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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.

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.

PB2452, a neutralizing monoclonal antibody fragment that binds the antiplatelet drug ticagrelor with high affinity, is being developed as a ticagrelor reversal agent. To identify a clinically useful intravenous (i.v.) reversal regimen, a semimechanistic exposure‐response model was developed during the PB2452 first‐in‐human phase I study. From a randomized, double‐blind, placebo‐controlled, single‐dose trial to evaluate the safety, efficacy, and pharmacokinetics (PKs) of PB2452 in 61 healthy volunteers pretreated with ticagrelor, sequential dose cohort data were used to build and refine an exposure‐response model that combined population PK models for ticagrelor (TICA), ticagrelor active metabolite (TAM), and PB2452, and related their binding relationships to the PK of uncomplexed TICA and TAM which is predictive of platelet inhibition. Platelet function was assessed by multiple assays. The model was developed using Bayesian methods in NONMEM. Human PK and pharmacodynamic data from sequential dose cohorts were used to initially define and then refine model parameters. Model simulations indicated that an initial i.v. bolus of PB2452, followed by a high‐rate infusion, and then a slower‐rate infusion would provide immediate and sustained reversal of the antiplatelet effects of ticagrelor. Based on model predictions, a 6 g i.v. bolus followed by 6 g infused over 4 h and then 6 g over 12 h was identified and tested in study subjects and shown to provide complete reversal within 5 min of infusion onset that was sustained for 20–24 h. The model is predictive of the reversal profile of PB2452 and will inform future trials of PB2452.

The accuracy of exposure judgments, particularly for scenarios where only qualitative information is available or a systematic approach is not used, have 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 towards 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.

Transfer of contaminants to and from the skin surface has been postulated to occur through a number of different pathways and compartments including: object(s)-to-skin, skin-to-skin, skin-to-clothing, skin-to-gloves, air-to-skin, skin-to-lips, and skin-to-saliva. However, many identified transfer pathways have been only minimally examined to determine the potential for measurable transfer. The purpose of this study was to quantitatively evaluate repeated transfer between different compartments using elemental metallic lead (Pb) in the solid form using a series of systematic measurements in human subjects. The results demonstrated that some transfer pathways and compartments are significantly more important than others. Transfer of Pb could not be measured from skin to cotton clothing or skin to laminate countertop surfaces. However, transfer was consistently measured for skin-to-skin and between the skin and the surface of nitrile gloves, suggesting the potential for significant transfer to or from these compartments in real-world exposure scenarios, and the importance of these pathways. With repeated contacts, transfer increased non-linearly between 1 and 5 contacts, but appeared to approach a steady state distribution among the compartments within 10 contacts. Consistent with other studies, relative to 100% transfer for a single contact, the quantitative transfer efficiency decreased with repeated contacts to 29% after 5 contacts and 11-12% after 10 contacts; for skin-to-skin transfer measurements, transfer efficiency after either 5 or 10 contacts was approximately 50% of the single contact transfer. These data are likely to be useful for refining current approaches to modeling of repeated contacts for dermal exposure and risk assessment.

BACKGROUND AND AIMS Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated for treatment of anemia due to chronic kidney disease (CKD). In global phase 3 trials, vadadustat has demonstrated non-inferiority to darbepoetin alfa for time to major adverse cardiovascular event (MACE) in patients with dialysis-dependent CKD (INNO2VATE trials), but not with non–dialysis-dependent CKD (NDD-CKD; PRO2TECT trials) [1,2]. In a prespecified subgroup analysis of the PRO2TECT trials, no difference in cardiovascular safety was observed in the USA, but a higher risk of MACE was found for patients treated with vadadustat outside the USA.1 We investigated regional differences in MACE in patients previously untreated with erythropoietin-stimulating agents (ESAs) in the PRO2TECT trial. METHOD Two phase 3, open-label, randomized, active-controlled clinical trials comparing vadadustat with darbepoetin alfa were conducted in North America, Latin America, Europe, Africa, and the Asia-Pacific region. This post hoc analysis evaluated MACE in patients in the PRO2TECT trial not treated with ESAs within 8 weeks of enrollment (correction trial; NCT02648347) and who received ≥1 dose of trial drug, stratified by region (USA versus Europe versus non-USA/non-Europe). MACE was defined as a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. Expanded MACE was defined as MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access failure. RESULTS A total of 1748 ESA-untreated patients receiving ≥1 dose of study drug were enrolled in the PRO2TECT trial, including 1058 patients in the USA, 139 in Europe and 551 outside the USA and Europe. Patients in the non-USA/non-European countries were younger and had a lower mean eGFR than patients in the USA or Europe. Furthermore, 34.7% of patients randomized to vadadustat had a baseline eGFR CONCLUSION Regional differences in time to first MACE were observed in patients with NDD-CKD who were not previously treated with ESAs and randomized to receive vadadustat or darbepoetin alfa as part of the PRO2TECT trial. The higher event rate in the vadadustat group in non-USA/non-European countries may have been related to randomization imbalances and/or design and methodological issues. These findings should help inform care providers as they assess the overall safety of vadadustat for the treatment of anemia associated with NDD-CKD.

Background Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. Meth...

