Comparing Antoine parameter sources for accurate vapor pressure prediction across a range of temperatures.

Determining the vapor pressure of a substance at the relevant process temperature is a key component in conducting an exposure assessment to ascertain worker exposure. However, vapor pressure data at various temperatures relevant to the work environment is not readily available for many chemicals. The Antoine equation is a mathematical expression that relates temperature and vapor pressure. The objective of this analysis was to compare Antoine parameter data from 3 independent data sources; Hansen, Yaws, and Custom data and identify the source that generates the most accurate vapor pressure values with the least bias, relative to the referent data set from the CRC Handbook of Chemistry and Physics. Temperatures predicted from 3 different Antoine sources across a range of vapor pressures for 59 chemicals are compared to the reference source. The results show that temperatures predicted using Antoine parameters from the 3 sources are not statistically significantly different, indicating that all 3 sources could be useful. However, the Yaws dataset will be used in the SDM 2.0 because the data is readily available and robust.

Micro-environmental factors impact breathing zone exposures: A simulated petrochemical manufacturing facility task.

This study investigates the impact of micro-environmental factors on worker breathing zone exposure levels in petrochemical facilities. A laboratory simulation study evaluated near-field exposure to methane for a typical maintenance task. Individual and combinations of micro-environmental factors significantly affected methane exposure. Airflow direction and speed were significant determinants of exposure concentration reduction. A side airflow direction at medium to high speed produced the lowest gas concentration in the breathing zone. Worker body orientation relative to the methane emission point was also a critical factor affecting gas concentration in the worker's breathing zone. The study provides insights into how variations in airflow and small changes in position impact near-field exposures for petrochemical tasks, guiding industrial hygiene professionals' training on qualitative exposure estimation and providing input for near-field exposure modeling to guide quantitative exposure and risk assessment.

Face anthropometry for filtering facepiece respirators: analysis of the association between facial dimensions and respirator fit.

OBJECTIVE: Ensuring proper respirator fit for individuals remains a persistent challenge in occupational environments, yet there is limited knowledge about how respirators interact with the face to "'fit." Previous studies have attempted to understand the association between face dimensions and respirator fit using traditional head/face anthropometry not specifically tailored for respirators. The purpose of this study was to assess and compare the ability of filtering facepiece respirator (FFR)-specific face anthropometry with traditional head/face anthropometry in exploring the relationship between facial dimensions and the fit of FFR. METHODS: The study utilized 3D face scans and quantitative fit factor scores from 56 participants to investigate the relationship between face anthropometry and FFR fit. Both FFR-specific and traditional anthropometric measurements were obtained through 3D anthropometric software. Intra-correlation of anthropometry was analyzed to evaluate the efficiency and effectiveness of FFR-specific and traditional anthropometry respectively. Principal component analysis (PCA) was conducted to test the usefulness of the PCA method for investigating various facial features. Logistic regression was used to develop fit association models by estimating the relationship between each face measurement set and the binary outcome of the fit test result. The prediction accuracy of the developed regression models was tested. RESULTS: FFR-specific face anthropometry consists of a set of measurements that can inform the detailed facial shape associated with the FFRs more effectively than traditional head/face anthropometry. While PCA may have been effective in reducing the variable dimensions for the relatively large parts of the human body such as upper and lower bodies in previous literature, PCA results of FFR-specific and traditional anthropometry were inconsistent and insufficient to describe face dimensions with complex anatomy in a small-detailed area, suggesting that facial shape should be understood through a variety of approaches including statistical methods. Logistic regression analysis results confirmed that the association models of FFR-specific face anthropometry were significant with higher prediction accuracy and had a better model's goodness of fit than those of traditional head/face anthropometry in 3 conditions inputting all measurements, all PC scores, or top 5 measurements from PCA. CONCLUSIONS: The findings showed that the FFR fit association model enables an understanding of the detailed association between face and respirator fit and allows for the development of a system to predict respirator fit success or failure based on facial dimensions. Future research would include testing the validity of the model and FFR-specific measurement set on different respirator types, expanding the population set, and developing an integrated approach using automated and machine learning technologies to inform FFR selection for occupation workers and the general population.

Guidelines for Specialized Epilepsy Centers: Executive Summary of the Report of the National Association of Epilepsy Centers Guideline Panel.

