Predictions of tissue concentrations of myclobutanil, oxyfluorfen, and pronamide in rat and human after oral exposures via GastroPlusTM physiologically based pharmacokinetic modelling.

Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.

Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies.

In 2022, the European Chemicals Agency issued advice on the selection of high dose levels for developmental and reproductive toxicity (DART) studies indicating that the highest dose tested should aim to induce clear evidence of reproductive toxicity without excessive toxicity and severe suffering in parental animals. In addition, a recent publication advocated that a 10% decrease in body weight gain should be replaced with a 10% decrease in bodyweight as a criterion for dose adequacy. Experts from the European Centre for Ecotoxicology and Toxicology of Chemicals evaluated these recent developments and their potential impact on study outcomes and interpretation and identified that the advice was not aligned with OECD test guidelines or with humane endpoints guidance. Furthermore, data analysis from DART studies indicated that a 10% decrease in maternal body weight during gestation equates to a 25% decrease in body weight gain, which differs from the consensus of experts at a 2010 ILSI/HESI workshop. Dose selection should be based on a biological approach that considers a range of other factors. Excessive dose levels that cause frank toxicity and overwhelm homeostasis should be avoided as they can give rise to effects that are not relevant to human health assessments.

Rationale, design, and protocol for a hybrid type 1 effectiveness-implementation trial of a proactive smoking cessation electronic visit for scalable delivery via primary care: the E-STOP trial.

BACKGROUND: Cigarette smoking remains the leading cause of preventable disease and death in the United States. Primary care offers an ideal setting to reach adults who smoke cigarettes and improve uptake of evidence-based cessation treatment. Although U.S. Preventive Services Task Force Guidelines recommend the 5As model (Ask, Advise, Assess, Assist, Arrange) in primary care, there are many barriers to its implementation. Automated, comprehensive, and proactive tools are needed to overcome barriers. Our team developed and preliminarily evaluated a proactive electronic visit (e-visit) delivered via the Electronic Health Record patient portal to facilitate evidence-based smoking cessation treatment uptake in primary care, with promising initial feasibility and efficacy. This paper describes the rationale, design, and protocol for an ongoing Hybrid Type I effectiveness-implementation trial that will simultaneously assess effectiveness of the e-visit intervention for smoking cessation as well as implementation potential across diverse primary care settings. METHODS: The primary aim of this remote five-year study is to examine the effectiveness of the e-visit intervention vs. treatment as usual (TAU) for smoking cessation via a clinic-randomized clinical trial. Adults who smoke cigarettes are recruited across 18 primary care clinics. Clinics are stratified based on their number of primary care providers and randomized 2:1 to either e-visit or TAU. An initial baseline e-visit gathers information about patient smoking history and motivation to quit, and a clinical decision support algorithm determines the best evidence-based cessation treatment to prescribe. E-visit recommendations are evaluated by a patient's own provider, and a one-month follow-up e-visit assesses cessation progress. Main outcomes include: (1) cessation treatment utilization (medication, psychosocial cessation counseling), (2) reduction in cigarettes per day, and (3) biochemically verified 7-day point prevalence abstinence (PPA) at six-months. We hypothesize that patients randomized to the e-visit condition will have better cessation outcomes (vs. TAU). A secondary aim evaluates e-visit implementation potential at patient, provider, and organizational levels using a mixed-methods approach. Implementation outcomes include acceptability, adoption, fidelity, implementation cost, penetration, and sustainability. DISCUSSION: This asynchronous, proactive e-visit intervention could provide substantial benefits for patients, providers, and primary care practices and has potential to widely improve reach of evidence-based cessation treatment. TRIAL REGISTRATION: NCT05493254.

Dissection of gastric homeostasis in vivo facilitates permanent capture of isthmus-like stem cells in vitro.

The glandular stomach is composed of two regenerative compartments termed corpus and antrum, and our understanding of the transcriptional networks that maintain these tissues is incomplete. Here we show that cell types with equivalent functional roles in the corpus and antrum share similar transcriptional states including the poorly characterized stem cells of the isthmus region. To further study the isthmus, we developed a monolayer two-dimensional (2D) culture system that is continually maintained by Wnt-responsive isthmus-like cells capable of differentiating into several gastric cell types. Importantly, 2D cultures can be converted into conventional three-dimensional organoids, modelling the plasticity of gastric epithelial cells in vivo. Finally, we utilized the 2D culture system to show that Sox2 is both necessary and sufficient to generate enterochromaffin cells. Together, our data provide important insights into gastric homeostasis, establish a tractable culture system to capture isthmus cells and uncover a role for Sox2 in enterochromaffin cells.