Lutetium Dotatate radiopharmaceutical therapy (Lutathera) was approved by the United States Food and Drug Administration in 2018 and is used to treat somatostatin receptor positive neuroendocrine tumors. With all new radiopharmaceutical therapies, the radiation exposure to members of the public from the patient who received the therapy must be within regulatory limits and safe. If the patient will expose members of the public to too much radiation, the therapy must be performed on an inpatient basis. This paper shows that the administration of Lutathera can be done on an outpatient basis and provides safety and travel restrictions that should be communicated to the patient prior to leaving. The guidance presented herein serves as a basis for medical institutions looking to use Lutathera to treat patients.

Associations between cleaning chemical exposures and asthma have previously been identified in professional cleaners and healthcare workers. Domestic workers, including housecleaners and caregivers, may receive similar exposures but in residential environments with lower ventilation rates. Study objectives were to compare exposures to occupational exposure limits (OELs), to determine relative contributions from individual cleaning tasks to overall exposure, and to evaluate the effects of ventilation and posture on exposure. Airborne chemical concentrations of sprayed cleaning chemicals (acetic acid or ammonia) were measured during typical cleaning tasks in a simulated residential work environment. Whole-house cleaning exposures (18 cleaning tasks) were measured using integrated personal sampling methods. Individual task exposures were measured with a sampling line attached to subjects' breathing zones, with readings recorded by a ppbRAE monitor, equipped with a photoionization detector calibrated for ammonia and acetic acid measurements. Integrated sampling results indicated no exposures above OELs occurred, but 95th percentile air concentrations would require risk management decisions. Exposure reductions were observed with increased source distance, with lower exposures from mopping floors compared to kneeling. Exposure reductions were also observed for most but not all tasks when ventilation was used, with implications that alternative exposure reduction methods may be needed.

C-type natriuretic peptide (CNP) is a pluripotent molecule produced by the endothelium and myocardium with therapeutic potential in pulmonary hypertension, myocardial infarction, and heart failure. However, the native peptide’s short elimination half-life of under 3 minutes limits its use clinically. To improve the pharmacokinetic profile of CNP we recombinantly expressed the CNP peptide as a fusion with an elastin-like polypeptide (ELP). ELPs are biopolymers that undergo reversible temperature-dependent phase separation and form a subcutaneous depot upon injection. CNP-ELP fusion proteins were expressed in E. coli , purified, and showed in vitro potency 2-4 fold less than native CNP. When administered subcutaneously in mice CNP-ELP showed a significantly enhanced PK profile due to the slow release of the fusion into the circulation with detectable fusion protein 24 hours after a single injection. In addition, the CNP-ELP increased growth velocity in mice significantly greater than that of native peptide indicating an in vivo activation of the CNP receptor, NPR-B. These findings represent a new method of administering a long acting CNP peptide for treatment of different cardiovascular diseases.

The Deepwater Horizon (DWH) drilling unit explosion above the Macondo oil well on 20 April 2010 caused the release of approximately 4.9 million barrels (779 million L) of oil into the Gulf of Mexico. As part of a larger spill response and clean-up effort, approximately 1.84 million gallons (6.81 million L) of chemical dispersants COREXIT™ EC9500A and COREXIT™ EC9527A were applied to the resultant oil slicks through spraying on the water surface by plane and by vessel and through injection at the release source near the seabed. The GuLF STUDY is investigating the health effects of workers involved in the oil spill response and clean-up after the DWH explosion, and estimates of possible exposure to chemical dispersants were needed. Exposures were estimated to the volatile components of COREXIT™ EC9500A [petroleum distillates, hydrotreated light, and propylene glycol (PG)] and of COREXIT™ EC9527A [2-butoxyethanol (2-BE) and PG] using two of AIHA IHMOD2.0© mathematical modeling tools along with the dispersants’ chemical and physical properties. Monte Carlo simulations were used to reflect uncertainty in input parameters with both the two-box, constant emission model and the near and mid field plume model for indoor and outdoor activities, respectively. Possible exposure scenarios considered various evaporation rates, sizes of the dispersant pool, wind speeds, and ventilation rates. For the two-box model, mean near field exposure estimates to 2-BE ranged from 0.9 to 5.7 ppm, while mean far field estimated exposures ranged from 0.3 to 3.5 ppm. Estimates of mean near field plume model exposures ranged from 0.01 to 3.7 ppm at 2.5 ft from the source, and

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.

IntroductionDespite all the efforts for optimizing epilepsy management in children over the past decades, there is no clear consensus regarding whether to treat or not to treat epileptiform discharges (EDs) after a first unprovoked seizure or the optimal duration of therapy with anti-seizure medication (ASM). It is therefore highly needed to find markers on scalp electroencephalogram (EEG) that can help identify pathological EEG discharges that require treatment.Aim of the studyThis retrospective study aimed to identify whether the coexistence of ripples/high-frequency oscillations (HFOs) with interictal EDs (IEDs) in routinely acquired scalp EEG is associated with a higher risk of seizure recurrence and could be used as a prognostic marker.Methods100 children presenting with new onset seizure to Children’s Medical Center- Dallas during 2015–2016, who were not on ASM and had focal EDs on an awake and sleep EEG recorded with sample frequency of 500 HZ, were randomly identified by database review. EEGs were analyzed blinded to the data of the patients. HFOs were visually identified using review parameters including expanded time base and adjusted filter settings.ResultsThe average age of patients was 6.3 years (±4.35 SD). HFOs were visually identified in 19% of the studied patients with an inter-rater reliability of 99% for HFO negative discharges and 78% agreement for identification of HFOs. HFOs were identified more often in the younger age group; however, they were identified in 11% of patients >5 years old. They were more frequently associated with spikes than with sharp waves and more often with higher amplitude EDs. Patients with HFOs were more likely to have a recurrence of seizures in the year after the first seizure (P < 0.05) and to continue to have seizures after 2 years (P < 0.0001). There was no statistically significant difference between the two groups with regards to continuing ASM after 2 years.ConclusionIncluding analysis for HFOs in routine EEG interpretation may increase the yield of the study and help guide the decision to either start or discontinue ASM. In the future, this may also help to identify pathological discharges with deleterious effects on the growing brain and set a new target for the management of epilepsy.

