Novel Catalytic Antioxidant Formulation Decreases Oxidative Stress, Neuroinflammation and Cognitive Dysfunction in a Model of Nerve Agent Intoxication.

Reactive oxygen species have an emerging role in the pathologic consequences of status epilepticus. We have previously demonstrated the efficacy of a water-for-injection formulation of the meso-porphyrin catalytic antioxidant, manganese (III) meso-tetrakis (N-N-diethylimidazole) porphyrin (AEOL10150) against oxidative stress, neuroinflammation, and neuronal death initiated by kainic acid, pilocarpine, diisopropylflurophosphate (DFP), and soman. This previous dose and dosing strategy of AEOL10150 required smaller multiple daily injections, precluding our ability to test its efficacy against delayed consequences of nerve agent exposure such as neurodegeneration and cognitive dysfunction. Therefore, we developed formulations of AEOL10150 designed to deliver a larger dose once daily with improved brain pharmacodynamics. We examined four new formulations of AEOL10150 that resulted in 8 times higher subcutaneous dose with lower acute toxicity, slower absorption, longer half-life, and higher maximal plasma concentrations compared with our previous strategy. AEOL10150 brain levels exhibited improved pharmacodynamics over 24 hours with all four formulations. We tested a subcutaneous dose of 40 mg/kg AEOL10150 in two formulations (2% carboxymethyl cellulose and 4% polyethylene glycol-4000) in the DFP rat model, and both formulations exhibited significant protection against DFP-induced oxidative stress. Additionally, and in one formulation (4% polyethylene glycol-4000), AEOL10150 significantly protected against DFP-induced neuronal death, microglial activation, delayed memory impairment, and mortality. These results suggest that reformulation of AEOL10150 can attenuate acute and delayed outcomes of organophosphate neurotoxicity. SIGNIFICANCE STATEMENT: Reformulation of manganese (III) meso-tetrakis (N-N-diethylimidazole) porphyrin allowed higher tolerated doses of the compound with improved pharmacodynamics. Specifically, one new formulation allowed fewer daily doses and improvement in acute and delayed outcomes of organophosphate toxicity.

Association of maternal risk factors with infant maltreatment: an administrative data cohort study.

OBJECTIVE: We aimed to evaluate the risk of infant maltreatment associated with commonly used criteria for home visiting programmes: young maternal age, maternal adversity (homelessness, substance abuse, intimate partner violence), newcomer status and mental health concerns in Ontario, Canada. DESIGN: This retrospective cohort study included infants born in hospital in Ontario from 1 April 2005 to 31 March 2017 captured in linked health administrative and demographic databases. Infants were followed from newborn hospitalisation until 1 year of age for child maltreatment captured in healthcare or death records. The association between type and number of maternal risk factors, and maltreatment, was analysed using multivariable logistic regression modelling, controlling for infant characteristics and material deprivation. Further modelling explored the association of each year of maternal age with maltreatment. RESULTS: Of 989 586 infants, 434 (0.04%) had recorded maltreatment. Maternal age <22 years conferred higher risk of infant maltreatment (adjusted OR (aOR) 5.5, 95% CI 4.5 to 6.8) compared with age ≥22 years. Maternal mental health diagnoses (aOR 2.0, 95% CI 1.6 to 2.5) were also associated with maltreatment, while refugee status appeared protective (aOR 0.6, 95% CI 0.4 to 1.0). The odds of maltreatment increased with higher numbers of maternal risk factors. Maternal age was associated with maltreatment until age 28 years. CONCLUSION: Infants born to young mothers are at greater risk of infant maltreatment, and this association remained until age 28 years. These findings are important for ensuring public health interventions are supporting populations experiencing structural vulnerabilities with the aim of preventing maltreatment.

Understanding the roles of the healthcare and child welfare systems in promoting the safety and well-being of children.

