately and controlled for practice size, in-person visit volume, zip code-level attributes, and patient characteristics.A total of nearly 1.5 million beneficiaries (53% female; mean [SD] age, 40 [22] years) were attributed to 4038 primary care practices. Compared with 2019 visit volumes, median telehealth use was 0.4% for the low telehealth tertile, 14.7% for the medium telehealth tertile, and 39.0% for the high telehealth tertile. The number of ACSC visits decreased in all tertiles, with adjusted rates changing from 24.3 to 14.9 per 1000 patients per year (low), 23.9 to 15.3 per 1000 patients per year (medium), and 27.5 to 20.2 per 1000 patients per year (high). In difference-in-differences analysis, high telehealth use was associated with a higher ACSC visit rate (2.10 more visits per 1000 patients per year; 95% CI, 0.22-3.97) compared with low telehealth practices; practices in the middle tertile did not differ significantly from the low tertile. No difference was found in ACSC visits across tertiles when acute and chronic ACSC visits were examined separately.In this cohort study that used a difference-in-differences analysis, the association between practice-level telehealth use and ACSC visits was mixed. High telehealth use was associated with a slightly higher overall ACSC visit rate than low telehealth practices. The association of telehealth with downstream care use should be closely monitored going forward.

There is increasing awareness of the importance of nutritional support in cancer treatment including the interaction with immunity. Immunonutrition is the provision of one or more nutrients (e.g. Vitamins A, D, or E, omega-3 fatty acids, arginine and glutamine) known to modulate immune function when given at levels above those normally encountered in the diet in order to support immune system function or modulate its activity, including control of inflammation. We reviewed the role of oral or enteral immunonutrition versus standard nutrition on infection and infection-related biomarkers in adult cancer patients undergoing chemotherapy.A systematic search of oral or enteral immunonutrition versus standard nutrition in adult cancer patients during chemotherapy with or without radiotherapy or haematopoietic stem cell transplant was conducted in MEDLINE, EMBASE and CENTRAL. The search was limited to randomised controlled trials. Our primary outcome was infectious episodes or immune-related biomarkers (e.g. immune cell numbers, inflammatory markers). Secondary outcomes included incidence of malnutrition or cachexia, non-infection related adverse events (AEs), rate of remission, survival, and delays or incomplete cycles of chemotherapy. Risk of bias was assessed using ROB 2.0 and study quality was assessed using CASP for RCTs.The search yielded seven studies involving 521 patients (261 immunonutrition, 260 control) for analysis. All studies enrolled patients with solid tumours (no haematological malignancies). Studies were heterogenous for cancer type (upper gastrointestinal, head and neck, pancreatic and lung), immunonutrient composition (omega-3 fatty acids, vitamin A, E, glutamine, arginine or nucleotides), delivery route (enteral nutrition or oral nutritional supplement) and control used. Intervention period ranged from 4 to 14 weeks. No study reported absolute number of infections. Three studies reported AEs including potential infectious episodes of febrile neutropenia, pneumonitis and mucositis with oral candidiasis. Some studies report a decrease in blood concentrations of CRP and TNF-α with immunonutrition.There is currently insufficient evidence to define a role for immunonutrition on infectious episodes during chemotherapy in adult cancer patients. Further well-defined studies that account for degree of malnutrition, dose, timing and duration of immunonutrition in specific well-defined cancer groups using a standardised outcome framework are needed.

Patients undergoing left ventricular assist device (LVAD) implantation are at risk for death and postoperative adverse outcomes. Interhospital variability and concordance of quality metrics were assessed using the Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs).A total of 22 173 patients underwent primary, durable LVAD implantation across 160 hospitals from 2012 to 2020, excluding hospitals performing10 implant procedures. Observed and risk-adjusted operative mortality rates were calculated for each hospital. Outcomes included operative and 90-day mortality, a composite of adverse events (operative mortality, bleeding, stroke, device malfunction, renal dysfunction, respiratory failure), and secondarily failure to rescue. Rates are presented as median (interquartile range [IQR]). Hospital performance was evaluated using observed-to-expected (O/E) ratios for mortality and the composite outcome.Interhospital variability existed in observed (median, 7.2% [IQR, 5.1%-9.6%]) mortality. The rates of adverse events varied across hospitals: major bleeding, 15.6% (IQR, 11.4%-22.4%); stroke, 3.1% (IQR, 1.6%-4.7%); device malfunction, 2.4% (IQR, 0.8%-3.7%); respiratory failure, 10.5% (IQR, 4.6%-15.7%); and renal dysfunction, 6.4% (IQR, 3.2%-9.6%). The O/E ratio for operative mortality varied from 0.0 to 6.1, whereas the O/E ratio for the composite outcome varied from 0.28 to 1.99. Hospital operative mortality O/E ratios were more closely correlated with the 90-day mortality O/E ratio (r = 0.74) than with the composite O/E ratio (r = 0.12).This study reported substantial interhospital variability in performance for hospitals implanting durable LVADs. These findings support the need to (1) report hospital-level performance (mortality, composite) and (2) undertake benchmarking activities to reduce unwarranted variability in outcomes.