Funding Information: The authors thank Prof. Paul Hewett (Exposure Assessment Solutions, Inc., Morgantown, WV) for his assistance with revising the probabilistic exposure model parametrization and interpretation of the results. Publisher Copyright: © 2021 Koivisto AJ et al. Background: The Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation requires the establishment of Conditions of Use (CoU) for all exposure scenarios to ensure good communication of safe working practices. Setting CoU requires the risk assessment of all relevant Contributing Scenarios (CSs) in the exposure scenario. A new CS has to be created whenever an Operational Condition (OC) is changed, resulting in an excessive number of exposure assessments. An efficient solution is to quantify OC concentrations and to identify reasonable worst-case scenarios with probabilistic exposure modeling. Methods: Here, we appoint CoU for powder pouring during the industrial manufacturing of a paint batch by quantifying OC exposure levels and exposure determinants. The quantification was performed by using stationary measurements and a probabilistic Near-Field/Far-Field (NF/FF) exposure model. Work shift and OC concentration levels were quantified for pouring TiO 2 from big bags and small bags, pouring Micro Mica from small bags, and cleaning. The impact of exposure determinants on NF concentration level was quantified by (1) assessing exposure determinants correlation with the NF exposure level and (2) by performing simulations with different OCs. Results: Emission rate, air mixing between NF and FF and local ventilation were the most relevant exposure determinants affecting NF concentrations. Potentially risky OCs were identified by performing Reasonable Worst Case (RWC) simulations and by comparing the exposure 95 th percentile distribution with 10% of the occupational exposure limit value (OELV). The CS was shown safe except in RWC scenario (ventilation rate from 0.4 to 1.6 1/h, 100 m 3 room, no local ventilation, and NF ventilation of 1.6 m 3/min). Conclusions: The CoU assessment was considered to comply with European Chemicals Agency (ECHA) legislation and EN 689 exposure assessment strategy for testing compliance with OEL values. One RWC scenario would require measurements since the exposure level was 12.5% of the OELV.

Guidance for managing potential dermal exposures has historically been qualitative in nature, for example, in the form of a DSEN notation. We propose a method that can provide quantitative guidance on how to establish and use surface wipe limits for skin sensitizers. The murine local lymph node assay (LLNA) is a validated test that not only identifies potential skin sensitizers but also provides an effective concentration (EC3) value. This provides quantitative dose–response information on induction of skin sensitization that permits estimates of sensitization thresholds and potency. Building upon the previously established correlation between LLNA EC3 values and human repeat insult patch testing no-effect levels, we present a quantitative method for setting surface wipe guidelines using the LLNA EC3. These limits can be used to assign compounds to occupational exposure bands and provide handling guidance for skin sensitizers of varying potency, supporting both exposure assessment and control strategies. A table is included that suggests a band of reasonable surface wipe limits (mg/100 cm2) for potentially all chemical sensitizers. When used in conjunction with a comprehensive industrial hygiene program that includes hazard communication, engineering controls, and personal protective equipment, skin exposure and consequent skin sensitization risks in the workplace can be minimized.

Exposure assessment models are deterministic models derived from physical–chemical laws. In real workplace settings, chemical concentration measurements can be noisy and indirectly measured. In addition, inference on important parameters such as generation and ventilation rates are usually of interest since they are difficult to obtain. In this article, we outline a flexible Bayesian framework for parameter inference and exposure prediction. In particular, we devise Bayesian state space models by discretizing the differential equation models and incorporating information from observed measurements and expert prior knowledge. At each time point, a new measurement is available that contains some noise, so using the physical model and the available measurements, we try to obtain a more accurate state estimate, which can be called filtering. We consider Monte Carlo sampling methods for parameter estimation and inference under nonlinear and non-Gaussian assumptions. The performance of the different methods is studied on computer-simulated and controlled laboratory-generated data. We consider some commonly used exposure models representing different physical hypotheses. Supplementary materials for this article are available online.