Introduction: The accurate identification and appropriate investigation of child maltreatment is a key priority for promoting the optimal health and development of children. Healthcare providers are often well-positioned professionals to report suspected child abuse and neglect, and, therefore, interact regularly with child welfare workers. Little research has examined the relationship between these two groups of professionals. Methods: We interviewed healthcare providers and child welfare workers in order to examine the referral and child welfare investigation processes to understand strengths and identify areas of improvement for future collaboration. Thirteen child welfare workers from child welfare agencies and eight healthcare providers from a pediatric tertiary care hospital in Ontario, Canada were interviewed to meet the study's objectives. Results: Healthcare providers spoke about positive experiences making reports, factors impacting reporting decisions, areas for improvement (e.g., difficulties communicating, lack of collaboration, and disruption of therapeutic alliance), training, and professional roles. For interviews with child welfare workers, identified themes included healthcare professionals' perceived expertise and understanding the role of child welfare. Both groups brought up the need for increased collaboration as well as systemic barriers and legacies of harm. Discussion: Our core finding was a reported lack of communication between the groups of professionals. Other identified barriers in collaboration included a lack of understanding of each other's roles, hesitation for healthcare providers making reports, as well as legacies of harm and systemic inequities in both institutions. Future research should build on this examination by including the voices of healthcare providers and child welfare workers to identify sustainable solutions for increased collaboration.

Subdural hemorrhages and severe retinal hemorrhages in a short fall with a rotational component.

We present the case of a 5-month-old referred for child abuse investigation with subdural hemorrhages and extensive retinal hemorrhages following a short fall from a swivel chair seen on video footage. Subdural hemorrhages with extensive retinal hemorrhages are not typically seen as the result of short household falls. Reviewing the footage, contributing factors may have included increased rotational and deceleration forces.

Neuronal SIRT3 Deletion Predisposes to Female-Specific Alterations in Cellular Metabolism, Memory, and Network Excitability.

Mitochondrial dysfunction is an early event in the pathogenesis of neurologic disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass spectrometry-based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons in the cortex and hippocampus produces altered neuronal excitability and metabolic dysfunction in female mice. Targeted deletion of SIRT3 from neuronal helix-loop-helix 1 (NEX)-expressing neurons resulted in mitochondrial hyperacetylation, female-specific superoxide dismutase-2 (SOD2) modification, increased steady-state superoxide levels, metabolic reprogramming, altered neuronal excitability, and working spatial memory deficits. Inducible neuronal deletion of SIRT3 likewise produced female-specific deficits in spatial working memory. Together, the data demonstrate that deletion of SIRT3 from forebrain neurons selectively predisposes female mice to deficits in mitochondrial and cognitive function.SIGNIFICANCE STATEMENT Mitochondrial SIRT3 is an enzyme shown to regulate energy metabolism and antioxidant function, by direct deacetylation of proteins. In this study, we show that neuronal SIRT3 deficiency renders female mice selectively vulnerable to impairment in redox and metabolic function, spatial memory, and neuronal excitability. The observed sex-specific effects on cognition and neuronal excitability in female SIRT3-deficient mice suggest that mitochondrial dysfunction may be one factor underlying comorbid neuronal diseases, such as Alzheimer's disease and epilepsy. Furthermore, the data suggest that SIRT3 dysfunction may predispose females to age-related metabolic and cognitive impairment.

Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response.

Mitochondrial superoxide (O2-) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2- to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2-, specifically in neurons, was sufficient to upregulate GFAP. These results suggest that neuron-specific mitochondrial O2- is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.

Refining interprofessional, outpatient transitions of care services to reduce hospital readmissions.

