Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.

Optical coherence tomography of human fetal membrane sub-layers during loading.

Fetal membranes have important mechanical and antimicrobial roles in maintaining pregnancy. However, the small thickness (<800 µm) of fetal membranes places them outside the resolution limits of most ultrasound and magnetic resonance systems. Optical imaging methods like optical coherence tomography (OCT) have the potential to fill this resolution gap. Here, OCT and machine learning methods were developed to characterize the ex vivo properties of human fetal membranes under dynamic loading. A saline inflation test was incorporated into an OCT system, and tests were performed on n = 33 and n = 32 human samples obtained from labored and C-section donors, respectively. Fetal membranes were collected in near-cervical and near-placental locations. Histology, endogenous two photon fluorescence microscopy, and second harmonic generation microscopy were used to identify sources of contrast in OCT images of fetal membranes. A convolutional neural network was trained to automatically segment fetal membrane sub-layers with high accuracy (Dice coefficients >0.8). Intact amniochorion bilayer and separated amnion and chorion were individually loaded, and the amnion layer was identified as the load-bearing layer within intact fetal membranes for both labored and C-section samples, consistent with prior work. Additionally, the rupture pressure and thickness of the amniochorion bilayer from the near-placental region were greater than those of the near-cervical region for labored samples. This location-dependent change in fetal membrane thickness was not attributable to the load-bearing amnion layer. Finally, the initial phase of the loading curve indicates that amniochorion bilayer from the near-cervical region is strain-hardened compared to the near-placental region in labored samples. Overall, these studies fill a gap in our understanding of the structural and mechanical properties of human fetal membranes at high resolution under dynamic loading events.

Epigenetic dysregulation of articular cartilage during progression of hip femoroacetabular impingement disease.

Femoroacetabular impingement (FAI) is an important trigger of hip osteoarthritis (OA). Epigenetic changes in DNA methyltransferase 3B (DNMT3B) attenuate catabolic gene expression in cartilage hemostasis. This study aimed to examine the articular chondrocyte catabolic state and DNMT3B and 4-aminobutyrate aminotransferase promoter (ABAT) expression during OA progression in FAI. Cartilage samples were collected from the impingement zone of 12 patients with cam FAI (early-FAI) and 12 patients with advanced OA secondary to cam FAI (late-FAI-OA). Five healthy samples were procured from cadavers (ND: nondiseased). Explants were cultured under unstimulated conditions, catabolic stimulus (IL1ß), or anabolic stimulus (TGFß). Histology was performed with safranin-O/fast-green staining. Gene expression was analyzed via qPCR for GAPDH, DNMT3B, ABAT, MMP-13, COL10A1. Methylation specific PCR assessed methylation status at the ABAT promoter. Cartilage samples in early-FAI and late-FAI-OA showed a histological OA phenotype and increased catabolic marker expression (MMP13/COL10A1, ND vs. early-FAI, p = 0.004/p < 0.001, ND vs. late-FAI-OA, p < 0.001/p < 0.001). RT-PCR confirmed DNMT3B underexpression (ND vs. early-FAI, p < 0.001, early-FAI vs. late-FAI-OA, p = 0.016) and ABAT overexpression (ND vs. early-FAI, p < 0.001, early vs. late-FAI-OA, p = 0.035) with advanced disease. End-stage disease showed ABAT promoter hypomethylation. IL1ß stimulus accentuated ABAT promoter hypomethylation and led to further ABAT and catabolic marker overexpression in early-FAI and late-FAI-OA while TGFß normalized these alterations in gene expression. Catabolic and epigenetic molecule expression suggested less catabolism in early-stage disease. Sustained inflammation induced ABAT promoter hypo-methylation causing a catabolic phenotype. Suppression of ABAT by methylation control could be a new target for therapeutic intervention to prevent OA progression in hip FAI.

The Use of Clevidipine for Hypertension in Pediatric Patients Receiving Mechanical Circulatory Support.