Understanding the relationship between consumer product use and risk of adverse health outcomes facilitates appropriate risk management and product stewardship. A preferred method for estimating the systemic and respiratory tract exposure and dose tailored to cleaning products use has been proposed, refining previously issued exposure guidance. Consistent with other exposure and risk-assessment frameworks, it is dependent upon high-quality exposure determinant data that also serve as model inputs. However, as publicly available exposure determinant data are scarce, the risk assessor is left with the option of estimating determinants such as the generation rate or employing empirical methods to estimate them. When the exposure scenario involves a chemical mixture, estimating the generation rate may not be feasible. We present an approach for estimating the time-varying generation rate of an aqueous acetic acid mixture representative of the base formulation for many consumer and DIY cleaning products that was previously assessed in a screening-level assessment. The approach involved measuring the evaporation rate for a reasonable worst-case scenario under controlled conditions. Knowing the mass applied, a time-varying generation rate was estimated. To evaluate its portability, a field study was conducted in a home where measurements were collected in an all-purpose room with the exterior door open (Room 1) and closed (Room 2), and a bathroom (Room 3) using a portable Fourier Transform Infrared (FTIR) spectrophotometer. Acetic acid concentrations were modeled using two common indoor air models, the Well Mixed Room model. Measured and modeled acetic acid concentrations were compared, with the WMR 95% confidence intervals encompassing measured concentrations for all three rooms, supporting the utility of the approach used and portability of the generation rate derived from it.

Ticagrelor is an oral P2YIn this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2YOf the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site.In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.).

The extent to which immune cell phenotypes in the peripheral blood reflect intratumoral immune activity prior to and early in cancer immunotherapy is unclear. Here we studied the population dynamics of immune cells and immune phenotypic changes, using clinical blood samples and a multicolor flow cytometry analysis. These samples were serially obtained from a cohort of high-grade glioma canine patients enrolled in a trial with an immunotherapy that targets the CD200/CD200R immunological synapse. This therapy consists of an alternative checkpoint inhibitor peptide (CD200AR-L) that modulates the CD200 immune checkpoint, currently being used in an adult phase I safety trial for recurrent glioblastoma trial (NCT04642937) and a canine high-grade spontaneous glioma trial (U01CA224160-01). We found evidence of a strong effect of the therapy on peripheral immune cells in responder versus nonresponder dogs. Upon initiation of therapy, immune effector cell proliferation increased in responsive patients, whereas in nonresponders immune cell populations either didn’t change significantly or an increase in immunosuppressive phenotypes was observed. Cell populations such as MDSC, regulatory T cells and exhausted T cells were predominantly higher in nonresponder dogs. These data showed that peripheral immune cell phenotypes were linked to the outcome of the immunotherapy, thus dogs with better immune cell profiles, including increased cytotoxic differentiation, had a better prognosis and longer overall survival rates. Taken together, these results suggest that variation in patient responsiveness can be explained by differences in peripheral immune cell proliferation and differentiation soon after the initiation of immunotherapy. Citation Format: Francisco W. Puerta Martinez, Sathya Schnell, Susan Arnold, Elizabeth G. Pluhar, Michael Olin. Circulating immune biomarkers in peripheral blood reflect the effect of a CD200 immune checkpoint targeted immunotherapy in pet dogs with high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1266.

9537 Background: Programmed death receptor-1 (PD-1)–blocking antibodies are approved as monotherapy treatment for patients (pts) with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or radiation. Cosibelimab is a high-affinity, fully human programmed death ligand-1 (PD-L1)–blocking antibody with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against tumor cells. Study CK-301-101 (NCT03212404) is a global, multicenter, multicohort, pivotal trial that enrolled pts with select advanced cancers for treatment with cosibelimab. Here we present the primary analysis of the registration-enabling expansion cohort in pts with metastatic CSCC. Methods: Adult pts with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had metastatic (nodal and/or distant) CSCC not amenable to local therapy were eligible to participate. Cosibelimab was administered as a fixed dose of 800 mg every 2 weeks (Q2W) intravenously. The primary endpoint was confirmed objective response rate (ORR; complete response [CR] + partial response [PR]) assessed by independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and the key secondary endpoint was duration of response. Results: Seventy-eight pts with metastatic CSCC were treated with cosibelimab and comprise the efficacy and safety populations (59M/19F; median age: 71 years). The confirmed ORR was 47.4% (95% CI: 36.0, 59.1; 6 CRs and 31 PRs) and the median duration of response was not reached at the time of data cutoff (median duration of follow-up: 15.2 months), with 76% of responses ongoing (range: 1.4-31.8+ months). The Kaplan–Meier estimated probability of maintaining a response at 6 and 24 months was 88.1% and 72.5%, respectively. Treatment-related adverse events (TRAEs) were reported in 54 pts (69.2%); 7 pts (9.0%) experienced at least 1 grade 3 TRAE (no grade 4 or grade 5 TRAEs were reported) with the most common being increased serum lipase in 2 pts. Conclusions: Treatment with cosibelimab monotherapy resulted in a robust ORR with durable responses and demonstrated a predictable and manageable safety profile in pts with metastatic CSCC, supporting its use in the treatment of this cancer. Clinical trial information: NCT03212404.

