In vitro evaluation of using ceftazidime/avibactam against carbapenem-resistant Acinetobacter baumannii.

OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a global concern as effective treatments are very limited. We previously used a modified susceptibility testing approach to predict growth suppression in carbapenem-resistant Enterobacterales, but there are uncertainties about the generalizability of the model. The objective of this study is to verify if a similar approach can be extended to CRAB. METHOD: A clinical isolate of CRAB resistant to ceftazidime/avibactam (CAZ/AVI, MIC=32/4 mg/L) was examined. CAZ susceptibility was determined using increasing concentrations of AVI (0-64 mg/L), and MIC reduction was characterized with a sigmoid inhibitory maximum effect (Emax) model. The effectiveness of CAZ/AVI was validated in a hollow fiber infection model (HFIM) over 72 hours, using simulated unbound serum / epithelial lining fluid (ELF) exposures of 2.5 g over 2 hours every 8 hours. Baseline inocula of approximately 5.5 log CFU/mL were examined. RESULTS: An AVI concentration-dependent reduction in CAZ MIC was observed (r2=0.99). Ceftazidime MIC was dramatically reduced from 512 mg/L (no AVI) to 32 mg/L (AVI=4 mg/L), and further to 8 mg/L (AVI=16 mg/L). Pharmacokinetic simulations were satisfactory in the HFIM (r2>0.96). Bacterial suppression was observed > 24 hours with the serum exposure, but not that from the ELF. CONCLUSION: Using multiple AVI concentrations within the clinically relevant range, our susceptibility testing approach could have better insights of treatment outcome for infections caused by CRAB. This could potentially lead to effective intervention(s) overlooked by conventional susceptibility testing method. This case highlights the importance of site-specific drug exposures on determining treatment outcome.

Zileuton ameliorates aminoglycoside and polymyxin-associated acute kidney injury in an animal model.

OBJECTIVES: Aminoglycosides and polymyxins are antibiotics with in vitro activity against MDR Gram-negative bacteria. However, their clinical use is hindered by dose-limiting nephrotoxicity. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury. METHODS: Sprague Dawley rats (n = 10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 min before antibiotic administration. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥2× elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was also conducted to characterize the extent of kidney injury. RESULTS: Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100%, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton at 4 and 10 mg/kg, respectively. Histopathology confirmed reduced kidney injury in animals receiving amikacin concomitant with zileuton. CONCLUSIONS: Our pilot data suggest that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat MDR Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and dosing in humans.

Prevalence of Glaucoma Following Paediatric Cataract Surgery in an Australian Tertiary Referral Centre.

Purpose: Secondary glaucoma following childhood cataract surgery remains the most common complication in the paediatric population. This study aimed to determine the incidence, time to progression and risk factors associated with the development of secondary glaucoma following childhood cataract surgery in a paediatric population. Outcome measures were the detection of secondary glaucoma, postoperative time frame to development of glaucoma and risk factors in its development. Patients and Methods: A retrospective case series was conducted between 2003 and 2017 at a tertiary children's hospital in Sydney. The patient population included those 16 years or less of age who underwent congenital cataract extraction, with or without an intraocular lens implantation and who had been followed up for a minimum of six months following surgery. Patients were excluded if they had cataract aetiology other than congenital idiopathic cataract. Multivariate Cox Regression analysis was used to determine relevant risk factors. Results: A total of 320 eyes in 216 patients were included in the study. Secondary glaucoma developed in 11.9% of eyes. In those that developed secondary glaucoma, the average time to onset from surgery was 3.2 years (median 2.75 years). The mean age of diagnosis of secondary glaucoma was 4.58 years (median 3.5 years, range 2.5 months to 13.23 years). Microcornea was the only adverse characteristic significantly associated with an increased risk of secondary glaucoma (HR 6.30, p 0.003). Conclusion: Despite modern surgical techniques, glaucoma remains a significant long-term sequela in children following cataract surgery.

In vitro model to simulate multiple drugs with distinct elimination half-lives.