The ability to visualize enzyme activity in a cell, tissue, or living organism can greatly enhance our understanding of the biological roles of that enzyme. While many aspects of cellular signaling are controlled by reversible protein phosphorylation, our understanding of the biological roles of the protein phosphatases involved is limited. Here, we provide an overview of progress toward the development of fluorescent probes that can be used to visualize the activity of protein phosphatases. Significant advances include the development of probes with visible and near-infrared (near-IR) excitation and emission profiles, which provides greater tissue and whole-animal imaging capabilities. In addition, the development of peptide-based probes has provided some selectivity for a phosphatase of interest. Key challenges involve the difficulty of achieving sufficient selectivity for an individual member of a phosphatase enzyme family and the necessity of fully validating the best probes before they can be adopted widely.

Background:Thirst is a sensation normally aroused by a lack of water and associated with a desire to drink more fluid.Aim:The aims of this brief review are twofold: (a) to summarize the thirst mechanism in how it is initiated and diminished, and (b) to describe techniques to assess human thirst accurately in a variety of situations.Discussion:Thirst is maintained via a feedback-controlled mechanism, regulated by central and peripheral factors, as well as social and psychological cues. Most studies of thirst have focused on the initiation of water intake and the neural mechanisms responsible for this vital behavior. Less attention has been paid to the stimuli and mechanisms that terminate a bout of drinking and limit fluid ingestion, such as oropharyngeal and gastric signals, coupled with osmotic sensations. Thirst perception is typically assessed by subjective ratings using a variety of questionnaires, rankings, or visual analog scales. However, the appropriate perceptual tool may not always be used for the correct assessment of thirst perception.Conclusions:In considering the many factors involved in thirst arousal and inhibition, similar questions need to be considered for the correct assessment of this ingestive behavior.

Modelling the thermodynamic and hydrodynamic interactions of suspended particles is a significant and ongoing numerical challenge. Addressing this is necessary in order to be able to fully model numerous industrial and scientific processes of practical interest. This paper describes extensions to a local and a non-local technique for the calculation of transient conjugate heat transfer within a lattice Boltzmann framework. The interface transition between phases in both methods has been incorporated via a partially saturated boundary condition that weights material properties and allows straight and curved boundaries to be captured. Transient and steady-state performance of the two methods has been compared using a number of static and dynamic problems to evaluate their suitability for modelling particle suspensions. In a number of the static tests the non-local method produced better results however for the dynamic cases the local method demonstrated more accurate behaviour.

The protein tyrosine phosphatase (PTP) family of enzymes includes many attractive therapeutic targets, such as those in the leukocyte common antigen-related (LAR) subfamily of receptor PTPs. Synthesis and PTP inhibitory activity of illudalic acid and its methyl ether are described, with a focus on selective inhibition of LAR PTP relative to a small collection of other representative PTPs. The synthesis comprises 16 steps and provides illudalic acid in up to 12% overall yield from neopentylene-fused benzoate 1 (20 steps from commercial materials). Illudalic acid dose-dependently (measured IC50 = 2.1 ± 0.2 μM) and time-dependently inhibits LAR consistent with previous reports of covalent binding. The kinetics of LAR inhibition by illudalic acid are consistent with a two-step mechanism in which the inhibitor and enzyme first interact noncovalently (KI = 130 ± 50 μM), followed by covalent ligation at a rate kinact = 1.3 ± 0.4 min-1. The kinact/KI ratio of 104 corresponds to a t∞1/2 of 0.5 min, as discussed herein. The phenol methyl ether of illudalic acid was found to be less potent in our dose-response assays (measured IC50 = 55 ± 6 μM) but more selective for LAR, with a weaker initial noncovalent interaction and faster covalent ligation of LAR as compared to illudalic acid itself. A truncated analogue of illudalic acid that lacks the neopentylene ring fusion was found to be devoid of significant activity under our assay conditions, in contrast to previous reports. These observations collectively help inform further development of illudalic acid analogues as potent and selective inhibitors of the LAR subfamily of tyrosine phosphatases.

