Emergency Department Visits at Veteran's Health Administration Hospitals Related to Alcohol Intoxication: A Ten-Year Retrospective.

We sought to quantify and describe the volume of emergency department visits related to alcohol intoxication at the Veterans Health Administration (VHA), the largest healthcare system in the United States. This is a retrospective cohort study of patients with VHA emergency department visits for alcohol intoxication from 2010-2019 as identified via ICD-9/10 code and/or serum ethanol concentration >50mg/dL. Encounters were identified and demographic and clinical data were acquired by automated query of the VHA Corporate Data Warehouse. Descriptive statistics and univariate analysis were performed. We identified 95,123 patients with a total of 251,310 emergency department visits. The annual number of visits increased over the study period, reaching 32,333 in 2019. Men aged 40-60 were the most common demographic group in the cohort (48% of all patients), and men made up a high proportion of patients in the database (94%) than the VHA population overall (90%). A disproportionate number of visits (32%) came from the top 4.4% of most frequent visitors. Most of the emergency department visits in the database (68%) were associated with medical or psychiatric admission, or interfacility transfer for admission elsewhere. Patients in the cohort accounted for 1.3% of all VHA emergency department visits during the study period, a proportion which is somewhat smaller than what has been reported at non-VHA facilities, and despite the high prevalence of addiction disorders in the VHA patient population. We submit that this lower-than-expected proportion of alcohol-related emergency department visits may be due to the access to primary and mental care which is afforded by VHA patient benefits.

Immune checkpoint inhibitor-related adverse events: Real-world experience from a single veterans' affairs medical center.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are antineoplastic agents associated with a multitude of immune-related adverse events (irAEs). Available data from clinical trials include highly selective patient populations which may limit their applicability to real-world clinical practice. METHODS: We present a retrospective cohort study of cancer patients treated with ICI therapy at the Zablocki VA Medical Center between 2014 and 2021. Information on demographics, cancer diagnosis, type of therapy, treatment duration, comorbidities, irAE type, and overall survival were collected. RESULTS: We identified 187 patients who received at least one dose of ICI. About half the patients experienced at least one irAE, the most common categories being fatigue, pulmonary, and endocrine irAEs. Approximately half of the irAEs were diagnosed within the first three months of starting ICI therapy, and 60.38% of those who experienced irAEs discontinued ICI therapy. Patients who experienced endocrine or intestinal irAEs had a significantly longer overall survival. CONCLUSION: Immune-related complications due to ICI therapy are common and can frequently lead to treatment discontinuation in the real-world setting. Endocrine and intestinal irAEs may correlate with improved survival. The ICI-treated patients who received palliative radiation therapy to the bone had less irAEs, possibly due to immunogenic cell death.

Cardiovascular Disease Risk in Calcium Pyrophosphate Deposition Disease: A Nationwide Study of Veterans.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease represents a common crystalline arthritis with a range of manifestations. Our goal was to investigate risks for cardiovascular events in patients with CPPD. METHODS: We performed a retrospective matched cohort analysis in the Veterans Health Administration Corporate Data Warehouse, 2010-2014. CPPD was defined by ≥1 International Classification of Diseases, Ninth Revision codes for chondrocalcinosis or calcium metabolism disorder. CPPD patients were age- and sex-matched to approximately 4 patients without codes for CPPD; we excluded patients with a cardiovascular event during the 365 days prior to the index date. Demographic information, traditional cardiovascular risk factors, medications, and health care utilization were assessed at baseline. The primary outcome was a major adverse cardiovascular event (MACE: myocardial infarction, acute coronary syndrome, coronary revascularization, stroke, or death). Secondary outcomes included individual components of MACE. Cox proportional hazards models estimated fully adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: We identified 23,124 CPPD patients matched to 86,629 non-CPPD patients with >250,000 person-years of follow-up. The study population was 96% male, mean age was 78 years, and 75% were White. The frequency of traditional cardiovascular risk factors was similar between the 2 cohorts. CPPD was not significantly associated with risk for MACE (HR 0.98 [95% CI 0.94-1.02]) in fully adjusted models, though risks of myocardial infarction, acute coronary syndrome, and stroke were significantly higher in the CPPD cohort compared to the non-CPPD cohort. CONCLUSION: CPPD did not confer an increased risk for MACE, a composite end point including all-cause mortality. Our results propose CPPD as a novel risk factor for MACE components, including myocardial infarction, acute coronary syndrome, and stroke.