OBJECTIVE: The prevalence of drug resistance in pathogens such as HIV and selected bacteria has been steadily rising, resulting in an increased need for using multiple agents concurrently. Agents used in these combination therapies may have different elimination half-lives in humans. There is an unmet need for in vitro models to evaluate the efficacy of these combinations to guide early drug development. In order to realistically reflect in vivo conditions, useful in vitro model systems must be capable of simulating multiple pharmacokinetic profiles with distinct elimination half-lives. The goal of this study was to experimentally simulate four pharmacokinetic profiles with distinct elimination half-lives in an in vitro hollow-fibre system. METHODS: For illustrative purposes, fluctuating exposures of ceftriaxone were simulated with distinct half-lives of 1, 2.5, 8, and 12 hours. A parallel experimental setup was used to independently connect four supplemental reservoirs to a central reservoir. Target maximum concentration was achieved by direct drug dosing into the central reservoir; supplemental reservoirs were also dosed to offset the rapid drug elimination rate from the central reservoir. Serial pharmacokinetic samples were obtained from the central reservoir, assayed by a spectrophotometric method, and characterized by a one-compartment model. RESULTS: The observed maximum concentrations and elimination half-lives were in agreement with the expected values obtained from the mathematical predictions. CONCLUSIONS: This in vitro experimental system can be used to evaluate the efficacy of up to four-drug combinations against multidrug-resistant bacteria or HIV-infected mammalian cells. The established framework represents an adaptable tool to advance the field of combination therapy.

Wildfires correlate with reductions in aboveground tree carbon stocks and sequestration capacity on forest land in the Western United States.

In the United States (US), forest ecosystems are the largest terrestrial carbon sink, offsetting the equivalent of >12 % of economy-wide greenhouse gas (GHG) emissions annually. In the Western US, wildfires have shaped much of the landscape by changing forest structure and composition, increasing tree mortality, impacting forest regeneration, and influencing forest carbon storage and sequestration capacity. Here, we used remeasurements of >25,000 plots from the US Department of Agriculture, Forest Service Forest Inventory and Analysis (FIA) program and auxiliary information (e.g., Monitoring Trends in Burn Severity) to characterize the role of fire along with other natural and anthropogenic drivers on estimates of carbon stocks, stock changes, and sequestration capacity on forest land in the Western US. Several biotic (e.g., tree size, species, and forest structure) and abiotic factors (e.g., warm climate, severe drought, compound disturbances, and anthropogenic interventions) influenced post-fire tree mortality and regeneration and had concomitant impacts on carbon stocks and sequestration capacity. Forest ecosystems in a high severity and low frequency wildfire regime had greater reductions in aboveground biomass carbon stocks and sequestration capacity compared to forests in a low severity and high frequency fire regime. Results from this study can improve our understanding of the role of wildfire along with other biotic and abiotic drivers on carbon dynamics in forest ecosystems in the Western US.

Multizone Aquatic Ecological Exposures to Landfill Contaminants from a Groundwater Plume Discharging to a Pond.

While it is recognized that groundwater contaminant plumes can impact surface waters, there remains little information on the magnitude, spatial extent, and especially temporal variability of the resulting exposure to the variety of aquatic organisms, particularly for stagnant surface waters (e.g., ponds). The present study of a historic landfill plume discharging to a pond investigated contaminant exposure to multiple aquatic zones (endobenthic, epibenthic, pelagic) over approximately 1 year within a temperate climate. Landfill tracers included the artificial sweetener saccharin, ammonium, chloride, and specific conductance. Sampling of pond sediment porewater (upwelling groundwater) and continuous geophysical imaging of the subsurface showed a relatively stable plume footprint covering approximately 26% of the pond, although with spatially varying leachate composition, revealing year-round exposure to endobenthic (within sediments) organisms. Substantial and variable contaminant exposure to epibenthic organisms within the plume footprint was shown by elevated specific conductance measured directly above the sediment interface. Exposure varied daily at times and increased through winter to values representing undiluted plume groundwater. Exposure to pelagic organisms (overlying water) covered a larger area (~50%) due to in-pond circulation. The stream outlet concentrations were stable at approximately 10 times dilution for chloride and saccharin, but were substantially less in summer for ammonium due to in-pond processes. Whereas groundwater contaminants are typically assumed elevated at base flows, the outlet stream contaminant mass discharges to downstream receptors were notably higher in winter than summer, following stream flow patterns. Insights from the present study into the timings and locations of contaminant plume exposure to multiple ecological zones of a pond can provide guidance to contaminated site and aquatic ecosystem managers on improved monitoring, assessment, and remediation protocols. Environ Toxicol Chem 2023;42:1667-1684. © 2023 His Majesty the King in Right of Canada and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. Reproduced with the permission of the Minister of Environment and Climate Change Canada.

