Multiscale biophysical analysis of nucleolus disassembly during mitosis.

During cell division, precise and regulated distribution of cellular material between daughter cells is a critical step and is governed by complex biochemical and biophysical mechanisms. To achieve this, membraneless organelles and condensates often require complete disassembly during mitosis. The biophysical principles governing the disassembly of condensates remain poorly understood. Here, we used a physical biology approach to study how physical and material properties of the nucleolus, a prominent nuclear membraneless organelle in eukaryotic cells, change during mitosis and across different scales. We found that nucleolus disassembly proceeds continuously through two distinct phases with a slow and reversible preparatory phase followed by a rapid irreversible phase that was concurrent with the nuclear envelope breakdown. We measured microscopic properties of nucleolar material including effective diffusion rates and binding affinities as well as key macroscopic properties of surface tension and bending rigidity. By incorporating these measurements into the framework of critical phenomena, we found evidence that near mitosis surface tension displays a power-law behavior as a function of biochemically modulated interaction strength. This two-step disassembly mechanism maintains structural and functional stability of nucleolus while enabling its rapid and efficient disassembly in response to cell cycle cues.

Designing Retirement Strategies for Coal-Fired Power Plants To Mitigate Air Pollution and Health Impacts.

Retiring coal power plants can reduce air pollution and health damages. However, the spatial distribution of those impacts remains unclear due to complex power system operations and pollution chemistry and transport. Focusing on coal retirements in Pennsylvania (PA), we analyze six counterfactual scenarios for 2019 that differ in retirement targets (e.g., reducing 50% of coal-based installed capacity vs generation) and priorities (e.g., closing plants with higher cost, closer to Environmental Justice Areas, or with higher CO2 emissions). Using a power system model of the PJM Interconnection, we find that coal retirements in PA shift power generation across PA and Rest of PJM, leading to scenario-varying changes in the plant-level release of air pollutants. Considering pollution transport and the size of the exposed population, these emissions changes, in turn, give rise to a reduction of 6-136 PM2.5-attributable deaths in PJM across the six scenarios, with most reductions occurring in PA. Among our designed scenarios, those that reduce more coal power generation yield greater aggregate health benefits due to air quality improvements in PA and adjacent downwind regions. In addition, comparing across the six scenarios evaluated in this study, vulnerable populations─in both PA and Rest of PJM─benefit most in scenarios that prioritize plant closures near Environmental Justice Areas in PA. These results demonstrate the importance of considering cross-regional linkages and sociodemographics in designing equitable retirement strategies.

Comparative Analysis of Inpatient Costs for Obstetrics and Gynecology Surgery Patients Treated With IV Acetaminophen and IV Opioids Versus IV Opioid-only Analgesia for Postoperative Pain.

BACKGROUND: Recovery from obstetrics and gynecology (OB/GYN) surgery, including hysterectomy and cesarean section delivery, aims to restore function while minimizing hospital length of stay (LOS) and medical expenditures. OBJECTIVE: Our analyses compare OB/GYN surgery patients who received combination intravenous (IV) acetaminophen and IV opioid analgesia with those who received IV opioid-only analgesia and estimate differences in LOS, hospitalization costs, and opioid consumption. METHODS: We performed a retrospective analysis of the Premier Database between January 2009 and June 2015, comparing OB/GYN surgery patients who received postoperative pain management with combination IV acetaminophen and IV opioids with those who received only IV opioids starting on the day of surgery and continuing up to the second postoperative day. We performed instrumental variable 2-stage least-squares regressions controlling for patient and hospital covariates to compare the LOS, hospitalization costs, and daily opioid doses (morphine equivalent dose) of IV acetaminophen recipients with that of opioid-only analgesia patients. RESULTS: We identified 225 142 OB/GYN surgery patients who were eligible for our study of whom 89 568 (40%) had been managed with IV acetaminophen and opioids. Participants averaged 36 years of age and were predominantly non-Hispanic Caucasians (60%). Multivariable regression models estimated statistically significant differences in hospitalization cost and opioid use with IV acetaminophen associated with $484.4 lower total hospitalization costs (95% CI = -$760.4 to -$208.4; P = 0.0006) and 8.2 mg lower daily opioid use (95% CI = -10.0 to -6.4), whereas the difference in LOS was not significant, at -0.09 days (95% CI = -0.19 to 0.01; P = 0.07). CONCLUSION: Compared with IV opioid-only analgesia, managing post-OB/GYN surgery pain with the addition of IV acetaminophen is associated with decreased hospitalization costs and reduced opioid use.