RATIONALE, AIMS AND OBJECTIVES: Transitions of care between healthcare facilities are associated with increased risk of adverse events and hospital readmissions. Previous studies employing pharmacists in transitions of care showed reduced 30-day readmissions, however, many were without an active comparator. There is no standardized approach to pharmacist involvement in transitions of care services, making it difficult to ascertain where pharmacist expertise is most meaningful. This paper aims to compare the 30-day hospital readmissions between an interprofessional hospital discharge visit (iHDV) with physician and pharmacist involvement to a non-interprofessional HDV (PHDV) without pharmacist involvement. METHOD: This was a retrospective quality improvement initiative examining patients of two outpatient clinical practices within a large, academic medical centre. The primary analysis compared 30-day hospital readmission rates for patients with a scheduled PHDV or iHDV within 30-days of index hospital discharge date, regardless of attendance at the HDV. The secondary outcome compared 30-day hospital readmission rates for patients who completed a PHDV or iHDV. Primary and secondary outcomes were evaluated using bivariate analysis and multivariate analysis by stepwise logistic regression, for both intention-to-treat (ITT) and per protocol (PP). RESULTS: This study found significantly lower 30-day hospital readmissions for patients scheduled for a PHDV compared to an iHDV (16.7% vs 21.5%, P = .0230) in an unadjusted analysis, but no significant difference in adjusted analyses (P = .4856). Per-protocol analysis found no significant difference in 30-day hospital readmission rates between groups in unadjusted and adjusted analyses. Visit completion rates were significantly different between groups, with approximately twice as many PHDV group patients completing visits as compared to the iHDV group (74.1% vs 61.5%, P < .0001). CONCLUSION: This study demonstrates an interprofessional clinic visit employing a clinical pharmacist in the post-hospital discharge visit did not significantly reduce 30-day hospital readmission rates compared to a post-hospital discharge visit without pharmacist involvement.

Antioxidant drug therapy as a neuroprotective countermeasure of nerve agent toxicity.

The use of chemical warfare agents is an ongoing, significant threat to both civilians and military personnel worldwide. Nerve agents are by far the most formidable toxicants in terms of their lethality and toxicity. Nerve agents initiate neurotoxicity by the irreversible inhibition of acetylcholinesterase and resultant accumulation of acetylcholine in excitable tissues. The cholinergic toxidrome presents as miosis, lacrimation, diarrhea, fasciculations, seizures, respiratory arrest and coma. Current medical countermeasures can attenuate acute mortality and confer limited protection against secondary neuronal injury when given rapidly after exposure. However, there is an urgent need for the development of novel, add-on neuroprotective therapies to prevent mortality and long-term toxicity of nerve agents. Increasing evidence suggests that pathways other than direct acetylcholinesterase inhibition contribute to neurotoxicity and secondary neuronal injury. Among these, oxidative stress is emerging as a key therapeutic target for nerve agent toxicity. In this review, we discuss the rationale for targeting oxidative stress in nerve agent toxicity and highlight research investigating antioxidant therapy as a neuroprotective medical countermeasure to attenuate oxidative stress, neuroinflammation and neurodegeneration.

Impact of an interprofessional transition of care service on 30-day hospital reutilizations.

The objective of this study was to evaluate the impact of an interprofessional Transitions of Care (TOC) service on 30-day hospital reutilization inclusive of hospital readmissions and ED visits. This was a retrospective cohort study including patients discharged from an academic medical center between September 2013 and October 2014. Patients scheduled for a hospital follow-up visit in the post-acute care clinic (PACC) were included in the intervention group and patients without a post-discharge interprofessional TOC service were included in the comparison group. The intervention included a hospital follow-up visit with an interprofessional healthcare team. The primary composite outcome was hospital reutilization, defined as a hospital readmission or ED visit within 30 days of the discharge date. Overall, 330 patients were included in each group. In the intention-to-treat analysis, the primary composite outcome was not significantly different between groups (16.97% vs. 19.39%, P = 0.4195) whereas in the per-protocol analysis (all patients who showed to their PACC appointment), the primary outcome was significantly different in favor of the intervention group (9.28% vs. 19.39%, P = 0.0009). When components were analyzed separately, there was a statistically significant difference in favor of intervention group for hospital readmissions, but there was no difference for ED visits. This study demonstrates that an outpatient interprofessional TOC service with patient engagement from a team of nurses, pharmacists, physicians, and social workers may reduce 30-day hospital readmissions but may not impact 30-day ED visits.