Background Public reporting of transcatheter aortic valve replacement (TAVR) claims–based outcome measures is used to identify high‐ and low‐performing centers. Whether claims‐based TAVR outcomes can reliably be used for center‐level comparisons is unknown. In this study, we sought to evaluate center variability in claims‐based TAVR outcomes used in public reporting. Methods and Results The study sample included 119 554 Medicare beneficiaries undergoing TAVR between January 2014 and October 2018 based on procedure codes in 100% Medicare inpatient claims. Multivariable hierarchical logistic regression was used to estimate center‐specific adjusted rates and reliability (R) of 30‐day mortality, discharge not to home/self‐care, 30‐day stroke, and 30‐day readmission. Reliability was defined as the ratio of between‐hospital variation to the sum of the between‐ and within‐hospital variation. The median (interquartile range [IQR]) center‐level adjusted outcome rates were 3.1% (2.9%–3.4%) for 30‐day mortality, 41.4% (31.3%–53.4%) for discharge not to home, 2.5% (2.3%–2.7%) for 30‐day stroke, and 14.9% (14.4%–15.5%) for 30‐day readmission. Median reliability was highest for the discharge not to home measure (R=0.95; IQR, 0.94–0.97), followed by the 30‐day stroke (R=0.92; IQR, 0.87–0.94), 30‐day mortality (R=0.86; IQR, 0.81–0.91), and 30‐day readmission measures (R=0.42; IQR, 0.35–0.51). Across outcomes, there was an inverse relationship between center volume and measure reliability. Conclusions Claims‐based TAVR outcome measures for mortality, discharge not to home, and stroke were reliable measures for center‐level comparisons, but readmission measures were unreliable. Stakeholders should consider these findings when evaluating claims‐based measures to compare center‐level TAVR performance.

ImportanceNonadherence to buprenorphine may increase patient risk of opioid overdose and increase health care spending. Quantifying the impacts of nonadherence can help inform clinician practice and policy.ObjectiveTo estimate the association between buprenorphine treatment gaps, opioid overdose, and health care spending.Design, Setting, and ParticipantsThis longitudinal case-control study compared patient opioid overdose and health care spending in buprenorphine-treated months with treatment gap months. Individuals who were US Medicare fee-for-service beneficiaries diagnosed with opioid use disorder who received at least 1 two-week period of continuous buprenorphine treatment between 2010 and 2017 were included. Analysis took place between January 2010 and December 2017.InterventionsA gap in buprenorphine treatment in a month lasting more than 15 consecutive days.Main Outcomes and MeasuresOpioid overdose and total, medical, and drug spending (combined patient out-of-pocket and Medicare spending).ResultsOf 34 505 Medicare beneficiaries (17 927 [520%] male; 16 578 [48.1%] female; mean [SD] age, 49.5 [12.7] years; 168 [0.5%] Asian; 2949 [8.5%] Black; 2089 [6.0%] Hispanic; 266 [0.8%] Native American; 28 525 [82.7%] White; 508 [1.5%] other race), 11 524 beneficiaries (33.4%) experienced 1 or more buprenorphine treatment gaps. Treatment gap beneficiaries, compared with nontreatment gap beneficiaries, were more likely to be younger, be male, have a disability, and be Medicaid dual-eligible while less likely to be White, close to a buprenorphine prescriber, and treated with buprenorphine monotherapy (ie, buprenorphine hydrochloride). Beneficiaries were 2.89 (95% CI, 2.20-3.79) times more likely to experience an opioid overdose during buprenorphine treatment gap months compared with treated months. During treatment gap months, spending was $196.41 (95% CI, $110.53-$282.30) more than in treated months. Patients who continued to take buprenorphine dosages of greater than 8 mg/d and 16 mg/d were 2.61 and 2.84 times more likely to overdose in a treatment gap month, respectively, while patients taking buprenorphine dosages of 8 mg/d or less were 3.62 times more likely to overdose in a treatment gap month (maintenance of >16 mg/d: hazard ratio (HR), 2.64 [95% CI, 1.80-3.87]; maintenance of >8 mg/d: HR, 2.84 [95% CI, 2.13-3.78]; maintenance of ≤8 mg/d: HR, 3.62 [95% CI, 1.54-8.50]). Buprenorphine monotherapy was associated with greater risk of overdose and higher spending during treatment gaps months than buprenorphine/naloxone.Conclusions and RelevanceMedicare patients treated with buprenorphine between 2010 and 2017 had a lower associated opioid overdose risk and spending during treatment months than treatment gap months.

ImportanceIn 2020, the Centers for Medicare & Medicaid Services revised its national coverage determination, removing the requirement to obtain review from a Medicare-approved heart transplant center to implant a durable left ventricular assist device (LVAD) for bridge-to-transplant (BTT) intent at an LVAD-only center. The association between center-level transplant availability and access to heart transplant, the gold-standard therapy for advanced heart failure (HF), is unknown.ObjectiveTo investigate the association of center transplant availability with LVAD implant strategies and subsequent heart transplant following LVAD implant before the Centers for Medicare & Medicaid Services policy change.Design, Setting, and ParticipantsA retrospective cohort study of the Society of Thoracic Surgeons Intermacs multicenter US registry database was conducted from April 1, 2012, to June 30, 2020. The population included patients with HF receiving a primary durable LVAD.ExposuresLVAD center transplant availability (LVAD/transplant vs LVAD only).Main Outcomes and MeasuresThe primary outcomes were implant strategy as BTT and subsequent transplant by 2 years. Covariates that might affect listing strategy and outcomes were included (eg, patient demographic characteristics, comorbidities) in multivariable models. Parameters for BTT listing were estimated using logistic regression with center-level random effects and for receipt of a transplant using a Cox proportional hazards regression model with death as a competing event.ResultsThe sample included 22 221 LVAD recipients with a median age of 59.0 (IQR, 50.0-67.0) years, of whom 17 420 (78.4%) were male and 3156 (14.2%) received implants at LVAD-only centers. Receiving an LVAD at an LVAD/transplant center was associated with a 79% increased adjusted odds of BTT LVAD designation (odds ratio, 1.79; 95% CI, 1.35-2.38; P Conclusions and RelevanceReceiving an LVAD at an LVAD-transplant center was associated with increased odds of BTT intent at implant and subsequent transplant receipt for patients at 2 years. The findings of this study suggest that Centers for Medicare & Medicaid Services policy change may have the unintended consequence of further increasing inequities in access to transplant among patients at LVAD-only centers.