Crystallization kinetics of binary colloidal monolayers.

Experiments and simulations are used to study the kinetics of crystal growth in a mixture of magnetic and nonmagnetic particles suspended in ferrofluid. The growth process is quantified using both a bond order parameter and a mean domain size parameter. The largest single crystals obtained in experiments consist of approximately 1000 particles and form if the area fraction is held between 65-70% and the field strength is kept in the range of 8.5-10.5 Oe. Simulations indicate that much larger single crystals containing as many as 5000 particles can be obtained under impurity-free conditions within a few hours. If our simulations are modified to include impurity concentrations as small as 1-2%, then the results agree quantitatively with the experiments. These findings provide an important step toward developing strategies for growing single crystals that are large enough to enable follow-on investigations across many subdisciplines in condensed matter physics.

Electrochemical evidence for intermolecular proton-coupled electron transfer through a hydrogen bond complex in a p-phenylenediamine-based urea. Introduction of the "wedge scheme" as a useful means to describe reactions of this type.

The electrochemistry of several p-phenylenediamine derivatives, in which one of the amino groups is part of an urea functional group, has been investigated in methylene chloride and acetonitrile. The ureas are abbreviated U(R)R', where R' indicates the substituent on the N that is part of the phenylenediamine redox couple and R indicates the substituent on the other urea N. Cyclic voltammetry and UV-vis spectroelectrochemical studies indicate that U(Me)H and U(H)H undergo an apparent 1e(-) oxidation that actually corresponds to 2e(-) oxidation of half the ureas to a quinoidal-diimine cation, U(R)(+). This is accompanied by proton transfer to the other half of the ureas to make the electroinactive cation HU(R)H(+). This explains the observed irreversibility of the oxidation of U(Me)H in both solvents and U(H)H in acetonitrile. However, the oxidation of U(H)H in methylene chloride is reversible at higher concentrations and slower scan rates. Several lines of evidence suggest that the most likely reason for this is the accessibility of a H-bond complex between U(H)(+) and HU(H)H(+) in methylene chloride. Reduction of the H-bond complex occurs at a less negative potential than that of U(H)(+), leading to reversible behavior. This conclusion is strongly supported by the appearance of a more negative reduction peak at lower concentrations and faster scan rates, conditions in which the H-bond complex is less favored. The overall reaction mechanism is conveniently described by a "wedge scheme", which is a more general version of the square scheme typically used to describe redox processes in which proton transfer accompanies electron transfer.

The Physical Biology of Nucleolus Disassembly.

During cell division, precise and regulated distribution of cellular material between daughter cells is a critical step and is governed by complex biochemical and biophysical mechanisms. To achieve this, membraneless organelles and condensates often require complete disassembly during mitosis. The biophysical principles governing the disassembly of condensates remain poorly understood. Here, we used a physical biology approach to study how physical and material properties of the nucleolus, a prominent nuclear membraneless organelle in eukaryotic cells, change during mitosis and across different scales. We found that nucleolus disassembly proceeds continuously through two distinct phases with a slow and reversible preparatory phase followed by a rapid irreversible phase that was concurrent with the nuclear envelope breakdown. We measured microscopic properties of nucleolar material including effective diffusion rates and binding affinities as well as key macroscopic properties of surface tension and bending rigidity. By incorporating these measurements into the framework of critical phenomena, we found evidence that near mitosis surface tension displays a power-law behavior as a function of biochemically modulated interaction strength. This two-step disassembly mechanism, which maintains structural and functional stability of nucleolus while allowing for its rapid and efficient disassembly in response to cell cycle cues, may be a universal design principle for the disassembly of other biomolecular condensates.

Interneuron Dysfunction in a New Mouse Model of SCN1A GEFS.