OBJECTIVES: Limited data exist regarding the management of hypertension in pediatric patients on mechanical circulatory support. Hypertension is a known risk factor for stroke and low cardiac output in patients requiring mechanical circulatory support and a narrow therapeutic window of blood pressure is often targeted. Traditional short-acting infusions to treat hypertension, such as sodium nitroprusside, may lead to accumulation of toxic metabolites in patients with renal dysfunction. Our primary objective was to describe use of clevidipine, a continuous short-acting calcium channel blocking medication, for blood pressure control in pediatric patients on mechanical circulatory support. DESIGN: Single-center retrospective cohort study. SETTING: A 26-bed quaternary cardiovascular ICU in a university-based pediatric hospital in California. PATIENTS: Mechanical circulatory support patients admitted to cardiovascular ICU who received clevidipine infusions between October 1, 2016, and March 31, 2019. INTERVENTIONS: Clevidipine infusion. MEASUREMENTS AND MAIN RESULTS: Data from a cohort of 38 patients who received a total of 45 clevidipine infusions were reviewed. The cohort had a median age of 2.7 years and included neonates. No patient had record of hypotensive events, code events, or received low-dose epinephrine or code-dosed epinephrine related to a clevidipine infusion. Median duration of clevidipine infusion was 4.1 days (1.5-9.2 d). Eleven patients transitioned from clevidipine to enteral antihypertensive agents, and 26 clevidipine infusions were administered as a single agent without sodium nitroprusside. Seven patients were switched from sodium nitroprusside to clevidipine to avoid cyanide toxicity, a majority of whom had elevated serum creatinine. CONCLUSIONS: In this pediatric cardiac cohort, clevidipine infusions were effective at hypertension management and were not associated with hypotensive or code events. This report details the largest cohort and longest duration of clevidipine administration within a pediatric population and did not demonstrate hypotensive events, even among neonatal populations. Clevidipine may be a reasonable cost-effective alternative antihypertensive medication compared to traditional short-acting agents.

Systemic Absorption of Lidocaine from Continuous Erector Spinae Plane Catheters After Congenital Cardiac Surgery: A Retrospective Study.

OBJECTIVES: To examine postoperative serum lidocaine levels in patients with intermittent lidocaine bolus erector spinae plane block (ESPB) catheters after cardiac surgery with or without cardiopulmonary bypass (CPB). DESIGN: A retrospective study. SETTING: Single-center pediatric quaternary teaching hospital. PARTICIPANTS: Patients who received ESPB catheters after congenital cardiac surgery from April 2018 to March 2019. INTERVENTIONS: Postoperative serum lidocaine levels were extracted from the record. MEASUREMENTS AND MAIN RESULTS: Twenty-seven of 40 patients were included in the final analyses (19 with CPB and 8 with no CPB, age 1-47 years, undergoing congenital heart repair). Patients who received ropivacaine or were missing data were excluded. The initial intraoperative bolus of lidocaine ranged from 0- to- 3.72 mg/kg, and the range of postoperative intermittent lidocaine boluses ranged from 0.35- to- 0.83 mg/kg, which were administered every hour. Serum lidocaine levels were measured by the hospital laboratory and ranged from <0.05- to- 3.0 µg/mL in the CPB group and from <0.05- to- 3.2 µg/mL in the no- CPB group. CPB was not associated with differences in lidocaine levels when controlling for time (P = 0.529). Lidocaine concentrations ranged from 0.50- to- 1.68 µg/mL in the CPB group and 0.86- to- 2.07 µg/mL in the no- CPB group. There was a normally distributed overall mean peak level of 1.818 ± standard deviation of 0.624 µg/mL, with 95% confidence interval of 0.57- to- 3.06 µg/mL. No patients had clinical signs of toxicity. CONCLUSION: Postoperative serum lidocaine concentrations did not appreciably differ due to CPB. Serum lidocaine concentrations did not reach near- toxic doses despite the presence of additional lidocaine in the cardioplegia. The results suggested that lidocaine for ESPBs after cardiac surgery is below systemic toxic range at the doses described.

Home Infliximab Infusions Are Associated With Suboptimal Outcomes Without Cost Savings in Inflammatory Bowel Diseases.