Tapered Dose Postoperative Opioid Prescriptions Following Inpatient Total Hip and Knee Arthroplasty: Quality Improvement Study and Retrospective Review.

BACKGROUND: Overprescription of pain medications directly fuels the opioid epidemic. Veterans are profoundly impacted. Tapered dose protocols may reduce excessive prescribing. METHODS: A retrospective study of adult veterans who presented to our institution for primary total knee arthroplasty or total hip arthroplasty (THA) was performed. Postdischarge opioid use was reviewed before and after an opioid taper prescription protocol. The preprotocol and postprotocol groups had 299 and 89 veterans, respectively. Total Morphine Milligram Equivalent (MME) prescribed postdischarge, number of tablets prescribed, number of refills issued, 30-day emergency department visits, and 30-day readmissions were compared. Opioid naïve and chronic opioid users were both included. RESULTS: Preprotocol and postprotocol implementation group, in combination with surgery type (total knee arthroplasty versus THA) and opioid naïve status, predicted MME. On average, the postprotocol group received 224 MME less, THA patients received 177 MME less, and nonopioid naïve patients received 152 MME more. CONCLUSION: The opioid taper protocol led to less opioid administration after discharge. Taper protocols should be considered for postoperative pain management. LEVEL OF EVIDENCE: III, retrospective comparison study.

New Opioid Persistence in Veterans Following Major and Minor Surgery.

INTRODUCTION: Opioids are often a mainstay of managing postsurgical pain. Persistent use of opioids for more than 90 days after surgery is problematic, and the incidence of this adverse outcome has been reported in the civilian population ranging from 0.4% to 7%. Veterans compose a special population exposed to trauma and stressful situations and consequently face increased risk for habit-forming behavior and drug overdose. This evaluation determined the prevalence of opioid persistence after surgery and its relationship to patient characteristics in a military veteran population. METHODS: A retrospective chart review was completed on 1,257 veterans who were opioid naive and had undergone a surgical procedure between January 2017 and May 2018. Patient characteristics, health conditions, and discharge opioid medications were recorded, and the incidence of persistent opioid use beyond 90 days was determined. RESULTS: The incidence of opioid persistence following major (3.3%) and minor (3.4%) procedures was similar. The incidence in patients younger than 45 years (3.3%), between 45 and 64 years (4.3%), and 65 years and older (2.2%) was also determined to be similar. Univariate patient factors associated with an increased risk for persistent opioid use include cancer (odds ratio [OR], 2.13; 95% CI, 1.11-4.09), mental health disorders (OR, 2.32; 95% CI, 1.17-4.60), and substance use disorders (OR, 2.09; 95% CI, 1.09-4.00). CONCLUSIONS: Among a cohort of over 1,200 opioid-naïve veterans undergoing surgery at a VA Medical Center, just over 3% went on to develop persistent opioid use beyond 3 months following their procedure. Persistent use was not found to be related to the type of procedure (major or minor) or patient age. Significant patient-level risk factors for opioid persistence were cancer and a history of mental health and substance use disorders.

Fatty acid amide hydrolase activity in the dorsal periaqueductal gray attenuates neuropathic pain and associated dysautonomia.

The complexity of neuropathic pain and its associated comorbidities, including dysautonomia, make it difficult to treat. Overlap of anatomical regions and pharmacology of sympathosensory systems in the central nervous system (CNS) provide targets for novel treatment strategies. The dorsal periaqueductal gray (dPAG) is an integral component of both the descending pain modulation system and the acute stress response and is critically involved in both analgesia and the regulation of sympathetic activity. Local manipulation of the endocannabinoid signaling system holds great promise to provide analgesia without excessive adverse effects and also influence autonomic output. Inhibition of fatty acid amide hydrolase (FAAH) increases brain concentrations of the endocannabinoid N-arachidonoylethanolamine (AEA) and reduces pain-related behaviors in neuropathic pain models. Neuropathic hyperalgesia and reduced sympathetic tone are associated with increased FAAH activity in the dPAG, which suggests the hypothesis that inhibition of FAAH in the dPAG will normalize pain sensation and autonomic function in neuropathic pain. To test this hypothesis, the effects of systemic or intra-dPAG FAAH inhibition on hyperalgesia and dysautonomia developed after spared nerve injury (SNI) were assessed in male and female rats. Administration of the FAAH inhibitor PF-3845 into the dPAG reduces hyperalgesia behavior and the decrease in sympathetic tone induced by SNI. Prior administration of the CB1 receptor antagonist AM281, attenuated the antihyperalgesic and sympathetic effects of FAAH inhibition. No sex differences were identified. These data support an integrative role for AEA/CB1 receptor signaling in the dPAG contributing to the regulation of both hyperalgesia behavior and altered sympathetic tone in neuropathic pain.