Aboveground live tree carbon stock and change in forests of conterminous United States: influence of stand age.

BACKGROUND: Sequestration of carbon on forest land is a common and practical component within many climate action plans developed by state or municipal governments. Initial planning often identifies the general magnitude of sequestration expected given the scope of the project. Because age plays a key role in forest carbon dynamics, we summarize both the carbon stock and accumulation rates in live trees by age class and region, allowing managers and policymakers to assess the influence of forest age class structure on forest carbon storage as represented in current inventories. State-level information is provided in supplementary tables. RESULTS: Average regional aboveground live tree carbon stocks (represented on a per area basis) range from 11.6 tC/ha in the Great Plains to 130 tC/ha in the Pacific Northwest West (west-side of Cascades) and increase with age in all regions, although in three regions carbon stock declined in the oldest age class. Regional average annual net change in live aboveground tree carbon varies from a low of - 0.18 tC /ha/yr in the Rocky Mountain South region to a high value of 1.74 tC/ha/yr in Pacific Northwest West. In all regions except Rocky Mountain South, accumulation rates are highest in the younger age classes and decline with age, with older age classes in several western regions showing negative rates. In the Southeast and Pacific Northwest West, intermediate age classes exhibit lower rates, likely due to harvesting activity. CONCLUSIONS: Aboveground live tree carbon stocks increase and rates of average change decrease with age with few exceptions; this pattern holds when examining hardwood and softwood types individually. Because multiple forest management objectives are often considered and tradeoffs need to be assessed, we recommend considering both measures-standing stock and average annual change-of carbon storage. The relative importance of each component depends on management and policy objectives and the time frame related to those objectives. Harvesting and natural disturbance also affect forest carbon stock and change and may need to be considered if developing projections of potential carbon storage. We present forest carbon summaries at a scale and scope to meet information needs of managers and policymakers.

Full Configuration Interaction Excited-State Energies in Large Active Spaces from Subspace Iteration with Repeated Random Sparsification.

We present a stable and systematically improvable quantum Monte Carlo (QMC) approach to calculating excited-state energies, which we implement using our fast randomized iteration method for the full configuration interaction problem (FCI-FRI). Unlike previous excited-state quantum Monte Carlo methods, our approach, which is based on an asymmetric variant of subspace iteration, avoids the use of dot products of random vectors and instead relies upon trial vectors to maintain orthogonality and estimate eigenvalues. By leveraging recent advances, we apply our method to calculate ground- and excited-state energies of challenging molecular systems in large active spaces, including the carbon dimer with 8 electrons in 108 orbitals (8e,108o), an oxo-Mn(salen) transition metal complex (28e,28o), ozone (18e,87o), and butadiene (22e,82o). In the majority of these test cases, our approach yields total excited-state energies that agree with those from state-of-the-art methods─including heat-bath CI, the density matrix renormalization group approach, and FCIQMC─to within sub-milliHartree accuracy. In all cases, estimated excitation energies agree to within about 0.1 eV.

Near-exact nuclear gradients of complete active space self-consistent field wave functions.

In this paper, we study the nuclear gradients of heat bath configuration interaction self-consistent field (HCISCF) wave functions and use them to optimize molecular geometries for various molecules. We show that HCISCF nuclear gradients are fairly insensitive to the size of the "selected" variational space, which allows us to reduce the computational cost without introducing significant errors. The ability of the HCISCF to treat larger active spaces combined with the flexibility for users to control the computational cost makes the method very attractive for studying strongly correlated systems, which require a larger active space than possible with a complete active space self-consistent field. Finally, we study the realistic catalyst, Fe(PDI), and highlight some of the challenges this system poses for density functional theory (DFT). We demonstrate how HCISCF can clarify the energetic stability of geometries obtained from DFT when the results are strongly dependent on the functional. We also use the HCISCF gradients to optimize geometries for this species and study the adiabatic singlet-triplet gap. During geometry optimization, we find that multiple near-degenerate local minima exist on the triplet potential energy surface.

