Leveraging intrinsic flexibility to engineer enhanced enzyme catalytic activity.

Dynamic motions of enzymes occurring on a broad range of timescales play a pivotal role in all steps of the reaction pathway, including substrate binding, catalysis, and product release. However, it is unknown whether structural information related to conformational flexibility can be exploited for the directed evolution of enzymes with higher catalytic activity. Here, we show that mutagenesis of residues exclusively located at flexible regions distal to the active site of Homo sapiens kynureninase (HsKYNase) resulted in the isolation of a variant (BF-HsKYNase) in which the rate of the chemical step toward kynurenine was increased by 45-fold. Mechanistic pre­steady-state kinetic analysis of the wild type and the evolved enzyme shed light on the underlying effects of distal mutations (>10 Å from the active site) on the rate-limiting step of the catalytic cycle. Hydrogen-deuterium exchange coupled to mass spectrometry and molecular dynamics simulations revealed that the amino acid substitutions in BF-HsKYNase allosterically affect the flexibility of the pyridoxal-5'-phosphate (PLP) binding pocket, thereby impacting the rate of chemistry, presumably by altering the conformational ensemble and sampling states more favorable to the catalyzed reaction.

Vancomycin Area Under the Curve to Predict Timely Clinical Response in the Treatment of Methicillin-resistant Staphylococcus aureus Complicated Skin and Soft Tissue Infections.

INTRODUCTION: Although recent guidelines have recommended monitoring vancomycin (VAN) area under the curve (AUC)/minimum inhibitory concentration (MIC) to ensure clinical efficacy and minimize toxicity in methicillin-resistant Staphylococcus aureus (MRSA) for various infections, there are no recommendations regarding complicated skin and soft tissue infections (cSSTIs). We aimed to evaluate the association between VAN AUC and clinical outcomes in MRSA cSSTIs. METHODS: This was a retrospective cohort study of adult patients treated with ≥72 hours of VAN for MRSA cSSTI from 2008 to 2013 at Detroit Medical Center. The primary outcome was timely clinical success (TCS) defined as (1) resolution of signs and symptoms of infection within 72 hours, (2) stabilization and/or reduction in lesion size, (3) alternative agents not required due to VAN failure or toxicity as elected by the prescribing clinician. Classification and regression tree (CART) analysis was performed to determine the AUC associated with TCS in the cohort. Multivariable logistic regression was used to evaluate the association between VAN-AUC and the primary outcome. RESULTS: A total of 154 patients were included in this analysis. CART identifed an AUC ≥435 mg*hr/L for TCS. Overall, 60.9% of patients experienced TCS; 69.7% in the target-AUC group versus 52.5% in the below-target AUC group, (P = .013). Target-AUC attainment was independently associated with increased odds of TCS (adjusted odds ratio [aOR], 2.208; 95% confidence interval [CI], 1.047-4.659). CONCLUSIONS: In adults treated with VAN for MRSA cSSTI, target-AUC attainment was independently associated with improved clinical outcomes and maybe most warranted for patients at high risk of VAN failure or VAN-associated toxicity.

Brain Structure and Function of Chronic Low Back Pain Patients on Long-Term Opioid Analgesic Treatment: A Preliminary Study.

Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.

Surface-Based Connectivity Integration: An atlas-free approach to jointly study functional and structural connectivity.

There has been increasing interest in jointly studying structural connectivity (SC) and functional connectivity (FC) derived from diffusion and functional MRI. Previous connectome integration studies almost exclusively required predefined atlases. However, there are many potential atlases to choose from and this choice heavily affects all subsequent analyses. To avoid such an arbitrary choice, we propose a novel atlas-free approach, named Surface-Based Connectivity Integration (SBCI), to more accurately study the relationships between SC and FC throughout the intra-cortical gray matter. SBCI represents both SC and FC in a continuous manner on the white surface, avoiding the need for prespecified atlases. The continuous SC is represented as a probability density function and is smoothed for better facilitation of its integration with FC. To infer the relationship between SC and FC, three novel sets of SC-FC coupling (SFC) measures are derived. Using data from the Human Connectome Project, we introduce the high-quality SFC measures produced by SBCI and demonstrate the use of these measures to study sex differences in a cohort of young adults. Compared with atlas-based methods, this atlas-free framework produces more reproducible SFC features and shows greater predictive power in distinguishing biological sex. This opens promising new directions for all connectomics studies.

Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin.