Characterizing the Heart Rate Effects From Administration of Sugammadex to Reverse Neuromuscular Blockade: An Observational Study in Patients.

BACKGROUND: Reversal of neuromuscular blockade (NMB) with sugammadex can cause marked bradycardia and asystole. Administration of sugammadex typically occurs in a dynamic period when anesthetic adjuvants and gas concentrations are being titrated to achieve emergence. This evaluation examined the heart rate (HR) responses to sugammadex to reverse moderate to deep NMB during a steady-state period and sought mechanisms for HR changes. METHODS: Patients with normal sinus rhythm, who were undergoing elective surgery that included rocuronium for NMB, were evaluated. After surgery, while at steady-state surgical depth anesthesia with sevoflurane and mechanical ventilation, patients received either placebo or 2 or 4 mg/kg of sugammadex to reverse moderate to deep NMB. Study personnel involved in data analysis were blinded to treatment. Continuous electrocardiogram (ECG) was recorded from the 5 minutes before and 5 minutes after sugammadex/placebo administration. R-R intervals were converted to HR and averaged in 1-minute increments. The maximum prolongation of an R-R interval after sugammadex was converted to an instantaneous HR. RESULTS: A total of 63 patients were evaluated: 8 received placebo, and 38 and 17 received 2 and 4 mg/kg sugammadex. Age, body mass index, and patient factors were similar in groups. Placebo did not elicit HR changes, whereas sugammadex caused maximum instantaneous HR slowing (calculated from the longest R-R interval), ranging from 2 to 19 beats/min. There were 7 patients with maximum HR slowing >10 beats/min. The average HR change and 95% confidence interval (CI) during the 5 minutes after 2 mg/kg sugammadex were 3.1 (CI, 2.3-4.1) beats/min, and this was not different from the 4 mg/kg sugammadex group (4.1 beats/min [CI, 2.5-5.6]). HR variability derived from the standard deviation of consecutive R-R intervals increased after sugammadex. CONCLUSIONS: Sugammadex to reverse moderate and deep NMB resulted in a fast onset and variable magnitude of HR slowing in patients. A difference in HR slowing as a function of dose did not achieve statistical significance. The observational nature of the investigation prevented a full understanding of the mechanism(s) of the HR slowing.

Understanding the relationship between patient characteristics and complication in veterans discharged on parenteral antibiotic therapy.

BACKGROUND: Many facilities utilize outpatient parenteral intravenous (IV) antimicrobial therapy (OPAT) to reduce cost, length of stay, and risk of nosocomial infections. OBJECTIVE: The objective of this study was to analyze patient demographics, substance use, mental and physical health diagnoses, and social determinants of health to seek relationships with complications for veterans discharged from the Zablocki Veterans Affairs Medical Center (ZVAMC) on OPAT. METHODS: This study was a retrospective chart review of veterans who completed OPAT between the years of 2013 and 2017 at the ZVAMC in Milwaukee, Wisconsin. Prior to discharge, patients were screened by the OPAT team for eligibility; patients were followed after discharge by pharmacy, home care, and providers. OPAT complication was defined as antibiotic change/dose adjustment, IV catheter complication, or an additional hospital visit secondary to current infection or therapy. RESULTS: 294 veterans' charts were reviewed. Of these patients, 106 (36.05%) had a complication. Tobacco use was the only factor significantly associated with OPAT complication. CONCLUSIONS: Cohabitation, employment status, mental health diagnosis and alcohol use were not associated with OPAT failure; however, tobacco use merits further review for use in OPAT screening protocols.

