An Intensive, Simulation-Based Communication Course for Pediatric Critical Care Medicine Fellows.

OBJECTIVE: Effective communication among providers, families, and patients is essential in critical care but is often inadequate in the PICU. To address the lack of communication education pediatric critical care medicine fellows receive, the Children's Hospital of Pittsburgh PICU developed a simulation-based communication course, Pediatric Critical Care Communication course. Pediatric critical care medicine trainees have limited prior training in communication and will have increased confidence in their communication skills after participating in the Pediatric Critical Care Communication course. DESIGN: Pediatric Critical Care Communication is a 3-day course taken once during fellowship featuring simulation with actors portraying family members. SETTING: Off-site conference space as part of a pediatric critical care medicine educational curriculum. SUBJECTS: Pediatric Critical Care Medicine Fellows. INTERVENTIONS: Didactic sessions and interactive simulation scenarios. MEASUREMENTS AND MAIN RESULTS: Prior to and after the course, fellows complete an anonymous survey asking about 1) prior instruction in communication, 2) preparedness for difficult conversations, 3) attitudes about end-of-life care, and 4) course satisfaction. We compared pre- and postcourse surveys using paired Student t test. Most of the 38 fellows who participated over 4 years had no prior communication training in conducting a care conference (70%), providing bad news (57%), or discussing end-of-life options (75%). Across all four iterations of the course, fellows after the course reported increased confidence across many topics of communication, including giving bad news, conducting a family conference, eliciting both a family's emotional reaction to their child's illness and their concerns at the end of a child's life, discussing a child's code status, and discussing religious issues. Specifically, fellows in 2014 reported significant increases in self-perceived preparedness to provide empathic communication to families regarding many aspects of discussing critical care, end-of-life care, and religious issues with patients' families (p < 0.05). The majority of fellows (90%) recommended that the course be required in pediatric critical care medicine fellowship. CONCLUSIONS: The Pediatric Critical Care Communication course increased fellow confidence in having difficult discussions common in the PICU. Fellows highly recommend it as part of PICU education. Further work should focus on the course's impact on family satisfaction with fellow communication.

Neuropsychiatric comorbidities in adults with phenylketonuria: A retrospective cohort study.

Adults with phenylketonuria (PKU) may experience neurologic and psychiatric disorders, including intellectual disability, anxiety, depression, and neurocognitive dysfunction. Identifying the prevalence and prevalence ratios of these conditions will inform clinical treatment. This nested, case-controlled study used International Classification of Diseases, Ninth Revision (ICD-9) codes from the MarketScan® insurance claims databases from 2006 to 2012 and healthcare claims data for US-based employer and government-sponsored health plans. Prevalence and prevalence ratio calculations of neuropsychiatric comorbidities for adults (≥20years old) with PKU were compared with two groups [diabetes mellitus (DM) and general population (GP)] matched by age, gender, geographic location, and insurance type. Age cohorts (i.e., 20-29, 30-39, 40-49, 50-59, 60-69, and 70+years, and a combined subset of 20-39) were used to stratify data. The PKU cohort experienced significantly higher rates of several comorbid neurologic, psychiatric and developmental conditions. Compared to GP, PKU was associated with significantly higher prevalence for numerous neuropsychiatric conditions, most notably for intellectual disability (PR=7.9, 95% CI: 6.4-9.9), autism spectrum disorder (PR=6.1, 95% CI: 3.6-10.4), Tourette/tic disorders (PR=5.4, 95% CI: 2.1-14.1), and eating disorders (4.0, 95% CI: 3.2-5.0). Rates of fatigue/malaise, epilepsy/convulsions, sleep disturbance, personality disorders, phobias, psychosis, and migraines among those with PKU exceeded rates for the GP but were comparable to those with DM, with significantly lower rates of concomitant disorders occurring in younger, compared to older, adults with PKU. Lifelong monitoring and treatment of co-occurring neuropsychiatric conditions are important for effective PKU management.

Development and evaluation of a record linkage protocol for Utah's Controlled Substance Database.