Proactive Electronic Visits for Smoking Cessation and Chronic Obstructive Pulmonary Disease Screening in Primary Care: Randomized Controlled Trial of Feasibility, Acceptability, and Efficacy.

BACKGROUND: Most smokers with chronic obstructive pulmonary disease (COPD) have not yet been diagnosed, a statistic that has remained unchanged for over two decades. A dual-focused telehealth intervention that promotes smoking cessation, while also facilitating COPD screening, could help address national priorities to improve the diagnosis, prevention, treatment, and management of COPD. The purpose of this study was to preliminarily evaluate an integrated asynchronous smoking cessation and COPD screening e-visit (electronic visit) that could be delivered proactively to adult smokers at risk for COPD, who are treated within primary care. OBJECTIVE: The aims of this study were (1) to examine e-visit feasibility and acceptability, particularly as compared to in-lab diagnostic pulmonary function testing (PFT), and (2) to examine the efficacy of smoking cessation e-visits relative to treatment as usual (TAU), all within primary care. METHODS: In a randomized clinical trial, 125 primary care patients who smoke were randomized 2:1 to receive either proactive e-visits or TAU. Participants randomized to the e-visit condition were screened for COPD symptoms via the COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE). Those with scores ≥2 were invited to complete both home spirometry and in-lab PFTs, in addition to two smoking cessation e-visits. Smoking cessation e-visits assessed smoking history and motivation to quit and included completion of an algorithm to determine the best Food and Drug Administration-approved cessation medication to prescribe. Primary outcomes included measures related to (1) e-visit acceptability, feasibility, and treatment metrics; (2) smoking cessation outcomes (cessation medication use, 24-hour quit attempts, smoking reduction ≥50%, self-reported abstinence, and biochemically confirmed abstinence); and (3) COPD screening outcomes. RESULTS: Of 85 participants assigned to the e-visits, 64 (75.3%) were invited to complete home spirometry and in-lab PFTs based on CAPTURE. Among those eligible for spirometry, 76.6% (49/64) completed home spirometry, and 35.9% (23/64) completed in-lab PFTs. At 1 month, all cessation outcomes favored the e-visit, with a significant effect for cessation medication use (odds ratio [OR]=3.22). At 3 months, all cessation outcomes except for 24-hour quit attempts favored the e-visit, with significant effects for cessation medication use (OR=3.96) and smoking reduction (OR=3.09). CONCLUSIONS: A proactive, asynchronous e-visit for smoking cessation and COPD screening may offer a feasible, efficacious approach for broad interventions within primary care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04155073; https://clinicaltrials.gov/ct2/show/NCT04155073.

Preventive Care Utilization by Patients Who Use Virtual Urgent Care.

Introduction: The use of direct to patient (DTP) telemedicine for common acute conditions is widespread. It provides certain advantages over in-person visits, but has led to concerns about fragmentation of care. It is unknown whether use of DTP telemedicine decreases use of primary care services in a way that leads to missed preventive screenings and immunizations. Methods: Virtual urgent care (VUC) is a DTP telemedicine service to treat common acute conditions. All VUC encounters completed at an academic health system from July 2018 to December 2019 were evaluated and analyzed in 2020. Only patients established with primary care (at least one primary care visit in the same year as VUC encounter) were included. Specific preventive screenings (breast cancer, gonorrhea/chlamydia, and cervical cancer) and immunizations (tetanus and influenza) were characterized as up to date based on national guidelines. Chi-squares and multivariate logistic regressions were used to assess receipt of screenings and immunizations. Regressions included VUC and primary care utilization and demographic factors. Results: Patients evaluated (N = 1025) were mostly 25-50 years old (69.7%), women (81.8%), and white (74.9%). More than half (56.5%) had only used VUC once. In multivariate analyses, VUC utilization was not negatively associated with any of the preventive services evaluated, whereas primary care utilization was associated with receipt of both immunizations and gonorrhea/chlamydia screening. Conclusions: Higher VUC utilization is not negatively associated with receipt of preventive services, as long as a primary care relationship is established. VUC may provide a useful method of encouraging receipt of preventive services, especially for younger patients.