INTRODUCTION: Biologic agents including infliximab are effective but costly therapies in the management of inflammatory bowel disease (IBD). Home infliximab infusions are increasingly payer-mandated to minimize infusion-related costs. This study aimed to compare biologic medication use, health outcomes, and overall cost of care for adult and pediatric patients with IBD receiving home vs office- vs hospital-based infliximab infusions. METHODS: Longitudinal patient data were obtained from the Optum Clinformatics Data Mart. The analysis considered all patients with IBD who received infliximab from 2003 to 2016. Primary outcomes included nonadherence (≥2 infliximab infusions over 10 weeks apart in 1 year) and discontinuation of infliximab. Secondary outcomes included outpatient corticosteroid use, follow-up visits, emergency room visits, hospitalizations, surgeries, and cost outcomes (out-of-pocket costs and annual overall cost of care). RESULTS: There were 27,396 patients with IBD (1,839 pediatric patients). Overall, 5.7% of patients used home infliximab infusions. These patients were more likely to be nonadherent compared with both office-based (22.2% vs 19.8%; P = .044) and hospital-based infusions (22.2% vs 21.2%; P < .001). They were also more likely to discontinue infliximab compared with office-based (44.7% vs 33.7%; P < .001) or hospital-based (44.7% vs 33.4%; P < .001) infusions. On Kaplan-Meier analysis, the probabilities of remaining on infliximab by day 200 of therapy were 64.4%, 74.2%, and 79.3% for home-, hospital-, and office-based infusions, respectively (P < .001). Home infliximab patients had the highest corticosteroid use (cumulative corticosteroid days after IBD diagnosis: home based, 238.2; office based, 189.7; and hospital based, 208.5; P < .001) and the fewest follow-up visits. Home infusions did not decrease overall annual care costs compared with office infusions ($49,149 vs $43,466, P < .001). DISCUSSION: In this analysis, home infliximab infusions for patients with IBD were associated with suboptimal outcomes including higher rates of nonadherence and discontinuation of infliximab. Home infusions did not result in significant cost savings compared with office infusions.

Intraoperative Methadone Is Associated with Decreased Perioperative Opioid Use Without Adverse Events: A Case-Matched Cohort Study.

OBJECTIVE: To determine if there is an association of intraoperative methadone use and total perioperative opioid exposure in patients undergoing congenital heart surgeries. DESIGN: Retrospective, case-match cohort study. SETTING: Single center quaternary care teaching hospital. PARTICIPANTS: Seventy-four patients with congenital heart disease (CHD) undergoing surgical repair or palliative surgery. INTERVENTION: Thirty-seven patients undergoing CHD surgeries receiving intraoperative methadone were matched to 37 patients based upon age and procedure who did not receive intraoperative methadone. The primary study outcome was to evaluate total opioid use in intravenous milligrams of morphine equivalents per kilogram (mg ME/kg) within the first 36-hours postoperatively. Mann-Whitney U test was used to compare total opioid exposure. MEASUREMENTS AND MAIN RESULTS: The total opioid use was compared between groups. The methadone cohort required less opioids intraoperatively, in the first 12 hours postoperatively, and during the first 36 hours postoperatively (2.51 v 4.39 mg ME/kg, p < 0.001; 0.43 v 1.28 mg ME/kg, p = 0.001; and 0.83 v 1.91 mg ME/kg, p < 0.001) compared with the matched control cohort. There were no differences in clinical outcomes or adverse events. A dose-dependent reduction in opioid consumption in high- versus low-dose groups also was not observed. CONCLUSION: Intraoperative methadone use was associated with a decrease in perioperative opioid exposure in patients undergoing congenital heart surgery and was not associated with adverse events or prolonged durations of mechanical ventilation or ICU stay.

Rasburicase versus intravenous allopurinol for non-malignancy-associated acute hyperuricemia in paediatric cardiology patients.