The National Association of Epilepsy Centers first published the guidelines for epilepsy centers in 1990, which were last updated in 2010. Since that update, epilepsy care and the science of guideline development have advanced significantly, including the importance of incorporating a diversity of stakeholder perspectives such as those of patients and their caregivers. Currently, despite extensive published data examining the efficacy of treatments and diagnostic testing for epilepsy, there remain significant gaps in data identifying the essential services needed for a comprehensive epilepsy center and the optimal manner for their delivery. The trustworthy consensus-based statements (TCBS) process produces unbiased, scientifically valid guidelines through a transparent process that incorporates available evidence and expert opinion. A systematic literature search returned 5937 relevant studies from which 197 articles were retained for data extraction. A panel of 41 stakeholders with diverse expertise evaluated this evidence and drafted recommendations following the TCBS process. The panel reached consensus on 52 recommendations covering services provided by specialized epilepsy centers in both the inpatient and outpatient settings in major topic areas including epilepsy monitoring unit care, surgery, neuroimaging, neuropsychology, genetics, and outpatient care. Recommendations were informed by the evidence review and reflect the consensus of a broad panel of expert opinions.

Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity.

OBJECTIVE: Characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. METHODS: Children 2 to <21 years old receiving standard of care oral levetiracetam across two opportunistic studies provided blood samples. Levetiracetam plasma PK data were analyzed with a nonlinear mixed-effects modeling approach. Indirect measures for body size and covariates were tested for model inclusion. Individual empirical Bayesian estimates using the final model parameters were compared by obesity status. Monte Carlo simulation using total body weight was performed in children with normal estimated glomerular filtration rate to identify dosing for children with obesity that resulted in comparable exposures to normal weight adults and children after receiving label dosing. RESULTS: The population PK model was developed from 341 plasma concentrations from 169 children. A 1-compartment model best fit the data with fat-free mass as a significant covariate. Compared with children with normal weight, children with obesity had significantly lower body weight-normalized clearance (median [range], 4.77 [1.49-10.44] and 3.71 [0.86-13.55] L/h/70 kg, respectively). After label dosing with the oral formulation in children with obesity 4 to <16 years old, maximum and minimum steady-state concentrations were higher (25% and 41%, respectively [oral solution] and 27% and 19%, respectively [tablet]) compared with children with normal weight. Comparable exposures between children with and without obesity were achieved with weight-tiered dosing regimens of <75 kg or ≥75 kg. CONCLUSIONS: Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight.

Comparison of peripheral leukocyte parameters in patients receiving conventionally and hypofractionated radiotherapy schemes for the treatment of newly diagnosed glioblastoma.

Introduction: Treatment for glioblastomas, aggressive and nearly uniformly fatal brain tumors, provide limited long-term success. Immunosuppression by myeloid cells in both the tumor microenvironment and systemic circulation are believed to contribute to this treatment resistance. Standard multi-modality therapy includes conventionally fractionated radiotherapy over 6 weeks; however, hypofractionated radiotherapy over 3 weeks or less may be appropriate for older patients or populations with poor performance status. Lymphocyte concentration changes have been reported in patients with glioblastoma; however, monocytes are likely a key cell type contributing to immunosuppression in glioblastoma. Peripheral monocyte concentration changes in patients receiving commonly employed radiation fractionation schemes are unknown. Methods: To determine the effect of conventionally fractionated and hypofractionated radiotherapy on complete blood cell leukocyte parameters, retrospective longitudinal concentrations were compared prior to, during, and following standard chemoradiation treatment. Results: This study is the first to report increased monocyte concentrations and decreased lymphocyte concentrations in patients treated with conventionally fractionated radiotherapy compared to hypofractionated radiotherapy. Discussion: Understanding the impact of fractionation on peripheral blood leukocytes is important to inform selection of dose fractionation schemes for patients receiving radiotherapy.

Efficacy and safety of cosibelimab, an anti-PD-L1 antibody, in metastatic cutaneous squamous cell carcinoma.

BACKGROUND: Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab. METHODS: In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety. RESULTS: Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported. CONCLUSIONS: Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT03212404.

Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non-Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Naïve Patients.