Advances in genome sequencing have identified over 1300 mutations in the SCN1A sodium channel gene that result in genetic epilepsies. However, it still remains unclear how most individual mutations within SCN1A result in seizures. A previous study has shown that the K1270T (KT) mutation, linked to genetic epilepsy with febrile seizure plus (GEFS+) in humans, causes heat-induced seizure activity associated with a temperature-dependent decrease in GABAergic neuron excitability in a Drosophila knock-in model. To examine the behavioral and cellular effects of this mutation in mammals, we introduced the equivalent KT mutation into the mouse (Mus musculus) Scn1a (Scn1aKT) gene using CRISPR/Cas9 and generated mutant lines in two widely used genetic backgrounds: C57BL/6NJ and 129X1/SvJ. In both backgrounds, mice homozygous for the KT mutation had spontaneous seizures and died by postnatal day (P)23. There was no difference in mortality of heterozygous KT mice compared with wild-type littermates up to six months old. Heterozygous mutants exhibited heat-induced seizures at ∼42°C, a temperature that did not induce seizures in wild-type littermates. In acute hippocampal slices at permissive temperatures, current-clamp recordings revealed a significantly depolarized shift in action potential threshold and reduced action potential amplitude in parvalbumin (PV)-expressing inhibitory CA1 interneurons in Scn1aKT/+ mice. There was no change in the firing properties of excitatory CA1 pyramidal neurons. These results suggest that a constitutive decrease in inhibitory interneuron excitability contributes to the seizure phenotype in the mouse model.

The burden of illness of hepatorenal syndrome (HRS) in the United States: a retrospective analysis of electronic health records.

OBJECTIVES: Hepatorenal Syndrome (HRS) is characterized by renal failure in patients with advanced chronic liver disease (CLD) and is the leading cause of hospitalizations in CLD. This study examines the clinical and economic burden, outcomes, and unmet need of HRS treatment in US hospitals. METHOD: A retrospective cohort study was conducted based on a large electronic health records database (Cerner HealthFacts) with records for hospitalized HRS patients from January 2009-June 2015. Demographics, clinical characteristics, treatment patterns, and economic outcomes were analyzed. Prognostic indicators of cirrhosis, kidney injury, end-stage liver disease, and acute-on-chronic liver failure were used to determine mortality risk. RESULTS: A total of 2,542 patients hospitalized with HRS were identified (average age = 57.9 years, 61.8% males, 74.2% Caucasian), with an average total hospital charge of $91,504 per patient and a mean length of stay (LOS) of 30.5 days. The mortality rate was 36.9% with 8.9% of patients discharged to hospice. Of all patients, 1,660 patients had acute kidney injury, 859 with Stage 3 disease, and 26.7% had dialysis. The 30-day readmission rate was 33.1%, 41% of which were unplanned. Nearly one-third of study patients had commercial insurance (30.2%), followed by Medicare (29.9%); hospital charges varied by LOS, receipt of dialysis, and discharge status. Regression analysis demonstrated that HRS costs are associated with LOS, dialysis, and hospital mortality. CONCLUSION: HRS is associated with poor outcomes and high hospital costs. Analysis of HRS cost drivers demonstrated an unmet need for additional treatment options to improve outcomes in this patient population.

The Burden of Hypoxic Respiratory Failure in Preterm and Term/Near-term Infants in the United States 2011-2015.

OBJECTIVES: This study quantified the burden of hypoxic respiratory failure (HRF)/persistent pulmonary hypertension of newborn (PPHN) in preterm and term/near-term infants (T/NTs) by examining health care resource utilization (HRU) and charges in the United States. METHODS: Preterms and T/NTs (≤34 and >34 weeks of gestation, respectively) having HRF/PPHN, with/without meconium aspiration in inpatient setting from January 1, 2011-October 31, 2015 were identified from the Vizient database (first hospitalization=index hospitalization). Comorbidities, treatments, HRU, and charges during index hospitalization were evaluated among preterms and T/NTs with HRF/PPHN. Logistic regression was performed to evaluate mortality-related factors. RESULTS: This retrospective study included 504 preterms and 414 T/NTs with HRF/PPHN. Preterms were more likely to have respiratory distress syndrome, neonatal jaundice, and anemia of prematurity than T/NTs. Preterms had significantly longer inpatient stays (54.1 vs 29.0 days), time in a neonatal intensive care unit (34.1 vs 17.5 days), time on ventilation (4.7 vs 2.2 days), and higher total hospitalization charges ($613 350 vs $422 558) (all P<0.001). Similar rates were observed for use of antibiotics (96.2% vs 95.4%), sildenafil (9.5% vs 8.2%), or inhaled nitric oxide (93.8% vs 94.2%). Preterms had a significantly higher likelihood of mortality than T/NTs (odds ratio: 3.6, 95% confidence interval: 2.3-5.0). CONCLUSIONS: The findings of more severe comorbidities, higher HRU, hospitalization charges, and mortality in preterms than in T/NTs underscore the significant clinical and economic burden of HRF/PPHN among infants. The results show significant unmet medical need; further research is warranted to determine new treatments and real-world evidence for improved patient outcomes.