Predicting downed woody material carbon stocks in forests of the conterminous United States.

Downed woody material (DWM) is a unique part of the forest carbon cycle serving as a pool between living biomass and subsequent atmospheric emission or transference to other forest pools. Thus, DWM is an individually defined pool in national greenhouse gas inventories. The diversity of DWM carbon drivers (e.g., decay, tree mortality, or wildfire) and associated high spatial variability make this a difficult-to-predict component of forest ecosystems. Using the now fully established nationwide inventory of DWM across the United States (US), we developed models, which substantially improved predictions of stand-level DWM carbon density relative to the current national-reporting model ('previous' model, here). The previous model was developed from published DWM carbon densities prior to the NFI DWM inventory. Those predictions were tested using NFI DWM carbon densities resulting in a poor fit to the data (coefficient of determination, or R2 = 0.03). We present new random forest (RF) and stochastic gradient boosted (SGB) regression models to prediction DWM carbon density on all NFI plots and spatially on all forest land pixels. We evaluated various biotic and abiotic regression predictors, and the most important were standing dead trees, long-term annual precipitation, and long-term maximum summer temperature. A RF model scored best for expanding predictions to NFI plots (R2 = 0.31), while an SGB model was identified for DWM carbon predictions based on purely spatial data (i.e., NFI-plot-independent, with R2 = 0.23). The new RF model predicts conterminous US DWM carbon stocks to be 15% lower than the previous model and 2% higher than NFI data expanded according to inventory design-based inference. The new NFI data-driven models not only improve the predictions of DWM carbon density on all plots, they also provide flexibility in extending these predictions beyond the NFI to make spatially explicit and spatially continuous estimates of DWM carbon on all forest land in the US.

Modeling Hepatitis C Elimination Among People Who Inject Drugs in New Hampshire.

Importance: The success of direct-acting antiviral therapies for chronic hepatitis C virus (HCV) infection led the World Health Organization to set elimination targets by 2030. For the United States to achieve these benchmarks, public health responses must target high-risk populations, such as people who inject drugs (PWID), a group with high rates of HCV incidence and low rates of treatment uptake. Objective: To evaluate potential improvements in the HCV care cascade among PWID, focusing on improved testing, treatment uptake, and access to harm reduction. Design, Setting, and Participants: This decision analytic model used a differential equation-based dynamic transmission model based on data from New Hampshire, an illustrative state with a large number of PWID and limited HCV treatment infrastructure. Surveillance data through 2020 was used for model parameterization, and the final analysis was conducted in May 2021. Main Outcomes and Measures: Model forecasts of chronic HCV cases and advanced-stage HCV outcomes from 2022 to 2045. Results: A total of 6 scenarios were tested: (1) the base case, (2) improved harm reduction, (3) improved testing, (4) improved treatment, (5) improved testing and treatment, and (6) improved testing, treatment, and harm reduction. All scenarios with improved testing, treatment uptake, and/or access to harm reduction were associated with decreases in forecasted HCV prevalence and HCV-associated mortality compared with the base case. Improving harm reduction, testing, and treatment individually were forecast to reduce prevalence of HCV in 2045 from 69.7% in the base case to 62.8%, 45.7%, and 35.5%, respectively. Combining treatment and testing improvements was associated with a 2045 prevalence of 0.3%; adding harm reduction improvements was associated with further reductions in prevalence forecasts (to 0.2%), with fewer total treatments (10 960 vs 13 219 from 2022-2045). Conclusions and Relevance: In this modeling study, no single intervention was projected to achieve World Health Organization HCV elimination targets. Scenarios with improvements in both testing and treatment were associated with a prevalence of less than 3% by 2030 and achieved elimination targets. Adding improvements in harm reduction was associated with faster reductions in prevalence and fewer treatments.

Current aboveground live tree carbon stocks and annual net change in forests of conterminous United States.