Utah's Controlled Substance Database prescription registry does not include master identifiers to link records for individual patients. We describe and evaluate a linkage protocol for Utah's Controlled Substance Database. Prescriptions (N = 22,401,506) dated 2005-2009 were linked using The Link King software and patient identifiers (e.g. names, dates of birth) for 2,232,725 patients. Review of 998 randomly selected record pairs classified 46 percent as definitely correct links and 54 percent as probably correct links. A correct link could not be confirmed for <1 percent. None were classified as probably incorrect links or definitely incorrect links. Record set reviews (N = 100 patients/set for 10 set sizes, randomly selected) classified 27-49 percent as definitely correct links and 39-63 percent as probably correct links. Fewer had too little information to confirm a link (5%-22%) or were probably incorrect (0%-6%). None were definitely incorrect. Overall, results suggest that Utah's Controlled Substance Database records were correctly linked. These data may be useful for cross-sectional and longitudinal studies of patient-controlled substance prescription histories.

Pulmonary function tests (maximum inspiratory pressure, maximum expiratory pressure, vital capacity, forced vital capacity) predict ventilator use in late-onset Pompe disease.

In patients with Late-Onset Pompe Disease (LOPD), progressive respiratory muscle involvement leads to reduced pulmonary function, with respiratory failure the most common cause of mortality. Early disease manifestations include sleep-disordered breathing, which can be treated with non-invasive ventilation; however, progressive diurnal deficits can require invasive ventilation. To determine if pulmonary function tests (PFTs) predict the thresholds for ventilation and wheelchair use, a systematic literature review identified cross-sectional clinical patient data (N = 174) that was classified into ventilation and wheelchair cohorts. PFTs included maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and vital capacity (VC), with vital capacities measured in the upright (-U) and supine (-S) positions. Receiver operating characteristic (ROC) curves were used to calculate cut-points (CP) and area under the curve (AUC). For all ventilation and mobility thresholds tested, ROC analyses demonstrated AUC values from 86-89% for MIP, 72-96% for MEP, and 74-96% for all vital capacity metrics. Thus, PFTs are useful in predicting the thresholds for nighttime ventilation, daytime ventilation, and wheelchair use, with MIP and VC-U having both high AUC values and consistency. The PFT mobility CPs were low (MIP CP = 0.9 kPa, MEP, CP = 2.6 kPa, VC-U CP = 19% predicted), suggesting an endurance component associated with wheelchair use.

Two pediatric cases of variant neurogenic stress cardiomyopathy after intracranial hemorrhage.

Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy, is an acquired form of left ventricular systolic dysfunction seen in the setting of physiologic stress and the absence of coronary artery disease. It is thought to be caused by excessive sympathetic stimulation. It is well described in the adult literature associated with subarachnoid hemorrhage where it is known as neurogenic stress cardiomyopathy (NSC), but few such pediatric cases have been reported. We describe our experience with 2 children (13- and 10-year-old girls) who presented with spontaneous intracranial hemorrhage followed by pulmonary edema and shock. Echocardiography revealed similar patterns of left ventricular wall motion abnormalities consistent with NSC, inverted Takotsubo variant. One child progressed to death, whereas the other made a remarkable recovery, including significant improvement in cardiac function over the course of 1 week. We argue that at least 1 of these cases represents true stress-induced cardiomyopathy. This report will alert pediatricians to this transient cardiomyopathy that is likely underdiagnosed in pediatric intensive care. We also highlight the challenges of managing both shock and elevated intracranial pressure in the setting of NSC.

Specialty of prescribers associated with prescription opioid fatalities in Utah, 2002-2010.

UNLABELLED: Opioid adverse events are widespread, and deaths have been directly attributed to opioids prescribed by medical professionals. Little information exists on the amount of opioids various medical specialties prescribe and the opioid fatality rate that would be expected if prescription opioid-related deaths were independent of medical specialty. OBJECTIVE: To compute the incidence of prescription opioid fatalities by medical specialty in Utah and to calculate the attributable risk (AR) of opioid fatality by medical specialty. DESIGN: Prevalence database study design linking the Utah Controlled Substance Database (CSD) for prescribing data with the Utah Medical Examiner data to identify prescription opioid fatalities. AR were calculated for each medical specialty and year. RESULTS: Opioid prescriptions are common with 23,302,892 recorded in the CSD for 2002-2010, 0.64% of which were associated with a fatality. We attached specialty to 90.2% of opioid prescriptions. Family medicine and internal medicine physicians wrote the largest proportion of prescriptions (24.1% and 10.8%) and were associated with the greatest number of prescription opioid fatalities. The number of active prescriptions at time of death decreased each year. The AR of fatality by provider specialty varied each year with some specialties, such as pain medicine and anesthesiology, consistently associated with more fatalities per 1,000 opioid prescriptions than internal medicine physicians the same year. CONCLUSIONS: Primary care providers were the most frequent prescribers and the most often associated with opioid fatalities and should be targeted for education about safe prescribing along with specialties that prescribe less frequently but are associated with a positive AR for opioid fatality.