Helping Residents Excel in Team-Based Care: An Interactive Case-Based Interprofessional Education Curriculum.

INTRODUCTION: Communication and collaboration with an interprofessional team is vital for patient care, yet teaching these skills to resident physicians faces multiple challenges. METHODS: We developed an interactive, case-based curriculum on interprofessional communication and collaboration and implemented it at a large Veterans Affairs hospital. A pre/post survey study design was used to evaluate the curriculum, with 31 residents completing both surveys (100% response rate). RESULTS: After the curriculum, there was improvement in the residents' knowledge, comfort, and satisfaction in communicating and collaborating with the interprofessional team. Satisfaction scores with clinic also improved in all measures. DISCUSSION/CONCLUSIONS: Overall, a curriculum aimed at teaching interprofessional communication and collaboration improved residents' comfort and satisfaction in this realm and may help them achieve competence in these challenging-to-teach skills.

Implementation of Veterans Affairs Primary Care Antimicrobial Stewardship Interventions For Asymptomatic Bacteriuria And Acute Respiratory Infections.

BACKGROUND: Outpatient antimicrobial prescribing is an important target for antimicrobial stewardship (AMS) interventions to decrease antimicrobial resistance. The objective of this study was to design, implement, and evaluate the impact of AMS interventions focused on asymptomatic bacteriuria (ASB) and acute respiratory infections (ARIs) in the primary care setting. METHODS: This stepped-wedge trial evaluated the impact of multifaceted educational interventions to providers on adult patients presenting to primary care clinics for ARIs and ASB. The primary outcome was percentage of overall antibiotic prescriptions as a composite of prescriptions for ASB, acute bronchitis, upper respiratory infection not otherwise specified, uncomplicated sinusitis, and uncomplicated pharyngitis. Secondary outcomes were the individual components of the primary outcome; a composite safety endpoint of related hospital, emergency department, or primary care visits within 4 weeks; antibiotic selection appropriateness; and patient satisfaction surveys. RESULTS: A total of 887 patients were included (405 preintervention and 482 postintervention). After controlling for type I error using Bonferroni correction, the primary outcome was not significantly different between groups (56% vs 49%). There was a statistically significant decrease in prescriptions for acute bronchitis (20.99% vs 12.66%; P = .0003). Appropriateness of antibiotic prescriptions for uncomplicated sinusitis (odds ratio [OR], 4.96 [95% confidence interval {CI}, 1.79-13.75]; P = .0021) and pharyngitis (OR, 5.36 [95% CI, 1.93-14.90]; P = .0013) was improved in the postintervention vs the preintervention group. The composite safety outcome and patient satisfaction surveys did not differ between groups. CONCLUSIONS: Multifaceted educational interventions targeting providers can improve antibiotic prescribing for indications rarely requiring antimicrobials without increasing re-visits or patient satisfaction surveys.

Transcriptomic Characterization of Inhalation Phosphine Toxicity in Adult Male Sprague-Dawley Rats.

Phosphine (PH3) is a highly toxic, corrosive, flammable, heavier-than-air gas that is a commonly used fumigant. When used as a fumigant, PH3 can be released from compressed gas tanks or produced from commercially available metal phosphide tablets. Although the mechanism of toxicity is unclear, PH3 is thought to be a metabolic poison. PH3 exposure induces multiorgan toxicity, and no effective antidotes or therapeutics have been identified. Current medical treatment consists largely of supportive care and maintenance of cardiovascular function. To better characterize the mechanism(s) driving PH3-induced toxicity, we have performed transcriptomic analysis on conscious adult male Sprague-Dawley rats following whole-body inhalation exposure to phosphine gas at various concentration-time products. PH3 exposure induced concentration- and time-dependent changes in gene expression across multiple tissues. These gene expression changes were mapped to pathophysiological responses using molecular pathway analysis. Toxicity pathways indicative of cardiac dysfunction, cardiac arteriopathy, and cardiac enlargement were identified. These cardiotoxic responses were linked to apelin-mediated cardiomyocyte and cardiac fibroblast signaling pathways. Evaluation of gene expression changes in blood revealed alterations in pathways associated with the uptake, transport, and utilization of iron. Altered erythropoietin signaling was also observed in the blood. Upstream regulator analysis identified several therapeutics predicted to counteract PH3-induced gene expression changes. These include antihypertensive drugs (losartan, candesartan, and prazosin) and therapeutics to reduce pathological cardiac remodeling (curcumin and TIMP3). This transcriptomics study has characterized molecular pathways involved in PH3-induced cardiotoxicity. These data will aid in elucidating a precise mechanism of toxicity for PH3 and guide the development of effective medical countermeasures for PH3-induced toxicity.