OBJECTIVES: Limited data exist for management of hyperuricemia in non-oncologic patients, particularly in paediatric cardiac patients. Hyperuricemia is a risk factor for acute kidney injury and may prompt treatment in critically ill patients. The primary objective was to determine if rasburicase use was associated with greater probability normalisation of serum uric acid compared to allopurinol. Secondary outcomes included percent reduction in uric acid, changes in serum creatinine, and cost of therapy. DESIGN: A single-centre retrospective chart review. SETTING: A 20-bed quaternary cardiovascular ICU in a university-based paediatric hospital in California. PATIENTS: Patients admitted to cardiovascular ICU who received rasburicase or intravenous allopurinol between 2015 and 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from a cohort of 14 patients receiving rasburicase were compared to 7 patients receiving IV allopurinol. Patients who were administered rasburicase for hyperuricemia were more likely to have a post-treatment uric acid level less than 8 mg/dl as compared to IV allopurinol (100 versus 43%; p = 0.0058). Patients who received rasburicase had a greater absolute reduction in post-treatment day 1 uric acid (-9 mg/dl versus -1.9 mg/dl; p = 0.002). There were no differences in post-treatment day 3 or day 7 serum creatinine or time to normalisation of serum creatinine. The cost of therapy normalised to a 20 kg patient was greater in the allopurinol group ($18,720 versus $1928; p = 0.001). CONCLUSION: In a limited paediatric cardiac cohort, the use of rasburicase was associated with a greater reduction in uric acid levels and associated with a lower cost compared to IV allopurinol.

Biomass production in the Lower Mississippi River Basin: Mitigating associated nutrient and sediment discharge to the Gulf of Mexico.

A watershed model was developed using the Soil and Water Assessment Tool (SWAT) that simulates nitrogen, phosphorus, and sediment loadings in the Lower Mississippi River Basin (LMRB). The LMRB SWAT model was calibrated and validated using 21 years of observed flow, sediment, and water-quality data. The baseline model results indicate that agricultural lands within the Lower Mississippi River Basin (LMRB) are the dominant sources of nitrogen and phosphorus discharging into the Gulf of Mexico. The model was further used to evaluate the impact of biomass production, in the presence of riparian buffers in the LMRB, on suspended-sediment and nutrient loading discharge from the Mississippi River into the Gulf of Mexico. The interplay among land use, riparian buffers, crop type, land slope, water quality, and hydrology were anlyzed at various scales. Implementing a riparian buffer in the dominant agricultural region within the LMRB could reduce suspended sediment, nitrogen, and phosphorus loadings at the regional scale by up to 65%, 38%, and 39%, respectively. Implementation of this land management practice can reduce the suspended-sediment content and improve the water quality of the discharge from the LMRB into the Gulf of Mexico and support the potential production of bioenergy and bio-products within the Mississippi River Basin.

Outcome of tacrolimus and vedolizumab after corticosteroid and anti-TNF failure in paediatric severe colitis.

BACKGROUND: Severe colitis flare from ulcerative colitis (UC) or Crohn's disease (CD) may be refractory to corticosteroids and antitumour necrosis factor (TNF) agents resulting in high colectomy rates. We aimed to describe the utility of tacrolimus to prevent colectomy during second-line vedolizumab initiation after corticosteroid and anti-TNF treatment failure in paediatric severe colitis. METHODS: A retrospective cohort analysis was performed between 1 October 2014 and 31 October 2016 at a single tertiary care centre. Inclusion criteria were patients with severe colitis who received tacrolimus before or during vedolizumab induction and previous exposure to anti-TNF therapy with or without corticosteroids. The initiation of tacrolimus was clinician dependent based on an institutional protocol. RESULTS: Twelve patients (10 UC, two CD; median age 16 years; three female) received at least one dose of vedolizumab 10 mg/kg (max of 300 mg) due to anti-TNF therapy failure and persistent flare not responsive to corticosteroids. Of the 12 patients, eight (67%) and four (33%) had failed one or two anti-TNF agents, respectively. Tacrolimus was initiated for acute disease severity during hospitalisation (58%) or ongoing flare during outpatient care (42%). 9 (75%) of 12 patients avoided colectomy or inflammatory bowel disease-related surgery at 24 weeks and eight (68%) continued on vedolizumab maintenance with no adverse events out to 80 weeks. CONCLUSION: We report real-world data on the outcome of tacrolimus around vedolizumab initiation in paediatric UC or CD after corticosteroid and anti-TNF therapy treatment failure. Our pilot experience indicates a potential benefit of concomitant tacrolimus when initiating vedolizumab therapy.

Frequency of Severe Infusion Reactions Associated With Outpatient Infusion of Infliximab Without Premedications.