Opioid prescribing knowledge and practices: provider survey following promulgation of guidelines-Utah, 2011.

OBJECTIVE: The Utah Department of Health published the Utah Clinical Guidelines on Prescribing Opioids for Treatment of Pain in 2010. The objective was to evaluate the impact of the Guidelines on provider behaviors such as documentation and use of screening tools. SETTING: Web-based questionnaire about opioid prescribing knowledge and practices distributed among 85 providers of a university-based, primary care community clinic system in the summer of 2011. MAIN OUTCOME MEASURES: Provider-reported knowledge about and comfort prescribing opioids and use of tools for managing opioid patients. RESULTS: Forty-seven providers who prescribe opioids on an outpatient basis completed the questionnaire after an initial e-mail invitation and two reminders (55 percent response rate). Providers most often used simple rating scales that can be included easily in the notes of the electronic medical record (EMR) to assess pain. When treating patients with chronic pain, 26 percent of respondents reported that they did not use any tool for patient assessment prior to treatment. Providers desire more training in opioid prescribing and feel that they lack referral resources for patients with chronic, noncancer pain. Prescription monitoring program use was common with 77 percent of providers reporting that they would access the system before prescribing opioids for a new patient. CONCLUSIONS: System-level changes such as inclusion of screening tools into EMRs will be needed to improve compliance with the Guidelines. Providers find treatment of chronic pain to be challenging and something for which they desire additional training and referral support.

Unintentional prescription opioid-related overdose deaths: description of decedents by next of kin or best contact, Utah, 2008-2009.

BACKGROUND: Little is known about the characteristics that may predispose an individual to being at risk for fatal overdose from prescription opioids. OBJECTIVE: To identify characteristics related to unintentional prescription opioid overdose deaths in Utah. DESIGN: Interviews were conducted (October 2008-October 2009) with a relative or friend most knowledgeable about the decedent's life. SUBJECTS: Analyses involved 254 decedents aged 18 or older, where cause of death included overdose on at least one prescription opioid. KEY RESULTS: Decedents were more likely to be middle-aged, Caucasian, non-Hispanic/Latino, less educated, not married, or reside in rural areas than the general adult population in Utah. In the year prior to death, 87.4 % were prescribed prescription pain medication. Reported potential misuse prescription pain medication in the year prior to their death was high (e.g., taken more often than prescribed [52.9 %], obtained from more than one doctor during the previous year [31.6 %], and used for reasons other than treating pain [29.8 %, almost half of which "to get high"]). Compared with the general population, decedents were more likely to experience financial problems, unemployment, physical disability, mental illness (primarily depression), and to smoke cigarettes, drink alcohol, and use illicit drugs. The primary source of prescription pain medication was from a healthcare provider (91.8 %), but other sources (not mutually exclusive) included: for free from a friend or relative (24 %); from someone without their knowledge (18.2 %); purchase from a friend, relative, or acquaintance (16.4 %); and purchase from a dealer (not a pharmacy) (11.6 %). CONCLUSIONS: The large majority of decedents were prescribed opioids for management of chronic pain and many exhibited behaviors indicative of prescribed medication misuse. Financial problems, unemployment, physical disability, depression, and substance use (including illegal drugs) were also common.

Risk factors for prescription opioid-related death, Utah, 2008-2009.