Heterogeneity in patterns of pain development after nerve injury in rats and the influence of sex.

The genesis of neuropathic pain is complex, as sensory abnormalities may differ between patients with different or similar etiologies, suggesting mechanistic heterogeneity, a concept that is largely unexplored. Yet, data are usually grouped for analysis based on the assumption that they share the same underlying pathogenesis. Sex is a factor that may contribute to differences in pain responses. Neuropathic pain is more prevalent in female patients, but pre-clinical studies that can examine pain development in a controlled environment have typically failed to include female subjects. This study explored patterns of development of hyperalgesia-like behavior (HLB) induced by noxious mechanical stimulation in a neuropathic pain model (spared nerve injury, SNI) in both male and female rats, and autonomic dysfunction that is associated with chronic pain. HLB was analyzed across time, using both discrete mixture modeling and rules-based longitudinal clustering. Both methods identified similar groupings of hyperalgesia trajectories after SNI that were not evident when data were combined into groups by sex only. Within the same hyperalgesia development group, mixed models showed that development of HLB in females was delayed relative to males and reached a magnitude similar to or higher than males. The data also indicate that sympathetic tone (as indicated by heart rate variability) drops below pre-SNI level before or at the onset of development of HLB. This study classifies heterogeneity in individual development of HLB and identifies sexual dimorphism in the time course of development of neuropathic pain after nerve injury. Future studies addressing mechanisms underlying these differences could facilitate appropriate pain treatments.

Routine Laboratory Screening for Acetaminophen and Salicylate Ingestion in Preadmission Psychiatric Patients Is Unnecessary.

STUDY OBJECTIVE: Screening preadmission psychiatric patients for acetaminophen or salicylate overdose is unnecessary in the absence of specific clinical concern for medication ingestion. METHODS: This was a multicenter retrospective cohort study of 3 Veteran's Administration emergency departments that medically evaluate patients prior to psychiatric admission. During the 10-year study period, these departments followed screening protocols that required the measurement of acetaminophen and salicylate levels on every patient prior to psychiatric admission. We examined all the acetaminophen and salicylate assays performed to see if any that were sent for screening led to a diagnosis of overdose and/or the administration of antidotal therapy. RESULTS: A total of 33,439 combined acetaminophen and salicylate assays were sent on 10,482 unique patients over approximately 17,000 patient encounters. An estimated 29,000 assays were sent for screening purposes only-87% (95% confidence interval [CI] 85% to 89%) of salicylate assays and 85% (95% CI 83% to 87%) of acetaminophen assays. We identified 43 patients with elevated acetaminophen levels and 11 with elevated salicylate levels. Among these patients, only 6 in total had their levels drawn for screening purposes only, with no history of suspected ingestion; in all but 1 patient, the levels were only slightly above the reference range. None of the patients with elevated levels identified by screening had clinical toxicity or received antidotal therapy. CONCLUSION: Over a 10-year period, 3 Veteran's Administration emergency departments performed psychiatric preadmission screening protocols with acetaminophen and salicylate assays approximately 17,000 times without diagnosing a single case of toxicity. Our results suggest that this practice is unnecessary and wasteful.

Wheelchair Athlete Concussion Baseline Data: A Pilot Retrospective Analysis.