Evidence supports vancomycin therapeutic-drug monitoring by area under the concentration-time curve (AUC), but data to establish an AUC upper limit are limited and published nephrotoxicity thresholds range widely. The objective of this analysis was to examine the association between initial vancomycin AUC and nephrotoxicity. This was a multicenter, retrospective cohort study of adult patients receiving intravenous vancomycin from 2014 to 2015. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/liter and 50% from baseline on consecutive measurements. Vancomycin exposure profile during the initial 48 h of therapy was estimated using maximum a posteriori probability Bayesian estimation. Vancomycin AUC and minimum-concentration (Cmin) thresholds most strongly associated with nephrotoxicity were identified via classification and regression tree (CART) analysis. Predictive performances of CART-derived and other candidate AUC thresholds was assessed through positive and negative predictive value and receiver operating characteristic curves. Poisson regression was used to quantify the association between exposure thresholds and nephrotoxicity while adjusting for confounders. Among 323 patients included, nephrotoxicity was significantly higher in patients with AUCs from 0 to 48 h (AUC0-48) of ≥1,218 mg · h/liter, AUC0-24 of ≥677 mg · h/liter, AUC24-48 of ≥683 mg · h/liter, and day 1 Cmin (Cmin24) of ≥18.8 mg/liter. Vancomycin exposure in excess of these thresholds was associated with a 3- to 4-fold-increased risk of nephrotoxicity in Poisson regression. The predictive performance of AUC for nephrotoxicity was maximized at daily AUC values between 600 and 800 mg · h/liter. Although these data support an AUC range for vancomycin-associated nephrotoxity rather than a single threshold, available evidence suggests that a daily AUC limit of 700 mg · h/liter is reasonable.

Regulating the Uptake of Viral Nanoparticles in Macrophage and Cancer Cells via a pH Switch.

Controlling the uptake of nanomaterials into phagocytes is a challenging problem. We describe an approach to inhibit the cellular uptake by macrophages and HeLa cells of nanoparticles derived from bacteriophage Qß by conjugating negatively charged terminal hexanoic acid moieties onto its surface. Additionally, we show hydrazone linkers can be installed between the surface of Qß and the terminal hexanoic acid moieties, resulting in a pH-responsive conjugate that, in acidic conditions, can release the terminal hexanoic acid moiety and allow for the uptake of the Qß nanoparticle. The installation of the "pH switch" did not change the structure-function properties of the hexanoic acid moiety and the uptake of the Qß conjugates by macrophages.

Ultrasound Assessment of the Transverse Abdominis During Functional Movement.

OBJECTIVES: The traditional activation ratio divides contracted muscle thickness by resting muscle thickness while an abdominal draw-in maneuver is performed during hook lying. Ultrasound imaging during function, such as standing or gait, or peak knee flexion in a single-leg squat allows for further visualization of muscle activity. The goal of this study was to examine activation ratio calculations for transverse abdominis function in supine versus loaded conditions to determine the most informative normalization strategy for muscle activity based on thickness values. METHODS: Transverse abdominis thickness was measured via ultrasound in 35 healthy participants under 4 different conditions. Comparisons were made between the traditional activation ratio tabletop, standing activation ratio (standing abdominal draw-in maneuver thickness/quiet standing thickness), and functional activation ratio (single-leg squat thickness/quiet standing thickness). Additionally, a cued activation ratio (single-leg squat with cued abdominal draw-in maneuver thickness/single-leg squat thickness) during the single-leg squat was obtained. Activation ratios of greater than 1.0 indicated that participants could activate the muscle during activity, and values were compared by analysis of variance. RESULTS: The participants included 23 women and 12 men with a mean age ± SD of 21.3 ± 2.7 years, mass of 66.1 ± 14.4 kg, and height of 168.5 ± 10.1 cm. Activation ratios exceeded 1.0 in 94.3% for the traditional activation ratio, 85.7% for the standing activation ratio, 82.9% for the cued activation ratio, and 82.9% for the functional activation ratio. With groups defined as tabletop activated or not, the standing, cued, and functional activation ratios were all significantly different (all P < .05). CONCLUSIONS: Normalizing muscle thickness to the corresponding functional position quiet value provides a useful functional activation ratio and may help clinicians better understand the transverse abdominis role during complex functional tasks. Assessment techniques using various formulas for activation ratios reveal that the muscle functions differently during weight bearing compared to traditional measures.

Sustainable Bioenergy from Biofuel Residues and Waste.