Evaluation of a telemedicine pilot program for the provision of HIV pre-exposure prophylaxis in the Southeastern United States.

Pre-exposure prophylaxis (PrEP) is a daily regimen that reduces the risk of acquiring HIV by up to 97%. There is limited information on the use of telehealth to provide PrEP in a program aimed toward the primary prevention of HIV. This was a 6-month telePrEP feasibility study that assessed process measures, clinical outcomes and patient satisfaction. Descriptive statistics and Chi-square analysis were used to evaluate measures and outcomes from the start to the end of the study. Twenty patients enrolled, and 80% completed the study. Participants were cisgender males (100%) with an average age of 35.6 years, white (95%), and were college graduates or higher (55%). The majority (75%) had very high comfort with video calls before the program. Self-reported adherence to PrEP medication remained high throughout the program (60%-70%). Without this program 31.2% of participants were unlikely to have received PrEP. For obtaining PrEP 56.3% preferred telemedicine only, and 31.2% preferred a combination of telemedicine and in-person office visits. PrEP is an effective method of preventing HIV infection for those at high risk. Our program shows that telemedicine can be useful to expand access to medication for patients at high risk.

Urinary lead level and colonization by antibiotic resistant bacteria: Evidence from a population-based study.

BACKGROUND: Infection by antibiotic resistant bacteria (ARB) is a global health crisis and asymptomatic colonization increases risk of infection. Nonhuman studies have linked heavy metal exposure to the selection of ARB; however, few epidemiologic studies have examined this relationship. This study analyzes the association between urinary lead level and colonization by ARB in a nonclinical human population. METHODS: Data came from the Survey of the Health of Wisconsin 2016-2017, and its ancillary Wisconsin Microbiome Study. Urinary lead levels, adjusted for creatinine, were used to assess exposure. ARB included methicillin resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), fluoroquinolone resistant Gram-negative bacilli (RGNB), and Clostridium difficile (C. diff), from skin, nose, and mouth swabs, and saliva and stool samples. Logistic regression, adjusted for covariates, was used to evaluate associations between Pb and ARB. Secondary analysis investigated Pb resistance from ARB isolates. RESULTS: Among 695 participants, 239 (34%) tested positive for ARB. Geometric mean urinary Pb (unadjusted) was 0.286 µg/L (95% confidence intervals [CI] = 0.263, 0.312) for ARB negative participants and 0.323 µg/L (95% CI = 0.287, 0.363) for ARB positive participants. Models adjusted for demographics, diet, and antibiotic use showed elevated odds of positive colonization for those in the 95th percentile (vs. below) of Pb exposure (odds ratio [OR] = 2.05, 95% CI = 0.95, 4.44), and associations were highest in urban residents (OR = 2.85, 95% CI = 1.07, 7.59). RGNB isolates were most resistant to Pb. DISCUSSION: These novel results suggest that Pb exposure is associated with increased colonization by ARB, and that RGNB are particularly resistant to Pb.

A Telehealth Initiative to Overcome Health Care Barriers for People Experiencing Homelessness.

People experiencing homelessness (PEH) encounter barriers to health care, increasing their vulnerability to illness, hospitalization, and death. Telehealth can improve access to health care, but its use in PEH has been insufficiently evaluated. Needs assessment surveys completed by clients at an urban drop-in center for PEH (n = 63) showed mental (58.7%) and physical (52.4%) health challenges were common, as was emergency department (ED) use (75.9%, n = 54). Surveys collected after in-person and telehealth clinical visits showed patient satisfaction was >90% for both visit types (n = 125, 44.0% telehealth and 56.0% in person). Without access to telehealth visits, 29.1% of patients would have gone to the ED and 38.2% would not have gotten care. Providers (n = 93, 69.6% telehealth and 30.4% in person) were more likely to agree/strongly agree they made a positive impact on patients' health through telehealth (92.2%) than in person (71.4%) (p = 0.019). Telehealth is a feasible and potentially cost-effective method to increase access to health care and reduce health outcome disparities in PEH.

STochastic Optical Reconstruction Microscopy (STORM) reveals the nanoscale organization of pathological aggregates in human brain.