Workplace violence is a significant problem in healthcare. It was believed that in the context of patient violence nurses faced a moral dilemma regarding conflicting duties to self and patients. A qualitative study was conducted with nurses who experienced physical violence perpetrated by a patient. The aim was to examine the ethical decision-making process nurses used to determine the "right" course of action. Nurses did not perceive the conflict between these two duties as the primary dilemma they faced. They appreciated their patients' vulnerability and the power differential inherent in the RN-patient relationship and maintained that their primary responsibility was patient safety. Interpretation of the event was the primary dilemma they described. Patient violence was framed as a dichotomous experience: an expected part of the job or a crime. The middle space between these two choices was bounded by a fuzzy, porous, extremely difficult to interpret line. The dichotomous interpretation resulted in a perception of dichotomous responses: do nothing or file criminal charges. Violence in the context of the RN-patient relationship is a complex phenomenon involving a host of factors. We need to direct more attention to this complexity, to individualized responses to workplace violence, and to depolarizing this issue.

The GuLF STUDY, initiated by the National Institute of Environmental Health Sciences, is investigating the health effects among workers involved in the oil spill response and clean-up (OSRC) after the Deepwater Horizon (DWH) explosion in April 2010 in the Gulf of Mexico. Clean-up included in situ burning of oil on the water surface and flaring of gas and oil captured near the seabed and brought to the surface. We estimated emissions of PM2.5 and related pollutants resulting from these activities, as well as from engines of vessels working on the OSRC. PM2.5 emissions ranged from 30 to 1.33e6 kg per day and were generally uniform over time for the flares but highly episodic for the in situ burns. Hourly emissions from each source on every burn/flare day were used as inputs to the AERMOD model to develop average and maximum concentrations for 1-, 12-, and 24-h time periods. The highest predicted 24-h average concentrations sometimes exceeded 5000 µg m−3 in the first 500 m downwind of flaring and reached 71 µg m−3 within a kilometer of some in situ burns. Beyond 40 km from the DWH site, plumes appeared to be well mixed, and the predicted 24-h average concentrations from the flares and in situ burns were similar, usually below 10 µg m−3. Structured averaging of model output gave potential PM2.5 exposure estimates for OSRC workers located in various areas across the Gulf. Workers located nearest the wellhead (hot zone/source workers) were estimated to have a potential maximum 12-h exposure of 97 µg m−3 over the 2-month flaring period. The potential maximum 12-h exposure for workers who participated in in situ burns was estimated at 10 µg m−3 over the ~3-month burn period. The results suggest that burning of oil and gas during the DWH clean-up may have resulted in PM2.5 concentrations substantially above the U.S. National Ambient Air Quality Standard for PM2.5 (24-h average = 35 µg m−3). These results are being used to investigate possible adverse health effects in the GuLF STUDY epidemiologic analysis of PM2.5 exposures.

Aim Occupational therapists are experts in determining domestic assistance levels. It is a complex multi-dimensional process resulting in different opinion regarding care hours. Method Therapists providing medicolegal reports on domestic care for the courts within Australia were surveyed. Results 58 occupational therapists responded with most aged between 41 to 50 years of age. There was a strong correlation between years of clinical and medicolegal experience (r = 0.730, n = 58, p = 0.000) as well as between years and numbers of medicolegal assessments conducted in 2017 (r = 0.264, n = 58, p = 0.420). Assessment based on occupational analysis interview combined observation of the claimant performing tasks in their home, medical information, and contextual factors such as family expectations. Translation of data to hours of care was based on therapist's clinical experience of medical diagnosis (x2 6.89, p = 0.009) and claimant's statements of performance combined with therapist's clinical experience (x2 = 5.58, p = 0.18). Therapists providing defendant only reports often use their own time to perform housework as a guide. Triangulation data combined confirmation of the person's statements through observation of performance, the environment in which they lived, and the occupational therapists own clinical reasoning skill. Conclusion Documenting all the factors influencing the occupational therapist's decision is the key to understanding clinical reasoning. Implication for rehabilitation When estimating domestic care occupational therapists should: •Provide written documentation that clearly explains the assessment methods used, the results and conclusion made regarding domestic care. •Triangulate data including claimant's statements of performance, confirmation by observation on tasks, medical report information in the context of the claimant's environmental and contextual factors. •Be aware their own years of experience do not equate to level of expertise.

Presurgical evaluation and surgery in the pediatric age group are unique in challenges related to caring for the very young, range of etiologies, choice of appropriate investigations, and surgical procedures. Accepted standards that define the criteria for levels of presurgical evaluation and epilepsy surgery care do not exist. Through a modified Delphi process involving 61 centers with experience in pediatric epilepsy surgery across 20 countries, including low-middle- to high-income countries, we established consensus for two levels of care. Levels were based on age, etiology, complexity of presurgical evaluation, and surgical procedure. Competencies were assigned to the levels of care relating to personnel, technology, and facilities. Criteria were established when consensus was reached (≥75% agreement). Level 1 care consists of children age 9 years and older, with discrete lesions including hippocampal sclerosis, undergoing lobectomy or lesionectomy, preferably on the cerebral convexity and not close to eloquent cortex, by a team including a pediatric epileptologist, pediatric neurosurgeon, and pediatric neuroradiologist with access to video-electroencephalography and 1.5-T magnetic resonance imaging (MRI). Level 2 care, also encompassing Level 1 care, occurs across the age span and range of etiologies (including tuberous sclerosis complex, Sturge-Weber syndrome, hypothalamic hamartoma) associated with MRI lesions that may be ill-defined, multilobar, hemispheric, or multifocal, and includes children with normal MRI or foci in/abutting eloquent cortex. Available Level 2 technologies includes 3-T MRI, other advanced magnetic resonance technology including functional MRI and diffusion tensor imaging (tractography), positron emission tomography and/or single photon emission computed tomography, source localization with electroencephalography or magnetoencephalography, and the ability to perform intra- or extraoperative invasive monitoring and functional mapping, by a large multidisciplinary team with pediatric expertise in epilepsy, neurophysiology, neuroradiology, epilepsy neurosurgery, neuropsychology, anesthesia, neurocritical care, psychiatry, and nursing. Levels of care will improve safety and outcomes for pediatric epilepsy surgery and provide standards for personnel and technology to achieve these levels.