Highlights • Post-TAVR HRQOL shows more rapid short-term improvement than SAVR within trials. • Higher TAVR use requires better real-world TAVR/SAVR cost-effectiveness comparisons. • Wearable devices should be used in real-world settings to compare TAVR/SAVR HRQOL., Background Aortic stenosis is a prevalent valvular heart disease that is treated primarily by surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR), which are common treatments for addressing symptoms secondary to valvular heart disease. This narrative review article focuses on the existing literature comparing recovery and cost-effectiveness for SAVR and TAVR. Methods Major databases were searched for relevant literature discussing HRQOL and cost-effectiveness of TAVR and SAVR. We also searched for studies analyzing the use of wearable devices to monitor post-discharge recovery patterns. Results The literature focusing on quality-of-life following TAVR and SAVR has been limited primarily to single-center observational studies and randomized controlled trials. Studies focused on TAVR report consistent and rapid improvement relative to baseline status. Common HRQOL instruments (SF-36, EQ-5D, KCCQ, MLHFQ) have been used to document that TF-TAVR is advantageous over SAVR at 1-month follow-up, with the benefits leveling off following 1 year. TF-TAVR is economically favorable relative to SAVR, with estimated incremental cost-effectiveness ratio values ranging from $50,000 to $63,000/QALY gained. TA-TAVR has not been reported to be advantageous from an HRQOL or cost-effectiveness perspective. Conclusions While real-world experiences are less described, large-scale trials have advanced our understanding of recovery and cost-effectiveness of aortic valve replacement treatment strategies. Future work should focus on scalable wearable device technology, such as smartwatches and heart-rate monitors, to facilitate real-world evaluation of TAVR and SAVR to support clinical decision-making and outcomes ascertainment.

Background: MicroRNAs (miRNAs) are important regulators of molecular pathways in psychiatric disease. Here, we examine differential miRNAs expression in lymphoblastoid cell lines (LCLs) derived from 10 individuals with autism spectrum disorder (ASD) and compare them to seven typically developing unrelated age- and gender-matched controls and 10 typically developing siblings. Small RNAseq analysis identified miRNAs, and selected miRNAs were validated using quantitative real-time polymerase reaction (qRT-PCR). KEGG analysis identified target pathways, and selected predicted mRNAs were validated using qRT-PCR. Results: Small RNAseq analysis identified that multiple miRNAs differentiated ASD from unrelated controls and ASD from typically developing siblings, with only one, hsa-miR-451a_R-1, being in common. Verification with qRT-PCR showed that miR-320a differentiated ASD from both sibling and unrelated controls and that several members of the miR-181 family differentiated ASD from unrelated controls. Differential expression of AKT2, AKT3, TNF α and CamKinase II predicted by KEGG analysis was verified by qRT-PCR. Expression of CamKinase II βwas found to be correlated with the severity of stereotyped behavior of the ASD participants. Conclusions: This study provides insight into the mechanisms regulating molecular pathways in individuals with ASD and identifies differentiated regulated genes involved in both the central nervous system and the immune system.

Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP‐protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well‐defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2‐week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed in‐person at study initiation (day 1) and on days 3 and 5. APAP‐protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full‐length keratin 18 [K18], and total high‐mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP‐protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP‐protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short‐term administration of low‐dose APAP (650 mg twice per day, The safety of acetaminophen (APAP) use in cirrhosis is highly controversial. In this study, we compared novel, sensitive biomarkers of liver injury and pharmacokinetics between non‐cirrhotic and cirrhotic subjects with repeated APAP use over 5 days. There was no APAP‐induced liver damage in either group, but there was evidence of greater APAP‐protein binding and reduced APAP‐protein adduct clearance in the cirrhosis group that warrants caution and further study.