Rationale & Objective: Prespecified analyses of the PRO2TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO2TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents. Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial. Setting and Participants: Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD. Intervention: Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa. Outcomes: The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis). Results: In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m2 and who may not have had access to dialysis. Limitations: Different regional treatment patterns of patients with NDD-CKD. Conclusions: The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.

Accuracy of professional judgments for dermal exposure assessment using deterministic models.

The accuracy of exposure judgments, particularly for scenarios where only qualitative information is available or a systematic approach is not used, has been evaluated and shown to have a relatively low level of accuracy. This is particularly true for dermal exposures, where less information is generally available compared to inhalation exposures. Relatively few quantitative validation efforts have been performed for scenarios where dermal exposures are of interest. In this study, a series of dermal exposure judgments were collected from 90 volunteer U.S. occupational health practitioners in a workshop format to assess the accuracy of their judgments for three specific scenarios. Accuracy was defined as the ability of the participants to identify the correct reference exposure category, as defined by the quantitative exposure banding categories utilized by the American Industrial Hygiene Association (AIHA®). The participants received progressively additional information and training regarding dermal exposure assessments and scenario-specific information during the workshop, and the relative accuracy of their category judgments over time was compared. The results of the study indicated that despite substantial education and training in exposure assessment generally, the practitioners had very little experience in performing dermal exposure assessments and a low level of comfort in performing these assessments. Further, contrary to studies of practitioners performing inhalation exposure assessments demonstrating a trend toward underestimating exposures, participants in this study consistently overestimated the potential for dermal exposure without quantitative data specific to the scenario of interest. Finally, it was found that participants were able to identify the reference or "true" category of dermal exposure acceptability when provided with relevant, scenario-specific dermal and/or surface-loading data for use in the assessment process. These results support the need for additional training and education of practitioners in performing dermal exposure assessments. A closer analysis of default loading values used in dermal exposure assessments to evaluate their accuracy relative to real-world or measured dermal loading values, along with consistent improvements in current dermal models, is also needed.

Developing wipe sampling strategy guidance for assessing environmental contamination of antineoplastic drugs.

Surveillance for environmental contamination of antineoplastic drugs has been recommended by authoritative bodies such as the United States Pharmacopeia and the National Association of Pharmacy Regulatory Authorities. Clear guidance is needed on how to develop sampling strategies that align with surveillance objectives efficiently and effectively. We conducted a series of simulations using previously collected surveillance data from nine cancer treatment centers to evaluate different sampling strategies. We evaluated the impact of sampling 2, 5, 10, or 20 surfaces, at monthly, quarterly, semi-annual, and annual frequencies, while employing either a random or sentinel surface selection strategy to assess contamination by a single antineoplastic drug (AD) or by a panel of three ADs. We applied two different benchmarks: a binary benchmark of above or below the limit of detection and AD-specific hygienic guidance values, based on 90th percentile values as quantitative benchmarks. The use of sentinel surfaces to evaluate a three-drug panel relative to 90th percentile hygienic guidance values (HGVs) resulted in the most efficient and effective surveillance strategy.

On-line untargeted metabolomics monitoring of an Escherichia coli succinate fermentation process.

The real-time monitoring of metabolites (RTMet) is instrumental for the industrial production of biobased fermentation products. This study shows the first application of untargeted on-line metabolomics for the monitoring of undiluted fermentation broth samples taken automatically from a 5 L bioreactor every 5 min via flow injection mass spectrometry. The travel time from the bioreactor to the mass spectrometer was 30 s. Using mass spectrometry allows, on the one hand, the direct monitoring of targeted key process compounds of interest and, on the other hand, provides information on hundreds of additional untargeted compounds without requiring previous calibration data. In this study, this technology was applied in an Escherichia coli succinate fermentation process and 886 different m/z signals were monitored, including key process compounds (glucose, succinate, and pyruvate), potential biomarkers of biomass formation such as (R)-2,3-dihydroxy-isovalerate and (R)-2,3-dihydroxy-3-methylpentanoate and compounds from the pentose phosphate pathway and nucleotide metabolism, among others. The main advantage of the RTMet technology is that it allows the monitoring of hundreds of signals without the requirement of developing partial least squares regression models, making it a perfect tool for bioprocess monitoring and for testing many different strains and process conditions for bioprocess development.

Seeking Opportunity in Crisis: Redesigning Care for High-risk Diabetics During the Pandemic.