Lafora's disease is a neurodegenerative disorder caused by recessive loss-of-function mutations in the EPM2A (laforin glycogen phosphatase) or EPM2B (malin E3 ubiquitin ligase) genes. Neuropathology is characterized by malformed precipitated glycogen aggregates termed Lafora bodies. Asymptomatic until adolescence, patients undergo first insidious then rapid progressive myoclonus epilepsy toward a vegetative state and death within a decade. Laforin and malin interact to regulate glycogen phosphorylation and chain length pattern, the latter critical to glycogen's solubility. Significant gaps remain in precise mechanistic understanding. However, demonstration that partial reduction in brain glycogen synthesis near-completely prevents the disease in its genetic animal models opens a direct present path to therapy.

Occupational therapists are experts in understanding the impact an injury has on a claimant's capacity to perform their pre-injury level of domestic activities. Lawyers use this information when litigating claims for domestic assistance support. This is the first study exploring lawyers' experiences with occupational therapy domestic assistance reports using an online survey. The online survey was completed by 20 lawyers who practise in New South Wales, Australia. Results indicated occupational therapy reports were used to determine the amount of gratuitous domestic care the claimant received, the impact injury has on daily function and tasks requiring assistance. Lawyers used therapists with medico-legal experience although the timeframe for receiving the report was also influential. A high-quality report uses supportive evidence linking function and recommendations for care. Therapists require a clear understanding of the legislation and transparent reasoning while lawyers need to provide sufficient information to assist therapists' conclusions.

IntroductionOccupational therapists provide care opinions when assessing a person's capacity to perform housework. This skill requires occupational therapists to understand healthy populations' att...

The extent to which immune cell phenotypes in the peripheral blood reflect intratumoral immune activity prior to and early in cancer immunotherapy is unclear. Here we studied the population dynamics of immune cells and immune phenotypic changes, using clinical blood samples and a multicolor flow cytometry analysis. These samples were serially obtained from a cohort of high-grade glioma canine patients enrolled in a trial with an immunotherapy that targets the CD200/CD200R immunological synapse. This therapy consists of an alternative checkpoint inhibitor peptide (CD200AR-L) that modulates the CD200 immune checkpoint, currently being used in an adult phase I safety trial for recurrent glioblastoma trial (NCT04642937) and a canine high-grade spontaneous glioma trial (U01CA224160-01). We found evidence of a strong effect of the therapy on peripheral immune cells in responder versus nonresponder dogs. Upon initiation of therapy, immune effector cell proliferation increased in responsive patients, whereas in nonresponders immune cell populations either didn’t change significantly or an increase in immunosuppressive phenotypes was observed. Cell populations such as MDSC, regulatory T cells and exhausted T cells were predominantly higher in nonresponder dogs. These data showed that peripheral immune cell phenotypes were linked to the outcome of the immunotherapy, thus dogs with better immune cell profiles, including increased cytotoxic differentiation, had a better prognosis and longer overall survival rates. Taken together, these results suggest that variation in patient responsiveness can be explained by differences in peripheral immune cell proliferation and differentiation soon after the initiation of immunotherapy.

Exposure judgments made without personal exposure data and based instead on subjective inputs tend to underestimate exposure, with exposure judgment accuracy not significantly more accurate than random chance. Therefore, objective inputs that contribute to more accurate decision making are needed. Models have been shown anecdotally to be useful in accurately predicting exposure but their use in occupational hygiene has been limited. This may be attributable to a general lack of guidance on model selection and use and scant model input data. The lack of systematic evaluation of the models is also an important factor. This research addresses the need to systematically evaluate two widely applicable models, the Well-Mixed Room (WMR) and Near-Field–Far-Field (NF-FF) models. The evaluation, conducted under highly controlled conditions in an exposure chamber, allowed for model inputs to be accurately measured and controlled, generating over 800 pairs of high quality measured and modeled exposure estimates. By varying conditions in the chamber one at a time, model performance across a range of conditions was evaluated using two sets of criteria: the ASTM Standard 5157 and the AIHA Exposure Assessment categorical criteria. Model performance for the WMR model was excellent, with ASTM performance criteria met for 88–97% of the pairs across the three chemicals used in the study, and 96% categorical agreement observed. Model performance for the NF-FF model, impacted somewhat by the size of the chamber was nevertheless good to excellent. NF modeled estimates met modified ASTM criteria for 67–84% of the pairs while 69–91% of FF modeled estimates met these criteria. Categorical agreement was observed for 72% and 96% of NF and FF pairs, respectively. These results support the use of the WMR and NF–FF models in guiding decision making towards improving exposure judgment accuracy.