Importance The Epic Sepsis Model (ESM), a proprietary sepsis prediction model, is implemented at hundreds of US hospitals. The ESM’s ability to identify patients with sepsis has not been adequately evaluated despite widespread use. Objective To externally validate the ESM in the prediction of sepsis and evaluate its potential clinical value compared with usual care. Design, Setting, and Participants This retrospective cohort study was conducted among 27 697 patients aged 18 years or older admitted to Michigan Medicine, the academic health system of the University of Michigan, Ann Arbor, with 38 455 hospitalizations between December 6, 2018, and October 20, 2019. Exposure The ESM score, calculated every 15 minutes. Main Outcomes and Measures Sepsis, as defined by a composite of (1) the Centers for Disease Control and Prevention surveillance criteria and (2)International Statistical Classification of Diseases and Related Health Problems, Tenth Revisiondiagnostic codes accompanied by 2 systemic inflammatory response syndrome criteria and 1 organ dysfunction criterion within 6 hours of one another. Model discrimination was assessed using the area under the receiver operating characteristic curve at the hospitalization level and with prediction horizons of 4, 8, 12, and 24 hours. Model calibration was evaluated with calibration plots. The potential clinical benefit associated with the ESM was assessed by evaluating the added benefit of the ESM score compared with contemporary clinical practice (based on timely administration of antibiotics). Alert fatigue was evaluated by comparing the clinical value of different alerting strategies. Results We identified 27 697 patients who had 38 455 hospitalizations (21 904 women [57%]; median age, 56 years [interquartile range, 35-69 years]) meeting inclusion criteria, of whom sepsis occurred in 2552 (7%). The ESM had a hospitalization-level area under the receiver operating characteristic curve of 0.63 (95% CI, 0.62-0.64). The ESM identified 183 of 2552 patients with sepsis (7%) who did not receive timely administration of antibiotics, highlighting the low sensitivity of the ESM in comparison with contemporary clinical practice. The ESM also did not identify 1709 patients with sepsis (67%) despite generating alerts for an ESM score of 6 or higher for 6971 of all 38 455 hospitalized patients (18%), thus creating a large burden of alert fatigue. Conclusions and Relevance This external validation cohort study suggests that the ESM has poor discrimination and calibration in predicting the onset of sepsis. The widespread adoption of the ESM despite its poor performance raises fundamental concerns about sepsis management on a national level.

Electronic health records (EHRs) adoption has become nearly universal during the past decade. Academic research into the effects of EHRs has examined factors influencing adoption, clinical care benefits, financial and cost implications, and more. We provide an interdisciplinary overview and synthesis of this literature, drawing on work in public and population health, informatics, medicine, management information systems, and economics. We then chart paths forward for policy, practice, and research.

Background Osteoporosis, an indicator of significant bone loss, has been consistently reported among older breast cancer survivors. Data are limited on the incidence of osteopenia, an earlier indicator of bone loss, and osteoporosis in younger breast cancer survivors compared with cancer-free women. Methods We prospectively examined bone loss in 211 breast cancer survivors (mean age at breast cancer diagnosis = 47 years) compared with 567 cancer-free women in the same cohort with familial risk for breast cancer. Multivariable-adjusted Cox proportional hazards models were used to estimate HRs and 95% CIs of osteopenia and/or osteoporosis incidence based on physician diagnosis. Results During a mean follow-up of 5.8 years, 66% of breast cancer survivors and 53% of cancer-free women reported having a bone density examination, and 112 incident cases of osteopenia and/or osteoporosis were identified. Breast cancer survivors had a 68% higher risk of osteopenia and osteoporosis compared to cancer-free women (HR = 1.68, 95% CI = 1.12–2.50). The association was stronger among recent survivors after only 2 years of follow-up (HR = 2.74, 95% CI = 1.37–5.47). A higher risk of osteopenia and osteoporosis was also observed among survivors aged ≤ 50 years, estrogen receptor-positive tumors, and those treated with aromatase inhibitors alone or chemotherapy plus any hormone therapy relative to cancer-free women. Conclusions Younger breast cancer survivors are at higher risk for osteopenia and osteoporosis compared to cancer-free women. Studies are needed to determine effective approaches to minimize bone loss in this population.

Although the current wide-scale adoption of the HeartMate 3 left ventricular assist device can be attributed to favorable clinical trial outcomes, restrictive clinical trial eligibility criteria may result in lack of generalizability to real-world populations. We assessed the generalizability of left ventricular assist device clinical trial outcomes and evaluated the prognostic value of specific inclusion and exclusion criteria.The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Therapy With HeartMate 3 (MOMENTUM 3) eligibility criteria were applied to patients identified in The Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) who underwent HeartMate 3 implantation (n = 4610) between August 2017 and March 2020. Patients were categorized as trial-eligible or trial-ineligible and by number of ineligibility criteria. The effect of trial eligibility on mortality was estimated using Cox models.Indications for HeartMate 3 implant included destination therapy (n = 2827, 61%), bridge to candidacy (n = 969, 21%), and bridge to transplant (n = 702, 15%). A total of 1941 recipients (42%) were trial-ineligible, with 1245 (27%) meeting one ineligibility criterion, 470 (10%) meeting two, and 226 (5%) meeting three or more. Estimated 1-year mortality for trial-ineligible recipients was higher than for trial-eligible recipients (17% ± 1% vs 10% ± 1%, P.001). Compared with trial-eligible patients, 1-year mortality was incrementally higher for patients meeting one ineligibility criterion (15% ± 1%), two criteria (16% ± 2%), and three or more criteria (30% ± 3%). Thrombocytopenia and elevated creatinine, bilirubin, and international normalized ratio in trial-ineligible patients were independently associated with increased mortality.Despite differences in mortality, both trial-eligible and trial-ineligible HeartMate 3 recipients had excellent outcomes in real-world practice, suggesting future trial eligibility criteria could be expanded.