In this report, we describe incremental changes, during a 2-year period at a single center with the administration of maintenance infliximab infusions. Given practice-driven changes consisting of 1-hour infusions and omission of premedications, we aimed to investigate if these changes contributed to severe infusion reactions. We reviewed approximately 900 infliximab infusions in a pediatric ambulatory infusion center from January 1, 2014, to December 31, 2015, for severe adverse reactions requiring either rescue epinephrine or a code blue or "rapid response" activation. In 2015, these practice changes resulted in a 51% decrease in total infusion hours (1281 to 630 infusion hours), despite a 9% increase in total number of infusions. No increase in severe adverse events associated with either rapid 1-hour infusion or omission of premedications. Our findings highlight a quality-improvement opportunity to standardize infliximab infusions to streamline care in an ambulatory setting.

Interprofessional Team's Perception of Care Delivery After Implementation of a Pediatric Pain and Sedation Protocol.

BACKGROUND: Pain and agitation are common experiences of patients in pediatric cardiac intensive care units. Variability in assessments by health care providers, communication, and treatment of pain and agitation creates challenges in management of pain and sedation. OBJECTIVES: To develop guidelines for assessment and treatment of pain, agitation, and delirium in the pediatric cardiac intensive unit in an academic children's hospital and to document the effects of implementation of the guidelines on the interprofessional team's perception of care delivery and team function. METHODS: Before and after implementation of the guidelines, interprofessional team members were surveyed about the members' perception of analgesia, sedation, and delirium management RESULTS: Members of the interprofessional team felt more comfortable with pain and sedation management after implementation of the guidelines. Team members reported improvements in team communication on patients' comfort. Members thought that important information was less likely to be lost during transfer of care. They also noted that the team carried out comfort management plans and used pharmacological and nonpharmacological therapies better after implementation of the guidelines than they did before implementation. CONCLUSIONS: Guidelines for pain and sedation management were associated with perceived improvements in team function and patient care by members of the interprofessional team.

Eplerenone for hypertension.

BACKGROUND: Eplerenone is an aldosterone receptor blocker that is chemically derived from spironolactone. In Canada, it is indicated for use as adjunctive therapy to reduce mortality for heart failure patients with New York Heart Association (NYHA) class II systolic chronic heart failure and left ventricular systolic dysfunction. It is also used as adjunctive therapy for patients with heart failure following myocardial infarction. Additionally, it is indicated for the treatment of mild and moderate essential hypertension for patients who cannot be treated adequately with other agents. It is important to determine the clinical impact of all antihypertensive medications, including aldosterone antagonists, to support their continued use in essential hypertension. No previous systematic reviews have evaluated the effect of eplerenone on cardiovascular morbidity, mortality, and magnitude of blood pressure lowering in patients with hypertension. OBJECTIVES: To assess the effects of eplerenone monotherapy versus placebo for primary hypertension in adults. Outcomes of interest were all-cause mortality, cardiovascular events (fatal or non-fatal myocardial infarction), cerebrovascular events (fatal or non fatal strokes), adverse events or withdrawals due to adverse events, and systolic and diastolic blood pressure. SEARCH METHODS: We searched the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers up to 3 March 2016. We handsearched references from retrieved studies to identify any studies missed in the initial search. We also searched for unpublished data by contacting the corresponding authors of the included studies and pharmaceutical companies involved in conducting studies on eplerenone monotherapy in primary hypertension. The search had no language restrictions. SELECTION CRITERIA: We selected randomized placebo-controlled trials studying adult patients with primary hypertension. We excluded studies in people with secondary or gestational hypertension and studies where participants were receiving multiple antihypertensives. DATA COLLECTION AND ANALYSIS: Three review authors independently reviewed the search results for studies meeting our criteria. Three review authors independently extracted data and assessed trial quality using a standardized data extraction form. A fourth independent review author resolved discrepancies or disagreements. We performed data extraction and synthesis using a standardized format on Covidence. We conducted data analysis using Review Manager 5. MAIN RESULTS: A total of 1437 adult patients participated in the five randomized parallel group studies, with treatment durations ranging from 8 to 16 weeks. The daily doses of eplerenone ranged from 25 mg to 400 mg daily. Meta-analysis of these studies showed a reduction in systolic blood pressure of 9.21 mmHg (95% CI -11.08 to -7.34; I2 = 58%) and a reduction of diastolic pressure of 4.18 mmHg (95% CI -5.03 to -3.33; I2 = 0%) (moderate quality evidence).There may be a dose response effect for eplerenone in the reduction in systolic blood pressure at doses of 400 mg/day. However, this finding is uncertain, as it is based on a single included study with low quality evidence. Overall there does not appear to be a clinically important dose response in lowering systolic or diastolic blood pressure at eplerenone doses of 50 mg to 400 mg daily. There did not appear to be any differences in the number of patients who withdrew due to adverse events or the number of patients with at least one adverse event in the eplerenone group compared to placebo. However, only three of the five included studies reported adverse events. Most of the included studies were of moderate quality, as we judged multiple domains as being at unclear risk in the 'Risk of bias' assessment. AUTHORS' CONCLUSIONS: Eplerenone 50 to 200 mg/day lowers blood pressure in people with primary hypertension by 9.21 mmHg systolic and 4.18 mmHg diastolic compared to placebo, with no difference of effect between doses of 50 mg/day to 200 mg/day. A dose of 25 mg/day did not produce a statistically significant reduction in systolic or diastolic blood pressure and there is insufficient evidence for doses above 200 mg/day. There is currently no available evidence to determine the effect of eplerenone on clinically meaningful outcomes such as mortality or morbidity in hypertensive patients. The evidence available on side effects is insufficient and of low quality, which makes it impossible to draw conclusions about potential harm associated with eplerenone treatment in hypertensive patients.