BACKGROUND: With the introduction of the Trillion Trees Initiative and similar programs, forests' ability to absorb carbon dioxide is increasingly in the spotlight. Many states have mandates to develop climate action plans, of which forest carbon is an important component, and planners need current information on forest carbon stocks and rates of change at relevant spatial scales. To this end, we examine rates of average annual change in live aboveground tree carbon in different forest type groups and provide state-wide and regional summaries of current live tree carbon stock and rates of change for the forests of the conterminous United States. Forest carbon summaries are presented in a format designed to meet the needs of managers, policymakers, and others requiring current estimates of aboveground live tree carbon at state and regional scales. RESULTS: Regional average aboveground live tree carbon stocks (represented on a per area basis) are generally between 40 and 75 tC/ha but range from 12.8 tC/ha in the Great Plains to 130 tC/ha in the Pacific Northwest West (west-side of Cascades). Regional average annual change in live aboveground tree carbon varies from a low of - 0.18 mtC/ha/y in the Rocky Mountain South to a high value of 1.74 mtC/ha/y in Pacific Northwest West. For individual states, carbon per unit area varies widely, from a low of 11.9 tC/ha in Nevada to a high of 96.4 tC/ha in Washington, with half the states falling between 50 and 75 tC/ha. Rates of average annual change in live aboveground tree carbon vary from a high of 1.82 tC/ha/y in Mississippi to a low of - 0.47 tC/ha/y in Colorado. CONCLUSIONS: Aboveground live tree carbon stocks and rates of average annual change vary by forest type within regions. While softwood forest types currently exhibit a higher rate of increase in the amount of carbon in aboveground live tree biomass, the current standing stock of carbon per unit area does not consistently follow this pattern. For this reason, we recommend computing and considering both measures -standing stock and average annual change-of carbon storage. The relative importance of each component will depend on management and policy objectives and the time frame related to those objectives. Harvesting and natural disturbance also affect forest carbon stock and change and may need to be considered if developing projections of potential carbon storage.

Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry.

PURPOSE: To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort. DESIGN: Retrospective clinical and molecular study. PARTICIPANTS: All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry. METHODS: We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma. MAIN OUTCOME MEASURES: The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age. RESULTS: A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n = 29, 23.2%) and heterozygous variants in MYOC (n = 24, 19.2%) and FOXC1 (n = 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P = 0.02). CONCLUSIONS: We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis.

Assessing and managing SARS-CoV-2 occupational health risk to workers handling residuals and biosolids.

Current wastewater worker guidance from the United States Environmental Protection Agency (USEPA) aligns with the Centers for Disease Control and Prevention (CDC) and the Occupational Safety and Health Administration (OSHA) recommendations and states that no additional specific protections against SARS-CoV-2, the virus that causes COVID-19 infections, are recommended for employees involved in wastewater management operations with residuals, sludge, and biosolids at water resource recovery facilities. The USEPA guidance references a document from 2002 that summarizes practices required for protection of workers handling class B biosolids to minimize exposure to pathogens including viruses. While there is no documented evidence that residuals or biosolids of any treatment level contain infectious SARS-CoV-2 or are a source of transmission of this current pandemic strain of coronavirus, this review summarizes and examines whether the provided federal guidance is sufficient to protect workers in view of currently available data on SARS-CoV-2 persistence and transmission. No currently available epidemiological data establishes a direct link between wastewater sludge or biosolids and risk of infection from the SARS-CoV-2. Despite shedding of the RNA of the virus in feces, there is no evidence supporting the presence or transmission of infectious SARS-CoV-2 through the wastewater system or in biosolids. In addition, this review presents previous epidemiologic data related to other non-enveloped viruses. Overall, the risk for exposure to SARS-CoV-2, or any pathogen, decreases with increasing treatment measures. As a result, the highest risk of exposure is related to spreading and handling untreated feces or stool, followed by untreated municipal sludge, the class B biosolids, while lowest risk is associated with spreading or handling Class A biosolids. This review reinforces federal recommendations and the importance of vigilance in applying occupational risk mitigation measures to protect public and occupational health.

Organic contaminants of emerging concern in leachate of historic municipal landfills.