AIMS: Histological analysis of brain tissue samples provides valuable information about the pathological processes leading to common neurodegenerative disorders. In this context, the development of novel high-resolution imaging approaches is a current challenge in neuroscience. METHODS: To this end, we used a recent super-resolution imaging technique called STochastic Optical Reconstruction Microscopy (STORM) to analyse human brain sections. We combined STORM cell imaging protocols with neuropathological techniques to image cryopreserved brain samples from control subjects and patients with neurodegenerative diseases. RESULTS: This approach allowed us to perform 2D-, 3D- and two-colour-STORM in neocortex, white matter and brainstem samples. STORM proved to be particularly effective at visualizing the organization of dense protein inclusions and we imaged with a <50 nm resolution pathological aggregates within the central nervous system of patients with Alzheimer's disease, Parkinson's disease, Lewy body dementia and fronto-temporal lobar degeneration. Aggregated Aß branches appeared reticulated and cross-linked in the extracellular matrix, with widths from 60 to 240 nm. Intraneuronal Tau and TDP-43 inclusions were denser, with a honeycomb pattern in the soma and a filamentous organization in the axons. Finally, STORM imaging of α-synuclein pathology revealed the internal organization of Lewy bodies that could not be observed by conventional fluorescence microscopy. CONCLUSIONS: STORM imaging of human brain samples opens further gates to a more comprehensive understanding of common neurological disorders. The convenience of this technique should open a straightforward extension of its application for super-resolution imaging of the human brain, with promising avenues to current challenges in neuroscience.

Cardiovascular Screening and Lipid Management in Breast Cancer Survivors.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death among breast cancer (BC) survivors. BC survivors are at increased risk of CVD due to a higher prevalence of risk factors. Current data are limited on the cardiovascular screening practices and lipid management in this population in primary care settings. METHODS: A retrospective case control study was performed with 105 BC survivors and 210 matched controls (based on age and medical comorbidities of diabetes, hypertension, and hyperlipidemia). BC survivors were established with primary care practices within a large academic institution and had completed primary cancer treatment. Data on screening for CVD and lipid management were collected via a retrospective chart review. RESULTS: The average BC survivor was 63 years old, with 9 years since diagnosis. Compared with matched controls, BC survivors had more cholesterol screening (88% vs 70%, P < .001) and active statin prescriptions (63% vs 40%, P < .05) if indicated by the Atherosclerotic Cardiovascular Disease Calculator. There were no differences in CVD screening in White and African American BC survivors. However, African American BC survivors were more likely to have hypertension (P < .01) and have a body mass index in the overweight and obese category (P < .001) than White BC survivors. Older BC survivors were more likely to receive cholesterol screening. DISCUSSION: This study demonstrates that BC survivors who have an established primary care provider have improved cholesterol screening and statin therapy based on their risk of developing chronic diseases.

[Health democracy: Patient partnership]. / Démocratie sanitaire : le patient partenaire de sa prise en charge.

In 2019, the scientific committee of the French society of radiation oncology (SFRO) created an ethics committee. Its mission is to provide our professional community with food for thought on ethical issues, and to identify its specificities within the radiation oncology departments. For the 2020 annual conference, the commission looked into the evolution of the patient-carer relationship, and more particularly to the strong idea of patient partnership. Indeed, the writing of the White Book of Cancer gave voice to sick people and stressed the need for new devices, such as the Caregiving Time. Patients can no longer be considered as objects of care but as people whose dignity and autonomy must be imperatively respected. The acquisition of knowledge allows a bilateral exchange, prerequisite of a dynamic collaboration. Patients can be partners in their own care, partners in training and research (expert patient), but also partners in health institutions and policies. It is this notion of partnership and involvement of the person in their path of care in radiation oncology that we will analyse here. It will be about defining it, by developing the concept of autonomy, and bringing out its complexity and ambivalence through two examples from our clinical practice: the shared decision-making process for patients with localized prostate cancer and the patient's involvement in the success of his radiotherapy.

Bicycling Rates and the Prevalence of Bicycle Helmet Usage in Wisconsin.