Intravenous Acetaminophen May Be Associated with Reduced Odds of 30-Day Readmission after Total Knee Arthroplasty.

The purpose of this study was (1) to evaluate 30-day readmission rates in total knee arthroplasty (TKA) patients who either received intravenous (IV) or oral (PO) acetaminophen (APAP) perioperatively and (2) to extrapolate the potential annual cost savings on the national level. This was a review of 190,691 TKA recipients between the years 2012 and 2015 who received either IV (n = 56,475) or PO APAP (n = 134,216). All-cause readmissions that occurred between patient discharge and 30 days postdischarge were recorded. Continuous and categorical variables were evaluated using t-test and chi-square test, respectively. A logistic regression analysis was conducted to assess the effect of IV APAP on 30-day readmission. We also performed a literature review on 30-day readmission rates and risk prediction tools for TKA and correlated these with our findings. In addition, we extrapolated potential cost savings on the national level. The readmission rate was 0.04% in the IV and 0.14% in the PO APAP cohort (69% decreased risk; odds ratio = 0.31; 95% confidence interval = 0.20-0.47; p < 0.001). The readmission rate in this patient population appears to be markedly lower, when compared with previous reports. This reduction in readmissions may potentially result in $160 million savings per year. The use of IV APAP in TKA patients resulted in lower readmission rates, which may be valuable in clinical decision making by surgeons and health care administrators looking to lower costs of care.

Analysis of predictors of opioid-free analgesia for management of acute post-surgical pain in the United States.

OBJECTIVES: Utilization of opioid-free analgesia (OFA) for post-surgical pain is a growing trend to counter the risks of opioid abuse and opioid-related adverse drug events (ORADEs). However, utilization patterns of OFA have not been examined. In this study, we investigated the utilization patterns and predictors of OFA in a surgical population in the United States. METHODS: Analysis of the Cerner Health Facts database (January 2011 to December 2015) was conducted to describe hospital and patient characteristics associated with OFA. Baseline characteristics, such as age, gender, race, discharge status, year of admission and chronic comorbidities at index admission were collected. Hospital characteristics and payer type at index admission were collected as reported in the electronic health record database. Descriptive statistics and logistic regression were used to identify statistically significant predictors of OFA on patient and institutional levels. RESULTS: The study identified 10,219 patients, from 187 hospitals, who received post-surgical OFA and 255,196 patients who received post-surgical opioids. OFA rates varied considerably by hospital. Patients more likely to receive OFA were older (OR = 1.06, 95% CI [1.03, 1.10]; p < .001), or had neurological disorders (OR = 1.24, 95% CI [1.10, 1.39]; p < .001), diabetes (OR = 1.20, 95% CI [1.08, 1.33]; p = .001) or psychosis (OR = 1.18, 95% CI [1.01, 1.37]; p = .030). Patients with obesity and depression were less likely to receive OFA (OR = 0.80, 95% CI [0.67, 0.95]; p = .010 OR = 0.85, 95% CI [0.73, 0.98]; p = .030, respectively). CONCLUSIONS: Use of post-surgical OFA was limited overall and was not favored in some patient groups prone to ORADEs, indicating missed opportunities to reduce opioid use and ORADE incidence. A substantial proportion of OFA patients was contributed by a few hospitals with especially high rates of OFA, suggesting that hospital policies, institutional structure and cross-functional departmental commitment to reducing opioid use may play a large role in the implementation of OFA.

Impact of Intravenous Acetaminophen on Lengths of Stay and Discharge Status after Total Knee Arthroplasty.