We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and N-acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model., Graphical abstract Exogenous phosphatidic acid (PA) increases interleukin-6 (IL-6) production in peripheral adipose tissue. The IL-6 then enters circulation and signals to the liver to reduce early acetaminophen (APAP)-induced liver injury.Image 1

The Conference on Health IT and Analytics (CHITA) is an annual health information technology and analytics research summit, including a doctoral consortium that each year gathers prominent scholars from more than 40 research institutes, and leading policy and practitioner attendees in a vibrant setting to discuss opportunities and challenges in the design, implementation and management of health information technologies and advanced analytics including artificial intelligence and machine learning systems. CHITA’s goal is to deepen our understanding of strategy, policy and systems fostering health IT and analytics effective use, to stimulate new ideas with both policy and business implications, and to support the development of a health IT and healthcare advanced analytics research agenda. These Proceedings of the 11th Conference on Health IT & Analytics (CHITA 2020) represent the work of 45 papers and 146 authors working on the digitally-enabled future of healthcare. Convened by the Center for Health Information & Decision Systems (CHIDS), support for CHITA is provided by the Robert H. Smith School of Business, the University of Michigan School of Public Health, and the U.S. Agency for Healthcare Research and Quality.

Research Objective The COVID‐19 pandemic forced a dramatic shift from in‐person care to telehealth, with an overall decrease in outpatient utilization. These changes particularly stressed outpatient care delivery and may have resulted in decreased availability and access to primary care for patients, potentially increasing otherwise avoidable emergency department (ED) visits and hospitalizations. One commonly used indicator of primary care access and quality is acute care visits for ambulatory care‐sensitive conditions (ACSCs), such as for pneumonia, uncontrolled diabetes, or congestive heart failure exacerbations. Our study examined differences in telehealth adoption across practices and evaluated the association between telehealth adoption and ACSC visits. TABLE 1 Differences‐in‐differences model of practice telemedicine conversion rate on acute care visits for acute and chronic ACSCs Acute ACSC aOR (95% CI) Chronic ACSC aOR (95% CI) Telemedicine tertile (mean telemedicine conversion rate) Low (9%) ref ref Medium (30%) 0.98 (0.91–1.07) 0.98 (0.76–1.26) High (66%) 1.07 (0.98–1.17) 1.14 (0.86–1.50) Study Design We conducted a retrospective study of claims data from a large commercial insurer in Michigan. We first profiled telehealth adoption by primary care practices during March–July 2020. We defined a practice's “telehealth conversion rate” as the proportion of visits conducted via telehealth during this period compared to the total number of visits during the same period in 2019. Then, to enable comparison between groups at a time when both outpatient and acute care visits were in flux, we used a differences‐in‐differences (DID) model to determine whether varying levels of primary care telehealth conversion were associated with differences in acute care visits (ED visits and hospitalizations) for ACSCs from June–September 2020. We examined visit rates for acute and chronic ACSCs separately, controlling for practice size, in‐person visit volume, and zip code‐level attributes as well as patient characteristics (age, gender, comorbidities). We performed sensitivity analyses using varying definitions of telemedicine conversion rates and multiple model specifications. Population Studied Six million Blue Cross Blue Shield of Michigan beneficiaries across 3780 primary care practices from January 2019 to September 2020. Principal Findings Average primary care practice telehealth conversion rate was 25% (median 10%), and 29% of practices had no telehealth claims identified. Practices that did not adopt telehealth tended to be smaller and were more likely to be in rural areas. We found no significant differences in the rate of ED visits and hospitalizations for ACSCs by practice‐level telemedicine conversion tertile after adjusting for practice case‐mix, as shown in Table 1. Sensitivity analyses showed similar results. Conclusions Beneficiaries within a large commercial payer experienced rapid shifts from in‐person to telehealth for their primary care, though telehealth adoption was not evenly distributed, with smaller and more rural practices being less likely to adopt telemedicine. These changes did not seem to obviously help or harm patients as ED visits and hospitalizations for ACSCs were similar across groups. Implications for Policy or Practice Widespread substitution of telehealth for in‐person care had little impact on cost of care with respect to avoidable ED visits and hospitalizations in the near‐term. Additional research should continue to monitor this trend as health care utilization stabilizes beyond the pandemic. Primary Funding Source University of Michigan Institute for Health Policy and Innovation.