INTRODUCTION: Bicycles are a source of transportation, recreation, and exercise throughout the world. Bicycling is associated with both health and environmental benefits but also poses a risk of injury. The use of bicycle helmets has been shown to reduce morbidity and mortality associated with cycling. It is unknown if helmet use differs across Wisconsin geographic areas and sociodemographic groups. METHODS: Data were obtained from the Survey of the Health of Wisconsin (SHOW). Bicycle use and helmet use frequency were determined from a self-administered questionnaire that contained questions specific to preventative health behaviors. Descriptive statistics summarized overall bicycle ridership. Chi-square and Student t tests were performed to assess relationships between bicycle and helmet use across geographic categories and sociodemographic groups. RESULTS: Differences between sex, race or ethnicity, and education level were found to be associated with bicycle ridership and the frequency of helmet use. Men were significantly more likely to report riding a bicycle and never wearing a helmet. Individuals from urban communities reported always wearing a helmet more often than rural communities. Higher education levels were associated with higher levels of bicycle and helmet use. Race or ethnicity was not associated with bicycle ridership but was associated with differences in helmet use frequency. CONCLUSION: Nearly half of those who ride bicycles in Wisconsin report never wearing a helmet. Since bicycle ridership and helmet use were found to be associated with a number of sociodemographic characteristics, any solution should consider the role of equity when attempting to increase ridership or helmet use.

[Research ethics: French regulations and applications in radiation oncology]. / Éthique de la recherche : réglementations françaises et applications en oncologie radiothérapie.

French regulations about research ethics are based on the so-called Jardé law, which defines researches involving human beings. Researches involving human beings require the submission of research protocols to a committee for protection of persons with a precise list of documents to submit for a favourable opinion. This law describes different categories of researches and determines the ethical procedures to apply before setting up a research protocol. This issue of categorisation is central and must be taken into account by researchers from the beginning of the research process. Researches considered as not involving human beings also require a set of ethical precautions focused on patients' information and the collection of their non-opposition (due to the application of the General Data Protection Regulation adopted by the European Parliament). Thus, many regulations exist and they require a real work for researchers to meet these requirements in research ethics. This article aims to summarise French regulations. Selected examples are specifically taken into the field of radiation oncology research.

Direct-to-Patient Telehealth: Opportunities and Challenges.

Provision of healthcare services through telehealth continues to increase. This rise is driven by the several factors, such as improved access, decreased cost, patient convenience and positive patient satisfaction. Direct-to-patient (DTP) care delivery is the most popular form of telehealth. However, barriers exist to its widespread use in practice, such as lack of reimbursement, concern that the convenience of these services may raise utilization to the point that spending increases without increasing quality of care, concern about quality of care provided and low uptake by underrepresented or at risk populations. DTP offers opportunities to improve population health and provide value-based care within integrated health systems, but requires thoughtful implementation strategies that address patient and provider barriers to its use.

Pilot Randomized Trial of a Self-Help Behavioral Activation Mobile App for Utilization in Primary Care.

Mobile technologies can be leveraged to meet the need for evidence-based psychological depression treatment via primary care. The purpose of the present study was to preliminarily examine the feasibility and efficacy of a self-help brief behavioral activation mobile application (app; "Moodivate") for depressive symptoms among adults treated via primary care. Participants (N = 52) were recruited from primary care practices between January and December 2017 and were randomized 2:2:1 to receive (a) Moodivate, (b) an active control cognitive-behavioral therapy-based mobile app ("MoodKit"), or (c) treatment as usual (TAU; no app). Participants completed assessments of depressive symptoms weekly for 8 weeks. App analytics data were captured to examine Moodivate feasibility (analytics unavailable for control app). Moodivate participants on average had 46.76 (SD = 30.10) app sessions throughout the trial duration, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total throughout the trial. Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period. A generalized estimating equation model examining change in depressive symptoms over time by treatment condition indicated a significant interaction between time and treatment condition (χ2 = 42.21, df = 14, p < .001). As compared to TAU, participants in both app conditions evidenced significant decreases in depressive symptoms over time, and these treatment gains were sustained across the trial period. These results preliminarily indicate feasibility of Moodivate as well as efficacy of both Moodivate and MoodKit for the treatment of depression among adults recruited via primary care. Future studies should focus on larger-scale examinations of treatment efficacy and effectiveness across primary care settings.

Role of Tumor-Associated Macrophages in the Clinical Course of Pancreatic Neuroendocrine Tumors (PanNETs).