The United States Pharmacopeia (USP) Chapter800guidelines will be adopted in the U.S. and Canada in 2019, requiring regular surface sampling for antineoplastic drug (AD) surface contamination as a means of environmental surveillance. USP Chapter800does not provide guidance on when and where to sample. Research to support the development of such guidance within a broader sampling strategy is limited. This study was conducted to help address some of the underlying information gaps by identifying surfaces pharmacy and nursing staff are likely to contact, presenting a potential dermal exposure risk. Observations were conducted at one regional and one urban clinic, providing insight into inter- and intra-worker variability and between-clinic differences based on size and patient load. Thirteen surfaces in the compounding pharmacies and 14 surfaces in the patient administration were initially selected for video observations. Following a preliminary assessment to eliminate surfaces that were touched infrequently or not at all, five commonly touched surfaces in the compounding pharmacy areas (vials, syringes, IV lines, IV bags, waste bags) and six commonly touched surfaces in the patient administration area (yellow containment bag, IV bag, IV line, patient port, computer workstation) were assessed further. Variability between healthcare staff and clinics in pharmacy staff was low for both the mean frequency and duration of touch to surfaces. Differences between clinics in frequency of contact among nursing staff in patient administration areas were significant (two-way ANOVA) for five of the six surfaces. Duration of contact was not significantly different except for duration of touching the IV pump. These insights will be used to give guidance in selecting locations for a longitudinal surveillance study and help tailor worker training to reduce exposure risks.

A 16 wk old intact female Gordon setter was examined for a 2 wk history of progressive cerebellovestibular ataxia. Eosinophilia was found on complete blood count, and the remaining blood work was normal. A trial treatment with clindamycin and anti-inflammatory prednisone did not result in improvement of clinical signs; therefore, the dog was euthanized. On histopathologic examination, cross sections of a 75 μm wide nematode larva with a 5 μm cuticle, prominent lateral cords, lateral alae, and coeloemyelian musculature were identified in a focally extensive region of cerebellar necrosis. The size and morphology of the parasites was most consistent with Baylisascaris procyonis. This case highlights a rare but important zoonotic disease that should be considered as a differential diagnosis in any dog exhibiting acute, progressive central nervous system signs, and peripheral eosinophilia. The index of suspicion should be elevated in dogs with an unknown deworming history and known or suspected exposure to raccoons. Because most anthelminthics have been shown to be effective against B. procyonis, annual deworming is recommended in the at-risk population to reduce the likelihood of aberrant migration and zoonosis.

Nicotine from electronic cigarette aerosol will deposit on surfaces immediately after vaping, but how long deposited nicotine will persist on various surfaces is unknown. This work exposed glass and terrycloth (cotton) materials to electronic cigarette aerosols for 1 hr, assessed the initial nicotine sorption, and characterized surface persistence over a 72-hr period. Exponential decay of surface concentration was observed for both materials. Terrycloth had higher initial nicotine deposition and retained nicotine substantially longer than glass. Residual nicotine concentrations persisted on both surface types for 72 hr. Statistical modeling predicted surface concentrations to reach background levels after 4 and 16 days for glass and terrycloth, respectively. Nicotine persistence was long enough to pose a potential thirdhand nicotine exposure risk, and reactions to produce tobacco-specific nitrosamines may be possible from nicotine deposition from electronic cigarette aerosols, but further study is needed.

Poor air quality is a leading contributor to the global disease burden and total number of deaths worldwide. Humans spend most of their time in built environments where the majority of the inhalation exposure occurs. Indoor Air Quality (IAQ) is challenged by outdoor air pollution entering indoors through ventilation and infiltration and by indoor emission sources. The aim of this study was to understand the current knowledge level and gaps regarding effective approaches to improve IAQ. Emission regulations currently focus on outdoor emissions, whereas quantitative understanding of emissions from indoor sources is generally lacking. Therefore, specific indoor sources need to be identified, characterized, and quantified according to their environmental and human health impact. The emission sources should be stored in terms of relevant metrics and statistics in an easily accessible format that is applicable for source specific exposure assessment by using mathematical mass balance modelings. This forms a foundation for comprehensive risk assessment and efficient interventions. For such a general exposure assessment model we need 1) systematic methods for indoor aerosol emission source assessment, 2) source emission documentation in terms of relevant a) aerosol metrics and b) biological metrics, 3) default model parameterization for predictive exposure modeling, 4) other needs related to aerosol characterization techniques and modeling methods. Such a general exposure assessment model can be applicable for private, public, and occupational indoor exposure assessment, making it a valuable tool for public health professionals, product safety designers, industrial hygienists, building scientists, and environmental consultants working in the field of IAQ and health. © 2019, This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 760840 and was partly supported by Academy of Finland project BATMAN ( 285672 ) and NordForsk under the Nordic Programme on Health and Welfare project # 75007 (NordicWelfAir), EU LIFE+ project Index-Air (LIFE15 ENV/PT/000674 ) and intramural funding by the participating institutes. The authors also wish to thank Tiina Santonen (Finnish Institute of Occupational Health) for her excellent comments.