Background and aim Acetaminophen (APAP) overdose is a major cause of acute liver injury, but the role of macrophages in the propagation of the hepatotoxicity is controversial. Early research revealed that macrophage inhibitors protect against APAP injury. However, later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate (LC) exacerbates the toxicity. To our surprise, during other studies, we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity, in contrast to acute pre-treatment. The aim of this study was to confirm that observation and to explore the mechanisms. Methods We treated mice with empty liposomes (LE) or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0, 2, and 6 h post-APAP. We then measured liver injury (serum alanine aminotransferase activity, histology), APAP bioactivation (total glutathione, APAP-protein adducts), oxidative stress (oxidized glutathione (GSSG)), glutamate-cysteine ligase subunit c (Gclc) mRNA, and nuclear factor erythroid 2-related factor (Nrf2) immunofluorescence. We also confirmed the ablation of macrophages by F4/80 immunohistochemistry. Results Pre-treatment twice with LC dramatically reduced F4/80 staining, protected against liver injury, and reduced oxidative stress at 6 h post-APAP, without affecting APAP bioactivation. Importantly, Gclc mRNA was higher in the LC group at 0 h and total glutathione was higher at 2 h, indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine ligase. Oxidative stress was lower in the LC groups at both time points. Finally, total Nrf2 immunofluorescence was higher in the LC group. Conclusions We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase. Investigators using twice or possibly more LC pre-treatments to deplete macrophages, including peritoneal macrophages, should be aware of this possible confounder.

Proceedings of the 10th Conference on Health IT & Analytics (CHITA 2019). CHITA is an annual health IT and analytics research summit, including a doctoral consortium that each year gathers prominent scholars from more than 40 research institutes, and leading policy and practitioner attendees in a vibrant setting to discuss opportunities and challenges in the design, implementation and management of health information technology, artificial intelligence and advanced analytics. Its goal is to deepen our understanding of strategy, policy and systems fostering health IT and analytics effective use and to stimulate new research ideas with both policy and business implications. This forum provides a productive venue to facilitate interaction and collaboration among academia, government, and industry. Now in its tenth year, each year CHITA draws over 100 participants. Convened by the Center for Health Information & Decision Systems (CHIDS), support for CHITA is provided by the Robert H. Smith School of Business, the University of Michigan School of Public Health, and the U.S. Agency for Healthcare Research and Quality.

An arteriovenous fistula, created by artificially connecting segments of a patient’s vasculature, is the preferred way to gain access to the bloodstream for kidney dialysis. The increasing power and availability of supercomputing infrastructure means that it is becoming more realistic to use simulations to help identify the best type and location of a fistula for a specific patient. We describe a 3D fistula model that uses the lattice Boltzmann method to simultaneously resolve blood flow in patient-specific arteries and veins. The simulations conducted here, comprising vasculatures of the whole forearm, demonstrate qualified validation against clinical data. Ongoing research to further encompass complex biophysics on realistic time scales will permit the use of human-scale physiological models for basic and clinical medicine.

Objective To assess whether an electronic health record (EHR) portal to enable health information exchange (HIE) between a hospital and three skilled nursing facilities (SNFs) reduced likelihood of patient readmission. Setting/data Secondary data; all discharges from a large academic medical center to SNFs between July 2013 and March 2017, combined with portal usage records from SNFs with HIE access. Design We use difference-in-differences to determine whether portal implementation reduced likelihood of readmission over time for patients discharged to HIE-enabled SNFs, relative to those discharged to nonenabled facilities. Additional descriptive analyses of audit log data characterize portal use within enabled facilities. Data collection Encounter-level clinical EHR data were merged with EHR audit log data that captured portal usage in the timeframe associated with a patient transition from hospital to SNF. Principal findings Declines in likelihood of 30-day readmission were not significantly different for patients in HIE-enabled vs control SNFs (diff-in-diff = 0.022; P = .431). We observe similar null effects with shorter readmission windows. The portal was used for 46 percent of discharges, with significant usage pattern variation within/across facilities. Conclusions Implementation of a hospital-SNF EHR portal did not reduce readmissions from enabled SNFs. Emergent HIE use cases need to be better defined and leveraged for design and implementation that generates value in the context of postacute transitions.

In order to obtain a detailed kinetic characterization, identify inhibitors, and elucidate the biological roles of an enzyme, it is advantageous to have a facile, sensitive enzyme assay protocol. Here we present a brief overview of the techniques available to monitor histidine phosphatase activity and provide protocols for measuring the activity and inhibition of PHPT1 in vitro using the fluorescent probe 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP). This assay uses small quantities of commercially available materials, making its use feasible for most laboratories.