This section presents a review of the scientific literature published in 2017 on topics relating to sustainable bioenergy from biofuel residues and waste. This review is divided into the following sections: Feedstocks, Bioethanol, Biodiesel, Biohydrogen, Hydrogen, Biofuel Residues, Microalgae, Lignocelluloses and other topics.

Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime.

BACKGROUND: Recent evidence suggests that among patients receiving vancomycin, receipt of concomitant piperacillin-tazobactam increases the risk of nephrotoxicity. Well-controlled, adequately powered studies comparing rates of acute kidney injury (AKI) among patients receiving vancomycin + piperacillin-tazobactam (VPT) compared to similar patients receiving vancomycin + cefepime (VC) are lacking. In this study we compared the incidence of AKI among patients receiving combination therapy with VPT to a matched group receiving VC. METHODS: A retrospective, matched, cohort study was performed. Patients were eligible if they received combination therapy for ≥48 hours. Patients were excluded if their baseline serum creatinine was >1.2mg/dL or they were receiving renal replacement therapy. Patients receiving VC were matched to patients receiving VPT based on severity of illness, intensive care unit status, duration of combination therapy, vancomycin dose, and number of concomitant nephrotoxins. The primary outcome was the incidence of AKI. Multivariate modeling was performed using Cox proportional hazards. RESULTS: A total of 558 patients were included. AKI rates were significantly higher in the VPT group than the VC group (81/279 [29%] vs 31/279 [11%]). In multivariate analysis, therapy with VPT was an independent predictor for AKI (hazard ratio = 4.27; 95% confidence interval, 2.73-6.68). Among patients who developed AKI, the median onset was more rapid in the VPT group compared to the VC group (3 vs 5 days P =< .0001). CONCLUSION: The VPT combination was associated with both an increased AKI risk and a more rapid onset of AKI compared to the VC combination.

A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity.

Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC24) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC24 and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure.

Fluorescent Functionalization across Quaternary Structure in a Virus-like Particle.

Proteinaceous nanomaterials and, in particular, virus-like particles (VLPs) have emerged as robust and uniform platforms that are seeing wider use in biomedical research. However, there are a limited number of bioconjugation reactions for functionalizing the capsids, and very few of those involve functionalization across the supramolecular quaternary structure of protein assemblies. In this work, we exploit the recently described dibromomaleimide moiety as part of a bioconjugation strategy on VLP Qß to break and rebridge the exposed and structurally important disulfides in good yields. Not only was the stability of the quaternary structure retained after the reaction, but the newly functionalized particles also became brightly fluorescent and could be tracked in vitro using a commercially available filter set. Consequently, we show that this highly efficient bioconjugation reaction not only introduces a new functional handle "between" the disulfides of VLPs without compromising their thermal stability but also can be used to create a fluorescent probe.

Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship.

Despite their common use as an empirical combination therapy for the better part of a decade, there has been a recent association between combination therapy with vancomycin and piperacillin-tazobactam and high rates of acute kidney injury (AKI). The reasons for this increased association are unclear, and this analysis was designed to investigate the association. Retrospective cohort and case-control studies were performed. The primary objective was to assess if there is an association between extended-infusion piperacillin-tazobactam in combination with vancomycin and development of AKI. The secondary objectives were to identify risk factors for AKI in patients on the combination, regardless of infusion strategy, and to evaluate the impact of AKI on clinical outcomes. AKI occurred in 105/320 (33%) patients from the cohort receiving combination therapy with vancomycin and piperacillin-tazobactam, with similar rates seen in those receiving intermittent (53/160 [33.1%]) and extended infusions (52/160 [32.5%]) of piperacillin-tazobactam. Independent risk factors for AKI in the cohort included having a documented Gram-positive infection, the presence of sepsis, receipt of a vancomycin loading dose (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.05 to 4.71), and receipt of any concomitant nephrotoxin (OR, 2.44; 95% CI, 1.41 to 4.22). For at-risk patients remaining on combination therapy, the highest rates of AKI occurred on days 4 (10.7%) and 5 (19.3%). The incidence of AKI in patients on combination therapy with vancomycin and piperacillin-tazobactam is high, occurring in 33% of patients. Receipt of piperacillin-tazobactam as an extended infusion did not increase this risk. Modifiable risk factors for AKI include receipt of a vancomycin loading dose, concomitant nephrotoxins, and longer durations of therapy.