Management of uncontrolled diabetic (DM) patients has always been a challenge across healthcare settings, but recently we noticed a surge in the number of uncontrolled DM patient in our clinic patients' population during the COVID19 pandemic. This in part a combination of disruptions to care, delayed or inaccessible care, and poor diet and physical activity. To address this issue, we formed a multidisciplinary Diabetes Initiative Team consisting of attending physicians, residents, clinical pharmacist, nurse manager, care manager, and coordinator, along with supportive staffs in our Internal Medicine Residency clinic. Our aim was to reengage diabetic patients in the outpatient setting and to overcome barriers limiting diabetic care.

Estimation of Aerosol Concentrations of Oil Dispersants COREXIT™ EC9527A and EC9500A during the Deepwater Horizon Oil Spill Response and Clean-up Operations.

The April 2010 Deepwater Horizon drilling unit explosion at the Macondo oil well resulted in the release of approximately 779 million l of oil into the Gulf of Mexico. As part of the response effort to break up oil slicks on the water's surface, 6.81 million l of chemical dispersants COREXIT™ EC9500A and COREXIT™ EC9527A were applied by plane or vessel or injected near the seabed. The GuLF Long-term Follow-up Study is investigating possible adverse health effects of workers involved in the oil spill response and clean-up (OSRC). In this paper, we describe potential dispersant-related air concentrations generated from aerial spraying of dispersants to provide insight as to what concentrations OSRC workers may have been exposed under worst-case conditions. Personal exposure measurement data were not collected. Modeling, therefore, was conducted to estimate airborne concentrations of total aerosol to COREXIT™ EC9527A and EC9500A. Using the AgDISP model, we estimated air concentrations to dispersant total aerosols, defined as all components of the dispersant including active ingredients, surfactants, and water, resulting from aerial and vessel applications, as average 1-h and 2-min concentrations. For comparison, 1-h air concentrations associated with aerial spraying were estimated using another model, AERMOD. At 152 m horizontal to the flight path, average 1-h total aerosol concentrations associated with aerial applications were estimated to be as high as 49.3 µg m-3 (9527A) and 45.4 µg m-3 (9500A), and both decreased with increased distance from the flight line. The estimates for spraying 9500A from vessels indicated that total aerosol concentrations were potentially as high as 0.33 µg m-3 at 10 m from the nozzles. These results suggest that personal exposures to dispersant aerosols were negligible.

Assessing Exposures from the Deepwater Horizon Oil Spill Response and Clean-up.

The GuLF Study is investigating adverse health effects from work on the response and clean-up after the Deepwater Horizon explosion and oil release. An essential and necessary component of that study was the exposure assessment. Bayesian statistical methods and over 135 000 measurements of total hydrocarbons (THC), benzene, ethylbenzene, toluene, xylene, and n-hexane (BTEX-H) were used to estimate inhalation exposures to these chemicals for >3400 exposure groups (EGs) formed from three exposure determinants: job/activity/task, location, and time period. Recognized deterministic models were used to estimate airborne exposures to particulate matter sized 2.5 µm or less (PM2.5) and dispersant aerosols and vapors. Dermal exposures were estimated for these same oil-related substances using a model modified especially for this study from a previously published model. Exposures to oil mist were assessed using professional judgment. Estimated daily THC arithmetic means (AMs) were in the low ppm range (<25 ppm), whereas BTEX-H exposures estimates were generally <1000 ppb. Potential 1-h PM2.5 air concentrations experienced by some workers may have been as high as 550 µg m-3. Dispersant aerosol air concentrations were very low (maximum predicted 1-h concentrations were generally <50 µg m-3), but vapor concentrations may have exceeded occupational exposure excursion guidelines for 2-butoxyethanol under certain circumstances. The daily AMs of dermal exposure estimates showed large contrasts among the study participants. The estimates are being used to evaluate exposure-response relationships in the GuLF Study.

Protective Masks Utilizing Nonendangered Components.