Postoperative pain remains difficult to control after total knee arthroplasty (TKA). While various modalities have been used, they have been associated with several side effects. For example, opioids have many side effects including: sedation, dizziness, nausea, vomiting, constipation, respiratory depression, and can lead to dependency. Recently, intravenous (IV) acetaminophen has been introduced as a method to manage postoperative pain. Therefore, the purpose of this study was to compare the postoperative outcomes of TKA patients who received oral acetaminophen versus IV acetaminophen. Specifically, this study evaluated: (1) the hospital lengths of stay (LOS) and (2) discharge dispositions. The Premier Database was used to review patients who underwent TKA from 2012 to 2015. A total of 134,216 TKA patients received oral acetaminophen, whereas 56,475 TKA patients received IV acetaminophen postoperatively. LOS were calculated as the number of days from the date of hospital admission to the date of discharge, and the discharge disposition was categorized as to home or to a skilled nursing facility (SNF). Compared with the oral group, the IV acetaminophen group had a 0.14 days shorter LOS (95% confidence interval [CI], -0.15 to -0.13; p < 0.001) and 22% higher chance of being discharged home (odds ratio [OR] = 1.22; 95% CI, 1.19-1.25; p < 0.001). Also, compared with the oral group, the IV group had a 13% lower chance of being discharged to a SNF (OR = 0.87; 95% CI, 0.85-0.90; p < 0.001). This study demonstrated that TKA patients who received IV acetaminophen were associated with a significantly shorter hospital LOS as well as being discharged home and fewer patients had to go to SNF. This may lead to a reduction in the total cost of health care, while, at the same time, decreasing the resource use in patients who undergo TKA.

Reduced length of stay and hospitalization costs among inpatient hysterectomy patients with postoperative pain management including IV versus oral acetaminophen.

OBJECTIVE: To compare the outcomes of hysterectomy patients who received standard pain management including IV acetaminophen (IV APAP) versus oral APAP. METHODS: We performed a retrospective analysis of the Premier Database (January 2012 to September 2015) comparing hysterectomy patients who received postoperative pain management including IV APAP to those who received oral APAP starting on the day of surgery and continuing up to the third post-operative day, with no exclusions based on additional pain management. We compared the groups on length of stay (LOS), hospitalization costs, and average daily morphine equivalent dose (MED). The quarterly rate of IV APAP use for all hospitalizations by hospital was used as an instrumental variable in two-stage least squares regressions also adjusting for patient demographics, clinical risk factors, and hospital characteristics. RESULTS: We identified 22,828 hysterectomy patients including 14,811 (65%) who had received IV APAP. Study subjects averaged 50 and 52 years of age, respectively in the IV APAP and oral APAP cohorts and were predominantly non-Hispanic Caucasians (≥60% in both cohorts). Instrumental variable models found IV APAP associated with 0.8 days shorter hospitalization (95% CI: -0.92 to -0.68, p<0.0001) and $2,449 lower hospitalization costs (95% CI: -$2,902 to -$1,996, p<0.0001). Average daily MED trended lower without statistical significance (-1.41 mg, 95% CI: -3.43 mg to 0.61 mg, p = 0.17). CONCLUSIONS: Compared to oral APAP, managing post-hysterectomy pain with IV APAP is associated with shorter LOS and lower total hospitalization costs.

Astrocyte-enriched feeder layers from cryopreserved cells support differentiation of spontaneously active networks of human iPSC-derived neurons.

BACKGROUND: Human induced pluripotent stem cell (hiPSC)-derived neuronal cultures are a useful tool for studying the mechanisms of neurological disorders and developing novel therapeutics. While plating hiPSC-derived neuronal progenitors onto glial feeder layers prepared from rodent cortex has been reported to promote functional differentiation of neuronal networks, this has not been examined in detail. NEW METHOD: Here we describe a method of using cryopreserved cells from primary cultures for generation of mouse astrocyte-enriched, neuron-free feeder layers that grow from 10% to 100% confluence in 1 week. RESULTS: Electrophysiological analysis demonstrated that compared to biochemical substrates alone, astrocyte-enriched feeder layers support more rapid differentiation of hiPSC-derived progenitors into excitable neurons that form spontaneously active networks in culture. There was a positive correlation between the degree of astroglial confluence at the time of progenitor plating and the average frequency of postsynaptic currents 3 weeks after plating. One disadvantage to plating on 100% confluent feeder layers was a high incidence of the astroglial layer with the overlying neurons detaching from the coverslips during transfer to the recording chamber. COMPARISON WITH EXISTING METHOD(S): Prevailing methods using primary glial feeder layers can result in possible contamination with rodent neurons and an unpredictable rate of growth. We provide a reliable method of generating mouse astroglial feeder layers from cryopreserved primary cultures to support differentiation of hiPSC-derived neurons. CONCLUSIONS: The ability to make astrocyte-enriched feeder layers of defined confluence from cryopreserved primary cultures will facilitate the use of human stem cell derived neuronal cultures for disease modeling.