Neuroprotective effects of a catalytic antioxidant in a rat nerve agent model.

Persistent inhibition of acetylcholinesterase resulting from exposure to nerve agents such as soman, is associated with prolonged seizure activity known as status epilepticus (SE). Without medical countermeasures, exposure to soman and resultant SE leads to high morbidity and mortality. Currently available therapeutics are effective in limiting mortality, however effects on morbidity are highly time-dependent and rely on the ability to suppress SE. We have previously demonstrated significant protection from secondary neuronal injury in surrogate nerve agent models by targeting oxidative stress. However, whether oxidative stress represents a relevant therapeutic target in genuine nerve agent toxicity is unknown. Here, we demonstrate that soman exposure results in robust region- and time-dependent oxidative stress. Targeting this oxidative stress in a post-exposure paradigm using a small molecular weight, broad spectrum catalytic antioxidant, was sufficient to attenuate brain and plasma oxidative stress, neuroinflammation and neurodegeneration. Thus, targeting of oxidative stress in a post-exposure paradigm can mitigate secondary neuronal injury following soman exposure.

Impact of a simulated electronic health record on pharmacy students' perceptions of preparedness for clinical practice.

BACKGROUND AND PURPOSE: The growing use of electronic health records (EHRs) in clinical practice highlights the need to incorporate simulated EHRs into the curriculum of healthcare professions. The purpose of this study was to evaluate the impact of a simulated EHR on student performance and to describe students' perceptions of preparedness to use an EHR in clinical practice. EDUCATIONAL ACTIVITY AND SETTING: A simulated EHR was introduced to third-year pharmacy students in a practice lab and case studies course series. The impact of the simulated EHR was measured by comparing student grades from acute patient care and ambulatory care advanced pharmacy practice experiences (APPEs) before and after EHR implementation. Data on students' perceptions of preparedness to use an EHR was collected by means of a questionnaire. FINDINGS: There was no significant difference between groups on student performance from the acute patient care APPE (p = 0.522) or from the ambulatory care APPE (p = 0.936). Questionnaire responses showed statistically significant improvements in students' perceptions of preparedness to use an EHR in clinical practice. DISCUSSION: Positive findings related to students' perceptions of preparedness to use an EHR in clinical practice were used to guide expansion of the simulated EHR throughout the didactic curriculum at the Philadelphia College of Pharmacy. SUMMARY: Implementation of a simulated EHR at the end of the PharmD didactic curriculum did not show a difference in student performance on select APPEs, but did show improvements in students' perceptions of preparedness to use an EHR in clinical practice.

Describing pharmacy student participation in an international, interprofessional medical mission trip as part of an advanced pharmacy practice experience (APPE).

BACKGROUND AND PURPOSE: Several schools of pharmacy across the United States have taken steps to incorporate international medical mission trips into the doctor of pharmacy (PharmD) curriculum. This study aims to describe the impact of advanced pharmacy practice experience (APPE)-level student pharmacists on an interprofessional team during an international medical mission trip to Jamaica. EDUCATIONAL ACTIVITY AND SETTING: The Jamaica Medical Mission (JMM) trip is an annual event involving healthcare professionals from several disciplines across multiple universities and healthcare systems. At this institution, the JMM trip is included as part of a rural health elective APPE rotation. Students electing to participate in this rotation are provided with the opportunity to serve as active participants on an interprofessional healthcare team in underserved and under-resourced communities throughout Jamaica. The JMM trip that took place during June 2016 included healthcare professionals and students in the fields of medicine, dentistry, optometry, nursing, and pharmacy. A total of five pharmacist preceptors and 10 pharmacy students attended the JMM trip in June 2016. Approximately three to five clinic sites per day were conducted simultaneously on each of the seven clinic days at various locations throughout Jamaica. The interprofessional healthcare teams provided free medical care, including physical exams and access to prescription and non-prescription medications. FINDINGS: The interprofessional healthcare team saw a total of 1014 patients and dispensed 1879 prescriptions during the seven clinic days. A total of 811 clinical recommendations were made by student pharmacists and/or pharmacy preceptors. Of these recommendations, 561 (69%) were made by student pharmacists without pharmacy preceptor prompting, 103 (13%) were made by the student pharmacist with preceptor prompting, and 147 (18%) were made by pharmacy preceptors. Over 70% of recommendations made by student pharmacists without pharmacy preceptor prompting were accepted by prescribers. DISCUSSION AND SUMMARY: This study sought to describe the impact of APPE-level student pharmacists on an interprofessional team during an international medical mission trip. Our findings demonstrate that APPE-level student pharmacists were capable of making a substantial number of clinical recommendations without preceptor prompting. The number of recommendations made by students without preceptor prompting were consistently greater than the number of recommendations made with preceptor prompting throughout the trip. Future studies should address student competence in achieving learning objectives associated with international, interprofessional APPE rotations.