Effects of backscattering in high-Q, large-area silicon-on-insulator ring resonators.

We demonstrate large-area silicon-on-insulator ring resonators with Q values of about 2×106 at critical coupling and 3.6×106 for heavily undercoupled conditions. A model has been developed to understand the impact of waveguide backscattering and subcomponent imperfections on the spectral response of our devices. The model predicts the appearance of signals at ports that would not have them under backscattering-free, ideal-power-splitting conditions. The predictions of our model are shown to match the phenomena observed in our measurements.

Nephrotoxicity comparison of two commercially available generic vancomycin products.

To date, no comparative clinical studies have investigated the effects of different vancomycin products on nephrotoxicity. The objective of this single-center, retrospective, matched-cohort study was to investigate the impact of two different vancomycin products on the development of nephrotoxicity. The study population included adults receiving a single vancomycin product, from either Pfizer or Hospira, for their entire course of therapy. Patients were matched based on underlying nephrotoxicity risk factors. Secondary outcomes included the need for renal replacement therapy, length of hospital stay, and in-hospital mortality. One-hundred forty-six matched pairs (n = 292) were included, and they had no significant differences in demographics, comorbid conditions, severity of illness, or vancomycin-associated nephrotoxicity risk factors. The frequency of nephrotoxicity was 8.9% in the Pfizer group and 11.0% in the Hospira group as defined by the 2009 consensus vancomycin guidelines (P = 0.56), 17.1% in the Pfizer group and 13.0% in the Hospira group as defined by the Acute Kidney Injury Network (AKIN) (P = 0.33), and 10.3% in the Pfizer group and 11.6% in the Hospira group as defined by RIFLE (risk, injury, failure, loss, and end-stage renal disease) criteria (P = 0.71). There were no differences between groups in regard to nephrotoxicity by any definition or in secondary outcomes. In multivariate analysis of overall nephrotoxicity risk factors, the type of vancomycin product was not independently associated with increased odds of developing nephrotoxicity according to the RIFLE criteria. Based on our results, there are no discernible differences between Pfizer and Hospira vancomycin products in the frequency of nephrotoxicity. Confirmation of these results with other types of vancomycin and different patient populations is warranted.

Dense dissimilar waveguide routing for highly efficient thermo-optic switches on silicon.

We analyze and demonstrate a method for increasing the efficiency of thermo-optic phase shifters on a silicon-on-insulator platform. The lack of cross-coupling between dissimilar waveguides allows highly dense waveguide routing under heating elements and a corresponding increase in efficiency. We demonstrate a device with highly dense routing of 9 waveguides under a 10 µm wide heater and achieve a low switching power of 95 µW, extinction ratio greater than 20 dB, and less than 0.1 dB ripple in the through spectrum with a footprint of less than 800 µm × 180 µm. The increase in waveguide density is found not to negatively impact the switch response time.

Wavelength tuning and stabilization of microring-based filters using silicon in-resonator photoconductive heaters.

We demonstrate that n-doped resistive heaters in silicon waveguides show photoconductive effects with high responsivities. These photoconductive heaters, integrated into microring resonator (MRR)-based filters, were used to automatically tune and stabilize the filter's resonance wavelength to the input laser's wavelength. This is achieved without requiring dedicated defect implantations, additional material depositions, dedicated photodetectors, or optical power tap-outs. Automatic wavelength stabilization of first-order MRR and second-order series-coupled MRR filters is experimentally demonstrated. Open eye diagrams were obtained for data transmission at 12.5 Gb/s while the temperature was varied by 5 °C at a rate of 0.28 °C/s. We theoretically show that series-coupled MRR-based filters of any order can be automatically tuned by using photoconductive heaters to monitor the light intensity in each MRR, and sequentially aligning the resonance of each MRR to the laser's wavelength.

Silicon-on-insulator sensors using integrated resonance-enhanced defect-mediated photodetectors.

A resonance-enhanced, defect-mediated, ring resonator photodetector has been implemented as a single unit biosensor on a silicon-on-insulator platform, providing a cost effective means of integrating ring resonator sensors with photodetectors for lab-on-chip applications. This method overcomes the challenge of integrating hybrid photodetectors on the chip. The demonstrated responsivity of the photodetector-sensor was 90 mA/W. Devices were characterized using refractive index modified solutions and showed sensitivities of 30 nm/RIU.

The influence of anthropogenic regulation and evaporite dissolution on earthquake-triggered ground failure.