OBJECTIVE: The aim of the study was to investigate whether a disabled athlete's underlying disability and concussion history impact the score on baseline testing from a disability modified Graded Symptoms Checklist, Standardized Assessment of Concussion, and Wheelchair Error Scoring System. STUDY DESIGN: This is a retrospective chart review of the 81 veteran wheelchair sports athletes who had baseline concussion evaluations. Demographic data including qualifying disability for the National Veterans Wheelchair Games, scores from the modified Graded Symptoms Checklist, Standardized Assessment of Concussion, and Wheelchair Error Scoring System were analyzed. RESULTS: Forty-three percent of wheelchair athletes reported a history of a concussion. Individuals with a history of a concussion displayed more symptoms on the modified Graded Symptoms Checklist (38.8 vs. 24.71, P = 0.0378) as did those who had a qualifying disability in the brain disorder category (54.87 vs. amputees 24.07 and spinal cord disorders 24.9, P = 0.0015). There was no difference in Standardized Assessment of Concussion examination or Wheelchair Error Scoring System scores based on concussion history or qualifying disability. CONCLUSIONS: Baseline symptom scores from a modified Graded Symptoms Checklist were higher in participants with a history of concussion, independent of their underlying disability, and higher if the athlete's disability was a brain disorder including multiple sclerosis and cerebral vascular accident. Scores on the Standardized Assessment of Concussion examination and Wheelchair Error Scoring System were not affected by the athlete's disability or concussion history. Baseline testing is integral for disabled athletes, especially those with underlying brain disorders and history of concussion.

Predisposing and Precipitating Factors Associated With Postoperative Delirium in Patients Undergoing Cardiac Surgery at a Veterans Affairs Medical Center: A Pilot Retrospective Analysis.

OBJECTIVE: Patients treated at Veterans Affairs (VA) medical centers are in poorer health, experience more medical and psychiatric conditions, and make greater use of medical resources than do patients in the general population. In the present pilot study, the authors examined their recent experience at a VA medical center to determine the incidence and risk factors associated with the development of postoperative delirium in VA patients after cardiac surgery and hypothesized that the risk factors for postoperative delirium after cardiac surgery are different between VA and non-VA patients. DESIGN: Retrospective cohort study. SETTING: Clement J. Zablocki Veterans Affairs Medical Center. PARTICIPANTS: The study comprised 250 consecutive patients undergoing cardiac surgery from July 2014 to March 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, coexisting diseases, and medications were obtained from the VA electronic medical record. The European System for Cardiac Operative Evaluation II mortality risk index was calculated for each patient. The type and duration of the procedure and the duration of bypass were recorded. Intraoperative crystalloid, colloid, cell saver, and blood product volumes were compiled. Progress notes and International Classification of Diseases, Tenth Revision, Clinical Modification codes were searched for documentation of postoperative delirium. Thirty-eight patients (15.2%) developed postoperative delirium. Stepwise logistic regression analysis demonstrated that the European System for Cardiac Operative Evaluation II mortality risk index (odds ratio [OR] 1.036, 95% confidence interval [CI] [1.003-1.070]; p = 0.0344), congestive heart failure (OR 2.223 [95% CI 1.046-4.722]; p = 0.0377), pre-existing cognitive impairment (OR 5.147 [95% CI 1.994-13.28]; p = 0.0007), and the presence of a neuropsychiatric disorder (OR 2.015 [95% CI 1.004-4.043]; p = 0.0487) were predisposing factors associated with higher odds of postoperative delirium. The duration of surgery; transfusion of blood products (including packed red blood cells, fresh frozen plasma, and platelets); the durations of mechanical ventilation and conscious sedation (using either propofol or dexmedetomidine); and the length of intensive care unit stay were precipitating factors associated with higher odds of postoperative delirium. CONCLUSIONS: The results demonstrate that congestive heart failure, pre-existing cognitive impairment, and the presence of a neuropsychiatric disorder are predisposing risk factors for postoperative delirium after cardiac surgery in VA patients, whereas the duration of surgery, transfusion of blood products, durations of mechanical ventilation and conscious sedation, and length of intensive care unit stay are precipitating factors for postoperative delirium. These findings in VA patients generally are similar to those observed in the civilian population despite the differences between these cohorts.

The physiology and toxicology of acute inhalation phosphine poisoning in conscious male rats.