Accountable Care in Transitions (ACTion): A Team-Based Approach to Reducing Hospital Utilization in a Patient-Centered Medical Home.

BACKGROUND: There is limited data describing the role of the patient-centered medical home (PCMH) in successful transitions programs and more information is needed to determine the transition points where pharmacist involvement is most impactful. METHODS: A family medicine center developed a multidisciplinary outpatient-based transitions program focused on reducing emergency department (ED) and hospital use in medically complex patients. Key team members were a medical provider, clinical pharmacist practitioner (CPP), and care manager. The objective was to evaluate the impact of the program by comparing utilization before and after the intervention and to identify patient and process characteristic predictors of 30-day rehospitalizations. RESULTS: Of the 268 patients included, the mean time to follow-up appointment attended was 11.6 (11.8) days after discharge. The majority of patients (72%) saw their primary care provider at follow-up. Patients experiencing the multidisciplinary intervention had lower 30-day rehospitalizations at 7, 14, and 30 days postdischarge with significance achieved at 14 and 30 days. Compared to before the intervention, reductions in both ED visits and hospitalizations as well as increases in clinic visits were seen at 1, 3, and 6 months. CPP involvement was associated with lower rehospitalizations (7.7% vs 18.8%; P = .04). CONCLUSION: A multidisciplinary outpatient-based transitions program embedded in the PCMH increased access to primary care and reduced hospital and ED utilization. Face-to-face CPP involvement significantly lowered rehospitalizations. This program describes a standardized approach to complex care needs with defined roles, a model that may be generalizable and reproduced in other medical homes.

Bacteremia in Patients With Liver Cirrhosis: Prevalence and Predictors of Multidrug Resistant Organisms.

GOALS: The objective of this study was to assess the prevalence and predictors of multidrug resistant organisms (MDRO) in cirrhotic patients with bacteremia at a large tertiary center in the United States. BACKGROUND: The epidemiology of bacteremia in patients with liver cirrhosis has not been well studied in the United States. STUDY: This case-case control study included 180 adults with liver cirrhosis hospitalized from 2011 to 2015. Case group 1 were patients with bacteremia due to a MDRO (n=30). Case group 2 were patients with bacteremia due to a non-MDRO (n=60). Control group comprised patients without bacteremia (n=90). MDRO was defined as bacteria that was nonsusceptible to ≥1 agent in ≥3 antimicrobial categories. RESULTS: Of the 90 bacteremia episodes, 44% were because of gram-positive bacteria, 50% were because of gram-negative bacteria, and 6% were polymicrobial. MDROs caused 30 of 90 (33%) bacteremia episodes, including methicillin-resistant Staphylococcus species [12% (11/90)], fluoroquinolone-resistant Enterobacteriaceae [10% (9/90)], and Enterococcus faecium [3% (3/90)]. Eight percent of Enterobacteriaceae produced extended-spectrum ß-lactamases. Four independent predictors of MDROs were identified: nonwhite race [adjusted odds ratio (aOR), 3.35; 95% confidence interval (CI), 1.19-9.38], biliary cirrhosis (aOR, 11.75; 95% CI, 2.08-66.32), blood cultures obtained >48 hours after hospital admission (aOR, 6.02; 95% CI, 1.70-21.40), and recent health care exposure (aOR, 9.81; 95% CI, 2.15-44.88). CONCLUSIONS: A significant proportion of bacteremia in cirrhotic patients was due to MDROs at a large US tertiary care center. Local epidemiology data and identification of risk factors associated with MDROs may help with optimal empiric antibiotic selection.