Remote sensing observations of Searles Lake following the 2019 moment magnitude 7.1 Ridgecrest, California, earthquake reveal an area where surface ejecta is arranged in a repeating hexagonal pattern that is collocated with a solution-mining operation. By analyzing geologic and geotechnical data, here we show that the hexagonal surface ejecta is likely not a result of liquefaction. Instead, we propose dissolution cavity collapse (DCC) as an alternative driving mechanism. We support this theory with pre-event Interferometric Synthetic Aperture Radar data, which reveals differential subsidence patterns and the creation of subsurface void space. We also find that DCC is likely triggered at a lower shaking threshold than classical liquefaction. This and other unknown mechanisms can masquerade as liquefaction, introducing bias into liquefaction prediction models that rely on liquefaction inventories. This paper also highlights the opportunities and drawbacks of using remote sensing data to disentangle the complex factors that influence earthquake-triggered ground failure.

Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L: a matched cohort study.

BACKGROUND: Recent reports have described decreased effectiveness with vancomycin treatment for methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) when the vancomycin minimum inhibitory concentration (MIC) is >1 µg/mL. METHODS: This matched, retrospective cohort study compared the clinical effectiveness of daptomycin with that of vancomycin for the treatment of MRSAB with vancomycin MICs >1 µg/mL. The primary outcome was clinical failure, defined as a composite of 30-day mortality or bacteremia persisting for ≥7 days. RESULTS: One hundred seventy patients were matched 1:1 with respect to the antimicrobial administered. In the daptomycin group, all patients received <72 hours of vancomycin (median, 1.7 days [interquartile range, 1.1-2.3 days]) prior to switching to daptomycin. The rate of clinical failure at 30 days was significantly lower in the daptomycin arm compared to the vancomycin arm (20.0% vs 48.2%; P < 0.001). Both 30-day mortality and persistent bacteremia were significantly lower in the daptomycin group compared to the vancomycin group (3.5% vs 12.9% [P = .047] and 18.8% vs 42.4% [P = .001], respectively). Logistic regression confirmed the association between vancomycin treatment and increased risk of clinical failure (adjusted odds ratio, 4.5; 95% confidence interval, 2.1-9.8). CONCLUSIONS: This is the first matched study comparing early daptomycin versus vancomycin for the treatment of MRSAB when the vancomycin MIC is >1 µg/mL. Treatment with daptomycin resulted in significantly improved outcomes, including decreased 30-day mortality and persistent bacteremia. These results support the practice of switching early from vancomycin to daptomycin for the treatment of MRSAB when the vancomycin MIC is >1 µg/mL.

State-scale perspective on water use and production associated with oil and gas operations, Oklahoma, U.S.

A common goal of water and energy management is to maximize the supply of one while minimizing the use of the other, so it is important to understand the relationship between water use and energy production. A larger proportion of horizontal wells and an increasing number of hydraulically fractured well bores are being completed in the United States, and consequently increasing water demand by oil and gas operations. Management, planning, and regulatory decisions for water, oil, and gas are largely made at the state-level; therefore, it is necessary to aggregate water use and energy production data at the state-scale. The purpose of this paper is to quantify annual volumes of water used for completion of oil and gas wells, coproduced during oil and gas production, injected via underground injection program wells, and used in water flooding operations. Data from well completion reports, and tax commission records were synthesized to arrive at these estimates for Oklahoma. Hydraulic fracturing required a median fluid volume of 11,350 m(3) per horizontal well in Oklahoma. Median fluid volume (~15,774 m(3)) and volume per perforated interval (15.73 m(3) m(-1)) were highest for Woodford Shale horizontal wells. State-scale annual water use for oil and gas well completions was estimated to be up to 16.3 Mm(3) in 2011 or less than 1% of statewide freshwater use. Statewide annual produced water volumes ranged from 128.5 to 146.6 Mm(3), with gas wells yielding an estimated 72.4% of the total coproduced water. Volumes of water injected into underground injection control program wells ranged from 206.8 to 305.4 Mm(3), which indicates that water flooding operations may use up to 167.0 Mm(3) per year. State-scale water use estimates for Oklahoma could be improved by requiring oil and gas operators to supplement well completion reports with water use and water production data. Reporting of oil and gas production data by well using a unique identifier (i.e., API number) would also allow for refinement of produced water quantity information. Reporting of wastewater disposal and water flooding volumes could be used to further develop state-scale water accounting and best management practices.