Phosphine (PH3) is a toxidrome-spanning chemical that is widely used as an insecticide and rodenticide. Exposure to PH3 causes a host of target organ and systemic effects, including oxidative stress, cardiopulmonary toxicity, seizure-like activity and overall metabolic disturbance. A custom dynamic inhalation gas exposure system was designed for the whole-body exposure of conscious male Sprague-Dawley rats (250-350 g) to PH3. An integrated plethysmography system was used to collect respiratory parameters in real-time before, during and after PH3 exposure. At several time points post-exposure, rats were euthanized, and various organs were removed and analyzed to assess organ and systemic effects. The 24 h post-exposure LCt50, determined by probit analysis, was 23,270 ppm × min (32,345 mg × min/m3). PH3 exposure affects both pulmonary and cardiac function. Unlike typical pulmonary toxicants, PH3 induced net increases in respiration during exposure. Gross observations of the heart and lungs of exposed rats suggested pulmonary and cardiac tissue damage, but histopathological examination showed little to no observable pathologic changes in those organs. Gene expression studies indicated alterations in inflammatory processes, metabolic function and cell signaling, with particular focus in cardiac tissue. Transmission electron microscopy examination of cardiac tissue revealed ultrastructural damage to both tissue and mitochondria. Altogether, these data reveal that in untreated, un-anesthetized rats, PH3 inhalation induces acute cardiorespiratory toxicity and injury, leading to death and that it is characterized by a steep dose-response curve. Continued use of our interdisciplinary approach will permit more effective identification of therapeutic windows and development of rational medical countermeasures and countermeasure strategies.

Adverse respiratory effects in rats following inhalation exposure to ammonia: respiratory dynamics and histopathology.

Acute respiratory dynamics and histopathology of the lungs and trachea following inhaled exposure to ammonia were investigated. Respiratory dynamic parameters were collected from male Sprague-Dawley rats (300-350 g) during (20 min) and 24 h (10 min) after inhalation exposure for 20 min to 9000, 20,000, and 23,000 ppm of ammonia in a head-only exposure system. Body weight loss, analysis of blood cells, and lungs and trachea histopathology were assessed 1, 3, and 24 h following inhalation exposure to 20,000 ppm of ammonia. Prominent decreases in minute volume (MV) and tidal volume (TV) were observed during and 24 h post-exposure in all ammonia-exposed animals. Inspiratory time (IT) and expiratory time (ET) followed similar patterns and decreased significantly during the exposure and then increased at 24 h post-exposure in all ammonia-exposed animals in comparison to air-exposed controls. Peak inspiratory (PIF) and expiratory flow (PEF) significantly decreased during the exposure to all ammonia doses, while at 24 h post-exposure they remained significantly decreased following exposure to 20,000 and 23,000 ppm. Exposure to 20,000 ppm of ammonia resulted in body weight loss at 1 and 3 h post-exposure; weight loss was significant at 24 h compared to controls. Exposure to 20,000 ppm of ammonia for 20 min resulted in increases in the total blood cell counts of white blood cells, neutrophils, and platelets at 1, 3, and 24 h post-exposure. Histopathologic evaluation of the lungs and trachea tissue of animals exposed to 20,000 ppm of ammonia at 1, 3, and 24 h post-exposure revealed various morphological changes, including alveolar, bronchial, and tracheal edema, epithelial necrosis, and exudate consisting of fibrin, hemorrhage, and inflammatory cells. The various alterations in respiratory dynamics and damage to the respiratory system observed in this study further emphasize ammonia-induced respiratory toxicity and the relevance of efficacious medical countermeasure strategies.

Implant Treatment in the Predoctoral Clinic: A Retrospective Database Study of 1091 Patients.