The composition of surface wax on trichomes of Arabidopsis thaliana differs from wax on other epidermal cells.

To protect plants against biotic and abiotic stress, the waxy cuticle must coat all epidermis cells. Here, two independent approaches addressed whether cell-type-specific differences exist between wax compositions on trichomes and other epidermal cells of Arabidopsis thaliana, possibly with different protection roles. First, the total waxes from a mutant lacking trichomes (gl1) were compared to waxes from wild type and a trichome-rich mutant (cpc tcl1 etc1 etc3). In the stem wax, compounds with aliphatic chains longer than 31 carbons (derived from C32 precursors) increased in relative abundance in cpc tcl1 etc1 etc3 over gl1. Similarly, the leaf wax from the trichome-rich mutant contained higher amounts of C32+ compounds as compared to gl1. Second, leaf trichomes were isolated, and their waxes were analyzed. The wax mixtures of the trichome-rich mutant and the wild type were similar, comprising alkanes and alkenes as well as branched and unbranched primary alcohols. The direct analyses of trichome waxes confirmed that they contained relatively high concentrations of C32+ compounds, compared with the pavement cell wax inferred from analysis of gl1 leaves. Finally, the cell-type-specific wax compositions were put into perspective with expression patterns of wax biosynthesis genes in trichomes and pavement cells. Analyses of published transcriptome data (Marks et al., ) revealed that core enzymes involved in elongation of wax precursors to various carbon chain lengths are expressed differentially between epidermis cell types. By combining the chemical and gene expression data, we identified promising gene candidates involved in the formation of C32+ aliphatic chains.

Utilization trends of anti-TNF agents and health outcomes in adults and children with inflammatory bowel diseases: a single-center experience.

BACKGROUND: Utilization trends and health effects of infliximab and adalimumab in inflammatory bowel disease (IBD) are incompletely understood. We aimed to describe utilization trends of these 2 anti-tumor necrosis factor (TNF) agents, determine the correlation between utilization with rates of hospitalization and surgery and describe differences in use between adults and children. METHODS: Longitudinal data were analyzed for drug utilization, hospitalization, and abdominal surgery. Descriptive statistics were used to show trends, and utilization quotients were compared for standardization. Multivariate logistic regression analysis assessed the association between drug use and rates of hospitalization and surgery. RESULTS: Four hundred thirty-eight pediatric and 2514 adult patients with IBD generated a total of 51,882 inpatient and outpatient encounters, representing 1185 Crohn's disease, 1531 ulcerative colitis, and 236 indeterminate colitis patients. From 2007 through 2012, utilization quotients declined for hospitalization but remained unchanged for surgery; adalimumab saw a 3-fold increase, despite continued dominance of infliximab. Median band and mean fitted plots showed downward hospitalization trends from 2006 to 2012. Utilization of infliximab peaked in 2008, Q4 with gradual decline to 2012, Q2; and adalimumab showed moderate increased utilization since 2007, Q1. Use of infliximab (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.70-0.83) and adalimumab (OR, 0.79; 95% CI, 0.72-0.87) was associated with decreased hospitalization risk but not associated with reduced abdominal surgery risk. Children had increased hospitalization (OR, 2.68; 95% CI, 2.49-2.88) but decreased risk for abdominal surgery (OR, 0.57; 95% CI, 0.46-0.70). CONCLUSIONS: Current infliximab use remains substantially greater than adalimumab use, despite recent increased use of adalimumab. Although trends for hospitalization for IBD are decreasing, it is not reflected in abdominal surgery rates in a tertiary IBD referral center.