OBJECTIVE: Utah prescription opioid death rates increased nearly fivefold during 2000-2009. Inadequate understanding of risk factors hinders prevention. The goal of this study was to determine risk factors for prescription opioid death in Utah. DESIGN: Case-control study. Cases were 254 Utah decedents with ≥1 prescription opioid causing death during 2008-2009 with nonintentional manner of death (information obtained via next-of-kin interviews). Controls were 1,308 Utah 2008 Behavioral Risk Factor Surveillance System respondents who reported prescription opioid use during the previous year. OUTCOME MEASURES: Exposure prevalence ratios (EPRs) for selected characteristics and confidence intervals (CIs) were calculated. RESULTS: Decedents were more likely than the comparison group to have used prescription pain medication more than prescribed (52.9% vs 3.2%; EPR, 16.5; 95% CI, 9.3-23.7), obtained prescription pain medication from nonprescription sources (39.6% vs 8.3%; EPR, 4.8; 95% CI, 3.6-6.0), smoked daily (54.5% vs 9.7%; EPR, 5.6; 95% CI, 4.4-6.9), not graduated high school (18.5% vs 6.2%; EPR, 3.0; 95% CI, 2.0-3.9), and been divorced or separated (34.6% vs 9.4%; EPR, 3.7; 95% CI, 3.0-4.4). Decedents were more likely to have had chronic pain than the comparison group (94.2% vs 31.6%; EPR, 3.0; 95% CI, 2.7-3.3). CONCLUSIONS: Use of pain medication outside prescription bounds was a risk factor for death. However, decedents were more likely to have had chronic pain, and the majority of both groups had obtained pain medication by prescription. Other factors (e.g., smoking status) might also play important roles in prescription opioid-related death. Prescribers should screen chronic pain patients for risk factors.

Studying adverse events related to prescription opioids: the Utah experience.

BACKGROUND: Epidemiologists at the Utah Department of Health (UDOH) began to study prescription drug-related harm in 2004. We have analyzed several types of data including vital statistics, medical examiner records, emergency department diagnoses, and the state prescription registry to estimate the scope and correlates of prescription drug-related harm. OBJECTIVES: To describe data sets analyzed in Utah related to the problem of prescription drug-related harm with the goal of designing interventions to reduce the burden of adverse events and death. RESULTS: Prescription drug-related harm in Utah primarily involved opioids and can be examined with secondary analysis of administrative databases, although each database has limitations. CONCLUSIONS: More analyses, likely from cohort studies, are needed to identify risky prescribing patterns and individual-level risk factors for opioid-related harm. Combining data sets via linkage procedures can generate individual-level drug exposure and outcome histories, which may be useful to simulate a prospective cohort.

An analysis of the root causes for opioid-related overdose deaths in the United States.

OBJECTIVE: A panel of experts in pain medicine and public policy convened to examine root causes and risk factors for opioid-related poisoning deaths and to propose recommendations to reduce death rates. METHODS: Panelists reviewed results from a search of PubMed and state and federal government sources to assess frequency, demographics, and risk factors for opioid-related overdose deaths over the past decade. They also reviewed results from a Utah Department of Health study and a summary of malpractice lawsuits involving opioid-related deaths. RESULTS: National data demonstrate a pattern of increasing opioid-related overdose deaths beginning in the early 2000s. A high proportion of methadone-related deaths was noted. Although methadone represented less than 5% of opioid prescriptions dispensed, one third of opioid-related deaths nationwide implicated methadone. Root causes identified by the panel were physician error due to knowledge deficits, patient non-adherence to the prescribed medication regimen, unanticipated medical and mental health comorbidities, including substance use disorders, and payer policies that mandate methadone as first-line therapy. Other likely contributors to all opioid-related deaths were the presence of additional central nervous system-depressant drugs (e.g., alcohol, benzodiazepines, and antidepressants) and sleep-disordered breathing. CONCLUSIONS: Causes of opioid-related deaths are multifactorial, so solutions must address prescriber behaviors, patient contributory factors, nonmedical use patterns, and systemic failures. Clinical strategies to reduce opioid-related mortality should be empirically tested, should not reduce access to needed therapies, should address risk from methadone as well as other opioids, and should be incorporated into any risk evaluation and mitigation strategies enacted by regulators.

State-level strategies for reducing prescription drug overdose deaths: Utah's prescription safety program.

INTRODUCTION: The Utah Department of Health created a program to decrease deaths and other harm from prescription pain medication. Program goals included educating the public, providers, and patients on prescription safety and creating guidelines for providers on prescribing opioids. PROGRAM INTERVENTIONS: The department's Prescription Pain Medication Program was organized in collaboration with many state agencies as well as public and private organizations. The program developed a statewide media campaign, running messages using the slogan "Use Only As Directed" from May 2008 to May 2009. The program facilitated the publication and distribution of opioid prescribing guidelines. PROGRAM OUTCOMES: Collaboration among stakeholders to develop educational materials furthered use of the materials. The program distributed more than 2,800 copies of the prescribing guidelines and more than 120,000 copies of print materials, including bookmarks, patient information cards, and posters. STATEWIDE DATA: In 2008, unintentional overdose deaths from prescription opioids dropped 14.0% compared with the number of deaths in 2007. In 2009, the number of deaths remained stable from 2008. The campaign funding ended in May 2009. State agencies have continued collaborating and have pooled money to renew the media campaign in 2011. Evaluation of the impact of the prescribing guidelines is ongoing. CONCLUSIONS: The state-funded educational campaign may have contributed to a reduction in overdose deaths. Collaboration among state agencies and a sustained educational effort are important aspects of a successful prevention campaign.