Background/aim Estimating domestic assistance requirements within the medicolegal field is a role for occupational therapists. It is a complex multidimensional process of clinical reasoning with no published research outlining how an occupational therapist translates assessment data into the number of hours of domestic assistance required. This study describes the current occupational therapy practice of estimating domestic assistance hours within the medicolegal context. Method Three focus groups, totalling 14 occupational therapists providing medicolegal reports in New South Wales, were conducted. Sydney University provided ethics approval. Focus group data were thematically analysed. Results Four themes were identified: Tasks included as housework. Assessment process - interview of pre-injury and recovery status; functional performance on specific tasks and a tour of the home. Influential factors - include legal system restrictions, medical management, cultural and society values, family expectations, location and impact of diagnosis. Strategies to determine care - triangulation of observed data with medical reports and clinical experience. Knowledge of community and own performance times within the framework of occupational therapy philosophy DISCUSSION: No single method of translating assessment data to hours of care was identified. Therapists use of their own housework performance raises ethical issues. Use of claimant only statements raises issues of inaccurate data on which to base decisions. Therapists should refer to occupational therapy process of clinical reasoning to explain their recommendations even though the reasoning does not give a definite number of care hours. Conclusion Therapists need to understand the factors influencing their clinical reasoning when integrating all available information into an estimating of domestic assistance hours. Further study analysing the content of medicolegal report may provide information as to how therapists document their clinical reasoning for court.

Most exposure assessments are conducted without the aid of robust personal exposure data and are based instead on qualitative inputs such as education and experience, training, documentation on the process chemicals, tasks and equipment, and other information. Qualitative assessments determine whether there is any follow-up, and influence the type that occurs, such as quantitative sampling, worker training, and implementing exposure and risk management measures. Accurate qualitative exposure judgments ensure appropriate follow-up that in turn ensures appropriate exposure management. Studies suggest that qualitative judgment accuracy is low. A qualitative exposure assessment Checklist tool was developed to guide the application of a set of heuristics to aid decision making. Practicing hygienists (n = 39) and novice industrial hygienists (n = 8) were recruited for a study evaluating the influence of the Checklist on exposure judgment accuracy. Participants generated 85 pre-training judgments and 195 Checklist-guided judgments. Pre-training judgment accuracy was low (33%) and not statistically significantly different from random chance. A tendency for IHs to underestimate the true exposure was observed. Exposure judgment accuracy improved significantly (p0.001) to 63% when aided by the Checklist. Qualitative judgments guided by the Checklist tool were categorically accurate or over-estimated the true exposure by one category 70% of the time. The overall magnitude of exposure judgment precision also improved following training. Fleiss' κ, evaluating inter-rater agreement between novice assessors was fair to moderate (κ = 0.39). Cohen's weighted and unweighted κ were good to excellent for novice (0.77 and 0.80) and practicing IHs (0.73 and 0.89), respectively. Checklist judgment accuracy was similar to quantitative exposure judgment accuracy observed in studies of similar design using personal exposure measurements, suggesting that the tool could be useful in developing informed priors and further demonstrating its usefulness in producing accurate qualitative exposure judgments.

Treatment of Dravet syndrome with anti-seizure medications is challenging and frequently disappointing in early childhood. Nonpharmacologic treatments for epilepsy including ketogenic diet, corpus callosotomy, and vagal nerve stimulation (VNS) are considered and used for management of medically refractory epilepsy. In this series, we report our experience with VNS in eight children with Dravet syndrome. Mean age at VNS implantation was 6.2 years. Duration of treatment with VNS ranged from 2 to 13 years. When compared with baseline, four of eight children had a 50 to 75% reduction in seizure frequency or duration. Four children had no significant improvement in seizures after VNS. The device was well tolerated in all patients without significant complications.

Background Current animal models of glioma are limited to small animal models, which are less predictive of treatment of human disease. Canines often develop gliomas de novo, but the natural history of the disease is not well described. Objective We provide data for naturally occurring canine gliomas; evaluating medical and surgical therapies. Methods We reviewed medical records of pet dogs with a presumptive diagnosis of glioma from MRI imaging that underwent surgery as part of the Canine Brain Tumor Clinical Trials Program. Breed, age, sex, median progression-free, and overall survival times and cause of death were recorded for multivariate analysis. Results Ninety five dogs (56 male; mean age = 8.3 years) were included, but nine were excluded as final pathology was non-neoplastic. Gross total resection was reported in 81 cases based on postoperative MRI. Seventy had high-grade tumors (grade III or IV). Eighty three dogs presented with seizures, being the most common presenting clinical sign. Median survival after surgery was 723 days (95% CI 343-1103) for grade II tumors, 301 days (197-404) for grade III and 200 days (126-274) for grade IV (p = .009 Kaplan-Meier survival analysis; Log Rank test). Age (cox regression, p = .14) or sex (Kaplan-Meier test, p = .22) did not predict survival. Conclusions This study establishes normative data for a model exploiting dogs with naturally occurring glioma, which can be used to test novel therapies prior to translation to human trials. Further work will focus on the effects of different therapies, including chemotherapy, radiation therapy, and immunotherapy.

Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes due to pleiotropic effects, such as the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-life owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics lead to 10 days of glycaemic control in three different mouse models of diabetes, as well as the reduction of glycosylated haemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics. An optimized formulation of glucagon-like peptide-1 recombinantly fused to an elastin-like polypeptide leads to zero-order release kinetics from a subcutaneous depot and to 10 days of glycaemic control in three mouse models of diabetes.