Cost-effectiveness of a modified two-step algorithm using a combined glutamate dehydrogenase/toxin enzyme immunoassay and real-time PCR for the diagnosis of Clostridium difficile infection.

The analytical performance and cost-effectiveness of the Wampole Toxin A/B EIA, the C. Diff. Quik Chek Complete (CdQCC) (a combined glutamate dehydrogenase antigen/toxin enzyme immunoassay), two RT-PCR assays (Progastro Cd and BD GeneOhm) and a modified two-step algorithm using the CdQCC reflexed to RT-PCR for indeterminate results were compared. The sensitivity of the Wampole Toxin A/B EIA, CdQCC (GDH antigen), BD GeneOhm and Progastro Cd RT-PCR were 85.4%, 95.8%, 100% and 93.8%, respectively. The algorithm provided rapid results for 86% of specimens and the remaining indeterminate results were resolved by RT-PCR, offering the best balance of sensitivity and cost savings per test (algorithm ∼US$13.50/test versus upfront RT-PCR ∼US$26.00/test).

Non-drug costs associated with outpatient infliximab administration in pediatric inflammatory bowel disease.

BACKGROUND: Infliximab is the most widely used biological agent for Crohn's disease (CD) and ulcerative colitis (UC) but requires outpatient infusion units because of its intravenous administration requirement. The aim of this study was (1) to determine the average non-drug costs associated with each outpatient use of infliximab for pediatric inflammatory bowel disease and (2) to determine the proportion of non-drug costs associated with each outpatient infliximab use relative to the total cost of each encounter. METHODS: Hospital administrative and pharmacy databases were queried for all short stay unit encounters at Lucile Packard Children's Hospital at Stanford University linked to infliximab infusions for inflammatory bowel disease between January 1, 2006, and December 31, 2011. Infliximab drug and non-drug costs associated with CD and UC were compared. RESULTS: A total of 771 unique encounters were generated for 76 pediatric patients (53 CD, 23 UC). For direct costs related to infliximab infusions for either CD or UC patients, more than 77% of the total health care costs per encounter were related to personnel (e.g., nursing), facility operations, and laboratory costs. Only 23% of the total costs were related to the actual infliximab drug costs. Based on an 80/20 payor mix of managed care versus government-subsidized insurance payers, 24.5% of the total reimbursements were applied to non-drug costs in CD and 20.9% in UC. CONCLUSIONS: Non-drug costs represent a substantial proportion of the total cost of outpatient infliximab-related actual costs in inflammatory bowel disease. Personnel costs represent the largest segment of the non-drug costs. The actual drug costs of infliximab represent a small proportion of the total costs.

Assessing county-level water footprints of different cellulosic-biofuel feedstock pathways.

While agricultural residue is considered as a near-term feedstock option for cellulosic biofuels, its sustainability must be evaluated by taking water into account. This study aims to analyze the county-level water footprint for four biofuel pathways in the United States, including bioethanol generated from corn grain, stover, wheat straw, and biodiesel from soybean. The county-level blue water footprint of ethanol from corn grain, stover, and wheat straw shows extremely wide variances with a national average of 31, 132, and 139 L of water per liter biofuel (L(w)/L(bf)), and standard deviation of 133, 323, and 297 L(w)/L(bf), respectively. Soybean biodiesel production results in a blue water footprint of 313 L(w)/L(bf) on the national average with standard deviation of 894 L(w)/L(bf). All biofuels show a greater green water footprint than the blue one. This work elucidates how diverse spatial resolutions affect biofuel water footprints, which can provide detailed insights into biofuels' implications on local water sustainability.