At the beginning of the COVID-19 pandemic when traditional N95 respirators were in short supply in the United States, there was a need for alternative products that did not rely on traditional avenues of sourcing and manufacturing. The purpose of this research was to develop and test alternatives to N95 respirators that could be produced locally without specialized materials and processes. Through an interdisciplinary team of experts, new mask designs that use repurposed filtration media and commercially available components were developed and tested for filtration and fit against current N95 standards. Filtration efficiency test results showed that the filtration media can be used for high-quality facemasks and quantitative fit testing demonstrated that the new mask designs could be viable alternatives to traditional N95 facemasks when those masks are in short supply. Manufacturing viability was tested utilizing a workforce to create 6000 masks over 10 days. The ability to quickly produce masks at scale using a workforce without specialized skills demonstrated the feasibility of the mask designs and manufacturing approach to address shortages of critical healthcare equipment, mitigate risk for healthcare and essential workers, and minimize the transmission and spread of disease.

Impact of the COVID-19 Pandemic on Epilepsy Center Practice in the United States.

BACKGROUND AND OBJECTIVES: Persons with epilepsy, especially those with drug resistant epilepsy (DRE), may benefit from inpatient services such as admission to the epilepsy monitoring unit (EMU) and epilepsy surgery. The COVID-19 pandemic caused reductions in these services within the US during 2020. This article highlights changes in resources, admissions, and procedures among epilepsy centers accredited by the National Association of Epilepsy Centers (NAEC). METHODS: We compared data reported in 2019, prior to the COVID-19 pandemic, and 2020 from all 260 level 3 and level 4 NAEC accredited epilepsy centers. Data were described using frequency for categorical variables and median for continuous variables and were analyzed by center level, center population category, and geographical location. Qualitative responses from center directors to questions regarding the impact from COVID-19 were summarized utilizing thematic analysis. Responses from the NAEC center annual reports as well as a supplemental COVID-19 survey were included. RESULTS: EMU admissions declined 23% (-21,515) in 2020, with largest median reductions in level 3 centers [-55 admissions (-44%)] and adult centers [-57 admissions (-39%)]. The drop in admissions was more substantial in the East North Central, East South Central, Mid Atlantic, and New England US Census divisions. Survey respondents attributed reduced admissions to re-assigning EMU beds, restrictions on elective admissions, reduced staffing, and patient reluctance for elective admission. Treatment surgeries declined by 371 cases (5.7%), with the largest reduction occurring in VNS implantations [-486 cases (-19%)] and temporal lobectomies [-227 cases (-16%)]. All other procedure volumes increased, including a 35% (54 cases) increase in corpus callosotomies. DISCUSSION: In the US, access to care for persons with epilepsy declined during the COVID-19 pandemic in 2020. Adult patients, those relying on level 3 centers for care, and many persons in the eastern half of the US were most affected.

Theoretical Background of Occupational-Exposure Models-Report of an Expert Workshop of the ISES Europe Working Group "Exposure Models".

On 20 October 2020, the Working Group "Exposure Models" of the Europe Regional Chapter of the International Society of Exposure Science (ISES Europe) organised an online workshop to discuss the theoretical background of models for the assessment of occupational exposure to chemicals. In this report, participants of the workshop with an active role before and during the workshop summarise the most relevant discussion points and conclusions of this well-attended workshop. ISES Europe has identified exposure modelling as one priority area for the strategic development of exposure science in Europe in the coming years. This specific workshop aimed to discuss the main challenges in developing, validating, and using occupational-exposure models for regulatory purposes. The theoretical background, application domain, and limitations of different modelling approaches were presented and discussed, focusing on empirical "modifying-factor" or "mass-balance-based" approaches. During the discussions, these approaches were compared and analysed. Possibilities to address the discussed challenges could be a validation study involving alternative modelling approaches. The wider discussion touched upon the close relationship between modelling and monitoring and the need for better linkage of the methods and the need for common monitoring databases that include data on model parameters.

United States Epilepsy Center Characteristics: A Data Analysis From the National Association of Epilepsy Centers.