Many types of contaminants of emerging concern (CECs), including per- and poly-fluoroalkyl substances (PFAS), have been found in leachate of operating municipal landfills. However, there is only limited information on CECs presence in leachate of historic landfills (≥3 decades since closure, often lacking engineered liners or leachate collection systems) at concentrations that may pose a risk to nearby wells and surface water ecosystems. In this study, 48 samples of leachate-impacted groundwater were collected from 20 historic landfills in Ontario, Canada. The CECs measured included artificial sweeteners (ASs), PFAS, organophosphate esters (OPE), pharmaceuticals, bisphenols, sulfamic acid, perchlorate, and substituted phenols. The common presence of the AS saccharin, a known indicator of old landfill leachate, combined with mostly negligible levels of the AS acesulfame, an indicator of modern wastewater, revealed that most samples were strongly influenced by leachate and not cross-contaminated by wastewater (which can contain these same CECs). Several landfills, including ones closed in the 1960s, had total PFAS concentrations similar to those previously measured at modern landfills, with a maximum observed here of 12.7 µg/L. Notably elevated concentrations of several OPE, sulfamic acid, cotinine, and bisphenols A and S were found at many 30-60 year-old landfills. There was little indication of declining concentrations with landfill age, suggesting historic landfills can be long-term sources of CECs to groundwater and that certain CECs may be useful tracers for historic landfill leachate. These findings provide guidance on which CECs may require monitoring at historic landfill sites and wastewater treatment plants receiving their effluent.

Using Lean Six Sigma techniques to improve efficiency in outpatient ophthalmology clinics.

BACKGROUND: Increasing patient numbers, complexity of patient management, and healthcare resource limitations have resulted in prolonged patient wait times, decreased quality of service, and decreased patient satisfaction in many outpatient services worldwide. This study investigated the impact of Lean Six Sigma, a service improvement methodology originally from manufacturing, in reducing patient wait times and increasing service capacity in a publicly-funded, tertiary referral outpatient ophthalmology clinic. METHODS: This quality improvement study compared results from two five-months audits of operational data pre- and post-implementation of Lean Six Sigma. A baseline audit was conducted to determine duration and variability of patient in-clinic time and number of patients seen per clinic session. Staff interviews and a time-in-motion study were conducted to identify issues reducing clinic service efficiency. Solutions were developed to address these root causes including: clinic schedule amendments, creation of dedicated postoperative clinics, and clear documentation templates. A post-implementation audit was conducted, and the results compared with baseline audit data. Significant differences in patient in-clinic time pre- and post-solution implementation were assessed using Mann-Whitney test. Differences in variability of patient in-clinic times were assessed using Brown-Forsythe test. Differences in numbers of patients seen per clinic session were assessed using Student's t-test. RESULTS: During the baseline audit period, 19.4 patients were seen per 240-minute clinic session. Median patient in-clinic time was 131 minutes with an interquartile range of 133 minutes (84-217 minutes, quartile 1- quartile 3). Targeted low/negligible cost solutions were implemented to reduce in-clinic times. During the post-implementation audit period, the number of patients seen per session increased 9% to 21.1 (p = 0.016). There was significant reduction in duration (p < 0.001) and variability (p < 0.001) of patient in-clinic time (median 107 minutes, interquartile range 91 minutes [71-162 minutes]). CONCLUSIONS: Lean Six Sigma techniques may be used to reduce duration and variability of patient in-clinic time and increase service capacity in outpatient ophthalmology clinics without additional resource input.

Intrinsic electronic spectra of cryogenically prepared protoporphyrin IX ions in vacuo - deprotonation-induced Stark shifts.

We present electronic spectra containing the Qx and Qy absorption bands of singly and doubly deprotonated protoporphyrin IX, prepared as mass selected ions in vacuo at cryogenic temperatures, revealing vibronic structure in both bands. We assign the vibronic progression of the Qx band using a Frank-Condon-Herzberg-Teller simulation based on time-dependent density functional theory, comparing the observed bands with those calculated for porphine. A comparison of the electronic spectra of the two charge states allows investigation of the electronic Stark effect with an electric field strength beyond the capabilities of typical laboratory setups. We analyze the differences in the electronic spectra of the two charge states using n-electron valence perturbation theory (NEVPT2) and simulated charge distributions.

Recent developments in the PySCF program package.

PySCF is a Python-based general-purpose electronic structure platform that supports first-principles simulations of molecules and solids as well as accelerates the development of new methodology and complex computational workflows. This paper explains the design and philosophy behind PySCF that enables it to meet these twin objectives. With several case studies, we show how users can easily implement their own methods using PySCF as a development environment. We then summarize the capabilities of PySCF for molecular and solid-state simulations. Finally, we describe the growing ecosystem of projects that use PySCF across the domains of quantum chemistry, materials science, machine learning, and quantum information science.