Assessing regional hydrology and water quality implications of large-scale biofuel feedstock production in the Upper Mississippi River Basin.

A recent U.S. Department of Energy study estimated that more than one billion tons of biofuel feedstock could be produced by 2030 in the United States from increased corn yield, and changes in agricultural and forest residue management and land uses. To understand the implications of such increased production on water resources and stream quality at regional and local scales, we have applied a watershed model for the Upper Mississippi River Basin, where most of the current and future crop/residue-based biofuel production is expected. The model simulates changes in water quality (soil erosion, nitrogen and phosphorus loadings in streams) and resources (soil-water content, evapotranspiration, and runoff) under projected biofuel production versus the 2006 baseline year and a business-as-usual scenario. The basin average results suggest that the projected feedstock production could change the rate of evapotranspiration in the UMRB by approximately +2%, soil-water content by about -2%, and discharge to streams by -5% from the baseline scenario. However, unlike the impacts on regional water availability, the projected feedstock production has a mixed effect on water quality, resulting in 12% and 45% increases in annual suspended sediment and total phosphorus loadings, respectively, but a 3% decrease in total nitrogen loading. These differences in water quantity and quality are statistically significant (p < 0.05). The basin responses are further analyzed at monthly time steps and finer spatial scales to evaluate underlying physical processes, which would be essential for future optimization of environmentally sustainable biofuel productions.

Assessment of the appropriateness of serum digoxin concentration measurement in a medical group setting.

BACKGROUND: Recent quality initiatives require that the routine annual therapeutic drug-monitoring (TDM) parameters for the high-risk medication digoxin include a measure of renal function and a serum potassium level but not a serum digoxin concentration (SDC) measurement. Several studies have shown that the majority of the SDCs obtained in hospital settings provide little clinically actionable information. OBJECTIVE: To evaluate the appropriateness and utility of SDCs ordered in a medical group practice setting by categorizing the reason the SDC was ordered and identifying action taken in response to the result. METHODS: The descriptive study was conducted as a retrospective, electronic medical record (EMR) review of 90 primary care patients with continuous prescriptions for digoxin current on their medication profile with no gaps in therapy for at least 2 years prior to an SDC result entered into the EMR between January 1, 2009, and September 30, 2009. The reason the SDC was ordered was abstracted independently by 2 reviewers, who then assigned it to 1 of 8 predefined indication categories based on previously published criteria and practice guidelines. A third reviewer resolved inter-reviewer discrepancy (n = 1). RESULTS: A total of 90 patients with at least 1 SDC met inclusion criteria. Routine monitoring was the most frequent SDC order indication category with 35 patients (38.9%), 17 (48.6%) of whom did not have the recommended monitoring measures of potassium or renal function drawn concurrently. Patients were included in other categories as follows: confirmation of signs/symptoms of toxicity 30 (33.3%); assessment of factors altering pharmacokinetics 5 (5.6%); assessment of dosage change 5 (5.6%); assessment of drug interaction 3 (3.3%); assessment of clinical response 3 (3.3%); assessment of adherence 1 (1.1%); and other 2 (2.2%). Across all categories, a total of 19 (21.1%) of SDC results were outside the therapeutic range of 0.5 nanograms (ng) per mL and 2.0 ng per mL, 18 of which were below 0.5 ng per mL, with none of the subtherapeutic levels leading to a change in digoxin therapy. Only 1 patient (1.1%) had therapy changed in response to an elevated abnormal SDC result of 2.1 ng per mL and was in the routine monitoring category. CONCLUSIONS: The majority of SDC results obtained in our medical group setting did not lead to clinical action, such as dose adjustment or drug discontinuation. SDCs were commonly measured as part of routine monitoring, which is considered an inappropriate indication, and often without being accompanied by better markers for digoxin toxicity such as serum potassium levels and measures of renal function as recommended by drug-monitoring quality initiatives. Provider education is needed regarding the most indicative digoxin TDM parameters to obtain in order to satisfy quality initiatives.