Improved Outcomes Associated With the Use of Intravenous Acetaminophen for Management of Acute Post-Surgical Pain in Cesarean Sections and Hysterectomies.

BACKGROUND: Post-surgical pain impacts many patient outcomes. Effective pain management increasingly relies on multimodal analgesia regimens in which acetaminophen (APAP) is a key component. The aim of our study was to examine the impact of oral APAP versus intravenous (IV) APAP as a component of post-surgical pain management after Cesarean sections and hysterectomies. METHODS: A retrospective analysis of the Cerner HealthFacts® database (from January, 2011 to December, 2015) was conducted to compare outcomes of Cesarean section and hysterectomy surgery patients who received oral APAP to those who received IV APAP post-surgically. Length of stay (LOS), daily morphine milligram equivalent (MME) consumption, the presence of potential opioid-related adverse events (ORADEs), and total pharmacy costs were assessed. Adjusted results were derived using inverse probability weighted regression adjustment (IPW-RA) estimators based on covariates that included demographics, comorbidities, patient clinical characteristics, and hospital characteristics. RESULTS: The study identified 29,124 Cesarean section patients (24,612 oral APAP; 4,512 IV APAP) and 9,767 hysterectomy surgery patients (5,586 oral APAP; 4,181 IV APAP). Compared to the oral APAP group, the IV APAP group had reductions in adjusted LOS (Cesarean section: -11.7% days (P < 0.001), hysterectomy: -11.8% days (P = 0.005)), lowered adjusted daily MME consumption from day 0 to day 3 (Cesarean section: -1.6 mg (P < 0.001), hysterectomy: -1.7 mg (P = 0.014)), and reduced risk of ORADEs for Cesarean sections (relative risk of 0.45, P < 0.001). Total pharmacy costs were not significantly different between the two APAP groups. CONCLUSIONS: Post-surgical pain managed with IV APAP in patients undergoing Cesarean section or hysterectomy was associated with shorter LOS, reduced risk of ORADEs, and lower opioid consumption compared to patients managed with oral APAP, without adversely impacting total pharmacy costs.

Hospitalization costs and resource allocation in cholecystectomy with use of intravenous versus oral acetaminophen.

OBJECTIVE: To evaluate intravenous (IV) acetaminophen (APAP) vs oral APAP use as adjunctive analgesics in cholecystectomy patients by comparing associated hospital length of stay (LOS), hospital costs, opioid use, and rates of nausea/vomiting, respiratory depression, and bowel obstruction. METHODS: We conducted a retrospective analysis of the Premier Database (January 2012 to September 2015) including cholecystectomy patients who received either IV APAP or oral APAP. Differences in LOS, hospitalization costs, mean daily morphine equivalent dose (MED), and potential opioid-related adverse events were estimated. Multivariable logistic regression was performed for the binary outcomes and instrumental variable regressions, using the quarterly rate of IV APAP use for all hospitalizations by hospital as the instrument in two-stage least squares regressions for continuous outcomes. Models were adjusted for patient demographics, clinical risk factors, and hospital characteristics. RESULTS: Among 61,017 cholecystectomy patients, 31,133 (51%) received IV APAP. Subjects averaged 51 and 57 years of age, respectively, in the IV and oral APAP cohorts. In the adjusted models, IV APAP was associated with 0.42 days shorter LOS (95% CI = -0.58 to -0.27; p < .0001), $1,045 lower hospitalization costs (95% CI = -$1,521 to -$569; p < .0001), 2 mg lower average daily MED (95% CI = -3 mg to -0.9 mg; p = .0005), and lower rates of respiratory depression (odds ratio [OR] = 0.89, 95% CI = 0.82-0.97; p = .006), and nausea and vomiting (OR = 0.86, 95% CI = 0.86-0.86; p < .0001). CONCLUSIONS: In patients having cholecystectomy, the addition of IV APAP to perioperative pain management is associated with shorter LOS, lower costs, reduced opioid use, and less frequent nausea/vomiting and respiratory depression compared to oral APAP. These findings should be confirmed in a prospective study comparing IV and oral APAP.