BACKGROUND AND OBJECTIVES: Patients with drug-resistant epilepsy (DRE) may benefit from specialized testing and treatments to better control seizures and improve quality of life. Most evaluations and procedures for DRE in the United States are performed at epilepsy centers accredited by the National Association of Epilepsy Centers (NAEC). On an annual basis, the NAEC collects data from accredited epilepsy centers on hospital-based epilepsy monitoring unit (EMU) size and admissions, diagnostic testing, surgeries, and other services. This article highlights trends in epilepsy center services from 2012 through 2019. METHODS: We analyzed data reported in 2012, 2016, and 2019 from all level 3 and level 4 NAEC accredited epilepsy centers. Data were described using frequency for categorical variables and median for continuous variables and were analyzed by center level and center population category. EMU beds, EMU admissions, epileptologists, and aggregate procedure volumes were also described using rates per population per year. RESULTS: During the period studied, the number of NAEC accredited centers increased from 161 to 256, with the largest increases in adult- and pediatric-only centers. Growth in EMU admissions (41%), EMU beds (26%), and epileptologists (109%) per population occurred. Access to specialized testing and services broadly expanded. The largest growth in procedure volumes occurred in laser interstitial thermal therapy (LiTT) (61%), responsive neurostimulation (RNS) implantations (114%), and intracranial monitoring without resection (152%) over the study period. Corpus callosotomies and vagus nerve stimulator (VNS) implantations decreased (-12.8% and -2.4%, respectively), while growth in temporal lobectomies (5.9%), extratemporal resections (11.9%), and hemispherectomies/otomies (13.1%) lagged center growth (59%), leading to a decrease in median volumes of these procedures per center. DISCUSSION: During the study period, the availability of specialty epilepsy care in the United States improved as the NAEC implemented its accreditation program. Surgical case complexity increased while aggregate surgical volume remained stable or declined across most procedure types, with a corresponding decline in cases per center. This article describes recent data trends and current state of resources and practice across NAEC member centers and identifies several future directions for driving systematic improvements in epilepsy care.

Evaluating the Theoretical Background of STOFFENMANAGER® and the Advanced REACH Tool.

STOFFENMANAGER® and the Advanced REACH Tool (ART) are recommended tools by the European Chemical Agency for regulatory chemical safety assessment. The models are widely used and accepted within the scientific community. STOFFENMANAGER® alone has more than 37 000 users globally and more than 310 000 risk assessment have been carried out by 2020. Regardless of their widespread use, this is the first study evaluating the theoretical backgrounds of each model. STOFFENMANAGER® and ART are based on a modified multiplicative model where an exposure base level (mg m-3) is replaced with a dimensionless intrinsic emission score and the exposure modifying factors are replaced with multipliers that are mainly based on subjective categories that are selected by using exposure taxonomy. The intrinsic emission is a unit of concentration to the substance emission potential that represents the concentration generated in a standardized task without local ventilation. Further information or scientific justification for this selection is not provided. The multipliers have mainly discrete values given in natural logarithm steps (…, 0.3, 1, 3, …) that are allocated by expert judgements. The multipliers scientific reasoning or link to physical quantities is not reported. The models calculate a subjective exposure score, which is then translated to an exposure level (mg m-3) by using a calibration factor. The calibration factor is assigned by comparing the measured personal exposure levels with the exposure score that is calculated for the respective exposure scenarios. A mixed effect regression model was used to calculate correlation factors for four exposure group [e.g. dusts, vapors, mists (low-volatiles), and solid object/abrasion] by using ~1000 measurements for STOFFENMANAGER® and 3000 measurements for ART. The measurement data for calibration are collected from different exposure groups. For example, for dusts the calibration data were pooled from exposure measurements sampled from pharmacies, bakeries, construction industry, and so on, which violates the empirical model basic principles. The calibration databases are not publicly available and thus their quality or subjective selections cannot be evaluated. STOFFENMANAGER® and ART can be classified as subjective categorization tools providing qualitative values as their outputs. By definition, STOFFENMANAGER® and ART cannot be classified as mechanistic models or empirical models. This modeling algorithm does not reflect the physical concept originally presented for the STOFFENMANAGER® and ART. A literature review showed that the models have been validated only at the 'operational analysis' level that describes the model usability. This review revealed that the accuracy of STOFFENMANAGER® is in the range of 100 000 and for ART 100. Calibration and validation studies have shown that typical log-transformed predicted exposure concentration and measured exposure levels often exhibit weak Pearson's correlations (r is <0.6) for both STOFFENMANAGER® and ART. Based on these limitations and performance departure from regulatory criteria for risk assessment models, it is recommended that STOFFENMANAGER® and ART regulatory acceptance for chemical safety decision making should be explicitly qualified as to their current deficiencies.