Neuroprotective Effects of AEOL10150 in a Rat Organophosphate Model.

Prolonged seizure activity or status epilepticus (SE) is one of the most critical manifestations of organophosphate exposure. Previous studies in our laboratory have demonstrated that oxidative stress is a critical mediator of SE-induced neuronal injury. The goal of this study was to determine if diisopropylflurorphoshate (DFP) exposure in rats resulted in oxidative stress and whether scavenging reactive oxygen species attenuated DFP-induced neurotoxicity. DFP treatment increased indices of oxidative stress in a time- and region- dependent manner. Neuronal loss measured by Fluoro-Jade B staining was significantly increased in the hippocampus, piriform cortex and amygdala following DFP. Similarly, levels of the proinflammatory cytokines, particularly TNF-α, IL-6, and KC/GRO were significantly increased in the piriform cortex and in the hippocampus following DFP treatment. The catalytic antioxidant AEOL10150, when treatment was initiated 5 min after DFP-induced SE, significantly attenuated indices of oxidative stress, neuroinflammation and neuronal damage. This study suggests that catalytic antioxidant treatment may be useful as a novel therapy to attenuate secondary neuronal injury following organophosphate exposure.

Metabolic Dysfunction and Oxidative Stress in Epilepsy.

The epilepsies are a heterogeneous group of disorders characterized by the propensity to experience spontaneous recurrent seizures. Epilepsies can be genetic or acquired, and the underlying mechanisms of seizure initiation, seizure propagation, and comorbid conditions are incompletely understood. Metabolic changes including the production of reactive species are known to result from prolonged seizures and may also contribute to epilepsy development. In this review, we focus on the evidence that metabolic and redox disruption is both cause and consequence of epileptic seizures. Additionally, we discuss the promise of targeting redox processes as a therapeutic option in epilepsy.

Central Arterial Function Measured by Non-invasive Pulse Wave Analysis is Abnormal in Patients with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutation of dystrophin. Cardiovascular involvement includes dilated cardiomyopathy. Non-invasive assessment of vascular function has not been evaluated in DMD. We hypothesize arterial wave reflection is abnormal in patients with DMD. Pulse wave analysis was performed on DMD patients with a SphygmoCor SCOR-PVx System to determine central blood pressure and augmentation index (AIx) as an assessment of arterial wave reflection. Results were compared to a control group. A total of 43 patients with DMD were enrolled, and compared to 43 normal controls. Central systolic blood pressure was lower, while both AIx-75 (7.8 ± 9.6% vs. 2.1 ± 10.4%, p 0.01, DMD vs. normal) and AIx-not corrected (16.8 ± 10.1% vs. -3.6 ± 10.9, p < 0.001, DMD vs. normal) were higher in the DMD compared to control. Using multivariable linear regression model, the variables found to have a significant effect on AIx-not corrected included diagnosis of DMD, height, and heart rate (r 2 = 0.257). The current data suggest that, despite lower central systolic blood pressure, patients with DMD have higher wave reflection when compared to normal controls, which may represent increased arterial stiffness. Overall there appears to be no effect on ventricular systolic function, however the long-term consequence in this group is unknown. Further study is required to determine the mechanism of these differences, which may be related to the effects of systemic steroids or the role of dystrophin in vascular function.