Association of Opioid-Related Adverse Drug Events With Clinical and Cost Outcomes Among Surgical Patients in a Large Integrated Health Care Delivery System.

Importance: Opioids are commonly used for pain control during and after invasive procedures. However, opioid-related adverse drug events (ORADEs) are common and have been associated with worse patient outcomes. Objectives: To examine the incidence of ORADEs in patients undergoing hospital-based surgical and endoscopic procedures and to evaluate the association of ORADEs with clinical and cost outcomes. Design, Setting, and Participants: In this retrospective study of clinical and administrative data, ORADEs were identified using International Classification of Diseases, Ninth Revision diagnosis codes for known adverse effects of opioids or by opioid antagonist use. Multivariable regression analysis was used to measure the association of ORADEs with outcomes after adjusting for potential confounding factors. The setting was 21 acute care hospitals in a large integrated health care delivery system. Participants were 135 379 patients (aged ≥18 years, admitted from January 1, 2013, to September 30, 2015) who underwent surgical and endoscopic procedures and were given opioids. Exposure: Opioid use, reported as morphine milligram equivalent doses. Main Outcomes and Measures: Opioid-related adverse drug events and their association with inpatient mortality, discharge to another care facility, length of stay, cost of hospitalization, and 30-day readmission. Results: Among 135 379 adult patients in this study (67.5% female), 14 386 (10.6%) experienced at least one ORADE. Patients with ORADEs were more likely to be older, of white race/ethnicity, and male and have more comorbidities. Patients with ORADEs received a higher total dose of opioids (median morphine milligram equivalent dose, 46.8 vs 30.0 mg; P < .001) and for a longer duration (median, 3.0 vs 2.0 days; P < .001). In adjusted analyses, ORADEs were associated with increased inpatient mortality (odds ratio [OR], 28.8; 95% CI, 24.0-34.5), greater likelihood of discharge to another care facility (OR, 2.9; 95% CI, 2.7-3.0), prolonged length of stay (OR, 3.1; 95% CI, 2.8-3.4), high cost of hospitalization (OR, 2.7; 95% CI, 2.4-3.0), and higher rate of 30-day readmission (OR, 1.3; 95% CI, 1.2-1.4). ORADEs were associated with a 2.9% increase in absolute mortality, an $8225 increase in cost for the index hospitalization, and a 1.6-day increase in length of stay for the index hospitalization. Conclusions and Relevance: Opioid-related adverse drug events were common among patients undergoing hospital-based invasive procedures and were associated with significantly worse clinical and cost outcomes. Hospital-acquired harm from ORADEs in the surgical patient population is an important opportunity for health systems to improve patient safety and reduce cost.

Comparative analysis of length of stay, hospitalization costs, opioid use, and discharge status among spine surgery patients with postoperative pain management including intravenous versus oral acetaminophen.