PURPOSE: This retrospective study was conducted at the Marquette University School of Dentistry to (1) characterize the implant patient population in a predoctoral clinic, (2) describe the implants inserted, and (3) provide information on implant failures. MATERIALS AND METHODS: The study cohort included 1091 patients who received 1918 dental implants between 2004 and 2012, and had their implants restored by a crown or a fixed dental prosthesis. Data were collected from patient records, entered in a database, and summarized in tables and figures. Contingency tables were prepared and analyzed by a chi-squared test. The cumulative survival probability of implants was described using a Kaplan-Meier survival curve. Univariate and multivariate frailty Cox regression models for clustered observations were computed to identify factors associated with implant failure. RESULTS: Mean patient age (±1 SD) at implantation was 59.7 ± 15.3 years; 53.9% of patients were females, 73.5% were Caucasians. Noble Biocare was the most frequently used implant brand (65.0%). Most implants had a regular-size diameter (59.3%). More implants were inserted in posterior (79.0%) than in anterior jaw regions. Mandibular posterior was the most frequently restored site (43%); 87.8% of implants were restored using single implant crowns. The overall implant-based cumulative survival rate was 96.4%. The patient-based implant survival rate was 94.6%. Implant failure risk was greater among patients than within patients (p < 0.05). Age (>65 years; hazard ratio [HR] = 3.2, p = 0.02), implant staging (two-stage; HR = 4.0, p < 0.001), and implant diameter (wide; HR = 0.4, p = 0.04) were statistically associated with implant failure. CONCLUSIONS: Treatment with dental implants in a supervised predoctoral clinic environment resulted in survival rates similar to published results obtained in private practice or research clinics. Older age and implant staging increased failure risk, while the selection of a wide implant diameter was associated with a lower failure risk.

Circadian clock regulates response to pesticides in Drosophila via conserved Pdp1 pathway.

Daily rhythms generated by the circadian clock regulate many life functions, including responses to xenobiotic compounds. In Drosophila melanogaster, the circadian clock consists of positive elements encoded by cycle (cyc) and Clock (Clk) and negative elements encoded by period (per) and timeless (tim) genes. The epsilon-isoform of the PAR-domain protein 1 (Pdp1epsilon) transcription factor is controlled by positive clock elements and regulates daily locomotor activity rhythms. Pdp1 target genes have not been identified, and its involvement in other clock output pathways is not known. Mammalian orthologs of Pdp1 have been implicated in the regulation of xenobiotic metabolism; therefore, we asked whether Pdp1 has a similar role in the fly. Using pesticides as model toxicants, we determined that disruption of Pdp1epsilon increased pesticide-induced mortality in flies. Flies deficient for cyc also showed increased mortality, while disruption of per and tim had no effect. Day/night and Pdp1-dependent differences in the expression of xenobiotic-metabolizing enzymes Cyp6a2, Cyp6g1, and alpha-Esterase-7 were observed and likely contribute to impaired detoxification. DHR96, a homolog of constitutive androstane receptor and pregnane X receptor, is involved in pesticide response, and DHR96 expression decreased when Pdp1 was suppressed. Taken together, our data uncover a pathway from the positive arm of the circadian clock through Pdp1 to detoxification effector genes, demonstrating a conserved role of the circadian system in modulating xenobiotic toxicity.

Does the clock make the poison? Circadian variation in response to pesticides.

BACKGROUND: Circadian clocks govern daily physiological and molecular rhythms, and putative rhythms in expression of xenobiotic metabolizing (XM) genes have been described in both insects and mammals. Such rhythms could have important consequences for outcomes of chemical exposures at different times of day. To determine whether reported XM gene expression rhythms result in functional rhythms, we examined daily profiles of enzyme activity and dose responses to the pesticides propoxur, deltamethrin, fipronil, and malathion. METHODOLOGY/PRINCIPAL FINDINGS: Published microarray expression data were examined for temporal patterns. Male Drosophila were collected for ethoxycoumarin-O-deethylase (ECOD), esterase, glutathione-S-transferase (GST), and, and uridine 5'-diphosphoglucosyltransferase (UGT) enzyme activity assays, or subjected to dose-response tests at four hour intervals throughout the day in both light/dark and constant light conditions. Peak expression of several XM genes cluster in late afternoon. Significant diurnal variation was observed in ECOD and UGT enzyme activity, however, no significant daily variation was observed in esterase or GST activity. Daily profiles of susceptibility to lethality after acute exposure to propoxur and fipronil showed significantly increased resistance in midday, while susceptibility to deltamethrin and malathion varied little. In constant light, which interferes with clock function, the daily variation in susceptibility to propoxur and in ECOD and UGT enzyme activity was depressed. CONCLUSIONS/SIGNIFICANCE: Expression and activities of specific XM enzymes fluctuate during the day, and for specific insecticides, the concentration resulting in 50% mortality varies significantly during the day. Time of day of chemical exposure should be an important consideration in experimental design, use of pesticides, and human risk assessment.