Mass spectrometric characterization and activity of zinc-activated proinsulin C-peptide and C-peptide mutants.

Numerous reports have demonstrated an active role for proinsulin C-peptide in ameliorating chronic complications associated with diabetes mellitus. It has been recently reported that some of these activities are dependent upon activation of C-peptide with certain metal ions, such as Fe(II), Cr(III) or Zn(II). In an effort to gain a greater understanding of the structure/function dependence of the peptide-metal interactions responsible for this activity, a series of experiments involving the use of electrospray ionization (ESI), matrix assisted laser desorption/ionization (MALDI) and collision-induced dissociation-tandem mass spectrometry (CID-MS/MS) of C-peptide in the presence or absence of Zn(II) have been carried out. Additionally, various C-peptide mutants with alanine substitution at individual aspartic acid or glutamic acid residues throughout the C-peptide sequence were analyzed. CID-MS/MS of wild type C-peptide in the presence of Zn(II) indicated multiple sites for metal binding, localized at acidic residues within the peptide sequence. Mutations of individual acidic residues did not significantly affect this fragmentation behavior, suggesting that no single acidic residue is critical for binding. However, ESI-MS analysis revealed an approximately 50% decrease in relative Zn(II) binding for each of the mutants compared to the wild type sequence. Furthermore, a significant decrease in activity was observed for each of the Zn(II)-activated mutant peptides compared to the wild type C-peptide, indicated by measurement of ATP released from erythrocytes, with a 75% decrease observed for the Glu27 mutant. Additional studies on the C-terminal pentapeptide of C-peptide EGSLQ, as well as a mutant C-terminal pentapeptide sequence AGSLQ, revealed that substitution of the glutamic acid residue resulted in a complete loss of activity, implicating a central role for Glu27 in Zn(II)-mediated C-peptide activity.

Affinity capture mass spectrometry of biomarker proteins using peptide ligands from biopanning.

Affinity capture mass spectrometry was used to isolate and ionize protein A from Staphylococcus aureus from both a commercial source and cell culture lysate using matrix assisted laser desorption/ionization (MALDI) mass spectrometry. Two surfaces are compared: gold surfaces with immunoglobulin G covalently immobilized and silica surfaces with a covalently bound small peptide discovered via biopanning. A detection limit of 2.22 bacterial cells/mL of culture fluid was determined for the immobilized peptide surfaces. This study emphasizes the ability to use peptide ligands to effectively capture a biomarker protein out of a complex mixture. This demonstrates the potential to use biopanning to generate capture ligands for a large variety of target proteins and subsequently detect the captured protein using MALDI mass spectrometry.

TrkB is necessary for pruning at the climbing fibre-Purkinje cell synapse in the developing murine cerebellum.

TrkB, the cognate receptor for brain-derived neurotrophic factor and neurotrophin-4, has been implicated in regulating synapse formation in the central nervous system. Here we asked whether TrkB plays a role in the maturation of the climbing fibre-Purkinje cell (CF-PC) synapse. In rodent cerebellum, Purkinje cells are initially innervated by multiple climbing fibres that are subsequently culled to assume the mature mono-innervated state, and whose contacts translocate from the soma to the dendrites. By employing transgenic mice hypomorphic or null for TrkB expression, our results indicated that perturbation of TrkB in the immature cerebellum resulted in ataxia, that Purkinje cells remained multiply innervated by climbing fibres beyond the normal developmental time frame, and that synaptic transmission at the parallel fibre-Purkinje cell synapse remained functionally unaltered. Mechanistically, we present evidence that attributes the persistence of multiple climbing fibre innervation to an obscured discrimination of relative strengths among competing climbing fibres. Soma-to-dendrite translocation of climbing fibre terminals was unaffected. Thus, TrkB regulates pruning but not translocation of nascent CF-PC synaptic contacts.