Although the importance of protein histidine phosphorylation in mammals has been a subject of increasing interest, few chemical probes are available for monitoring and manipulating PHP activity. Here, we present an optimized and validated protocol for assaying the activity of PHPT1 using the fluorogenic substrate DiFMUP. The kinetic parameters of our optimized assay are significantly improved as compared with other PHPT1 assays in the literature, with a kcat of 0.39 ± 0.02 s–1, a Km of 220 ± 30 μM, and a kcat/Km of 1800 ± 200 M–1 s–1. In addition, the assay is significantly more sensitive as a result of using a fluorescent probe, requiring only 109 nM enzyme as compared with 2.4 μM as required by previously published assays. In the process of assay optimization, we discovered that PHPT1 is sensitive to a reducing environment and inhibited by transition-metal ions, with one apparent Cu(II) binding site with IC50 value of 500 ± 20 μM and two apparent Zn(II) binding sites with IC50 values of 25 ± 1 and 490 ±...

Introduction Experiential pharmacy preceptors should provide formative and summative feedback during a learning experience. Preceptors are required to provide colleges and schools of pharmacy with assessments or evaluations of students’ performance. Students and experiential programs value on-time completion of midpoint evaluations by preceptors. The objective of this study was to determine the number of on-time electronically documented formative midpoint evaluations completed by preceptors during advanced pharmacy practice experiences (APPEs). Methods Compliance rates of on-time electronically documented formative midpoint evaluations were reviewed by the Office of Experiential Education of a five-member consortium during the two-year study period prior to the adoption of Standards 2016. Pearson chi-square test and generalized linear models were used to determine if statistically significant differences were present. Results Average midpoint compliance rates for the two-year research period were 40.7% and 41% respectively. No statistical significance was noted comparing compliance rates for year one versus year two. However, statistical significance was present when comparing compliance rates between schools during year two. Feedback from students and preceptors pointed to the need for brief formal midpoint evaluations that require minimal time to complete, user friendly experiential management software, and methods for documenting verbal feedback through student self-reflection. Conclusions Additional education and training to both affiliate and faculty preceptors on the importance of written formative feedback at midpoint is critical to remaining in compliance with Standards 2016.

ObjectiveThe federal electronic health record (EHR) certification process was intended to ensure a baseline level of system quality and the ability to support meaningful use criteria. We sought to assess whether there was variation across EHR vendors in the degree to which hospitals using products from those vendors were able to achieve high levels of performance on meaningful use criteria.Materials and MethodsWe created a cross-sectional national hospital sample from the Office of the National Coordinator for Health Information Technology EHR Products Used for Meaningful Use Attestation public use file and the Centers for Medicare & Medicaid Services Medicare EHR Incentive Program Eligible Hospitals public use file. We used regression models to assess the relationship between vendor and hospital performance on 6 Stage 2 Meaningful Use criteria, controlling for hospital characteristics. We also calculated how much variation in performance is explained by vendor choice.ResultsWe found significant associations between specific vendor and level of hospital performance for all 6 meaningful use criteria. Epic was associated with significantly higher performance on 5 of the 6 criteria; relationships for other vendors were mixed, with some associated with significantly worse performance on multiple criteria. EHR vendor choice accounted for between 7% and 34% of performance variation across the 6 criteria.DiscussionA nontrivial proportion of variation in hospital meaningful use performance is explained by vendor choice, and certain vendors are more often associated with better meaningful use performance than others. Our results suggest that policy-makers should improve the certification process by including more “real-world” scenario testing and provider feedback or ratings to reduce this variation. Hospitals can use these results to guide interactions with vendors.ConclusionVendor choice accounts for a meaningful proportion of variation in hospital meaningful use performance, and specific vendors are consistently associated with higher or lower performance across criteria.

Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) Hep-aRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6–559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

We investigate determinants of market entry and premiums within the context of the Affordable Care Act's Marketplaces for individual insurance. Using Bresnahan and Reiss (1991) as the conceptual framework, we study how competition and firm heterogeneity relate to premiums in 36 states using Federally Facilitated or Supported Marketplaces in 2016. Our primary data source is the Qualified Health Plan Landscape File, augmented with market characteristics from the American Community Survey and Area Health Resource File as well as insurer-level information from federal Medical Loss Ratio annual reports. We first estimate a model of insurer entry and then investigate the relationship between a market's predicted number of entrants and insurer-level premiums. Our entry model results suggest that competition is increasing with the number of insurers, most notably as the market size increases from 3 to 4 entrants. Results from the premium regression suggest that each additional entrant is associated with approximately 4% lower premiums, controlling for other factors. An alternative explanation for the relationship between entrants and premiums is that more efficient insurers (who can price lower) are the ones that enter markets with many entrants, and this is reflected in lower premiums. An exploratory analysis of insurers' non-claims costs (a proxy for insurer efficiency) reveals that average costs among entrants are rising slightly with the number of insurers in the market. This pattern does not support the hypothesis that premiums decrease with more entrants because those entrants are more efficient, suggesting instead that the results are being driven mostly by price competition.