PURPOSE: This study evaluated the potential role of immune cells and molecules in the pathogenesis and clinical course of pancreatic neuroendocrine tumors (PanNET). EXPERIMENTAL DESIGN: Surgically resected PanNETs (N = 104) were immunohistochemically analyzed for Ki67 index, mitotic rate, macrophage, CD4+ cells, and CD8+ T-cell infiltration, as well as HLA class I, PD-L1, and B7-H3 expression. Results were correlated with clinicopathologic characteristics as well as with disease-free (DFS) and disease-specific (DSS) survival. RESULTS: The median age of the 57 WHO grade 1 and 47 WHO grade 2 patients was 55 years. High intratumoral CD8+ T-cell infiltration correlated with prolonged DFS (P = 0.05), especially when the number of tumor-associated macrophages (TAM) was low. In contrast, high peritumoral CD4+ cell and TAM infiltration was associated with a worse DFS and DSS. PD-L1 and B7-H3 were expressed in 53% and 78% PanNETs, respectively. HLA class I expression was defective in about 70% PanNETs. HLA-A expression correlated with favorable DSS in PD-L1-negative tumors (P = 0.02). TAM infiltration (P = 0.02), WHO grade (P = 0.04), T stage (P = 0.01), and lymph node positivity (P = 0.04) were independent predictors of DFS. TAM infiltration (P = 0.026) and T stage (P = 0.012) continued to be predictors of DFS in WHO grade 1 PanNET patients. TAM infiltration was the sole independent predictor of DSS for WHO grade 1 and 2 patients (P = 0.02). Therefore, this biomarker may contribute to identifying WHO grade 1 patients with poor prognosis. CONCLUSIONS: TAM infiltration appears to be the most informative prognostic biomarker in PanNET. It may represent a useful immunotherapeutic target in patients with PanNET.

Performance evaluation of the GastroPlusTM software tool for prediction of the toxicokinetic parameters of chemicals.

The accurate prediction of toxicokinetic parameters arising from oral, dermal and inhalation routes of chemical exposure is a key element in chemical safety assessments. In this research, the physiologically based pharmacokinetic (PBPK) GastroPlusTM software was evaluated against a series of chemicals for the prediction of toxicokinetic parameters. Overall, 67% of predicted intrinsic clearance (Clint) values were within 1- to 10-fold of empirical data for 463 compounds, and 87% of the predicted fraction unbounded in plasma (Fup) values were 1- to 3-fold of empirical data for 441 compounds. The r2 (coefficient of determination) of predicted Cmax (maximum plasma concentration) and AUC (Area Under Curve) values versus the corresponding empirical values from oral, inhalation and dermal exposures ranged from 0.04 to 0.92. Among the three exposures, the highest r2 values, ranging from 0.80 to 0.92, were observed for oral exposure predictions, where 88% of the compounds had 1- to 10-fold differences between predicted and empirical values for Cmax and AUC. The predicted plasma Css (steady-state plasma concentration) values were consistent with those Css values calculated by in vitro-to-in vivo extrapolation (IVIVE) approaches using experimental parameters. Based on the evaluation results, GastroPlus™ can be used as a QSAR/PBPK tool for toxicokinetic parameter predictions.

Nurse Satisfaction With Medical Emergency Team Nurses: A 3-Year Study.

BACKGROUND: This 3-year study measured the satisfaction of staff nurses with medical emergency team (MET) nurse services at a 573-bed hospital in the south from 2015 through 2017. Nurse satisfaction is a key management issue. Barriers to effective MET use can negatively impact patient outcomes, staffing, and nurse turnover. OBJECTIVES: The purpose of this study was to assess nurse satisfaction with MET nurses at a large county hospital in the south over a 3-year period. METHODS: Satisfaction was analyzed by shift, nurse role, the number of times the nurse contacted the MET nurse, and the way in which contact was initiated (MET nurse initiated vs nurse initiated). In addition, nurses responded to open-ended questions. RESULTS: Nurse satisfaction with MET nurse services was improved with both education and communication over time and stabilized over the 3-year period. More than 95% of nurses were satisfied or very satisfied overall with MET nurse services. There were statistically significant differences in satisfaction by shift worked, nurse role, and method of activation. There were no statistically significant differences by nursing floor. DISCUSSION: Nurse leaders can consider this MET nurse service as a potential model to help with increasing staff satisfaction, staff engagement, and, potentially, staff retention. More than 95% of nurses were satisfied or very satisfied overall with MET nurse services.

Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation.

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.