BACKGROUND: Recovery from spine surgery is oriented toward restoring functional health outcomes while reducing resource use. Optimal pain management is a key to reaching these objectives. We compared outcomes of spine surgery patients who received standard pain management including intravenous (IV) acetaminophen (APAP) vs. oral APAP. METHODS: We performed a retrospective analysis of the Premier database (January 2012 to September 2015) comparing spine surgery patients who received pain management with IV APAP to those who received oral APAP, with no exclusions based on additional pain management. We performed multivariable logistic regression for the discharge and all cause 30-day readmission to the same hospital outcomes and instrumental variable regressions using the quarterly rate of IV APAP use for all hospitalizations by hospital as the instrument in two-stage least squares regressions for length of stay (LOS), hospitalization costs, and average daily morphine equivalent dose (MED) outcomes. Models adjusted for age, gender, race, admission type, 3M All Patient Refined Diagnosis Related Group severity of illness and risk of mortality, hospital size, and indicators for whether the hospital was an academic center and whether it was urban or rural. RESULTS: We identified 112,586 spine surgery patients with 51,835 (46%) having received IV APAP. Subjects averaged 57 and 59 years of age respectively in the IV APAP and oral APAP cohorts and were predominantly non-Hispanic Caucasians and female. In our adjusted models, IV APAP was associated with 0.68 days shorter LOS (95% CI: -0.76 to -0.59, p < .0001), $1175 lower hospitalization costs (95% CI: -$1611 to -$739, p < .0001), 13 mg lower average daily MED (95% CI: -14 mg to -12 mg, p < .0001), 34% lower risk of discharge to a skilled nursing facility (95% CI: 0.63 to 0.69, p < .0001), and 13% less risk of 30-day readmission (95% CI: 0.73 to 1.03). CONCLUSIONS: Compared to oral APAP, managing post-spine-surgery pain with IV APAP is associated with less resource use, lower costs, lower doses of opioids, and improved discharge status.

Phase diagram and aggregation dynamics of a monolayer of paramagnetic colloids.

We have developed a tunable colloidal system and a corresponding theoretical model for studying the phase behavior of particles assembling under the influence of long-range magnetic interactions. A monolayer of paramagnetic particles is subjected to a spatially uniform magnetic field with a static perpendicular component and a rapidly rotating in-plane component. The sign and strength of the interactions vary with the tilt angle θ of the rotating magnetic field. For a purely in-plane field, θ=90^{∘}, interactions are attractive and the experimental results agree well with both equilibrium and out-of-equilibrium predictions based on a two-body interaction model. For tilt angles 50^{∘}≲θ≲55^{∘}, the two-body interaction gives a short-range attractive and long-range repulsive interaction, which predicts the formation of equilibrium microphases. In experiments, however, a different type of assembly is observed. Inclusion of three-body (and higher-order) terms in the model does not resolve the discrepancy. We further characterize the anomalous regime by measuring the time-dependent cluster size distribution.

Hospitalization Costs for Patients Undergoing Orthopedic Surgery Treated With Intravenous Acetaminophen (IV-APAP) Plus Other IV Analgesics or IV Opioid Monotherapy for Postoperative Pain.

INTRODUCTION: To assess the impact on hospitalization costs of multimodal analgesia (MMA), including intravenous acetaminophen (IV-APAP), versus IV opioid monotherapy for postoperative pain management in patients undergoing orthopedic surgery. METHODS: Utilizing the Truven Health MarketScan® Hospital Drug Database (HDD), patients undergoing total knee arthroplasty (TKA), total hip arthroplasty (THA), or surgical repair of hip fracture between 1/1/2011 and 8/31/2014 were separated into postoperative pain management groups: MMA with IV-APAP plus other IV analgesics (IV-APAP group) or an IV opioid monotherapy group. All patients could have received oral analgesics. Baseline characteristics and total hospitalization costs were compared. Additionally, an inverse probability treatment weighting [IPTW] with propensity scores analysis further assessed hospitalization cost differences. RESULTS: The IV-APAP group (n = 33,954) and IV opioid monotherapy group (n = 110,300) differed significantly (P < 0.0001) across baseline characteristics, though the differences may not have been clinically meaningful. Total hospitalization costs (mean ± standard deviation) were significantly lower for the IV-APAP group than the IV opioid monotherapy group (US$12,540 ± $9564 vs. $13,242 ± $35,825; P < 0.0001). Medical costs accounted for $701 of the $702 between-group difference. Pharmacy costs were similar between groups. Results of the IPTW-adjusted analysis further supported the statistically significant cost difference. CONCLUSIONS: Patients undergoing orthopedic surgery who received MMA for postoperative pain management, including IV-APAP, had significantly lower total costs than patients who received IV opioid monotherapy. This difference was driven by medical costs; importantly, there was no difference in pharmacy costs. Generalizability of the results may be limited to patients admitted to hospitals similar to those included in HDD. Dosing could not be determined, so it was not possible to quantify utilization of IV-APAP or ascertain differences in opioid consumption between the 2 groups. This study did not account for healthcare utilization post-discharge.